Effects of low intensity pulsed ultrasound on expression of B-cell lymphoma-2 and BCL2-Associated X in premature ovarian failure mice induced by 4-vinylcyclohexene diepoxide.
Xu Haopeng,Xia Yi,Qin Juan,Xu Jie,Li Chongyan,Wang Yan
Reproductive biology and endocrinology : RB&E
BACKGROUND:Premature ovarian failure (POF) is a common disease in the field of Gynecology. Low intensity pulsed ultrasound (LIPUS) can promote tissue repair and improve function. This study was performed to determine the effects of LIPUS on granulosa cells (GCs) apoptosis and protein expression of B-cell lymphoma-2 (Bcl-2) and BCL2-Associated X (Bax) in 4-vinylcyclohexene diepoxide (VCD)-induced POF mice and investigate the mechanisms of LIPUS on ovarian function and reserve capacity. METHODS:The current POF mice model was administrated with VCD (160 mg/kg) by intraperitoneal injection for 15 consecutive days. The mice were divided into the POF group, LIPUS group and control group. In the LIPUS group, the right ovary of mice was treated by LIPUS (acoustic intensity was 200 mW/cm, frequency was 0.3 MHz, and duty cycle was 20%) for 20 min, 15 consecutive days from day 16. The mice of the POF group and control group were treated without ultrasonic output. The basic observation and body weight were recorded. Hematoxylin and eosin staining (H&E staining) and enzyme-linked immunosorbent assay (ELISA) were applied to detect ovarian follicle development, ovarian morphology and sex hormone secretion. Ovarian GCs apoptosis was detected by TUNEL assay and immunohistochemistry. RESULTS:The results showed that VCD can induce estrus cycle disorder, follicular atresia, sex hormone secretion decreased and GCs apoptosis in mice to establish POF model successfully. LIPUS significantly promoted follicular development, increased sex hormone secretion, inhibited excessive follicular atresia and GCs apoptosis. The mechanism might be achieved by increasing the protein expression of Bcl-2 and decreasing the expression of Bax in ovaries. CONCLUSIONS:LIPUS can improve the POF induced by VCD. These findings have the potential to provide novel methodological foundation for the future research, which help treat POF patients in the clinic.
Adoptive transfers of CD4 CD25 Tregs partially alleviate mouse premature ovarian insufficiency.
Liu Dan,Tu Xiaojuan,Huang Chuanmengyuan,Yuan Yuncang,Wang Ying,Liu Xiaona,He Wei
Molecular reproduction and development
This study was designed to investigate the protective effect of CD4 CD25 regulatory T cells (Tregs) against zona pellucida glycoprotein 3 peptide (pZP3) immunization-induced premature ovarian insufficiency (POI) in mice. A mouse POI model was induced by two subcutaneous injections of pZP3 (50 nmol/L). Mice in the pZP3-Treg group were intraperitoneally injected with 5 × 10 CD4 CD25 Tregs after the POI model was established. Sex hormone levels, follicle numbers, apoptotic events, and the Akt/FOXO3a signaling pathway molecules in the ovaries were assessed. Compared with control group, the weight of ovaries in both pZP3 group and pZP3-Treg group was decreased and no difference was found between them. The number of follicles in the Treg transferred mice, like in pZP3 group, was significantly reduced compared to the control group, but showed a modest improvement when compared the pZP3 group alone. Significantly lower serum concentrations of follicle-stimulating hormone, luteinizing hormone, and anti-zona pellucida antibodies (AZPAbs) were found, while the concentrations of estradiol and anti-Mullerian hormone increased. In mechanism, Treg cell transfer to ZP3 treated mice restored the levels of Caspase3 to control levels, and partially restored Bax, however, had no effect on Bcl-2. Moreover, Treg cell transfer to ZP3 treated mice partially restored the levels of Akt and FOXO3a, and partially restored the ratios of p-Akt/Akt and p-FOXO3a/FOXO3a. In conclusion, Treg cells improved some aspects of ZP3-induced POI which may be mediate by suppressing ovarian cells apoptosis and involving the Akt/FOXO3a signaling pathway. Therefore, Treg cells may be protective against autoimmune POI.
A homozygous truncating variant in GDF9 in siblings with primary ovarian insufficiency.
Verma Kunal P,Thompson Bryony,Wolfe James,Price Sarah,Djukiadmodjo Frida,Trainer Alison
Journal of assisted reproduction and genetics
Premature or primary ovarian insufficiency (POI) affects approximately 1% of women and can be due to a variety of causes. Genetic causes include syndromic and non-syndromic POI. There are several promising candidate genes for whom a clear Mendelian association with non-syndromic POI has not yet been conclusively established, including GDF9. GDF9 is an oocyte-secreted factor and is part of the TGF-beta superfamily of morphogens. It has an important role in follicular development and granulosa cell maturation. We report the case of two siblings with primary ovarian insufficiency (POI) and a homozygous truncating variant in GDF9 (c.604C>T; p.(Gln202*). This report helps establish a clear gene-disease association between GDF9 and POI and argues for routine evaluation for GDF9 variants in patients undergoing genomic investigation for POI.
Onco-fertility and personalized testing for potential for loss of ovarian reserve in patients undergoing chemotherapy: proposed next steps for development of genetic testing to predict changes in ovarian reserve.
Sun Bei,Yeh John
Fertility research and practice
Women of reproductive age undergoing chemotherapy face the risk of irreversible ovarian insufficiency. Current methods of ovarian reserve testing do not accurately predict future reproductive potential for patients undergoing chemotherapy. Genetic markers that more accurately predict the reproductive potential of each patient undergoing chemotherapy would be critical tools that would be useful for evidence-based fertility preservation counselling. To assess the possible approaches to take to develop personalized genetic testing for these patients, we review current literature regarding mechanisms of ovarian damage due to chemotherapy and genetic variants associated with both the damage mechanisms and primary ovarian insufficiency. The medical literature point to a number of genetic variants associated with mechanisms of ovarian damage and primary ovarian insufficiency. Those variants that appear at a higher frequency, with known pathways, may be considered as potential genetic markers for predictive ovarian reserve testing. We propose developing personalized testing of the potential for loss of ovarian function for patients with cancer, prior to chemotherapy treatment. There are advantages of using genetic markers complementary to the current ovarian reserve markers of AMH, antral follicle count and day 3 FSH as predictors of preservation of fertility after chemotherapy. Genetic markers will help identify upstream pathways leading to high risk of ovarian failure not detected by present clinical markers. Their predictive value is mechanism-based and will encourage research towards understanding the multiple pathways contributing to ovarian failure after chemotherapy.
Stem cell-secreted factor therapy regenerates the ovarian niche and rescues follicles.
Buigues Anna,Marchante María,de Miguel-Gómez Lucia,Martinez Jessica,Cervelló Irene,Pellicer Antonio,Herraiz Sonia
American journal of obstetrics and gynecology
BACKGROUND:Ovarian senescence is a normal age-associated phenomenon, but increasingly younger women are affected by diminished ovarian reserves or premature ovarian insufficiency. There is an urgent need for developing therapies to improve ovarian function in these patients. In this context, previous studies suggest that stem cell-secreted factors could have regenerative properties in the ovaries. OBJECTIVE:This study aimed to test the ability of various human plasma sources, enriched in stem cell-secreted factors, and the mechanisms behind their regenerative properties, to repair ovarian damage and to promote follicular development. STUDY DESIGN:In the first phase, the effects of human plasma enriched in bone marrow stem cell soluble factors by granulocyte colony-stimulating factor mobilization, umbilical cord blood plasma, and their activated forms on ovarian niche, follicle development, and breeding performance were assessed in mouse models of chemotherapy-induced ovarian damage (n=7 per group). In addition, the proteomic profile of each plasma was analyzed to find putative proteins and mechanism involved in their regenerative properties in ovarian tissue. In the second phase, the most effective plasma treatment was validated in human ovarian cortex xenografted in immunodeficient mice (n=4 per group). RESULTS:Infusion of human plasma enriched bone marrow stem cell soluble factors by granulocyte colony-stimulating factor mobilization or of umbilical cord blood plasma-induced varying degrees of microvessel formation and cell proliferation and reduced apoptosis in ovarian tissue to rescue follicular development and fertility in mouse models of ovarian damage. Plasma activation enhanced these effects. Activated granulocyte colony-stimulating factor plasma was the most potent inducing ovarian rescue in both mice and human ovaries, and proteomic analysis indicated that its effects may be mediated by soluble factors related to cell cycle and apoptosis, gene expression, signal transduction, cell communication, response to stress, and DNA repair of double-strand breaks, the most common form of age-induced damage in oocytes. CONCLUSION:Our findings suggested that stem cell-secreted factors present in both granulocyte colony-stimulating factor-mobilized and umbilical cord blood plasma could be an effective treatment for increasing the reproductive outcomes in women with impaired ovarian function owing to several causes. The activated granulocyte colony-stimulating factor plasma, which is already enriched in both stem cell-secreted factors and platelet-enclosed growth factors, seems to be the most promising treatment because of its most potent restorative effects on the ovary together with the autologous source.
The Crazy Ovary.
Monget Philippe,McNatty Ken,Monniaux Danielle
From fetal life until senescence, the ovary is an extremely active tissue undergoing continuous structural and functional changes. These ever-changing events are best summarized by a quotation attributed to Plato when describing motion in space and time-'nothing ever is but is always becoming…'. With respect to the ovary, these changes include, at the beginning, the processes of follicular formation and thereafter those of follicular growth and atresia, steroidogenesis, oocyte maturation, and decisions relating to the number of mature oocytes that are ovulated for fertilization and the role of the corpus luteum. The aims of this review are to offer some examples of these complex and hitherto unknown processes. The ones herein have been elucidated from studies undertaken in vitro or from normal in vivo events, natural genetic mutations or after experimental inactivation of gene function. Specifically, this review offers insights concerning the initiation of follicular growth, pathologies relating to poly-ovular follicles, the consequences of premature loss of germ cells or oocytes loss, the roles of (anti-Müllerian hormone) and (bone morphogenetic protein) genes in regulating follicular growth and ovulation rate together with species differences in maintaining luteal function during pregnancy. Collectively, the evidence suggests that the oocyte is a key organizer of normal ovarian function. It has been shown to influence the phenotype of the adjacent somatic cells, the growth and maturation of the follicle, and to determine the ovulation rate. When germ cells or oocytes are lost prematurely, the ovary becomes disorganized and a wide range of pathologies may arise.
HDAC6 regulates primordial follicle activation through mTOR signaling pathway.
Zhang Tuo,He Meina,Zhao Lihua,Qin Shaogang,Zhu Zijian,Du Xinhua,Zhou Bo,Yang Yi,Liu Xinfeng,Xia Guoliang,Chen Tengxiang,Wang Yuanxi,Zhang Hua,Wang Chao
Cell death & disease
Primordial follicle pool established perinatally is a non-renewable resource which determines the female fecundity in mammals. While the majority of primordial follicles in the primordial follicle pool maintain dormant state, only a few of them are activated into growing follicles in adults in each cycle. Excessive activation of the primordial follicles accelerates follicle pool consumption and leads to premature ovarian failure. Although previous studies including ours have emphasized the importance of keeping the balance between primordial follicle activation and dormancy via molecules within the primordial follicles, such as TGF-β, E-Cadherin, mTOR, and AKT through different mechanisms, the homeostasis regulatory mechanisms of primordial follicle activation remain unclear. Here, we reported that HDAC6 acts as a key negative regulator of mTOR in dormant primordial follicles. In the cytoplasm of both oocytes and granulosa cells of primordial follicles, HDAC6 expressed strong, however in those activated primordial follicles, its expression level is relatively weaker. Inhibition or knockdown of HDAC6 significantly promoted the activation of limited primordial follicles while the size of follicle pool was not affected profoundly in vitro. Importantly, the expression level of mTOR in the follicle and the activity of PI3K in the oocyte of the follicle were simultaneously up-regulated after inhibiting of HDAC6. The up-regulated mTOR leads to not only the growth and differentiation of primordial follicles granulosa cells (pfGCs) into granulosa cells (GCs), but the increased secretion of KITL in these somatic cells. As a result, inhibition of HDAC6 awaked the dormant primordial follicles of mice in vitro. In conclusion, HDAC6 may play an indispensable role in balancing the maintenance and activation of primordial follicles through mTOR signaling in mice. These findings shed new lights on uncovering the epigenetic factors involved physiology of sustaining female reproduction.
Emergency Fertility Preservation in a Young Woman With Non-Hodgkin Lymphoma.
Salama Mahmoud,Isachenko Evgenia,Rahimi Gohar,Mallmann Peter,Isachenko Vladimir
Oncology (Williston Park, N.Y.)
A nulliparous woman, age 25 years, had received a diagnosis of non-Hodgkin lymphoma (NHL) and now presented with stage IIA diffuse large B-cell lymphoma (DLBCL). According to her hematological oncologist's treatment plan, chemotherapy had to start immediately (within 1 week), with the patient receiving 6 courses of the standard R-CHOEP21 regimen (rituximab 375 mg/m², cyclophosphamide 750 mg/m², hydroxydaunorubicin 50 mg/m², vincristine 1.4 mg/m², etoposide 100 mg/m², prednisone 40 mg/m²). Due to potential risks of chemotherapy-induced gonadotoxicity and subsequent iatrogenic premature ovarian failure (POF) and fertility loss, the patient was referred to the reproductive medicine department for fertility preservation counseling and further management.
Dysregulation of anti-Mullerian hormone expression levels in mural granulosa cells of FMR1 premutation carriers.
Friedman-Gohas Moran,Orvieto Raoul,Michaeli Abigael,Aizer Adva,Kirshenbaum Michal,Cohen Yoram
FMR1 premutation (55-200 CGG repeats) results in fragile X-associated primary ovarian insufficiency (FXPOI). We evaluated expression levels of folliculogenesis-related mediators, follicle-stimulating hormone (FSH) receptor and anti-Mullerian hormone (AMH), to gain insights into the mechanisms underlying the reduced ovarian function. Mural granulosa cells (MGCs) were collected from FMR1 premutation carriers and noncarriers undergoing IVF treatments. At baseline, MGCs of carriers demonstrated significantly higher mRNA expression levels of AMH (3.5 ± 2.2, n = 12 and 0.97 ± 0.5, n = 17, respectively; p = 0.0003) and FSH receptor (5.6 ± 2.8 and 2.7 ± 2.8, respectively; p = 0.02) and higher AMH protein expression on immunostaining. Accordingly, FMR1 premutation-transfected COV434 cells exhibited higher AMH protein expression than COV434 cells transfected with 20 CGG repeats. We conclude that FMR1 premutation may lead to dysregulation of AMH expression levels, probably due to a compensatory mechanism. Elucidating the pathophysiology of FXPOI may help in early detection of ovarian dysfunction and tailoring IVF treatments to FMR1 premutation carriers.
Therapeutic Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Female Reproductive Diseases.
Liao Zhiqi,Liu Chang,Wang Lan,Sui Cong,Zhang Hanwang
Frontiers in endocrinology
Reproductive disorders, including intrauterine adhesion (IUA), premature ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS), are great threats to female reproduction. Recently, mesenchymal stem cells derived-extracellular vesicles (MSC-EVs) have presented their potentials to cure these diseases, not only for the propensity ability they stemmed from the parent cells, but also for the higher biology stability and lower immunogenicity, compared to MSCs. EVs are lipid bilayer complexes, functional as mediators by transferring multiple molecules to recipient cells, such as proteins, microRNAs, lipids, and cytokines. EVs appeared to have a therapeutic effect on the female reproductive disorder, such as repairing injured endometrium, suppressing fibrosis of endometrium, regulating immunity and anti-inflammatory, and repressing apoptosis of granulosa cells (GCs) in ovaries. Although the underlying mechanisms of MSC-EVs have reached a consensus, several theories have been proposed, including promoting angiogenesis, regulating immunity, and reducing oxidate stress levels. In the current study, we summarized the current knowledge of functions of MSC-EVs on IUA, POI, and PCOS. Given the great potentials of MSC-EVs on reproductive health, the critical issues discussed will guide new insights in this rapidly expanding field.
An exome-wide exploration of cases of primary ovarian insufficiency uncovers novel sequence variants and candidate genes.
Alvarez-Mora Maria Isabel,Todeschini Anne-Laure,Caburet Sandrine,Perets Lilach Peled,Mila Montserrat,Younis Johnny S,Shalev Stavit,Veitia Reiner A
Primary ovarian insufficiency (POI) implies the cessation of menstruation for several months in women before the age of 40 years and is a major cause of infertility. The study of the contribution of genetic factors to POI has been fueled by the use of whole exome sequencing (WES). Here, to uncover novel causative pathogenic variants and risk alleles, WES has been performed in 12 patients with familial POI (eight unrelated index cases and two pairs of sisters) and six women with early menopause and family history of POI (four index cases and one pair of sisters). Likely causative variants in NR5A1 and MCM9 genes were identified as well as a variant in INHA that requires further investigation. Moreover, we have identified more than one candidate variant in 3 out of 15 familial cases. Taken together, our results highlight the genetic heterogeneity of POI and early menopause and support the hypothesis of an oligogenic inheritance of such conditions, in addition to monogenic inheritance.
Sodium alginate-bioglass-encapsulated hAECs restore ovarian function in premature ovarian failure by stimulating angiogenic factor secretion.
Huang Yating,Ma Zhijie,Kuang Xiaojun,Zhang Qiuwan,Li Haiyan,Lai Dongmei
Stem cell research & therapy
BACKGROUND:Human amniotic epithelial cells (hAECs) exhibit a strong capability to restore ovarian function in chemotherapy-induced premature ovarian failure (POF). However, the therapeutic efficacy of hAECs is usually affected by the limited number and proliferative ability of grafted hAECs in target organs. The transplantation of stem cells encapsulated in sodium alginate-bioglass (SA-BG) composite hydrogel has recently been shown to be an effective strategy for tissue regeneration. The current study aims to investigate the therapeutic potential of hAECs or hAEC-derived conditioned medium (CM) encapsulated in SA-BG in mice with chemotherapy-induced POF. METHODS:C57BL/6 mice were intraperitoneally injected with chemotherapy drugs to induce POF. hAECs or CM were harvested and encapsulated in SA-BG composite hydrogel, which were transplanted onto the injured ovaries of mice with POF. Follicle development, granulosa cell function, and ovarian angiogenesis were evaluated by morphological methods. To further elucidate the effect of SA-BG-encapsulated hAECs/CM on vascularization, the tube formation of human umbilical vein epithelial cells (hUVECs) was conducted in vitro. Cytokine array and ELISA were used to analyze and quantify the effects of bioactive components released by SA-BG on the secretion of angiogenic factors by hAECs. RESULTS:The transplantation of SA-BG-encapsulated hAECs/CM restored follicle development, repaired granulosa cell function, and enhanced ovarian angiogenesis in POF mice. The further study showed that SA-BG significantly promoted the tube formation of hUVECs in vitro. Moreover, encapsulating hAECs could facilitate the effect of SA-BG on inducing the formation of the capillary tube in a paracrine manner. In addition, we found that SA-BG extracts significantly enhanced the viability of hAECs and stimulated the secretion of pro-angiogenic factors of hAECs. Notably, compared with SA-BG/CM, SA-BG/hAECs achieve better therapeutic effects, possibly because stimulation of BG enhanced the viability and paracrine capacity of hAECs. CONCLUSIONS:The present study initially demonstrates that SA-BG-encapsulated hAECs or CM can exert a therapeutic effect on chemotherapy-induced POF mainly by protecting granulosa cell function and enhancing ovarian vascularization, which might provide a novel strategy for the delivery of hAECs for treating POF.
Optimizing Fertility in Primary Ovarian Insufficiency: Case Report and Literature Review.
Piedade Kensuly C,Spencer Hillary,Persani Luca,Nelson Lawrence M
Frontiers in genetics
Primary ovarian insufficiency (POI) is a clinical spectrum of ovarian dysfunction. Overt POI presents with oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years. Overt POI involves chronic health problems to include increased morbidity and mortality related to estradiol deficiency and the associated osteoporosis and cardiovascular disease as well as psychological and psychiatric disorders related to the loss of reproductive hormones and infertility. Presently, with standard clinical testing, a mechanism for Overt POI can only be identified in about 10% of cases. Now discovery of new mechanisms permits an etiology to be identified in a research setting in 25-30% of overt cases. The most common genetic cause of Overt POI is premutation in . The associated infertility is life altering. Oocyte donation is effective, although many women prefer to conceive with their own ova. Surprisingly, the majority who have Overt POI still have detectable ovarian follicles (70%). The major mechanism of follicle dysfunction in Overt POI has been histologically defined by a prospective NIH study: inappropriate follicle luteinization due to the tonically elevated serum LH levels. A trial of physiologic hormone replacement therapy, clinically proven to suppress the elevated LH levels in these women, may improve follicle function and increase the chance of ovulation. Here, we report the case of a woman with Overt POI diagnosed at age 35 years. To attempt pregnancy, she elected a trial of intrauterine insemination (IUI) in conjunction with follicle monitoring and physiologic hormone replacement therapy. She conceived on the eighth cycle of treatment and delivered a healthy baby. Our report calls for a concerted effort to define the best methods by which to optimize fertility for women who have POI.
[miR-483-5p aggravates cisplatin-induced premature ovarian insufficiency in rats by targeting FKBP4].
Zhao H,Gu W,Pan W,Zhang H,Shuai L,Diao R,Wang L
Nan fang yi ke da xue xue bao = Journal of Southern Medical University
OBJECTIVE:To investigate the role of FKBP4 protein in cisplatin-induced premature ovarian insufficiency (POI). OBJECTIVE:We performed ITRAQ assay of the ovarian tissues from 4 mice with cisplatin-induced POI and 4 control mice, and identified FKBP4 as a significantly down-regulated protein in the oocytes and granulosa cells following cisplatin treatment. TargetScan software was used for target analysis of FKBP4, and qRT-PCR and Western blotting were used to verify the expression levels of miR-483-5p and FKBP4 in the mouse models. Serum samples were collected from patients with POI and healthy women for detecting miR-483-5p level with qRT-PCR. Cell transfection and dual-luciferase assay were performed to determine the relationship between miR-483-5p and FKBP4. In primary granulosa cells and KGN cells, we examined the effect of miR-483-5p alone, miR-483-5p and cisplatin, and miR-483-5p combined with both cisplatin and FKBP4 on cell apoptosis. We also assessed ovarian function in a transgenic mouse model with ovarian miR-483-5p overexpression in comparison wigh wildtype mice using immunofluorescence assay, hybridization and ELISA. OBJECTIVE:Ovarian FKBP4 expression was significantly decreased in mice with cisplatin-induced POI. Analysis using TargetScan software indicated that FKBP4 was the potential target of miR-483-5p, which was highly expressed in the ovaries and serum of POI mice and in the serum of patients with POI. experiments further confirmed that FKBP4 was the target of miR-483-5p. In KGN and primary granulosa cells, FKBP4 overexpression significantly reduced cell apoptosis induced by both cisplatin and miR-483-5p overexpression (= 0.0045 and 0.0177, respectively). In the transgenic mice with miR-483-5p overexpression in the oocytes, cisplatin induced more severe ovarian damages as compared with those in the wild-type mice. OBJECTIVE:miR-483-5p/FKBP4 is a new and important pathway in cisplatin-induced POI, in which cisplatin increases ovarian miR- 483-5p expression to result in targeted downregulation of FKBP4. Up-regulation of miR-483-5p may increase ovarian sensitivity to cisplatin and cause severe ovarian dysfunction. Detection of serum miR-483-5p level may help to predict the occurrence and development of POI.
Ovarian dysfunction with moderate-dose intravenous cyclophosphamide (modified NIH regimen) and mycophenolate mofetil in young adults with severe lupus: a prospective cohort study.
Sharma Shefali Khanna,Jain Siddharth,Bahl Pooja,Potturi Pragna,Rathi Manish,Naidu Shankar,Sachdeva Naresh,Dhir Varun,Jain Sanjay
Arthritis research & therapy
BACKGROUND:Ovarian toxicity is a dreaded complication of cyclophosphamide (CYC). With the use of lower cumulative doses of intravenous CYC (modified NIH regimens) and availability of better markers of ovarian toxicity, the incidence of ovarian dysfunction needs reassessment. Lupus disease activity, by itself, is also believed to affect ovarian function negatively. METHODS:This single-centre prospective cohort study recruited 50 female patients of severe lupus aged 18-40 years. Twenty-five patients each received induction with either monthly intravenous CYC (0.5-0.75 g/m) for 6-9 months or daily oral mycophenolate mofetil (MMF). Details of menstrual irregularities; serum levels of FSH, LH, estradiol, AMH, and inhibin B; and sonographic assessment of ovarian volume and antral follicular count were done at baseline and 6 months after treatment. Amenorrhoeic patients were re-evaluated at 1 year. RESULTS:Mean (SD) age of subjects in the CYC and MMF groups was 31.4 (6.3) and 28.4 (4.4) years, respectively. Mean (SD) SLEDAI at the initiation of therapy was 7.2 (2.5) in the CYC group and 5.8 (3.4) in the MMF group. The mean cumulative dose of CYC used was 4.6 (1.8) g. Three patients in the CYC group (versus none in MMF) had amenorrhoea at 6 months-two of these regained menses within 6 months, while only one (4%) developed sustained amenorrhoea (lasting more than 12 months) at 41 years of age, likely menopause. Serum FSH levels increased (p = 0.03), while AMH (p = 0.002) and inhibin B (p < 0.001) levels decreased significantly with 6 months of CYC therapy. Ovarian volume also reduced significantly (p = 0.005) with 6 months of CYC therapy, while antral follicular count reduced numerically (p = 0.32). Levels of AMH, inhibin-B, estradiol, ovarian volume, and antral follicular count after 6 months therapy were significantly lesser in the CYC group compared to the MMF group, despite being similar before the start of therapy. CONCLUSIONS:Ovarian dysfunction with monthly intravenous CYC (modified NIH regimen) was predominantly subclinical, with a negative effect on ovarian reserve. No premature ovarian failure was noted at 1 year. No ovarian dysfunction occurred in the MMF group, despite having patients with severe background lupus. Use of intravenous CYC for induction may thus not be restricted in young lupus females with incomplete families for fear of gonadotoxicity, especially in life- or organ-threatening situations, where the benefits outweigh this subclinical risk.
Perimenopause and Postmenopause - Diagnosis and Interventions. Guideline of the DGGG and OEGGG (S3-Level, AWMF Registry Number 015-062, September 2020).
Inwald Elisabeth C,Albring Christian,Baum Erika,Beckermann Maria,Bühling Kai J,Emons Günter,Gudermann Thomas,Hadji Peyman,Imthurn Bruno,Kiesel Ludwig,Klemperer David,Klose Petra,König Klaus,Krüger Stephanie,Langhorst Jost,Leitzmann Michael,Ludolph Albert,Lüftner Diana,Müller Dorothea,Neulen Joseph,Nothacker Monika, ,Prautzsch Horst,Regitz-Zagrosek Vera,Schaudig Kathrin,Schütz Florian,Schwenkhagen Anneliese,Strowitzki Thomas,Stute Petra,Taute Bettina-Maria,Tempfer Clemens,Arnim Christine V,Wildt Ludwig,Windler Eberhard,Ortmann Olaf
Geburtshilfe und Frauenheilkunde
The aim of the interdisciplinary S3-guideline Perimenopause and Postmenopause - Diagnosis and Interventions is to provide help to physicians as they inform women about the physiological changes which occur at this stage of life and the treatment options. The guideline should serve as a basis for decisions taken during routine medical care. This short version lists the statements and recommendations given in the long version of the guideline together with the evidence levels, the level of recommendation, and the strength of consensus. The statements and recommendations are largely based on methodologically high-quality publications. The literature was evaluated by experts and mandate holders using evidence-based medicine (EbM) criteria. The search for evidence was carried out by the Essen Research Institute for Medical Management (EsFoMed). To some extent, this guideline also draws on an evaluation of the evidence used in the NICE guideline on Menopause and the S3-guidelines of the AWMF and has adapted parts of these guidelines. Recommendations are given for the following subjects: diagnosis and therapeutic interventions for perimenopausal and postmenopausal women, urogynecology, cardiovascular disease, osteoporosis, dementia, depression, mood swings, hormone therapy and cancer risk, as well as primary ovarian insufficiency.
Transient impact of paclitaxel on mouse fertility and protective effect of gonadotropin‑releasing hormone agonist.
Ma Nieying,Chen Ge,Chen Jing,Cui Mengge,Yin Ye,Liao Qiuyue,Tang Minghui,Feng Xue,Li Xi,Zhang Sijia,Ma Ding,Chen Gang,Li Kezhen,Ai Jihui
Paclitaxel (PXL) is a chemotherapeutic agent widely used in solid tumors. However, whether PXL causes premature ovarian insufficiency in women of reproductive age remains controversial. The aim of the present study was to answer how and for how long PXL affects fertility, and to identify the protective effect of gonadotropin‑releasing hormone agonist (GnRHa) in mice. A single dose of PXL was administered to 7‑week‑old female ICR mice. Mice were treated with GnRHa for 1 estrous cycle prior to chemotherapy, and for another following chemotherapy. On the days 1, 6, 11 and 16 following the administration of PXL, mice were assessed by ovarian histology, ovarian stimulation and mating experiment. Multiple doses of PXL were also administered to verify the duration of the gonadotoxicity of PXL. It was determined that PXL only destroyed antral follicles on day 1 following chemotherapy without reducing primordial follicles. In vitro experiments revealed that PXL impaired oocytes in metaphase, excluding those at the germinal vesicle stage. The number and quality of retrieved metaphaseⅡ(MⅡ) oocytes in PXL‑exposed mice were reduced on day 1 following chemotherapy, which was recovered on day 11. MⅡ oocytes from mice pretreated with GnRHa recovered on day 6 following chemotherapy. Following 3 estrous cycles in mice after the last dose of the 3‑dose paclitaxel administration, follicles in all stages and retrieved MII oocytes were recovered. It was concluded that the impairment caused by PXL on follicles and oocytes in mice lasted for <3 estrous cycles, which was shortened by pretreatment of GnRHa.
Intraovarian PRP Injection Improved Hot Flashes in a Woman With Very Low Ovarian Reserve.
Merhi Zaher,Seckin Serin,Mouanness Marco
Reproductive sciences (Thousand Oaks, Calif.)
PRP, rich in growth factors and cytokines, has been gaining considerable attention as an adjunct therapy to fertility treatment for women with very low ovarian reserve and premature ovarian insufficiency. To date, most prior studies have focused on the effect of PRP on ovarian response pertaining to oocyte production and pregnancy outcome following assisted reproductive technology. This report presents a patient with very low ovarian reserve, with medical problems that preclude her from taking hormone replacement therapy, who presented for fertility treatment with PRP and then accidentally reported significant improvement of menopausal symptoms including her hot flashes for 14 weeks following PRP intra-ovarian injection. The purpose of this case report is to increase awareness of clinicians about the use of PRP as a potential alternative therapy for hot flashes in women who have contraindications for hormone replacement therapy.
A form of secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism as new infertility diagnosis.
Gleicher Norbert,Darmon Sarah,Molinari Emanuela,Zhang Lin,Hu Jianjun,Albertini David F,Barad David H
BACKGROUND:Mediated via the androgen receptor on granulosa cells, models of small growing follicle stages demonstrate dependence on testosterone. Androgen deficiency reduces ovarian response to follicle stimulation hormone (FSH), granulosa cell mass and estradiol (E2) production falls and FSH, therefore, rises. Though potentially of adrenal and/or ovarian origin, androgen deficiency in association with female infertility is almost universally primarily of adrenal origin, raising the possibility that women with presumptive diagnosis of primary ovarian insufficiency (POI), also called primary ovarian failure (POF) may actually suffer from secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism that leads to follicular arrest at small-growing follicle stages. METHODS:This retrospective cohort study was performed in a private, academically affiliated infertility center in New York City. We searched the center's anonymized electronic research data bank for consecutive patients who presented with a diagnosis of POI, defined by age <41 year, FSH > 40.0 mIU/mL, amenorrhea for at least 6 month, and low testosterone (T), defined as total T (TT) in the lowest age-specific quartile of normal range. This study did not include patients with oophoritis. Since dehydroepiandrosterone sulfate (DHEAS) is the only androgen almost exclusively produce by adrenals, adrenal hypoandrogenism was defined by DHEAS < 100ug/dL. Thirteen of 78 presumed POI women (16.67%) qualified and represented the original study population. POI patients are usually treated with third-party egg donation; 6/13, however, rejected egg donation for personal or religious reasons and insisted on undergoing at least one last IVF cycle attempt (final study population). In preparation, they were supplemented with DHEA 25 mg TID and CoQ10 333 mg TID for at least 6 weeks prior to ovarian stimulation for IVF with FSH and human menopausal gonadotropins (hMG). Since POI patients are expected to be resistant to ovarian stimulation, primary outcome for the study was ovarian response, while secondary outcome was pregnancy/delivery. RESULTS:Though POI/POF patients usually are completely unresponsive to ovarian stimulation, to our surprise, 5/6 (83.3%) patients demonstrated an objective follicle response. In addition, 2/6 (33.3%) conceived spontaneously between IVF cycles, while on DHEA and CoQ10 supplementation and delivered healthy offspring. One of those is currently in treatment for a second child. CONCLUSIONS:This preliminary report suggests that a surprising portion of young women below age 41, tagged with a diagnosis of POI/POF, due to adrenal hypoandrogenism actually suffer from a form of SOI, at least in some cases amenable to treatment by androgen supplementation. Since true POI/POF usually requires third-party egg donation, correct differentiation between POI and SOI in such women appears of great importance and may warrant a trial stimulation after androgen pre-supplementation for at least 6 weeks.
Human mesenchymal stem cell treatment of premature ovarian failure: new challenges and opportunities.
Fu Yun-Xing,Ji Jing,Shan Fang,Li Jialing,Hu Rong
Stem cell research & therapy
Premature ovarian failure (POF) is one of the common disorders found in women leading to 1% female infertility. Clinical features of POF are hypoestrogenism or estrogen deficiency, increased gonadotropin level, and, most importantly, amenorrhea. With the development of regenerative medicine, human mesenchymal stem cell (hMSC) therapy brings new prospects for POF. This study aimed to describe the types of MSCs currently available for POF therapy, their biological characteristics, and their mechanism of action. It reviewed the latest findings on POF to provide the theoretical basis for further investigation and clinical therapy.
Body composition in women with premature ovarian insufficiency using hormone therapy and the relation to cardiovascular risk markers: A case-control study.
Freitas Alberto T A,Donovan Giraldo Andrea E,Pravatta Rezende Gabriela,Yela Daniela A,Jales Rodrigo M,Benetti-Pinto Cristina L
OBJECTIVE:To compare body composition between women with premature ovarian insufficiency (POI) using hormone therapy and controls with normal ovarian function, and to correlate body composition with cardiovascular risk markers in the POI group. PATIENTS AND DESIGN:A case-control study of 70 women with POI matched by age and body mass index with 70 controls. MEASUREMENTS:All were submitted to whole-body dual-energy X-ray absorptiometry (DXA) to analyse body composition. In the POI group, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, triglycerides, glucose, insulin, transaminases and C-reactive protein levels were measured, as well as the thickness of the carotid artery intima-media complex. RESULTS:Total mass, fat mass, lean mass (total, percentage and index) and the android/gynoid (A/G) ratio were similar in both groups; however, bone mineral content was lower (P < .001) in the POI group. Lean and fat mass indexes were 14.19 ± 1.63 and 11.04 ± 3.58, respectively, and the percentage of gynoid to android fat was higher (51.17 ± 6.71% versus 47.74 ± 9.19%; A/G ratio = 0.93 ± 0.15) in the POI group. In addition, the increase in total mass correlated positively with glucose and ALT levels and negatively with HDL-cholesterol. Increased A/G ratio was the measurement most frequently associated with cardiovascular risk markers. CONCLUSION:The body composition of women with POI using hormone therapy is similar to that of women with normal ovarian function with regard to lean and fat mass content and fat distribution. In women with POI, the higher the A/G ratio, the worse the cardiovascular risk markers.
Concentrated exosomes from menstrual blood-derived stromal cells improves ovarian activity in a rat model of premature ovarian insufficiency.
Zhang Siwen,Huang Boxian,Su Peng,Chang Qiyuan,Li Pingping,Song Aixin,Zhao Xinyang,Yuan Zhengwei,Tan Jichun
Stem cell research & therapy
BACKGROUND:Premature ovarian insufficiency (POI) is one of the major causes of infertility. We previously demonstrated that transplantation of menstrual blood-derived stromal cells (MenSCs) effectively improved ovarian function in a murine model of POI. Recent studies indicated that mesenchymal stem cell-derived exosomes were important components in tissue repair. In this study, we investigated the therapeutic effects of MenSCs-derived exosomes (MenSCs-Exos) in a rat model of POI and its mechanism in restoring ovulation. METHODS:Ovaries of 4.5-day-old Sprague Dawley rats (SD rats) were cultured in vitro to evaluate the effects of MenSCs-Exos exposure on early follicle development. Furthermore, POI in rats was induced by intraperitoneal administration of 4-vinylcyclohexene diepoxide (VCD). Forty-eight POI rats were randomly assigned to four groups, each receiving a different treatment: PBS, MenSCs, MenSCs-Exos, and Exo-free culture supernatant of MenSCs. Estrous cyclicity, ovarian morphology, follicle dynamics, serum hormones, pregnancy outcomes, and molecular changes were investigated. RESULTS:Exposure to MenSCs-Exos promoted the proliferation of granulosa cells in primordial and primary follicles in vitro and increased the expression of early follicle markers Deleted In Azoospermia Like (DAZL) and Forkhead Box L2 (FOXL2) while inhibiting follicle apoptosis. In vivo, MenSCs-Exos transplantation effectively promoted follicle development in the rat model of POI and restored the estrous cyclicity and serum sex hormone levels, followed by improving the live birth outcome. In addition, transplantation of MenSCs-Exos regulated the composition of the ovarian extracellular matrix and accelerated the recruitment of dormant follicles in the ovarian cortex and increased proliferation of granulosa cells in these follicles. CONCLUSION:MenSCs-Exos markedly promoted follicle development in vitro and in vivo and restored fertility in POI rats, suggesting a restorative effect on ovarian functions. The therapeutic effect of MenSCs-Exos transplantation was sustainable, consistent with that of MenSCs transplantation. Our results suggested that MenSCs-Exos transplantation may be a promising cell-free bioresource in the treatment of POI.
Can Some Anticancer Treatments Preserve the Ovarian Reserve?
Vallet Nicolas,Boissel Nicolas,Elefant Elisabeth,Chevillon Florian,Pasquer Hélène,Calvo Charlotte,Dhedin Nathalie,Poirot Catherine
BACKGROUND:Preventing premature ovarian failure (POF) is a major challenge in oncology. With conventional regimens, cytotoxicity-associated POF involves primordial follicles (PF) pool depletion by apoptosis or overactivation mechanisms, notably mediated by the ABL/TAp63 and PI3K/Akt/mTOR pathways. New anticancer treatments have been designed to target pathways implicated in tumor growth. Although concerns regarding fertility arise with these targeted therapies, we hypothesized that targeted therapies may exert off-tumor effects on PF that might delay POF. We provide an overview of evidence concerning these off-tumor effects on PF. Limitations and future potential implications of these findings are discussed. DESIGN:PubMed was searched by combining Boolean operators with the following keywords: fertility, ovarian, follicle, anti-tumoral, cancer, targeted, cytotoxic, and chemotherapy. RESULTS:Cisplatin-related PF apoptosis via the ABL/TAp63 pathway was targeted with a tyrosine kinase inhibitor, imatinib, in mice, but effects were recently challenged by findings on human ovarian xenografts in mice. In cyclophosphamide-treated mice, PI3K/Akt/mTOR pathway inhibition with mTOR inhibitors and AS101 preserved the PF pool. Proteasome and GSK3 inhibitors were evaluated for direct and indirect follicle DNA damage prevention. Surprisingly, evidence for cytotoxic drug association with PF pool preservation was found. We also describe selected non-anticancer molecules that may minimize gonadotoxicity. CONCLUSION:Not all anticancer treatments are associated with POF, particularly since the advent of targeted therapies. The feasibility of associating a protective drug targeting PF exhaustion mechanisms with cytotoxic treatments should be evaluated, as a way of decreasing the need for conventional fertility preservation techniques. Further evaluations are required for transfer into clinical practice. IMPLICATIONS FOR PRACTICE:Anticancer therapies are associated with infertility in 10%-70% of patients, which is the result of primordial follicles pool depletion. Alone or associated with gonadotoxic treatments, some targeted therapies may exert favorable off-targets effects on the primordial follicle pool by slowing down their exhaustion. Current evidence of these effects relies on murine models or human in vitro models. Evaluation of these protective strategies in humans is challenging; however, if these results are confirmed with clinical and biological data, it not only could be a new approach to female fertility preservation but also would change standard fertility strategies.
Genetics of premature ovarian insufficiency and the association with X-autosome translocations.
Di-Battista Adriana,Moysés-Oliveira Mariana,Melaragno Maria Isabel
Reproduction (Cambridge, England)
Premature ovarian insufficiency (POI) is the cessation of menstruation before the age of 40 and can result from different etiologies, including genetic, autoimmune, and iatrogenic. Of the genetic causes, single-gene mutations and cytogenetic alterations, such as X-chromosome aneuploidies and chromosome rearrangements, can be associated with POI. In this review, we summarize the genetic factors linked to POI and list the main candidate genes. We discuss the association of these genes with the ovarian development, the functional consequences of different mutational mechanisms and biological processes that are frequently disrupted during POI pathogenesis. Additionally, we focus on the high prevalence of X-autosome translocations involving the critical regions in Xq, known as POI1 and POI2, and ddiscuss in depth the main hypotheses proposed to explain this association. Although the incorrect pairing of chromosomes during meiosis could lead to oocyte apoptosis, the reason for the prevalence of X-chromosome breakpoints at specific regions remains unclear. In most cases, studies on genes disrupted by balanced structural rearrangements cannot explain the ovarian failure. Thus, the position effect has emerged as a putative explanation for genetic mechanisms as translocations possibly result in changes in overall chromatin topology due to chromosome repositioning. Given the tremendous impact of POI on women's quality of life, we highlight the value of investigations in to the interplay between ovarian function and gene regulation to deepen our understanding of the molecular mechanisms related to this disease, with the ultimate goal of improving patients' care and assistance.
Application of Stem Cell Therapy for Infertility.
Saha Sarama,Roy Partha,Corbitt Cynthia,Kakar Sham S
Infertility creates an immense impact on the psychosocial wellbeing of affected couples, leading to poor quality of life. Infertility is now considered to be a global health issue affecting approximately 15% of couples worldwide. It may arise from factors related to the male (30%), including varicocele, undescended testes, testicular cancer, and azoospermia; the female (30%), including premature ovarian failure and uterine disorders; or both partners (30%). With the recent advancement in assisted reproduction technology (ART), many affected couples (80%) could find a solution. However, a substantial number of couples cannot conceive even after ART. Stem cells are now increasingly being investigated as promising alternative therapeutics in translational research of regenerative medicine. Tremendous headway has been made to understand the biology and function of stem cells. Considering the minimum ethical concern and easily available abundant resources, extensive research is being conducted on induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSC) for their potential application in reproductive medicine, especially in cases of infertility resulting from azoospermia and premature ovarian insufficiency. However, most of these investigations have been carried out in animal models. Evolutionary divergence observed in pluripotency among animals and humans requires caution when extrapolating the data obtained from murine models to safely apply them to clinical applications in humans. Hence, more clinical trials based on larger populations need to be carried out to investigate the relevance of stem cell therapy, including its safety and efficacy, in translational infertility medicine.
Exosomal miRNA-17-5p derived from human umbilical cord mesenchymal stem cells improves ovarian function in premature ovarian insufficiency by regulating SIRT7.
Ding Chenyue,Zhu Liping,Shen Han,Lu Jiafeng,Zou Qinyan,Huang Chao,Li Hong,Huang Boxian
Stem cells (Dayton, Ohio)
Premature ovarian insufficiency (POI) is clinically irreversible in women aged over 40 years. Although numerous studies have demonstrated satisfactory outcomes of mesenchymal stem cell therapy, the underlying therapeutic mechanism remains unclear. Exosomes were collected from the culture medium of human umbilical cord mesenchymal stem cells (hUMSCs) and assessed by electron microscopy and Western blot (WB) analysis. Then, exosomes were added to the culture medium of cyclophosphamide (CTX)-damaged human granulosa cells (hGCs), and the mixture was injected into the ovaries of CTX-induced POI model mice before detection of antiapoptotic and apoptotic gene expression. Next, the microRNA expression profiles of hUMSC-derived exosomes (hUMSC-Exos) were detected by small RNA sequencing. The ameliorative effect of exosomal microRNA-17-5P (miR-17-5P) was demonstrated by miR-17-5P knockdown before assessment of ovarian phenotype and function, reactive oxygen species (ROS) levels and SIRT7 expression. Finally, SIRT7 was inhibited or overexpressed by RNA interference or retrovirus transduction, and the protein expression of PARP1, γH2AX, and XRCC6 was analyzed. The ameliorative effect of hUMSC-Exos on POI was validated. Our results illustrated that hUMSC-Exos restored ovarian phenotype and function in a POI mouse model, promoted proliferation of CTX-damaged hGCs and ovarian cells, and alleviated ROS accumulation by delivering exosomal miR-17-5P and inhibiting SIRT7 expression. Moreover, our findings elucidated that miR-17-5P repressed PARP1, γH2AX, and XRCC6 by inhibiting SIRT7. Our findings suggest a critical role for exosomal miR-17-5P and its downstream target mRNA SIRT7 in hUMSC transplantation therapy. This study indicates the promise of exosome-based therapy for POI treatment.
Single-Oocyte Gene Expression Suggests That Curcumin Can Protect the Ovarian Reserve by Regulating the PTEN-AKT-FOXO3a Pathway.
Lv Yue,Cao Rui-Can,Liu Hong-Bin,Su Xian-Wei,Lu Gang,Ma Jin-Long,Chan Wai-Yee
International journal of molecular sciences
A better understanding of the mechanism of primordial follicle activation will help us better understand the causes of premature ovarian insufficiency (POI), and will help us identify new drugs that can be applied to the clinical treatment of infertility. In this study, single oocytes were isolated from primordial and primary follicles, and were used for gene profiling with TaqMan array cards. Bioinformatics analysis was performed on the gene expression data, and Ingenuity Pathway Analysis was used to analyze and predict drugs that affect follicle activation. An ovarian in vitro culture system was used to verify the function of the drug candidates, and we found that curcumin maintains the ovarian reserve. Long-term treatment with 100 mg/kg curcumin improved the ovarian reserve indicators of AMH, FSH, and estradiol in aging mice. Mechanistic studies show that curcumin can affect the translocation of FOXO3, thereby inhibiting the PTEN-AKT-FOXO3a pathway and protecting primordial follicles from overactivation. These results suggest that curcumin is a potential drug for the treatment of POI patients and for fertility preservation.
Circadian Rhythms Within the Female HPG Axis: From Physiology to Etiology.
Shao Shuyi,Zhao Huanqiang,Lu Zhiying,Lei Xiaohong,Zhang Ying
Declining female fertility has become a global health concern. It results partially from an abnormal circadian clock caused by unhealthy diet and sleep habits in modern life. The circadian clock system is a hierarchical network consisting of central and peripheral clocks. It not only controls the sleep-wake and feeding-fasting cycles but also coordinates and maintains the required reproductive activities in the body. Physiologically, the reproductive processes are governed by the hypothalamic-pituitary-gonadal (HPG) axis in a time-dependent manner. The HPG axis releases hormones, generates female characteristics, and achieves fertility. Conversely, an abnormal daily rhythm caused by aberrant clock genes or abnormal environmental stimuli contributes to disorders of the female reproductive system, such as polycystic ovarian syndrome and premature ovarian insufficiency. Therefore, breaking the "time code" of the female reproductive system is crucial. In this paper, we review the interplay between circadian clocks and the female reproductive system and present its regulatory principles, moving from normal physiology regulation to disease etiology.
Follicle-stimulating hormone receptor autoantibody associated primary ovarian insufficiency successfully treated with corticosteroids: a case report.
Riestenberg Carrie,Ahern Susan,Shamonki Mousa
Objective:To report a case of successful controlled ovarian stimulation (COH) for oocyte cryopreservation in a patient with autoimmune primary ovarian insufficiency (POI) and polyglandular autoimmune syndrome (PGAS) type 2. Design:Case report. Setting:Private in vitro fertilization clinic. Patients:25-Year-old woman, G0, with autoimmune POI and PGAS type 2. Interventions:Diagnosis of autoimmune interference with FSH signaling, with subsequent high-dose corticosteroid immune suppression and successful oocyte cryopreservation. Main Outcomes Measures:Successful stimulation with exogenous gonadotropins, oocyte retrieval, and cryopreservation. Results:Retrieval and cryopreservation of 36 metaphase-II (MII) oocytes. Conclusions:Scrutiny of POI cases will facilitate identification of a subset of patients in whom immune suppression with short-term, high-dose corticosteroids may enable successful COH.
Investigation of the role of serum telomerase levels in patients with occult primary ovarian insufficiency: a prospective cross-sectional study.
Tugrul Ersak Duygu,Yilmaz Nafiye,Cavkaytar Sabri,Ersak Burak,Ustun Yaprak
Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology
This study was designed to investigate serum telomerase levels of occult primary ovarian insufficiency (POI) and the relationship between fertilisation (IVF) results of these patients and serum telomerase levels. A cross-sectional case-control study was conducted between May and October 2017 including 78 patients at University of Health Science, Turkey. Occult POI was defined as women with a history of follicle-stimulating hormone (FSH) elevation between 12 and 25 IU/L and low ovarian reserve before initiation of IVF ( = 39). The control group were patients attending the hospital for contraception, with no history of infertility, having at least one healthy child ( = 39). Telomerase levels in serum samples were determined using enzyme-linked immunosorbent assay method. There was no statistically significant difference in serum telomerase levels in occult POI patients when compared with the control group.Impact statement Clinical studies investigating the role of telomerase on reproductive function and fertilisation (IVF) outcomes in occult primary ovarian insufficiency (POI) patients are limited with no clear consensus and in all these studies polymerase chain reaction technique was used to evaluate telomere length. Regarding our knowledge, this is the first study in the literature investigating the role of serum telomerase levels in occult POI patients. In contrast to the previous studies, in this study no statistically significant difference was found in serum telomerase levels in occult POI patients when compared with the fertile control patients. The occult POI patients examined in this study are overlooked until they apply with infertility. Serum telomerase measurement is not useful to support the diagnosis of occult POI. Nevertheless, in order to confirm these findings, further studies in larger populations are needed.
Novel inactivating follicle-stimulating hormone receptor mutations in a patient with premature ovarian insufficiency identified by next-generation sequencing gene panel analysis.
Sassi Asma,Désir Julie,Janssens Véronique,Marangoni Martina,Daneels Dorien,Gheldof Alexander,Bonduelle Maryse,Van Dooren Sonia,Costagliola Sabine,Delbaere Anne
Objective:To find the genetic etiology of premature ovarian insufficiency (POI) in a patient with primary amenorrhea and hypergonadotropic hypogonadism. Design:Case report. Setting:University hospital. Patients:A Belgian woman aged 32 years with POI at the age of 17, her parents, and her sister whose POI was diagnosed at age 29. Interventions:Analysis of a panel of 31 genes implicated in POI (POIGP) using next-generation sequencing (NGS), Sanger sequencing, and in vitro functional study. Main Outcome Measures:Gene variants, family mutational segregation, and in vitro functional impact of the mutant proteins. Results:The analysis of the gene panel using NGS identified the presence of two novel follicle-stimulating hormone receptor () missense mutations at a compound heterozygous state in the affected patient: c.646 G>A, p.Gly216Arg, and c.1313C>T, p.Thr438Ile. Sanger sequencing showed the presence of each mutation at heterozygous state in the patient's parents and at heterozygous compound state in the affected sister. Both substituted amino acids (Gly216 and Thr438) were conserved in of several vertebrate species as well as in other glycoproteins receptors ( and ), suggesting a potentially important role in glycoprotein receptor function. An in vitro functional study showed similar results for both variants with more than 90% reduction of their cell surface expression and a 55% reduction of their FSH-induced cyclic adenosine 3':5' monophosphate (cAMP) production compared with the wild-type . Conclusions:The analysis of a gene panel of 31 genes implicated in POI allowed us to identify two novel partially inactivating mutations of that are likely responsible for the POI phenotype of the proband and of her affected sister.
Characterization of a novel mutation V136L in bone morphogenetic protein 15 identified in a woman affected by POI.
Ferrarini Eleonora,De Marco Giuseppina,Orsolini Francesca,Gianetti Elena,Benelli Elena,Fruzzetti Franca,Simoncini Tommaso,Agretti Patrizia,Tonacchera Massimo
Journal of ovarian research
BACKGROUND:Premature ovarian insufficiency (POI) is an ovarian defect characterized by primary or secondary amenorrhea, hypergonadotropism and hypoestrogenism which occurs before the age of 40 years with a major genetic component. In this study we performed clinical evaluation and genetic analysis of a group of 18 patients with POI. The study involved 18 consecutive women with POI. Karyotiping and genetic analysis for research of mutations in GDF9 (Growth Differentation Factor 9) and BMP15 (Bone morphogentic protein 15) genes and FMR1 (Fragile X Mental Retardation 1) premutation were carried out. In vitro functional study of the novel BMP15 mutation was performed using COV434 (Human ovarian granulosa tumour cells 434) cells of ovarian granulosa, which consistently express BMP responsive element, and luciferase reporter assay. RESULTS:Three patients (17%) had a family history of POI. Ten patients (56%) had a family history of autoimmune diseases and nine patients (50%) showed a personal history of one or more autoimmune diseases. Of patients for whom morphological assessment was available, almost half (44%) had poor follicle assets or small ovaries's size at pelvic US. Two patients (13%) showed reduced bone density at DEXA (Dual Energy X-ray Absorptiometry). All the women had normal female kariotype and no mutations in the GDF-9 gene or FMR1 premutations were found. A novel heterozygous mutation c.406G > C (V136L) of BMP15 gene was identified in one patient. After transfection in COV434 cells, BMP15 variant showed a significantly reduced luciferase activity compared to wild type. CONCLUSIONS:POI is a multifactorial disease with several health implications. Autoimmunity and genetics represent the most common aetiology. We identified and characterized a novel BMP15 mutation, providing an additional elucidation of molecular basis of this complex disorder.
Primary ovarian insufficiency, meiosis and DNA repair.
Veitia Reiner A
Premature ovarian insufficiency (POI) is a major cause of female infertility. It is a heterogeneous disease that affects about 1% of women under 40 years of age. POI may be due to abnormal follicle stock formation, increased follicular atresia, impaired recruitment of dominant follicles, blocked follicular maturation or rapid depletion of the follicular stock. It remains idiopathic in most cases but the existence of familial cases shows that it can have a genetic origin. Next generation sequencing (NGS) strategies have allowed the identification of new genes involved in the etiology of POI. Here, I briefly describe some studies demonstrating that pathogenic variants in 'DNA repair and meiotic genes' underlie POI. Some of the examples show the power of the combination of classical genetics and NGS in the discovery of novel 'POI genes'.
The hypothetical molecular pathways of ursolic acid to attenuate the premature ovarian failure in human.
Premature ovarian failure, which is also called premature menopause, refers to the stop of menstruation and the formation of oocyte before 40 years old. As a disease which is closely related to the formation of oocyte and relevant meiosis, the role of adjacent cells such as ovarian granulosa cell or the membranous follicular cells in the pathogenesis of premature ovarian failure is currently being investigated. One of the most popular theories concludes that premature ovarian failure is due to the apoptosis of the ovarian granulosa cells, as they are responsible for the synthesis and regulation of multiple types of hormones and internal factors that are related to reproduction, for example, the inhibin, activin, and follistatin. The apoptosis of the ovarian granulosa cells can be initiated by various of internal or external environmental factors such as the hazardous chemicals in the ovarian or the excessive exposure to the physical radiation as a result of the occupation. While the detailed underlying mechanisms to cause the apoptosis of the ovarian granulosa cell are still unclear. The ursolic acid is white concrete at room temperature, and many studies have elucidated that it can relieve hypoxia and endoplasmic reticulum stress. In this article, the author proposed five molecular pathways of ursolic acid to relieve or cure premature ovarian failure in humans.
T deficiency-mediated T 1 response causes human premature ovarian insufficiency through apoptosis and steroidogenesis dysfunction of granulosa cells.
Jiao Xue,Zhang Xiruo,Li Nianyu,Zhang Dunfang,Zhao Shidou,Dang Yujie,Zanvit Peter,Jin Wenwen,Chen Zi-Jiang,Chen Wanjun,Qin Yingying
Clinical and translational medicine
Immune dysregulation has long been proposed as a component of premature ovarian insufficiency (POI), but the underlying mediators and mechanisms remain largely unknown. Here we showed that patients with POI had augmented T helper 1 (T 1) responses and regulatory T (T ) cell deficiency in both the periphery and the ovary compared to the control women. The increased ratio of T 1:T cells was strongly correlated with the severity of POI. In mouse models of POI, the increased infiltration of T 1 cells in the ovary resulted in follicle atresia and ovarian insufficiency, which could be prevented and reversed by T cells. Importantly, interferon (IFN) -γ and tumor necrosis factor (TNF) -α cooperatively promoted the apoptosis of granulosa cells and suppressed their steroidogenesis by modulating CTGF and CYP19A1. We have thus revealed a previously unrecognized T cell deficiency-mediated T 1 response in the pathogenesis of POI, which should have implications for therapeutic interventions in patients with POI.
Intraovarian injection of platelet-rich plasma in assisted reproduction: too much too soon?
Atkinson Lloyd,Martin Francesca,Sturmey Roger G
Human reproduction (Oxford, England)
The prospect of ovarian rejuvenation offers the tantalising prospect of treating age-related declines in fertility or in pathological conditions such as premature ovarian failure. The concept of ovarian rejuvenation was invigorated by the indication of the existence of oogonial stem cells (OSCs), which have been shown experimentally to have the ability to differentiate into functional follicles and generate oocytes; however, their clinical potential remains unknown. Furthermore, there is now growing interest in performing ovarian rejuvenation in situ. One proposed approach involves injecting the ovary with platelet rich plasma (PRP). PRP is a component of blood that remains after the in vitro removal of red and white blood cells. It contains blood platelets, tiny anucleate cells of the blood, which are responsible for forming athrombus to prevent bleeding. In addition, PRP contains an array of cytokines and growth factors, as well as a number of small molecules.The utility ofPRP has been investigatedin a range of regenerative medicine approaches and has been shown to induce differentiation of a range of cell types, presumably through the action of cytokines. A handful ofcasereports have described the use of PRP injections into the ovaryin the human, and while these clinical data report promising results, knowledge on the mechanisms and safety of PRP injections into the ovary remain limited.In this article, we summarise some of the physiological detail of platelets and PRP, before reviewing the existing emerging literature in this area. We then propose potential mechanisms by which PRP may be eliciting any effects before reflecting on some considerations for future studies in the area. Importantly, on the basis of our existing knowledge, we suggest that immediate use of PRP in clinical applications is perhaps premature and further fundamental and clinical research on the nature of ovarian insufficiency, as well as the mechanism by which PRP may act on the ovary, is needed to fully understand this promising development.
Temporal transcriptomic landscape of postnatal mouse ovaries reveals dynamic gene signatures associated with ovarian aging.
Zhou Zixue,Yang Xi,Pan Yuncheng,Shang Lingyue,Chen Siyuan,Yang Jialin,Jin Li,Zhang Feng,Wu Yanhua
Human molecular genetics
The ovary is the most important organ for maintaining female reproductive health, but it fails before most other organs. Aging-associated alterations in gene expression patterns in mammalian ovaries remain largely unknown. In this study, the transcriptomic landscape of postnatal mouse ovaries over the reproductive lifespan was investigated using bulk RNA sequencing in C57BL/6 mice. Gene expression dynamics revealed that the lifespan of postnatal mouse ovaries comprised four sequential stages, during which 2517 genes were identified as differentially enriched. Notably, the DNA repair pathway was found to make a considerable and specific contribution to the process of ovarian aging. Temporal gene expression patterns were dissected to identify differences in gene expression trajectories over the lifespan. In addition to DNA repair, distinct biological functions (including hypoxia response, epigenetic modification, fertilization, mitochondrial function, etc.) were overrepresented in particular clusters. Association studies were further performed to explore the relationships between known genes responsible for ovarian function and differentially expressed genes identified in this work. We found that the causative genes of human premature ovarian insufficiency were specifically enriched in distinct gene clusters. Taken together, our findings reveal a comprehensive transcriptomic landscape of the mouse ovary over the lifespan, providing insights into the molecular mechanisms underlying mammalian ovarian aging and supporting future etiological studies of aging-associated ovarian disorders.
Perinatal hypoxia leads to primordial follicle activation and premature depletion of ovarian reserve.
Gutzeit Ola,Iluz Roee,Ginsberg Yuval,Nebenzahl Keren,Beloosesky Ron,Weiner Zeev,Fainaru Ofer
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians
BACKGROUND:The human ovary contains 6-million follicles during the 20th week of embryonic development and 1 million at birth. Girls born at small for gestational age weight demonstrate higher FSH levels during infancy, an earlier onset of puberty, and menarche. In light of these observations, we hypothesized that exposure to hypoxia at the early neonatal period might impact the primordial follicular pool and lead to premature depletion of ovarian reserve. METHODS:Ovarian development in the rat model at days 1-5 postpartum reflects its human counterpart in the late perinatal period. We exposed newborn rat pups ( = 5) to controlled hypoxia, (5% oxygen/95% nitrogen) for 10 min three times daily for days 1-5 postpartum. On day 5, ovaries were harvested, H&E, Ki-67, and TUNEL staining were performed. RESULTS:The percentage of primordial follicles out of total follicles in ovaries of pups exposed to hypoxia was lower compared to control (76 ± 8.2% and 90.33 ± 6.3% respectively, < .05). Correspondingly the percentage of primary and secondary follicles was higher than in control. The mean stromal Ki67 staining score was significantly lower in the study group (1.67 ± 0.58 and 2.5 ± 0.55 respectively, < .05). TUNEL staining demonstrated no difference in stromal apoptosis rates between both groups. CONCLUSIONS:We provide evidence for the first time that perinatal hypoxia causes premature activation and growth initiation of dormant follicles. These changes were associated with decreased stromal cell proliferation, suggesting hypoxia-induced impairment of the support cell pool as a possible mechanism for accelerated follicular activation.
Ovarian Reserve Markers in Premature Ovarian Insufficiency: Within Different Clinical Stages and Different Etiologies.
Jiao Xue,Meng Tingting,Zhai Yiwei,Zhao Lijuan,Luo Wei,Liu Peihao,Qin Yingying
Frontiers in endocrinology
Objective:To characterize the ovarian reserve indicators for premature ovarian insufficiency (POI) at different disease stages and with various etiologies. Methods:According to different FSH levels and menstrual conditions, patients with normal ovarian reserve (NOR with 5 IU/L<FSH<10 IU/L, n=987), precursor stage of POI (pre-POI with 10 IU/L<FSH ≤ 25 IU/L, n=410), early POI (25 IU/L<FSH ≤ 40 IU/L n=147), and premature ovarian failure (POF with FSH>40 IU/L, n=454) were retrospectively screened and their records were abstracted from Reproductive Hospital Affiliated to Shandong University between 2014 and 2019. Based on the known etiologies, POI patients were subdivided into genetic, iatrogenic, autoimmune and idiopathic subsets according to the known etiologies. The phenotypic features were compared within different subgroups, and the predictive value of ovarian reserve markers was analyzed. Results:The ovarian reserve indicators consecutively deteriorated with the progress of ovarian insufficiency, indicated as an increase of FSH and LH but decrease of AMH, inhibin B, AFC, E and T (P<0.01). Most of them changed significantly from NOR to pre-POI while remained relatively stable at a low level or even undetectable at early POI and POF stage. AMH showed the highest predictive value for pre-POI (AUC 0.932, 95% CI 0.918-0.945) and POI (AUC 0.944, 95% CI 0.933-0.954), and the combination of AMH and AFC was highly promising for early prediction. Additionally, significant differences existed in AMH, inhibin B and AFC among women with different etiologies of POI (P<0.05), and the genetic POI presented the worst hormone status. Conclusions:Our study indicated a high heterogeneity of POI in both endocrine hormones and etiological phenotypes. The quantitative changes and cutoff values of AMH and AFC could provide new insights in the prediction and early diagnosis of POI.
Impact of Dietary Selenium on Modulation of Expression of Several Non-Selenoprotein Genes Related to Key Ovarian Functions, Female Fertility, and Proteostasis: a Transcriptome-Based Analysis of the Aging Mice Ovaries.
Qazi Izhar Hyder,Cao Yutao,Yang Haoxuan,Angel Christiana,Pan Bo,Zhou Guangbin,Han Hongbing
Biological trace element research
Female reproductive (ovarian) aging is characterized by a marked decline in quantity and quality of follicles and oocytes, as well as alterations in the surrounding ovarian stroma. In our previous report, we have shown that dietary selenium (Se) insufficiency and supplementation differentially impacted the reproductive efficiency in aging mice; however, the precise understanding of such modulation is still incomplete. In the present study, we sought to determine the impact of low (mildly low level) and moderately high (medium level) Se diets on expression profile of non-selenoprotein genes in the ovaries of aging mice. For this purpose, the aged mice were divided in two groups and fed either a low Se (Se-L; 0.08 mg Se/kg) diet or a moderately high Se (Se-M; 0.33 mg Se/kg) diet. RNA-seq analysis revealed that a total of 168 genes were differentially expressed between the two groups. From these, 72 and 96 differentially expressed genes (DEGs) were found to be upregulated and downregulated, respectively. Gene Ontology (GO) and pathways enrichment (KEGG) analyses revealed that these DEGs were enriched in several key GO terms and biological pathways including PI3K-Akt signaling pathway, steroid hormone biosynthesis, signaling pathways regulating pluripotency of stem cells, Hippo signaling pathway, ovarian steroidogenesis, and Wnt signaling pathway. Further filtering of RNA-seq data revealed that several DEGs such as Star, Hsd3b6, Scd1, Bmp7, Aqp8, Gas1, Fzd1, and Wwc1 were implicated in key ovarian- and fertility-related functions. In addition, some of the DEGs were related to ER homeostasis and/or proteostasis. These results highlight that dietary low and moderately high (medium level) Se diets, in addition to modulation of selenoproteins, can also have an impact on expression of several non-selenoprotein genes in the ovaries of aging mice. To sum up, these findings add more value to our understanding of Se modulation of ovarian functions and female fertility and will pave a way for the focused mechanistic and functional studies in this domain.
hUMSC transplantation restores ovarian function in POI rats by inhibiting autophagy of theca-interstitial cells via the AMPK/mTOR signaling pathway.
Lu Xueyan,Bao Hongchu,Cui Linlu,Zhu Wenqian,Zhang Lianshuang,Xu Zheng,Man Xuejing,Chu Yongli,Fu Qiang,Zhang Hongqin
Stem cell research & therapy
BACKGROUND:Previous studies of primary ovarian insufficiency (POI) have focused on granulosa cells (GCs) and ignored the role of theca-interstitial cells (TICs). This study aims to explore the mechanism of the protective effects of human umbilical cord-derived mesenchymal stem cells (hUMSCs) on ovarian function in POI rats by regulating autophagy of TICs. METHODS:The POI model was established in rats treated with cisplatin (CDDP). The hUMSCs were transplanted into POI rats by tail vein. Enzyme-linked immunosorbent assay (ELISA) analysis, hematoxylin and eosin (HE) staining, and immunohistochemistry were used to measure the protective effects of hUMSCs. The molecular mechanisms of injury and repairment of TICs were assessed by immunofluorescence, transmission electron microscope (TEM), flow cytometry (FCM), western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS:In vivo, hUMSC transplantation restored the ovarian function and alleviated the apoptosis of TICs in POI rats. In vitro, hUMSCs reduced the autophagy levels of TICs by reducing oxidative stress and regulating AMPK/mTOR signaling pathway, thereby alleviating the apoptosis of TICs. CONCLUSION:This study indicates that hUMSCs protected ovarian function in POI by regulating autophagy signaling pathway AMPK/mTOR.
Novel PMM2 missense mutation in a Chinese family with non-syndromic premature ovarian insufficiency.
Peng Tianliu,Lv Chao,Tan Hangjing,Huang Jiafeng,He Hailun,Wang Yan,Zeng Minghua,Yi Dajing,Li Jie,Deng Hongwen,Shi Xiaobo,Xiao Hongmei
Journal of assisted reproduction and genetics
PURPOSE:This study sought to identify a disease-related gene in a consanguineous Chinese family in which there were two premature ovarian insufficiency (POI) sisters. METHOD:We used whole-exome sequencing and Sanger sequencing to identify the disease-causing gene. Results were verified using an assay of mutant protein and in silico analyses. RESULT:We identified a novel missense mutation (NM_000303: c.556G>A, p.Gly186Arg) in the PMM2 gene. The two sisters suffer from premature ovarian insufficiency (POI) only and have no other symptoms of congenital disorder of glycosylation type-1a (CDG-Ia). We found that the enzymic activity of the mutant PMM2 protein was reduced by 55.21% (p < 0.05) when compared with wild type, and many in silico tools suggested the mutation is disease-related. CONCLUSION:This particular gene modification results in changes in activity of phosphomannomutase modification, which could lead to PMM2-CDG-Ia with an uncommon phenotype.
Cardiometabolic health in premature ovarian insufficiency.
Stevenson J C,Collins P,Hamoda H,Lambrinoudaki I,Maas A H E M,Maclaran K,Panay N
Climacteric : the journal of the International Menopause Society
Premature ovarian insufficiency (POI) is an increasing public health problem with a prevalence now approaching 4%. POI results in adverse effects on the skeleton and central nervous system as well as disturbances of metabolic and cardiological factors that predispose to a major increased risk of cardiovascular disease (CVD). This article reviews the effects of the premature loss of ovarian function on lipids and lipoproteins, glucose and insulin metabolism, body composition, hemostasis and blood pressure, together with effects on the development of metabolic syndrome and diabetes mellitus. The article examines the effects of POI on vascular endothelial function and inflammation that result in arterial disease, and reviews the effects of hormone replacement therapy (HRT) on these various metabolic processes and on cardiovascular outcomes. It is essential that women with POI receive hormonal treatment to help prevent the development of CVD, and that this treatment is continued at least until the normal age of menopause. It appears that HRT has a more favorable effect than the combined oral contraceptive, but larger clinical trials are needed to establish the optimal treatment. Other therapeutic measures may need to be added to correct existing metabolic abnormalities and, in particular, attention to lifestyle factors such as diet and exercise must be encouraged.
Influence of Autologous Activation of Ovaries by Stem Cells and Growth Factors on Endocrine and Reproductive Function of Patients with Ovarian Insufficiency-A Clinical Trial Study.
Tinjić Suada,Abazović Džihan,Ljubić Dušica,Vojvodić Danilo,Božanović Tatjana,Ibrišimović Mirza,Marković Sergije,Ljubić Aleksandar
International journal of fertility & sterility
Background:Premature ovarian failure (POF) can be found in 1% of women at the age of 35-40, mostly due to unknown causes. PI3K-Akt signaling is associated with both ovarian function and growth of primordial follicles. In this study, we examined the effects of autologous ovarian activation with stem cells and autologous growth factors on reproductive and endocrine function in patients with ovarian impairment. Materials and Methods:The longitudinal prospective observational study included 50 patients (between 30 and 50 years) with a diagnosis of POF and infertility. This multicenter study was performed at Jevremova Special Hospital in Belgrade, Saint James Hospital (Malta), and Remedica Skoplje Hospital, between 2015 and 2018. All patients went through numerous laboratory testings, including hormonal status. The autologous bone marrow mesenchymal stem cells (BMSCs) and growth factors were used in combination for activation of ovarian tissue before its re-transplantation. The software package SPSS 20.0 was used for statistical analysis of the results. Results:Differences in follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone (PG) hormone concentrations before and after 3, 6, and 12 months post-transplantation were tested in correlation with the volume of transplanted ovarian tissue. A significant correlation (P=0.029) was found between the change in E2 level after 3 months and the volume of re-transplanted tissues. Also after re-transplantation, 64% of the patients had follicles resulting in aspiration of oocytes in 25% of positive women with follicles. Conclusion:The SEGOVA method could potentially solve many human reproductive problems in the future due to the large number of patients diagnosed with POF, as well asthe possibility of delaying menopause, thus improving the quality of life and general health (Registration number: NCT04009473).
The PREgnancy and FERtility (PREFER) Study Investigating the Need for Ovarian Function and/or Fertility Preservation Strategies in Premenopausal Women With Early Breast Cancer.
Blondeaux Eva,Massarotti Claudia,Fontana Valeria,Poggio Francesca,Arecco Luca,Fregatti Piero,Bighin Claudia,Giannubilo Irene,Ruelle Tommaso,Razeti Maria Grazia,Boni Luca,Anserini Paola,Del Mastro Lucia,Lambertini Matteo
Frontiers in oncology
Background:Offering ovarian function and/or fertility preservation strategies in premenopausal women with newly diagnosed breast cancer candidates to undergo chemotherapy is standard of care. However, few data are available on uptake and main reasons for refusing these options. Methods:The PREFER study (NCT02895165) is an observational, prospective study enrolling premenopausal women with early breast cancer, aged between 18 and 45 years, candidates to receive (neo)adjuvant chemotherapy. Primary objective is to collect information on acceptance rates and reasons for refusal of the proposed strategies for ovarian function and/or fertility preservation available in Italy. Results:At the study coordinating center, 223 patients were recruited between November 2012 and December 2020. Median age was 38 years (range 24 - 45 years) with 159 patients (71.3%) diagnosed at ≤40 years. Temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) was accepted by 58 out of 64 (90.6%) patients aged 41-45 years and by 151 out of 159 (95.0%) of those aged ≤40 years. Among patients aged ≤40 years, 57 (35.8%) accepted to access the fertility unit to receive a complete oncofertility counseling and 29 (18.2%) accepted to undergo a cryopreservation technique. Main reasons for refusal were fear of delaying the initiation of antineoplastic treatments and contraindications to the procedure or lack of interest in future childbearing. Patients with hormone-receptor positive breast cancer had a tendency for a higher acceptance rates of ovarian function and/or fertility preservation strategies than those with hormone-receptor negative disease. Conclusions:More than 90% of premenopausal women with early breast cancer, and particularly those with hormone receptor-positive disease, were concerned about the potential risk of chemotherapy-induced premature ovarian insufficiency and/or infertility and accepted GnRHa administration. Less than 1 out of 5 women aged ≤40 years accepted to undergo cryopreservation strategies.
A woman with primary ovarian insufficiency had two live births resulting from intrauterine inseminations during 10 years of ovarian follicle monitoring.
The journal of obstetrics and gynaecology research
Women with primary ovarian insufficiency rarely ovulate and even more rarely achieve a spontaneous pregnancy. A patient with primary ovarian insufficiency who had only 13 follicle development cycles during 13 years, but had 2 live births resulting from intrauterine inseminations is reported. She was diagnosed with primary ovarian insufficiency at 19 years of age and started infertility treatment at 23 years of age. During 10 of the 13 years that she was not pregnant and not breastfeeding, she underwent cyclic estrogen and progestin therapy with biweekly monitoring of follicle development. She delivered the first and second child at 30 and 37 years of age, respectively. This case report suggests that continuous follicle monitoring may increase the probability of having a child in a subset of patients with primary ovarian insufficiency and desired fertility, although the validity and efficacy of such management has not been established.
Endothelial cell-specific-molecule-1 (endocan) levels in women with premature ovarian insufficiency: a prospective comparative study.
Ovayolu Ali,Karaman Erbil,Turgut Abdulkadir,Cekici Yusuf,Ortabag Tulay,Chiara Rapisarda Agnese Maria,Noventa Marco,Cianci Antonio
Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology
There is an increased risk of cardiovascular disease in women with premature ovarian insufficiency (POI). A relationship between cardiovascular disease and endocan levels has been shown. Endocan is a marker that is prominent in many diseases caused by endothelial dysfunction and can be measured in the blood. POI is also associated with endothelial dysfunction. The causes of POI include chromosomal and genetic defects, autoimmune processes, chemotherapy, radiation, infections and surgery, but many are unidentified (idiopathic). This study aimed to evaluate serum endocan levels in women with idiopathic POI. The blood for analysis was obtained at the early follicular phase of the menstrual cycle and endocan levels were measured using a commercially available enzyme-linked immunosorbent assay kit. There were 38 patients with idiopathic POI in the study group and 39 healthy subjects in the control group. The median ages of the women were not significantly different between the groups 34  years vs. 34  years, respectively ( = .862). The median endocan level was not different in the POI and control group 769  vs. 1077  pg/mL, respectively ( = .603). Endocan is not associated with the cardiovascular diseases risk linked with endothelial dysfunction in idiopathic POI. NCT03932877 (Clinicaltrials.gov)IMPACT STATEMENT There is an increased risk of cardiovascular disease in premature ovarian insufficiency (POI) due to the decreased level of oestrogen, which is linked with endothelial dysfunction. This study showed that endocan is not associated with the cardiovascular disease risk linked with endothelial dysfunction in idiopathic POI. A marker to be used to predict the risk of cardiovascular disease in patients with POI could facilitate in improving the quality of life of these patients. Moreover, advantageous and easy-to-measure markers are needed in larger sample studies to better understand the cardiovascular diseases risk in POI.
Primary Ovarian Insufficiency in Women With Addison's Disease.
Vogt Elinor C,Breivik Lars,Røyrvik Ellen C,Grytaas Marianne,Husebye Eystein S,Øksnes Marianne
The Journal of clinical endocrinology and metabolism
CONTEXT:Primary ovarian insufficiency (POI) is defined by menopause before 40 years of age. POI prevalence is higher among women with autoimmune Addison's disease (AAD) than in the general population, but their clinical characteristics are insufficiently studied. OBJECTIVE:To assess the prevalence of POI in a large cohort of women with AAD and describe clinical, immunological, and genetic characteristics. METHODS:An observational population-based cohort study of the Norwegian National Addison Registry. The Norwegian Prescription Database was used to assess prescription of menopausal hormone replacement therapy (HRT). A total of 461 women with AAD were studied. The primary outcome measure was prevalence of POI. Secondary outcomes were clinical characteristics, autoantibodies, and genome-wide single nucleotide polymorphism variation. RESULTS:The prevalence of POI was 10.2% (47/461) and one-third developed POI before 30 years of age. POI preceded or coincided with AAD diagnosis in more than half of the women. The prevalence of concomitant autoimmune diseases was 72%, and AAD women with POI had more autoantibodies than AAD women without (≥2 autoantibodies in 78% vs 25%). Autoantibodies against side-chain cleavage enzyme (SCC) had the highest accuracy with a negative predictive value for POI of 96%. HRT use was high compared to the age adjusted normal population (11.3 % vs 0.7%). CONCLUSION:One in 10 women with AAD have POI. Autoantibodies against SCC are the most specific marker for autoimmune POI. We recommend testing women with AAD <40 years with menstrual disturbances or fertility concerns for autoantibodies against SCC.
The relationship between vitamin E level and premature ovarian insufficiency.
Ma Linjuan,Chen Guili,Xu Wenxian,Chen Peiqiong,Lan Yibing,Huang Yizhou,Li Chunming,Zhou Jianhong
The journal of obstetrics and gynaecology research
AIM:The aim of this study is to investigate the role of vitamin E in the etiology of premature ovarian insufficiency (POI). METHODS:This study included a total of 96 matched cases and controls, including the case group composed of 40 women with POI, and the control group composed of 56 women with normal menstrual cycles. Serum levels of vitamin E (also known as α-tocopherol), total cholesterol, follicle stimulating hormone (FSH), luteinizing hormone (LH) and anti-Müllerian hormone (AMH) were determined. The relationship of α-tocopherol with FSH, LH and AMH levels in women were evaluated using regression models. RESULTS:We found a negative association of α-tocopherol levels with FSH and LH levels, and a positive correlation between a-tocopherol and AMH levels in the whole study population. In this study, α-tocopherol levels were significantly lower in women with POI than those in women with normal menstrual cycles. CONCLUSION:Vitamin E levels showed significantly statistical difference between the POI and control group (P < 0.001). Therefore, vitamin E is correlated to POI.
Tributyltin and high-refined carbohydrate diet lead to metabolic and reproductive abnormalities, exacerbating premature ovary failure features in the female rats.
Zanol Jordana F,Niño Oscar M S,da Costa Charles S,Freitas-Lima Leandro C,Miranda-Alves Leandro,Graceli Jones B
Reproductive toxicology (Elmsford, N.Y.)
Exposure to the obesogen tributyltin (TBT) alone or high carbohydrate diet (HCD) alone leads to obesity and reproductive complications, such as premature ovary failure (POF) features. However, little is known about interactions between TBT and nutrition and their combined impact on reproduction. In this study, we assessed whether acute TBT and HCD exposure results in reproductive and metabolic irregularities. Female rats were treated with TBT (100 ng/kg/day) and fed with HCD for 15 days and metabolic and reproductive outcomes were assessed. TBT and HCD rats displayed metabolic impairments, such as increased adiposity, abnormal lipid profile and triglyceride and glucose (TYG) index, worsening adipocyte hypertrophy in HCD-TBT rats. These metabolic consequences were linked with reproductive disorders. Specifically, HCD-TBT rats displayed irregular estrous cyclicity, high follicle-stimulating hormone (FSH) levels, low anti-Müllerian hormone (AMH) levels, reduction in ovarian reserve, and corpora lutea (CL) number, with increases in atretic follicles, suggesting that HCD-TBT exposure exacerbated POF features. Further, strong negative correlations were observed between adipocyte hypertrophy and ovarian reserve, CL number and AMH levels. HCD-TBT exposure resulted in reproductive tract inflammation and fibrosis. Collectively, these data suggest that TBT plus HCD exposure leads to metabolic and reproductive abnormalities, exacerbating POF features in female rats.
hUMSCs regulate the differentiation of ovarian stromal cells via TGF-β/Smad3 signaling pathway to inhibit ovarian fibrosis to repair ovarian function in POI rats.
Cui Linlu,Bao Hongchu,Liu Zhongfeng,Man Xuejing,Liu Hongyuan,Hou Yun,Luo Qianqian,Wang Siyuan,Fu Qiang,Zhang Hongqin
Stem cell research & therapy
OBJECTIVE:The basic pathological changes of primary ovarian insufficiency (POI) include ovarian tissue fibrosis and follicular development disorders. The human umbilical cord mesenchymal stem cell (hUMSC) transplantation has been shown an effective method to improve the ovarian function in POI rat model; however, the exact mechanisms are still unclear. The purpose of this study is to investigate whether the recovery of ovarian function in POI rats is related to the inhibition of tissue fibrosis following hUMSC transplantation. Furthermore, the transforming growth factor-β (TGF-β) signaling pathway is explored to determine the mechanisms of ovarian function recovery through its inhibition of tissue fibrosis. METHODS:The primary ovarian insufficiency (POI) rat model was established by intraperitoneal injection of chemotherapy drug cisplatin (CDDP) for 7 days. The levels of serum sex hormones were measured using enzyme-linked immunosorbent assay (ELISA). The tissue fibrosis in the ovary was examined using Masson staining and Sirius red staining. The collagen fibers in the ovarian tissues were detected by Western blot analysis. To investigate the mechanisms of ovarian function recovery following hUMSC transplantation, ovarian stromal cells were isolated from the ovarian cortex of immature rats. The expression of Cytochrome P450 17A1 (Cyp17a1) and fibrosis marker of alpha smooth muscle actin (α-SMA) in ovarian stromal cells was examined using immunofluorescence analysis. Also, the protein levels of Cyp17a1 and α-SMA in ovarian stromal cells were examined by Western blot analysis. The expression of TGF-β and Smad3 signals was measured by Western blot and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis. RESULTS:The results show that the function of the ovary in POI rats was significantly improved after hUMSC transplantation. The expression of fibrosis markers (α-SMA) and production of Collagen Type I (Collagen I) and Collagen Type III (Collagen III) in POI rats were significantly inhibited in POI rats following hUMSC transplantation. In the cultured ovarian stromal cells, the decrease of TGF-β and p-Smad3 protein expression was observed in hUMSC-treated POI rats. The treatment with TGF-β inhibitor of SB431542 further confirmed this signal pathway was involved in the process. CONCLUSION:Our study demonstrated that the TGF-β/Smad3 signaling pathway was involved in the inhibition of ovarian tissue fibrosis, which contributed to the restoration of ovarian function in POI rats following hUMSC transplantation.
Perfluoroalkyl and polyfluoroalkyl substances (PFAS) and their effects on the ovary.
Ding Ning,Harlow Siobán D,Randolph John F,Loch-Caruso Rita,Park Sung Kyun
Human reproduction update
BACKGROUND:Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are found widespread in drinking water, foods, food packaging materials and other consumer products. Several PFAS have been identified as endocrine-disrupting chemicals based on their ability to interfere with normal reproductive function and hormonal signalling. Experimental models and epidemiologic studies suggest that PFAS exposures target the ovary and represent major risks for women's health. OBJECTIVE AND RATIONALE:This review summarises human population and toxicological studies on the association between PFAS exposure and ovarian function. SEARCH METHODS:A comprehensive review was performed by searching PubMed. Search terms included an extensive list of PFAS and health terms ranging from general keywords (e.g. ovarian, reproductive, follicle, oocyte) to specific keywords (including menarche, menstrual cycle, menopause, primary ovarian insufficiency/premature ovarian failure, steroid hormones), based on the authors' knowledge of the topic and key terms. OUTCOMES:Clinical evidence demonstrates the presence of PFAS in follicular fluid and their ability to pass through the blood-follicle barrier. Although some studies found no evidence associating PFAS exposure with disruption in ovarian function, numerous epidemiologic studies, mostly with cross-sectional study designs, have identified associations of higher PFAS exposure with later menarche, irregular menstrual cycles, longer cycle length, earlier age of menopause and reduced levels of oestrogens and androgens. Adverse effects of PFAS on ovarian folliculogenesis and steroidogenesis have been confirmed in experimental models. Based on laboratory research findings, PFAS could diminish ovarian reserve and reduce endogenous hormone synthesis through activating peroxisome proliferator-activated receptors, disrupting gap junction intercellular communication between oocyte and granulosa cells, inducing thyroid hormone deficiency, antagonising ovarian enzyme activities involved in ovarian steroidogenesis or inhibiting kisspeptin signalling in the hypothalamus. WIDER IMPLICATIONS:The published literature supports associations between PFAS exposure and adverse reproductive outcomes; however, the evidence remains insufficient to infer a causal relationship between PFAS exposure and ovarian disorders. Thus, more research is warranted. PFAS are of significant concern because these chemicals are ubiquitous and persistent in the environment and in humans. Moreover, susceptible groups, such as foetuses and pregnant women, may be exposed to harmful combinations of chemicals that include PFAS. However, the role environmental exposures play in reproductive disorders has received little attention by the medical community. To better understand the potential risk of PFAS on human ovarian function, additional experimental studies using PFAS doses equivalent to the exposure levels found in the general human population and mixtures of compounds are required. Prospective investigations in human populations are also warranted to ensure the temporality of PFAS exposure and health endpoints and to minimise the possibility of reverse causality.
Recovery of ovarian function by human embryonic stem cell-derived mesenchymal stem cells in cisplatin-induced premature ovarian failure in mice.
Yoon Sook Young,Yoon Jung Ah,Park Mira,Shin Eun-Young,Jung Sookyung,Lee Jeoung Eun,Eum Jin Hee,Song Haengseok,Lee Dong Ryul,Lee Woo Sik,Lyu Sang Woo
Stem cell research & therapy
BACKGROUND:Clinical use of mesenchymal stem cells (MSCs) requires a uniform cell population, and their harvesting is invasive and produces a limited number of cells. Human embryonic stem cell-derived MSCs (hESC-MSCs) can differentiate into three germ layers and possess immunosuppressive effects in vitro. Anticancer treatment is a well-known risk factor for premature ovarian failure (POF). In this study, we investigated the effect of hESC-MSC on recovery of ovarian function in cisplatin-induced POF in mice. METHODS:Female mice received intraperitoneal cisplatin for 10 days. On day 12, CHA15-derived hESC-MSCs were transplanted into the mice by tail vein injection. An injection of PBS served as the negative control. Ovaries were removed 28 days after transplantation for assessment of ovarian histology, immunostaining, and fertility testing by superovulation and in vitro fertilization. hESC-MSC transplantation into mice with cisplatin-induced damage restored body weight and ovary size. RESULTS:Mean primary and primordial follicle counts in the hESC-MSC group were significantly improved compared to the PBS group (P < 0.05), and counts of zona pellucida remnants, an apoptotic sign in ovarian follicles, were significantly reduced (P < 0.05). TUNEL assays and cleaved PARP immunostaining indicated apoptosis, which led to loss of ovarian stromal cells in negative control mice, while Ki-67 was higher in the hESC-MSC group and in non-cisplatin-treated controls than in the PBS group. Ovulation was reduced in the PBS group but recovered significantly in the hESC-MSC group. Rates of blastocyst formation from ovulated eggs and live births per mouse also recovered significantly in the hESC-MSC group. CONCLUSIONS:hESC-MSC restored structure and function in the cisplatin-damaged ovary. Our study provides new insights into the great clinical potential of human hESC-MSC in treating POF.
Vitamin C improves the therapeutic potential of human amniotic epithelial cells in premature ovarian insufficiency disease.
Hou Shunyu,Ding Chenyue,Shen Han,Qian Chunfeng,Zou Qinyan,Lu Jiafeng,Huang Boxian,Tan Jichun,Li Hong
Stem cell research & therapy
BACKGROUND:Human amniotic epithelial cell (hAEC) transplantation holds great promise in treating premature ovarian insufficiency (POI). However, some deficient biological characteristics of hAECs restrict their application. METHODS:Vitamin C (VC) was added to the culture media of hAECs for 2 weeks. Then, the proliferative ability, migration ability, pluripotency, and self-renewal of VC-treated hAECs (VC-hAECs) were determined. Next, hAECs and VC-hAECs were transplanted into the ovaries of cyclophosphamide (CTX)-induced POI model mice. The ovarian function of POI mice was evaluated after transplantation by counting follicle numbers and measuring the blood levels of AMH, E2, and FSH. The rescue effects of VC-hAECs and hAECs were unveiled by coculturing with CTX-damaged human ovarian granulosa cells (hGCs) and analyzing relative marker expression. Additionally, ovarian marker expression and transplant survival were detected in POI mice after transplantation to verify the beneficial effect of VC-hAECs. The cytokine profiles of VC-hAECs and hAECs were revealed by performing a cytokine array and an ELISA to show their paracrine function. RESULTS:Our results indicated that VC promoted the proliferation, migration, pluripotency, and self-renewal of hAECs in vitro. The most effective concentration of VC was 50 μg/ml. After transplantation into the POI mouse model, VC-hAECs reversed ovarian function more powerfully than hAECs. Human granulosa cell marker expression in CTX-damaged hGCs was increased after coculture with VC-hAECs compared with hAECs. In the ovaries of the POI mice, ovarian marker expression was greater after VC-hAEC transplantation than after hAEC transplantation. VC-hAECs showed higher transplant survival than hAECs. Furthermore, VC-hAECs secreted more growth factors than hAECs. CONCLUSION:Treatment with VC promoted the proliferation, migration, self-renewal, and paracrine functions of hAECs. Additionally, VC elevated the therapeutic potential of hAECs in treating POI.
Human umbilical cord mesenchymal stem cells restore the ovarian metabolome and rescue premature ovarian insufficiency in mice.
Zhao Yan,Ma Jiao,Yi Peiye,Wu Jun,Zhao Feiyan,Tu Wan,Liu Wenjing,Li Tianda,Deng Yan,Hao Jie,Wang Hongmei,Yan Long
Stem cell research & therapy
BACKGROUND:Premature ovarian insufficiency (POI) is an ovarian dysfunction that seriously affects a woman's physiological health and reproduction. Mesenchymal stem cell (MSC) transplantation offers a promising treatment option for ovarian restoration in rodent POI models. However, the efficacy and mechanism of it remain unclear. METHODS:POI mice model was generated by cyclophosphamide and busulfan, followed with the treatment of tail-vein injection of the human umbilical cord mesenchymal stem cells (hUCMSCs). Maternal physiological changes and offspring behavior were detected. To reveal the pathogenesis and therapeutic mechanisms of POI, we first compared the metabolite profiles of healthy and POI ovarian tissues using untargeted metabolomics analyses. After stem cell therapy, we then collected the ovaries from control, POI, and hUCMSC-treated POI groups for lipid metabolomics and pseudotargeted metabolomics analysis. RESULTS:Our results revealed remarkable changes of multiple metabolites, especially lipids, in ovarian tissues after POI generation. Following the transplantation of clinical-grade hUCMSCs, POI mice exhibited significant improvements in body weight, sex hormone levels, estrous cycles, and reproductive capacity. Lipid metabolomics and pseudotargeted metabolomics analyses for the ovaries showed that the metabolite levels in the POI group, mainly lipids, glycerophospholipids, steroids, and amino acids changed significantly compared with the controls', and most of them returned to near-healthy levels after receiving hUCMSC treatment. Meanwhile, we also observed an increase of monosaccharide levels in the ovaries from POI mice and a decrease after stem cell treatment. CONCLUSIONS:hUCMSCs restore ovarian function through activating the PI3K pathway by promoting the level of free amino acids, consequently improving lipid metabolism and reducing the concentration of monosaccharides. These findings provide potential targets for the clinical diagnosis and treatment of POI.
[The Effect and Mechanism of Hyperin on Ovarian Reserve of Tripterygium Glycosides-Induced POI Mice].
Ma Wei-Rong,Tan Yong
Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition
Objective:To investigate the effect and mechanism of hyperin on the improvement of ovarian reserve of tripterygium glycosides (TG)-induced primary ovarian insufficiency (POI) in mice. Methods:Adult female BALB/c mice were used as research subjects and were randomly assigned to the control group, POI model group and hyperin treatment group, with 40 mice in each group. TG was given at 40 mg/kg twice a day by gavage for 2 weeks to create the POI mouse model. Mice in the hyperin treatment group were given hyperin at 75 mg/(kg·d) by gavage for 4 weeks after the model was established. The body mass of the mice was weighed and the gonadal index was calculated. Ovarian histological changes were observed by HE staining, and the number of follicles at all levels was calculated. Serum estradiol (E ), follicle-stimulating hormone (FSH), anti-mullerian hormone (AMH), superoxide dismutase (SOD) and catalase (CAT) were assessed with ELISA. The mRNA and protein levels of nuclear factor (erythroid-derived 2)-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1), Caspase3, Bcl-2 and Bax in ovarian granulosa cells were measured by RT-qPCR and Western blot. The protein levels of phosphorylated phosphatidylinositol 3-hydroxy kinase (p-PI3K) and phosphorylated protein kinase B (p-Akt) were measured by Western blot. The reactive oxygen species (ROS) levels in granulosa cells were determined by H2DCFDA. The apoptosis of granulosa cells was examined by TUNEL assay. Results:Compared with mice in the POI model group, the body mass and gonadal index of hyperin-treated mice increased (all <0.05). The pathological damage of the ovary decreased, and the number of follicles at all levels and corpora lutea increased (all <0.05). Serum E , AMH, SOD and CAT levels increased, and FSH level decreased (all <0.05). At the molecular level, the expression of Nrf-2, HO-1, p-PI3K, p-Akt and Bcl-2 in ovarian granulosa cells increased, while the expression of Caspase3 and Bax decreased (all <0.05). ROS level decreased ( <0.05). TUNEL assay showed reduced apoptosis of granulosa cells ( <0.05). Conclusion:Hyperin improved ovarian reserve in TG-induced POI mice through Nrf-2/HO-1antioxidant stress response and the anti-apoptotic effect of PI3K/Akt pathways.
A segregating human allele of SPO11 modeled in mice disrupts timing and amounts of meiotic recombination, causing oligospermia and a decreased ovarian reserve†.
Tran Tina N,Schimenti John C
Biology of reproduction
A major challenge in medical genetics is to characterize variants of unknown significance (VUS). Doing so would help delineate underlying causes of disease and the design of customized treatments. Infertility has presented an especially difficult challenge with respect to not only determining if a given patient has a genetic basis, but also to identify the causative genetic factor(s). Though genome sequencing can identify candidate variants, in silico predictions of causation are not always sufficiently reliable so as to be actionable. Thus, experimental validation is crucial. Here, we describe the phenotype of mice containing a non-synonymous (proline-to-threonine at position 306) change in Spo11, corresponding to human SNP rs185545661. SPO11 is a topoisomerase-like protein that is essential for meiosis because it induces DNA double stranded breaks (DSBs) that stimulate pairing and recombination of homologous chromosomes. Although both male and female Spo11P306T/P306T mice were fertile, they had reduced sperm and oocytes, respectively. Spermatocyte chromosomes exhibited synapsis defects (especially between the X and Y chromosomes), elevated apoptotic cells, persistent markers of DSBs, and most importantly, fewer Type 1 crossovers that causes some chromosomes to have none. Spo11P306T/- mice were sterile and made fewer meiotic DSBs than Spo11+/- animals, suggesting that the Spo11P306T allele is a hypomorph and likely is delayed in making sufficient DSBs in a timely fashion. If the consequences are recapitulated in humans, it would predict phenotypes of premature ovarian failure, reduced sperm counts, and possible increased number of aneuploid gametes. These results emphasize the importance of deep phenotyping in order to accurately assess the impact of VUSs in reproduction genes.
Identification of potential causal variants for premature ovarian failure by whole exome sequencing.
Jin Haengun,Ahn JuWon,Park YoungJoon,Sim JeongMin,Park Han Sung,Ryu Chang Soo,Kim Nam Keun,Kwack KyuBum
BMC medical genomics
BACKGROUND:Premature ovarian failure (POF) is a highly heterogeneous disorder that occurs in 1% of women of reproductive age. Very few causative genes and variants contributing to POF have been detected, and the disease remains incompletely understood. In this study, we used whole exome sequencing (WES) to identify potential causal variants leading to POF. METHODS:WES was conducted to identify variants in 34 Korean patients with POF, alongside 10 normal controls. Detected variants were filtered using a range of characterized bioinformatics analyses, and the machine learning tools, CADD and VEST, were used to predict pathogenic variants that could cause disease. VarSome was used for a comprehensive interpretation of the variants. Potential causal variants finally screened by these analyses were confirmed using Sanger sequencing. RESULTS:We identified nine potential causative variants in genes previously associated with POF in 8 of 34 (24%) Korean patients by WES variant analysis. These potentially pathogenic variants included mutations in the MCM8, MCM9, and HFM1 genes, which are involved in homologous recombination, DNA repair, and meiosis, and are established as causing POF. Using a combination of CADD and VEST, 72 coding variants were also identified in 72 genes, including ADAMTSL1 and FER1L6, which have plausible functional links to POF. CONCLUSIONS:WES is a useful tool to detect genetic variants that cause POF. Accumulation and systematic management of data from a number of WES studies in specialized groups of patients with POF (family data, severe case populations) are needed to better comprehend the genetic landscape underlying POF.
Spontaneous Pregnancy in the Setting of Primary Ovarian Insufficiency and Breastfeeding: Does Immunosuppression Play a Role?
Ayers Caleb D,Carlson Karen S
The American journal of case reports
BACKGROUND Primary ovarian insufficiency is defined as primary hypogonadism in a woman under the age of 40 years. It commonly presents clinically with amenorrhea and infertility. It is often thought to be an autoimmune process. Breastfeeding also reduces the rate of conception by reducing pulsatile gonadotropin secretion, resulting in lactational amenorrhea. CASE REPORT Here, we present a case of a patient with primary ovarian insufficiency. FSH and LH levels at diagnosis were in the menopausal range. After undergoing fertility treatments and failing to become pregnant, she achieved a first pregnancy with donor eggs through in vitro fertilization. After delivery, while solely breastfeeding her first baby, menses returned to normal and FSH and LH levels returned to normal. She then spontaneously conceived. She delivered a second baby without the need for assisted reproductive technology. CONCLUSIONS Pregnancy alters the maternal immune system to produce maternal-fetal tolerance through complex mechanisms that are not completely understood. The immunosuppression of pregnancy in this patient may have repressed the autoimmune process in her ovaries, allowing her to ovulate and thus reverse her primary ovarian insufficiency. Several previous case reports and studies show that immunosuppression has reduced the symptoms of primary ovarian insufficiency and allowed conception in some patients. These studies and this case report raise the question of immunosuppression as a treatment for infertility caused by primary ovarian insufficiency.
Combining fertility preservation procedures to spread the eggs across different baskets: a feasibility study.
Delattre S,Segers I,Van Moer E,Drakopoulos P,Mateizel I,Enghels L,Tournaye H,De Vos M
Human reproduction (Oxford, England)
STUDY QUESTION:What is the reproductive potential following combinations of ovarian stimulation, IVM and ovarian tissue cryopreservation (OTC) in female patients seeking fertility preservation (FP)? SUMMARY ANSWER:In selected patients, combining different FP procedures is a feasible approach and reproductive outcomes after FP in patients who return to attempt pregnancy are promising. WHAT IS KNOWN ALREADY:FP is increasingly performed in fertility clinics but an algorithm to select the most suitable FP procedure according to patient characteristics and available timeframe is currently lacking. Vitrification of mature oocytes (OV) and OTC are most commonly performed, although in some clinical scenarios a combination of procedures including IVM, to spread the sources of gametes, may be considered in order to enhance reproductive options for the future. STUDY DESIGN, SIZE, DURATION:Retrospective, observational study in a university-based, tertiary fertility centre involving all female patients who underwent urgent medical FP between January 2012 and December 2018. Descriptive analysis of various FP procedures, either stand-alone or combined, was performed, and reproductive outcomes of patients who attempted pregnancy in the follow-up period were recorded. PARTICIPANTS/MATERIALS, SETTING, METHODS:In total, 207 patients underwent medical FP. Patient-tailored strategies and procedures were selected after multidisciplinary discussion. When deemed feasible, FP procedures were combined to cryopreserve different types of reproductive tissue for future use. The main primary outcome measure was the number of mature oocytes. Live birth rates were evaluated in patients who returned for reproductive treatment. MAIN RESULTS AND THE ROLE OF CHANCE:Among patients seeking FP, 95/207 (46%) had breast cancer, 43/207 (21%) had haematological malignancies and 31/207 (15%) had a gynaecological tumour. Mean ± SD age was 27.0 ± 8.3 years. Eighty-five (41.1%) patients underwent controlled ovarian stimulation (COS), resulting in 10.8 ± 7.1 metaphase II (MII) oocytes for vitrification. Eleven (5.3%) patients had multiple COS cycles. Transvaginal oocyte retrieval for IVM was performed in 17 (8.2%) patients, yielding 9.2 ± 10.1 MII oocytes. Thirty-four (16.4%) patients underwent OTC combined with IVM of oocytes retrieved from ovarian tissue 'ex vivo' (OTO-IVM), yielding 4.0 ± 4.3 MII oocytes in addition to ovarian fragments. Seventeen (8.2%) patients had OTC combined with OTO-IVM and transvaginal retrieval of oocytes for IVM from the contralateral ovary, resulting in 13.5 ± 9.7 MII oocytes. In 13 (6.3%) patients, OTC with OTO-IVM was followed by controlled stimulation of the contralateral ovary, yielding 11.3 ± 6.6 MII oocytes in total. During the timeframe of the study, 31/207 (15%) patients have returned to the fertility clinic with a desire for pregnancy. Of those, 12 (38.7%) patients had preserved ovarian function and underwent ART treatment with fresh oocytes, resulting in nine (75%) livebirth. The remaining 19 (61.3%) patients requested warming of their cryopreserved material because of ovarian insufficiency. Of those, eight (42.1%) patients had a livebirth, of whom three after OTO-IVM. To date, 5/207 patients (2.4%) achieved an ongoing pregnancy or livebirth after spontaneous conception. LIMITATIONS, REASONS FOR CAUTION:Our FP programme is based on a patient-tailored approach rather than based on an efficiency-driven algorithm. The data presented are descriptive, which precludes firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS:Combining different FP procedures is likely to enhance the reproductive fitness of patients undergoing gonadotoxic treatment but further follow-up studies are needed to confirm this. STUDY FUNDING/COMPETING INTEREST(S):No external funding was used for this study and the authors have no competing interests. TRIAL REGISTRATION NUMBER:N/A.
AMH assessment five or more years after an initially low AMH level.
Desongnis Sarah,Robin Geoffroy,Dewailly Didier,Pigny Pascal,Catteau-Jonard Sophie
European journal of obstetrics, gynecology, and reproductive biology
PURPOSE:Anti-Müllerian hormone (AMH) is a biomarker reflecting ovarian reserve. A low AMH level before 39 years may be associated with a risk of menopause between 40 and 45 years. The risk of onset of premature ovarian insufficiency (POI) is, however, poorly documented. The objective of the study was to determine the prevalence of POI 5-10 years after an AMH assay below 8 pmol/L. METHODS:We included women aged younger than 36 years who underwent a complete workup for infertility between January 2008 and December 2013 at the University Hospital and had an AMH level less than 8 pmol/L. In 2018, 47 of these women were assessed clinically, and 21 of them agreed to undergo an ovarian reserve test. RESULTS:The prevalence of POI after at least 5 years was 8/47, or 17 % [8 %-31 %]. The median time to diagnosis was 5.1 years [2.9-7.3]. There was a significant difference at T0 in the regularity of cycles between the two groups (p = 0.024) and in their baseline serum AMH level: 6.0 pmol/L in the non-POI group vs 4.2 pmol/L in the POI group (p = 0.002). CONCLUSION:Serum AMH < 8 pmol/L before the age of 36 years appears to be a risk factor for POI. These women require regular follow-up, especially if their cycles are irregular.
The Molecular Regulation in the Pathophysiology in Ovarian Aging.
Li Chia-Jung,Lin Li-Te,Tsai Hsiao-Wen,Chern Chyi-Uei,Wen Zhi-Hong,Wang Peng-Hui,Tsui Kuan-Hao
Aging and disease
The female reproductive system is of great significance to women's health. Aging of the female reproductive system occurs approximately 10 years prior to the natural age-associated functional decline of other organ systems. With an increase in life expectancy worldwide, reproductive aging has gradually become a key health issue among women. Therefore, an adequate understanding of the causes and molecular mechanisms of ovarian aging is essential towards the inhibition of age-related diseases and the promotion of health and longevity in women. In general, women begin to experience a decline in ovarian function around the age of 35 years, which is mainly manifested as a decrease in the number of ovarian follicles and the quality of oocytes. Studies have revealed the occurrence of mitochondrial dysfunction, reduced DNA repair, epigenetic changes, and metabolic alterations in the cells within the ovaries as age increases. In the present work, we reviewed the possible factors of aging-induced ovarian insufficiency based on its clinical diagnosis and performed an in-depth investigation of the relevant molecular mechanisms and potential targets to provide novel approaches for the effective improvement of ovarian function in older women.
Telomere length in granulosa cells and leukocytes: a potential marker of female fertility? A systematic review of the literature.
Fattet Anne-Julie,Toupance Simon,Thornton Simon N,Monnin Nicolas,Guéant Jean-Louis,Benetos Athanase,Koscinski Isabelle
Journal of ovarian research
In the context of a continuously increased delay of motherhood and of an increase of the incidence of premature ovarian failure, it is of the greatest interest to dispose of a predictive marker of the duration of the fertility window. Unfortunately, current available markers of women's fertility (hormonal rates or echography count of small follicles) have a poor predictive value of premature ovarian failure. In the last ten years, some studies have suggested that telomere length may be correlated with premature ovarian failure, but the results of these studies are contradictory.In accordance with guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), this systematic review of the literature selected studies evaluating telomere length or telomerase activity in granulosa cells and/or in leukocytes as a premature ovarian failure marker.Five publications (252 premature ovarian failure patients) were included in this review of experimental evidence. Two of them studied telomere length and/or telomerase activity in granulosa cells and 4 in leukocytes in women with premature ovarian failure. For each study, authors determined if there was a positive or a negative correlation between telomeric parameters and premature ovarian failure.3 studies (178 premature ovarian failure patients) found shorter telomere length in granulosa cells and/or leukocytes and/or lower telomerase activity in premature ovarian failure patients. 2 studies (74 premature ovarian failure patients) presented contradictory results about the correlation of leucocyte telomere length with premature ovarian failure.Shorter telomeres and diminished telomerase activity in granulosa cells appear to be associated with ovarian insufficiency. However, the number of studies and of subjects within are low and the methodology questionable. The confirmation of these results is essential with more subjects, better defined populations and more adapted methodology, in order to consider telomere length in granulosa cells and/or in leucocytes as an early and reliable marker for the decline of ovarian function.
Next Generation Sequencing Should Be Proposed to Every Woman With "Idiopathic" Primary Ovarian Insufficiency.
Eskenazi Sarah,Bachelot Anne,Hugon-Rodin Justine,Plu-Bureau Genevieve,Gompel Anne,Catteau-Jonard Sophie,Molina-Gomes Denise,Dewailly Didier,Dodé Catherine,Christin-Maitre Sophie,Touraine Philippe
Journal of the Endocrine Society
Context:Primary ovarian insufficiency (POI) affects 1% of women under 40 years of age. POI is idiopathic in more than 70% of cases. Though many candidate genes have been identified in recent years, the prevalence and pathogenicity of abnormalities are still difficult to establish. Objective:Our primary objective was to evaluate the prevalence of gene variations in a large prospective multicentric POI cohort. Our secondary objective was to evaluate the correlation between phenotype and genotype. Methods:Two hundred and sixty-nine well-phenotyped POI patients were screened for variants of 18 known POI genes (, , , , , , , , , , , , , , , , , and by next generation sequencing (NGS). Abnormalities were classified as "variant" or "variant of unknown signification" (VUS) according to available functional tests or algorithms (SIFT, Polyphen-2, MutationTaster). Results:One hundred and two patients (38%) were identified as having at least 1 genetic abnormality. Sixty-seven patients (25%) presented at least 1 variant. Forty-eight patients presented at least 1 VUS (18%). Thirteen patients (5%) had combined abnormalities. variants were the most common gene variants involved in POI (9%). Interestingly, we saw no significant differences in the previous family history of POI, ethnic origin, age at onset of POI, primary amenorrhea, or secondary menstrual disturbances between the different genotypes. Conclusion:In our study, a high percentage of patients presented gene variants detected by NGS analysis (38%). Every POI patient should undergo NGS analysis to improve medical cares of the patients.
TRDMT1 participates in the DNA damage repair of granulosa cells in premature ovarian failure.
Sha Chunli,Chen Lu,Lin Li,Li Taoqiong,Wei Hong,Yang Meiling,Gao Wujiang,Zhao Dan,Chen Qi,Liu Yueqin,Chen Xiaofang,Xu Wenlin,Li Yuefeng,Zhu Xiaolan
The molecular mechanisms underlying premature ovarian failure, which seriously impacts the physical and psychological health of patients, are not fully understood. Here, we present the role of TRDMT1 in reactive oxygen species-induced granulosa cells death, which is considered an important cause of premature ovarian failure. We found that reactive oxygen species were increased in a HO dose-dependent manner and accompanied by the nuclear shuttling of TRDMT1, increased DNA damage and increased apoptosis of granulosa cells. In addition, reactive oxygen species-induced granulosa cells apoptosis could be prevented by the antioxidant N-acetylcysteine or overexpression of TRDMT1. Furthermore, DNA repair following reactive oxygen species induction was severely impaired/enhanced in TRDMT1 mutants, which exhibited reduced/increased RNA m5C methylation activity. Altogether, our results reveal a novel role of TRDMT1 in the regulation of premature ovarian failure through the repair of reactive oxygen species-triggered DNA damage in granulosa cells and provide an improved understanding of the mechanisms underlying granulosa cells apoptosis, which could potentially be useful for future clinical treatments of premature ovarian failure.
Homozygous variants in cause premature ovarian insufficiency.
He Wen-Bin,Tan Chen,Zhang Ya-Xin,Meng Lan-Lan,Gong Fei,Lu Guang-Xiu,Lin Ge,Du Juan,Tan Yue-Qiu
Journal of medical genetics
BACKGROUND:The genetic causes of the majority of cases of female infertility caused by premature ovarian insufficiency (POI) are unknown. OBJECTIVE:To identify the genetic causes of POI in 110 patients. METHODS:Whole-exome sequencing was performed on 110 patients with POI, and putative disease-causative variants were validated by Sanger sequencing. Bioinformatic and in vitro functional analyses were performed for functional characterisation of the identified candidate disease-causative variants. RESULTS:We identified two homozygous variants (NM_001040274: c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in in two patients, which had co-segregated with POI in these families. Bioinformatic analysis predicted that the two variants are deleterious, and in vitro functional analysis showed that mutant SYCP2L proteins exhibited mislocalisation and loss of function. CONCLUSIONS: is a novel gene found to be responsible for human POI. Our findings provide a potential molecular marker for POI and improve the understanding of the genetic basis of female infertility.
Fresh insight into premature ovarian insufficiency.
Karska Paula,Matonog Aleksandra,Sieradzka Paulina,Kowalczyk Karolina,Madej Pawel
Premature ovarian insufficiency (POI) is one of the vital reasons of anovulatory infertility among women under 40 years old. However, because of the unacknowledged causative factor in most cases, it still remains a huge challenge in gynecology. Recently, the most promising opportunities in diagnosing are connected with the use of some serum biomarkers, such as interleukin-17 (IL-17), Frizzled-5 protein, Soggy-1 protein and other cytokines. Additionally, environmental toxicants such as chemicals and heavy metals might be relevant in the near future when investigating the causes of premature ovarian insufficiency. One of the main aims of the therapy is to focus on maintaining fertility among women with POI, since it is essential for patients considering their young age. Among the newest approaches listed there are different types of stem cells, oocytes donation and in-vitro activation, all of which are recently gaining in importance.
Alteration in angiogenic potential of granulosa-lutein cells and follicular fluid contributes to luteal defects in polycystic ovary syndrome.
Patil Krutika,Hinduja Indira,Mukherjee Srabani
Human reproduction (Oxford, England)
STUDY QUESTION:Is angiogenic potential of follicular fluid (FF) and granulosa-lutein cells (GLCs) altered in polycystic ovary syndrome (PCOS) and does it play a role in corpus luteum (CL) defect observed in them? SUMMARY ANSWER:FF and GLCs of women with PCOS show reduced expression of pro-angiogenic factors compared to controls and exhibit a diminished capacity to induce angiogenesis. WHAT IS KNOWN ALREADY:In women with PCOS, CL insufficiency and frequent miscarriage are reported, which may be due to defect in CL. The development of new blood vessels is essential to promote ovarian folliculogenesis and functional CL formation. The vasculature formation in CL which is important for its function is still unexplored in these women. STUDY DESIGN, SIZE, DURATION:This case-control study was conducted in 30 healthy control women and 30 women with PCOS undergoing controlled ovarian hyperstimulation for IVF. The FF, GLCs and serum were collected from all participants during ovum pick up. PARTICIPANTS/MATERIALS, SETTING, METHODS:The capacity of FF to induce angiogenesis was assessed by measuring levels of pro-angiogenic factors vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) and its tube formation and wound healing potential using human umbilical vein endothelial cells (HUVECs). We investigated the angiogenic potential and endothelial cell-like nature of GLCs using several approaches such as the expression of angiogenic genes by quantitative PCR, DiI-conjugated acetylated low-density lipoproteins (Dil-Ac-LDL) internalization assay, tube formation assay, expression of endothelial cell markers by immunofluorescence analysis. In addition, correlation of transcript levels of angiogenic genes with oocyte parameters was studied. MAIN RESULTS AND THE ROLE OF CHANCE:FF and serum levels of VEGF and FGF2 were significantly higher and lower, respectively, in PCOS compared to controls. The tube formation and wound healing capacity of HUVECs was found to be reduced when measured after supplementation with FF of women with PCOS compared to controls. This suggests a decreased angiogenic capacity of FF in women with PCOS. Tube formation (P = 0.003) and Dil-Ac-LDL internalization (P = 0.03) ability of GLCs were significantly reduced in women with PCOS compared to controls. Protein expression levels of endothelial markers, vascular endothelial growth factor A (VEGFA) (P = 0.004), vascular endothelial growth factor receptor 2 (VEGFR2) (P = 0.011), TEK Receptor Tyrosine Kinase (Tie-2) (P = 0.026), fibroblast growth factor receptor 1 (FGFR1) (P = 0.026) and CD31 (P = 0.035) and transcript levels of angiogenic genes VEGFA (P = 0.042), hypoxia inducing factor 1A (HIF1A) (P = 0.025), FGF2 (P = 0.038), angiopoietin 1 (ANGPT1) (P = 0.028), heparin sulfate proteoglycan 2 (HSPG2) (P = 0.016), ADAM metallopeptidase with thrombospondin type1 motif, 1 (ADAMTS1) (P = 0.027) and fibronectin 1 (FN1) (P = 0.016) were found to be low in GLCs of PCOS compared to controls. Thus, the findings of this study indicate that endothelial cell-like characteristics of GLCs were significantly decreased in PCOS. Furthermore, transcript levels of VEGFA (r = 0.46, P = 0.009), ADAMTS1 (r = 0.55, P = 0.001), FGF2 (r = 0.42, P = 0.022) and ANGPT2 (r = 0.47, P = 0.008) showed a positive correlation with oocyte fertilization rate. LIMITATIONS, REASONS FOR CAUTION:The vasculature formation in CL is not possible to study in women, but we explored the angiogenic characteristics of FF and GLC obtained from women with PCOS to speculate any vascularization defect of CL in these women. The FF and GLCs were obtained from the stimulated cycle during oocyte retrieval, which may not exactly mimic the in-vivo condition. The small sample size is another limitation of this study. Larger sample size and support by color Doppler studies on CL blood flow would help to strengthen our findings. WIDER IMPLICATIONS OF THE FINDINGS:Our findings suggest that the altered angiogenic potential of FF and GLCs may affect vasculature development required for CL formation and function in PCOS. These findings pave the way to devise therapeutic strategies to support angiogenesis process in follicle of women with PCOS, which may improve CL insufficiency, progesterone levels and prevent frequent miscarriages in these women. Furthermore, our study also hypothesizes that the vascularization around the ovarian follicles is also compromised which may lead to the growth arrest of the follicles in PCOS, however, this needs thorough investigations. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by Grant BT/PR16524/MED/97/346/2016 from the Department of Biotechnology, Government of India. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER:N/A.
Management of Early Menopause/Premature Ovarian Insufficiency in Women with or at High Risk of Breast Cancer.
Brennan Annabelle,Hickey Martha
Seminars in reproductive medicine
The global incidence of breast cancer is increasing, as is the efficacy of treatments. Consequently, increasing survival rates reinforce the importance of survivorship issues, including posttreatment menopausal symptoms, sexual function, and mental health and well-being. Breast cancer patients can experience a range of menopausal symptoms associated with their treatment. Most commonly women may experience vasomotor symptoms, including hot flushes and night sweats. Particularly for women on maintenance tamoxifen therapy, up to 80% will experience hot flushes, with almost one-third of these women reporting severe symptoms. Breast cancer patients may also experience genitourinary symptoms of menopause, which may include vaginal dryness and irritation, dyspareunia, and dysuria. Hormonal therapy has long been established as the most effective treatment for vasomotor symptoms. However, the hormonal nature of breast malignancies renders systemic hormone therapies unsuitable for these patients, posing a unique treatment challenge, which may result in clinicians not feeling confident to manage them. Consequently, this review outlines pharmacological and nonpharmacological options for women with bothersome menopausal symptoms after breast cancer treatment and provides practical, evidence-based guidance for clinicians.
Laboratory testing for fragile X, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).
Spector Elaine,Behlmann Andrea,Kronquist Kathryn,Rose Nancy C,Lyon Elaine,Reddi Honey V,
Genetics in medicine : official journal of the American College of Medical Genetics
Molecular genetic testing of the FMR1 gene is commonly performed in clinical laboratories. Pathogenic variants in the FMR1 gene are associated with fragile X syndrome, fragile X-associated tremor ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). This document provides updated information regarding FMR1 pathogenic variants, including prevalence, genotype-phenotype correlations, and variant nomenclature. Methodological considerations are provided for Southern blot analysis and polymerase chain reaction (PCR) amplification of FMR1, including triplet repeat-primed and methylation-specific PCR.The American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee has the mission of maintaining high technical standards for the performance and interpretation of genetic tests. In part, this is accomplished by the publication of the document ACMG Technical Standards for Clinical Genetics Laboratories, which is now maintained online ( http://www.acmg.net ). This subcommittee also reviews the outcome of national proficiency testing in the genetics area and may choose to focus on specific diseases or methodologies in response to those results. Accordingly, the subcommittee selected fragile X syndrome to be the first topic in a series of supplemental sections, recognizing that it is one of the most frequently ordered genetic tests and that it has many alternative methods with different strengths and weaknesses. This document is the fourth update to the original standards and guidelines for fragile X testing that were published in 2001, with revisions in 2005 and 2013, respectively.This versionClarifies the clinical features associated with different FMRI variants (Section 2.3)Discusses important reporting considerations (Section 188.8.131.52)Provides updates on technology (Section 4.1).
Premature ovarian insufficiency patients with viable embryos derived from autologous oocytes through repeated oocyte retrievals could obtain reasonable cumulative pregnancy outcomes following frozen-embryo transfer.
Zhu Xiuxian,Ye Jing,Fu Yonglun
Annals of translational medicine
Background:Women with premature ovarian insufficiency (POI) are often discouraged from using autologous oocytes; however, some patients have a strong desire to be genetically linked to their offspring. In the present study, we aimed to estimate cumulative pregnancy outcomes following frozen-embryo transfer (FET) in POI patients who could obtain viable embryos with their eggs during in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatments. Methods:In this matched-retrospective cohort study, only patients undergoing IVF/ICSI treatments with a freeze-all strategy were screened, and 103 POI patients were matched with 515 normal controls in terms of the same number of viable embryos obtained at the same age. The primary outcome was the cumulative clinical pregnancy rate (CCPR) following FET per patient. Results:Patients with POI and normal ovarian reserve had comparable CCPRs of 62.14% (64/103) and 65.24% (336/515), respectively (P=0.547), and no statistical difference was found in the cumulative live-birth rate (CLBR) between the study group (43.69%) and the control group (53.01%). Based on binary logistic regression, the CCPR and CLBR showed no association with the type of ovarian function (POI or normal ovarian reserve). The number of embryos per transfer and the sum of all viable embryos per patient were positively associated with the CCPR and CLBR. The clinical pregnancy rate (CPR) per FET cycle was 38.17% for the study group and 52.1% for the control group, while the CPRs per oocyte retrieval cycle in the 2 groups were 11.25% and 69.9%, respectively, and both were statistically different (P<0.05). Moreover, POI patients had a lower implantation rate (27.8% 37.94%) and a higher early miscarriage rate per transfer (26.76% 15%) than patients in the control group (P<0.05). Conclusions:Cumulative pregnancy outcomes following FET were reasonable for POI patients using viable embryos derived from autologous oocytes through repeated oocyte retrievals.
Narrative review on Morbus Fabry: diagnosis and management of cardiac manifestations.
Linhart Aleš,Paleček Tomáš
Cardiovascular diagnosis and therapy
Fabry disease (FD) is an X-linked lysosomal storage disorder due to reduced or undetectable α-galactosidase A (AGAL-A) enzyme activity caused by pathogenic variants in the AGAL-A gene (). Tissue and organ changes are caused by widespread progressive accumulation of globotriaosylceramide (Gb) and globotriaosylsphingosine (lysoGb). The classical form of FD is multisystemic with cutaneous (angiokeratomas), neurological (peripheral neuropathy, premature stroke), renal (proteinuria and renal insufficiency), and cardiac involvement. Later onset variants may be limited to the heart. The objective of this review is to summarize the current knowledge on cardiac manifestations of FD and effects of targeted therapy. Cardiac involvement is characterized by progressive hypertrophy, fibrosis, arrhythmias, heart failure and sudden cardiac death (SCD). Targeted therapy is based on enzyme replacement therapy (ERT). Recently, small molecular chaperone, migalastat, became available for patients carrying amenable pathogenic GLA variants. The management of cardiac complications requires a complex approach. Several measures differ from standard clinical guidelines. Betablockers should be used with caution due to bradycardia risk, amiodarone avoided if possible, and anticoagulation used from the first appearance of atrial fibrillation. In Fabry cardiomyopathy SCD calculators are inappropriate. The awareness of FD manifestations is essential for early identification of patients and timely treatment initiation.
Adolescent ovarian thecoma presenting as progressive hyperandrogenism: case report and review of the literature.
Gaspari Laura,Paris Françoise,Taourel Patrice,Soyer-Gobillard Marie-Odile,Kalfa Nicolas,Sultan Charles
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
Hyperandrogenism is frequent and under investigated in adolescent girls. A 15-year-6-month-old French girl presented with oligomenorrhea and slowly progressing virilization 2 years post-menarche. Medical history revealed prenatal pesticide exposure through maternal professional activity and recurrent premature thelarche. Severe hirsutism, mild facial acne and clitoromegaly were noted. Serum androgens (testosterone: 94 ng/dL, 4-androstenedione: 8.23 ng/mL) were high and non-classic 21-hydroxylase deficiency was excluded. Pelvic ultrasonography showed a left ovarian mass, confirmed by computed tomography scan. Tumor markers were negative. Laparoscopic surgery was performed. The pathological diagnosis was benign luteinized thecoma. Postoperatively, the menstrual cycle and serum androgens became normal and hirsutism slowly improved. Hyperandrogenism 2 years after menarche should be systematically investigated, even if slowly progressive, since it may be a symptom of a rare virilizing ovarian tumor, like thecoma.
Impact of Thyroid Autoimmunity on Ovarian Reserve, Pregnancy Outcomes, and Offspring Health in Euthyroid Women Following Fertilization/Intracytoplasmic Sperm Injection.
Ke Hanni,Hu Jingmei,Zhao Lijuan,Ding Lingling,Jiao Xue,Qin Yingying
Thyroid : official journal of the American Thyroid Association
Thyroid autoimmunity (TAI) is the most frequent autoimmune disease among reproductive-aged women. It has been related to premature ovarian insufficiency, but the mechanisms remain elusive, and its association with ovarian reserve in euthyroid women is debatable. Moreover, the impact of TAI on assisted reproduction is controversial: especially for women with diminished ovarian reserve (DOR), few studies are available. Therefore, the present study was aimed to look for an association between TAI and DOR, and to evaluate the effect of TAI on pregnancy outcomes and offspring health following assisted reproductive technology stratified by ovarian reserve. A total of 6213 euthyroid women from the Reproductive Hospital Affiliated to Shandong University between 2012 and 2017 were retrospectively included. The prevalence of DOR in women with negative or positive TAI was calculated, and pregnancy and neonatal outcomes after fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles were compared between the TAI-positive and TAI-negative groups both in women with DOR and in those with normal ovarian reserve (NOR). Longitudinal growth parameters and temperament type of the offspring were also observed in the TAI-positive and TAI-negative groups. The prevalence of DOR in women with positive TAI and those with negative TAI was not significantly different (4.09% vs. 2.96%, = 0.053), even after stratifying patients by age. In women with DOR, the live birth rate, pregnancy loss rate, neonatal complication rate, and offspring outcomes between the TAI-positive and TAI-negative groups were comparable ( > 0.05). In women with NOR, a higher rate of live births (44.94% vs. 40.34%, = 0.027) and a higher prevalence of congenital anomalies (4.68% vs. 2.14%, = 0.005) were observed in the TAI-positive group. TAI had no impact on ovarian reserve in euthyroid women and had no association with IVF/ICSI outcomes in women with DOR. Although an increased incidence of congenital anomalies in the TAI-positive group was observed in women with NOR, an association between neonatal anomalies and TAI cannot be demonstrated. Large cohort studies to evaluate the effects of TAI on offspring health are warranted, and further experimental studies are required to explore the underlying mechanisms.
Intra-ovarian injection of platelet-rich plasma into ovarian tissue promoted rejuvenation in the rat model of premature ovarian insufficiency and restored ovulation rate via angiogenesis modulation.
Ahmadian Shahin,Sheshpari Sepideh,Pazhang Mohammad,Bedate Alberto Miranda,Beheshti Rahim,Abbasi Mehran Mesgari,Nouri Mohammad,Rahbarghazi Reza,Mahdipour Mahdi
Reproductive biology and endocrinology : RB&E
Premature Ovarian Insufficiency (POI) is viewed as a type of infertility in which the menopausal status occurs before the physiological age. Several therapeutic strategies have been introduced in clinic for POI treatment, although the outputs are not fully convincing. Platelet-rich plasma (PRP) is a unique blood product widely applied in regenerative medicine, which is based on the releasing of the growth factors present in platelets α-granules. In the current investigation, we examined the effectiveness of PRP as a therapeutic alternative for POI animals. POI in Wistar albino rats was induced by daily intraperitoneal (IP) administration of gonadotoxic chemical agent, 4-vinylcyclohexene dioxide (VCD) (160 mg/ kg) for 15 consecutive days. After POI induction, the PRP solution was directly injected intra-ovarian in two concentrations via a surgical intervention. Every two weeks post-injection, pathological changes were monitored in the ovaries using Hematoxylin-Eosin staining method, until eight weeks. Follicle Stimulating Hormone (FSH) content in serum was measured, together with the expression of the angiogenic-related transcripts ANGPT2 and KDR by real-time qPCR. Furthermore the fertility status of the treated rats was evaluated by mating trials. Histopathological examination revealed successful POI induction via the depletion of morphologically normal follicles in rats following VCD treatment compared to the control rats. The injection of PRP at two concentrations reduced the number and extent of the follicular atresia and inflammatory responses (p < 0.05). The expression of both ANGPT2 and KDR transcripts were significantly increased in POI rats due to enhanced inflammation, while these values were modulated after PRP administration (p < 0.05) compared to POI rats. FSH showed a decreased trend in concentration eight weeks after PRP treatment, but not statistically significant (p > 0.05). Nevertheless, a clear improvement in litter counts was found in POI rats receiving PRP compared to the non-treated POI group, being able to consider PRP as a facile, quick, accessible, safe and relatively cheap alternative therapeutic strategy to revert POI-related pathologies.
The significance of FMR1 CGG repeats in Chinese women with premature ovarian insufficiency and diminished ovarian reserve.
Tang Ruiyi,Yu Qi
Reproductive biology and endocrinology : RB&E
BACKGROUND:Previous studies have shown that there is an association between FMR1 CGG repeats and ovarian dysfunction. The aim of this study is to assess the association between the number of CGG repeats in FMR1 in Chinese patients with premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR). METHODS:This is a cross-sectional, case-control study, which enrolled 124 patients with POI, 57 patients with DOR and 111 normal menopausal controls. The demographic details along with other clinical data were recorded. The FMR1 CGG repeats were analyzed by polymerase chain reaction and microfluidic capillary electrophoresis. RESULTS:We could detect two premutation carriers in the POI group (1.6%) and one in the control group (0.9%). No premutation carriers were identified in the DOR group. The frequency of FMR1 premutations was not different between POI or DOR and controls. The most common CGG repeat was 29 and 30, and the repeat length for allele 2 had a secondary peak around 36-39 repeats. The CGG repeats were divided into groups of five consecutive values, and the distribution of allele 1 in the POI group was different from that in the control group (P < 0.001). No statistically significant differences were found for allele 1 between DOR group vs. controls, and for allele 2 between three groups (P > 0.05). CONCLUSIONS:The study shows that the frequency of FMR1 premutations is relatively low (1.6%) in Chinese women with POI. The distribution of allele 1 CGG repeat in patients with POI showed difference from that in healthy women.
Premature and Early Menopause in Relation to Cardiovascular Disease.
Schipper Izaäk,Louwers Yvonne V
Seminars in reproductive medicine
Postmenopausal women have an increased risk for cardiovascular diseases. It has been postulated that the loss of ovarian function and subsequent deficiency of endogenous estrogens after menopause contributes to this elevated risk of cardiovascular disease in postmenopausal women. Compared with woman entering menopause at the mean age of 51 years, in women with early menopause or premature ovarian insufficiency the risk for cardiovascular disease is even greater. These women lack the cardioprotective effect of endogenous estrogens for many more years than do women entering natural menopause. The majority of data assessing the risk of cardiovascular disease in relation to age at menopause and specifically premature menopause are derived from large epidemiological cohort studies. In addition, observations in women undergoing bilateral oophorectomy at an early age provide convincing evidence regarding association between early menopause or POI and the development of cardiovascular events and mortality. Moreover, genetic variants associated with earlier age at menopause have also been found to increase the risk of cardiovascular events in women. It has been substantiated that hormone replacement therapy (HRT) decreases the risk for ischemic heart disease and eliminates the increased cardiovascular disease mortality. It is therefore crucial to start HRT as soon as possible, particularly in women with premature ovarian insufficiency.
Exogenous progesterone for LH surge prevention is redundant in ovarian stimulation protocols.
Messinis Ioannis E,Messini Christina I,Anifandis George,Daponte Alexandros
Reproductive biomedicine online
During ovarian stimulation for IVF-embryo transfer treatment, a premature LH surge may lead to progesterone elevation that disrupts endometrial maturation and affects the probability of pregnancy following fresh embryo transfer. Preventing this LH surge and progesterone elevation using gonadotrophin-releasing hormone (GnRH) analogues is considered a standard practice. The same policy applies to cycles in which the 'freeze-all' protocol has been selected from the outset (e.g. donors), but the need for this has not been discussed. Moreover, in 'freeze-all' cycles, exogenous progesterone administration tends to replace GnRH antagonists, without reducing efficacy after embryo transfer in frozen-thawed cycles. Nevertheless, as exogenous progesterone is expected to have the same impact on the endometrium as endogenous progesterone, it is clear that, unlike in fresh cycles, in 'freeze-all' cycles an endogenous LH surge prevention does not seem necessary. Therefore, both GnRH antagonists and exogenous progesterone appear to be redundant in 'freeze-all' cycles, and in this context the indications for the use of GnRH analogues in ovarian stimulation protocols need to be revisited.
Women's Experiences of Diagnosis and Treatment of Early Menopause and Premature Ovarian Insufficiency: A Qualitative Study.
Johnston-Ataata Kate,Flore Jacinthe,Kokanović Renata
Seminars in reproductive medicine
Early menopause (EM) and premature ovarian insufficiency (POI) affect an estimated 10% of women and can precipitate a wide range of physiological and personal impacts. Receiving a diagnosis of EM/POI and navigating treatment can be complex experiences for women; however, qualitative research exploring these aspects of the condition is limited. Our study aimed to increase understanding of women's lived experiences of EM/POI encompassing its medical, social, and emotional dimensions. We conducted narrative interviews with 30 women aged 28 to 51 years with spontaneous and iatrogenic EM/POI and menopausal symptoms resulting from ovarian suppression therapy, and analyzed transcripts thematically. This article examines the prominent and under-researched themes of women's experiences of navigating "diagnosis" and treatment. Diagnosis emerged as a complex and changeable process wherein women had to negotiate a diagnosis of spontaneous EM/POI and grasp the meaning and probability of iatrogenic EM/POI. Navigating treatment entailed further complexity as women grappled with the risks and efficacy of hormonal and non-hormonal medications. The findings underline the intricacies of EM/POI as a biomedical phenomenon and highlight the need for health practitioners to recognize and respond to the challenges women face in coming to terms with the condition and managing its embodied effects.
Fragile X premutation and associated health conditions: A review.
Tassanakijpanich Nattaporn,Hagerman Randi J,Worachotekamjorn Juthamas
Fragile X syndrome (FXS) is the most common single gene disorder, which causes autism and intellectual disability. The fragile X mental retardation 1 (FMR1) gene is silenced when cytosine-guanine-guanine (CGG) triplet repeats exceed 200, which is the full mutation that causes FXS. Carriers of FXS have a CGG repeat between 55 and 200, which is defined as a premutation and transcription of the gene is overactive with high levels of the FMR1 mRNA. Most carriers of the premutation have normal levels of fragile X mental retardation protein (FMRP) and a normal intelligence, but in the upper range of the premutation (120-200) the FMRP level may be lower than normal. The clinical problems associated with the premutation are caused by the RNA toxicity associated with increased FMR1 mRNA levels, although for some mildly lowered FMRP can cause problems associated with FXS. The RNA toxicity causes various health problems in the carriers including but not limited to fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X-associated neuropsychiatric disorders. Since some individuals with neuropsychiatric problems do not meet the severity for a diagnosis of a "disorder" then the condition can be labeled as fragile X premutation associated condition (FXPAC). Physicians must be able to recognize these health problems in the carriers and provide appropriate management.
Association analysis of FMR1 genetic variants and primary ovarian insufficiency in South Indian women with a novel approach of CGG repeats classification.
Komaravalli Prasanna Latha,Rani S Vasantha,Dalal Ashwin,Jahan Parveen
European journal of medical genetics
Around 20-28% of FMR1gene CGG premutation (PM) carriers are at augmented risk towards an infertility related disorder, Fragile X-associated primary ovarian insufficiency (FXPOI). Except the effect of CGG repeats, reports are not available on the mechanism through which the cis-acting variations, namely, SNPs involved in POI susceptibility. Addressing the hypothesis that the FMR1 gene polymorphisms [CGG repeats, rs25731(T > A) and rs4949(A > G)] might increase their individual and combined impact in disease predisposition, we tested the genetic variants in 200 south Indian DNA samples consists of 100 patients and 100 healthy volunteers. We used gene scan method to score the CGG repeat length, and ARMS and RFLP methods to genotype the SNPs. Only 0.5% of each Gray zone and PM alleles were found among patient group, however, no disease association was noticed with repeat length. The rs25731 showed protection [OR:0.32; (0.13-0.76), p = 0.006] and rs4949 reported a 2.5-fold risk towards the disease predisposition [OR:2.46; (1.06-5.74), p = 0.031] but, both found insignificant after Bonferroni correction was done under different Genetic Models. Novel classification of genotype combinations, 'Normal&Variant Homozygote' [OR:2.89,(1.12-7.9), p < 0.05] and 'Allele2-T-G' haplotype block (6%vs.1%, p = 0.08) were noticed to be at marginal risk for POI. We demonstrated a susceptible role of the combined effect of variant allele-G and Allele-2 (repeat allele outside the normal range) for FXPOI. To support our findings of its first kind, further studies with large samples are warranted in understanding the role of FMR1 genetic variants in FXPOI etio-pathophysiology, the outcome might help in providing better reproductive treatment options for females, who are at risk for FXPOI.
A novel PPRC1 point mutation in a Chinese family with premature ovarian failure: A case study.
Zhang Xiao-Jin,Gu Yu,Fu Wei
The journal of gene medicine
BACKGROUND:Patients with premature ovarian failure (POF) have an at least 6-month history of amenorrhea and elevated follicle-stimulating hormone levels in plasma. Most of the POF causes are idiopathic and hereditary, and chromosomal abnormalities have been associated with POF development. A pedigree study was performed on a family with idiopathic POF to observe the possible link between gene mutation and POF development. METHODS:In total, eight women were diagnosed with POF and seven POF patients and five non-POF members from the same family were evaluated by whole exome sequencing and Sanger sequencing. An apoptotic assay, senescence staining, real-time polymerase chain reaction (qPCR) and overexpression of the peroxisome proliferator-activated receptor gamma coactivator-related 1 (PPRC1) gene were performed to examine the association of POF in vitro. RESULTS:Through whole exome sequencing and Sanger sequencing, a novel point mutation (NM_015062: c.2902C>T:p.Thr958Ile) was identified and verified in the PPRC1 gene on chromosome 10 (10q24.32). The point mutation only presented in all the seven POF cases and not in non-POF cases or public databases. Subsequent expression of PPRC1 in COV434 granulosa cells showed that PPRC1 might be involved in regulating granulosa cell apoptosis but not senescence-associated POF development. CONCLUSIONS:A novel point mutation in the PPRC1 gene was identified by the pedigree study and by sequence analysis of the case series with idiopathic POF in the present study. The subsequent PPRC1 expression analysis showed that PPRC1 was not involved in senescence-associated POF development. Further studies will be needed to confirm the link between PPRC1 gene mutation and POF.
Premature ovarian insufficiency: A toolkit for the primary care physician.
Lambrinoudaki Irene,Paschou Stavroula A,Lumsden Mary Ann,Faubion Stephanie,Makrakis Evangelos,Kalantaridou Sophia,Panay Nick
Premature ovarian insufficiency (POI) refers to the loss of ovarian activity before the age of 40 years, which leads to hypoestrogenism and amenorrhoea. The diagnosis of POI in a young woman has potentially life-changing physical and emotional consequences for both the patient and her family. Therefore, it is very important that the diagnosis is correct and that it is made in a timely manner. Unfortunately, the diagnosis and therefore the effective treatment of POI are often delayed, which underlines the need for education of the broad medical community on the issue. A panel of menopause experts reviewed and critically appraised the literature, and present: 1) the diagnostic approach to POI, 2) the investigation of the etiology of this condition, 3) the therapeutic strategy regarding both hormone replacement therapy (HRT) and fertility and 4) the long-term follow-up and management for ensuring quality of life, as well as urogenital, cardiovascular, bone and mental health. The ultimate goal is to provide a complete toolkit for the primary care physician to have easy access to all the information needed for the optimal management of women with POI, in the context of evidence-based and personalized medicine.
Female Fertility and Environmental Pollution.
Canipari Rita,De Santis Lucia,Cecconi Sandra
International journal of environmental research and public health
A realistic picture of our world shows that it is heavily polluted everywhere. Coastal regions and oceans are polluted by farm fertilizer, manure runoff, sewage and industrial discharges, and large isles of waste plastic are floating around, impacting sea life. Terrestrial ecosystems are contaminated by heavy metals and organic chemicals that can be taken up by and accumulate in crop plants, and water tables are heavily contaminated by untreated industrial discharges. As deadly particulates can drift far, poor air quality has become a significant global problem and one that is not exclusive to major industrialized cities. The consequences are a dramatic impairment of our ecosystem and biodiversity and increases in degenerative or man-made diseases. In this respect, it has been demonstrated that environmental pollution impairs fertility in all mammalian species. The worst consequences are observed for females since the number of germ cells present in the ovary is fixed during fetal life, and the cells are not renewable. This means that any pollutant affecting hormonal homeostasis and/or the reproductive apparatus inevitably harms reproductive performance. This decline will have important social and economic consequences that can no longer be overlooked.
[¢s experience in treatment of primary ovarian insufficiency].
Pang Jin-Bang,Wang Yin
Zhongguo zhen jiu = Chinese acupuncture & moxibustion
The clinical experience of professor in the treatment of primary ovarian insufficiency are summarized. Regarding acupoints selection, the , named "heaven-earth-human being" method is adopted, focusing on the regulation of the middle and (mind/spirit). Regarding needling technique, the elongated needle is used in preference. Besides, the bloodletting and cupping method with filiform-fire needle are innovated to achieve both the reinforcing and the reducing purposes as well as to eliminate stasis. The periodic therapy is applied to comply with the changes in the physiological cycle of gynecology. Acupuncture, Chinese herbal medicine, or the combination of them is selected in consideration of the concrete individual cases of primary ovarian insufficiency.
The Treatment of Complementary and Alternative Medicine on Premature Ovarian Failure.
Lin Jing,Wu Denghui,Jia Liyan,Liang Mengmeng,Liu Siyu,Qin Zhen,Zhang Jiao,Han Yanhua,Liu Songjiang,Zhang Yuehui
Evidence-based complementary and alternative medicine : eCAM
It has been confirmed by growing evidence that common hormone replacement therapy is associated with an increasing risk of causing cardiovascular disease and cancer, while complementary and alternative medicine (CAM) is gaining popularity and application in more and more patients with premature ovarian failure (POF). Although there is little data concerning the clinical safety and efficacy of CAM, the literature includes application studies on the phytoestrogen-rich herbal, acupuncture treatment and intervention therapy. This article reviews recent literature on CAM therapy for POF, aiming to provide theoretical support for clinical application.
Haploinsufficiency in non-homologous end joining factor 1 induces ovarian dysfunction in humans and mice.
Li Guoqing,Yang Xi,Wang Lingbo,Pan Yuncheng,Chen Siyuan,Shang Lingyue,Zhang Yicheng,Wu Yucheng,Zhou Zixue,Chen Qing,Zhang Xue,Zhang Ling,Wang Yingchen,Li Jinsong,Jin Li,Wu Yanhua,Zhang Xiaojin,Zhang Feng
Journal of medical genetics
BACKGROUND:Premature ovarian insufficiency (POI) is a common disease in women that leads to a reduced reproductive lifespan. The aetiology of POI is genetically heterogeneous, with certain double-strand break (DSB) repair genes being implicated in POI. Although non-homologous end joining (NHEJ) is an efficient DSB repair pathway, the functional relationship between this pathway and POI remains unknown. METHODS AND RESULTS:We conducted whole-exome sequencing in a Chinese family and identified a rare heterozygous loss-of-function variant in non-homologous end joining factor 1 (): c.532C>T (p.R178*), which co-segregated with POI and irregular menstruation. The amount of NHEJ1 protein in the proband was half of the normal level, indicating a link between haploinsufficiency and POI. Furthermore, another rare heterozygous variant c.500A>G (p.Y167C) was identified in one of 100 sporadic POI cases. Both variants were predicted to be deleterious by multiple in silico tools. In vitro assays showed that knock-down of in human KGN ovarian cells impaired DNA repair capacity. We also generated a knock-in mouse model with a heterozygous variant equivalent to p.R178* in familial patients. Compared with wild-type mice, heterozygous -mutated female mice required a longer time to first birth, and displayed reduced numbers of primordial and growing follicles. Moreover, these mice exhibited higher sensitivity to DSB-inducing drugs. All these phenotypes are analogous to the progressive loss of ovarian function observed in POI. CONCLUSIONS:Our observations in both humans and mice suggest that haploinsufficiency is associated with non-syndromic POI, providing novel insights into genetic counselling and clinical prevention of POI.
Efficacy and Safety of First-line Single-Agent Carboplatin vs Carboplatin Plus Paclitaxel for Vulnerable Older Adult Women With Ovarian Cancer: A GINECO/GCIG Randomized Clinical Trial.
Falandry Claire,Rousseau Frédérique,Mouret-Reynier Marie-Ange,Tinquaut Fabien,Lorusso Domenica,Herrstedt Jørn,Savoye Aude-Marie,Stefani Laetitia,Bourbouloux Emmanuelle,Sverdlin Robert,D'Hondt Veronique,Lortholary Alain,Brachet Pierre-Emmanuel,Zannetti Alain,Malaurie Emmanuelle,Venat-Bouvet Laurence,Trédan Olivier,Mourey Loïc,Pujade-Lauraine Eric,Freyer Gilles,
Importance:Single-agent carboplatin is often proposed instead of a conventional carboplatin-paclitaxel doublet in vulnerable older patients with ovarian cancer. Such an approach could have a detrimental effect on outcomes for these patients. Objective:To compare the feasibility, efficacy, and safety of single-agent carboplatin every 3 weeks, weekly carboplatin-paclitaxel, or conventional every-3-weeks carboplatin-paclitaxel in vulnerable older patients with ovarian cancer. Design, Setting, and Participants:This international, open-label, 3-arm randomized clinical trial screened 447 women 70 years and older with newly diagnosed stage III/IV ovarian cancer by determining their Geriatric Vulnerability Score; 120 patients with a Geriatric Vulnerability Score of 3 or higher were stratified by country and surgical outcome. Enrollment took place at 48 academic centers in France, Italy, Finland, Denmark, Sweden, and Canada from December 11, 2013, to April 26, 2017. Final analysis database lock April 2019. Data analysis was performed from February 1 to December 31, 2019. Interventions:Patients were randomized to receive 6 cycles of (1) carboplatin, area under the curve (AUC) 5 mg/mL·min, plus paclitaxel, 175 mg/m2, every 3 weeks; (2) single-agent carboplatin, AUC 5 mg/mL·min or AUC 6 mg/mL·min, every 3 weeks; or (3) weekly carboplatin, AUC 2 mg/mL·min, plus paclitaxel, 60 mg/m2, on days 1, 8, and 15 every 4 weeks. Main Outcomes and Measures:The primary outcome was treatment feasibility, defined as the ability to complete 6 chemotherapy cycles without disease progression, premature toxic effects-related treatment discontinuation, or death. Results:A total of 120 women were randomized. The mean and median age was 80 (interquartile range, 76-83; range, 70-94) years; 43 (36%) had a Geriatric Vulnerability Score of 4 and 13 (11%) had a Geriatric Vulnerability Score of 5; 40 (33%) had stage IV disease. During its third meeting, the independent data monitoring committee's recommendation led to the termination of the trial because single-agent carboplatin was associated with significantly worse survival. Six cycles were completed in 26 of 40 (65%), 19 of 40 (48%), and 24 of 40 (60%) patients in the every-3-weeks combination, single-agent carboplatin, and weekly combination groups, respectively. Treatment-related adverse events were less common with the standard every-3-weeks combination (17 of 40 [43%]) than single-agent carboplatin or weekly combination therapy (both 23 of 40 [58%]). Treatment-related deaths occurred in 4 patients (2 of 40 [5%] in each combination group). Conclusions and Relevance:This randomized clinical trial shows that compared with every-3-weeks or weekly carboplatin-paclitaxel regimens, single-agent carboplatin was less active with significantly worse survival outcomes in vulnerable older patients with ovarian cancer. Trial Registration:ClinicalTrials.gov Identifier: NCT02001272.
LncRNA ZNF674-AS1 regulates granulosa cell glycolysis and proliferation by interacting with ALDOA.
Li Duan,Wang Xiaoyan,Li Guangyu,Dang Yujie,Zhao Shidou,Qin Yingying
Cell death discovery
Granulosa cell (GC) is a critical somatic component of ovarian follicles to support oocyte development, while the regulatory role of long noncoding RNA (lncRNA) in GCs is largely unknown. Here, we identified a down-regulated lncRNA ZNF674-AS1 in GCs from patients with biochemical premature ovarian insufficiency (bPOI), and its expression correlates with serum levels of clinical ovarian reserve indicators. Functional experiments showed that ZNF674-AS1 is induced by energy stress, and regulates the proliferation and glycolysis of GCs, which possibly leads to follicular dysfunction. Mechanistically, low-expressed ZNF674-AS1 reduced the enzymatic activity of aldolase A (ALDOA), concomitant with promoting the association between ALDOA and v-ATPase to activate the lysosome localized AMP-activated protein kinase (AMPK). These findings identified a new lncRNA-ALDOA complex through which ZNF674-AS1 exerts its functions, expanding the understanding of epigenetic regulation of GCs function and POI pathogenesis.
Demographic, clinical and hormonal characteristics of patients with premature ovarian insufficiency and those of early menopause: data from two tertiary premature ovarian insufficiency centers in Greece.
Bompoula Maria Sotiria,Valsamakis Georgios,Neofytou Spyridoula,Messaropoulos Pantelis,Salakos Nikolaos,Mastorakos George,Kalantaridou Sophia N
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
The aim of the study was to compare demographic, hormonal and clinical parameters in patients with premature ovarian insufficiency (POI) and women with early menopause in Greece. One hundred thirty-nine women of Greek origin, aged 14-45 years, referring for oligomenorrhea and having elevated FSH concentrations were divided into three groups regarding the age of menstrual disturbances onset [POI: </=30 years ( = 42); POI: 31-39 years ( = 36); early menopause: 40-45 years ( = 61)]. The mean age of menstrual disturbances onset and that of diagnosis in all POI and early menopause patients were 28.7 years (28.7 ± 7.7) versus 42.1 years (42.1 ± 1.5) and 33.8 years (33.8 ± 7.2) versus 43.3 years (43.3 ± 1.4), respectively. POI patients and women with early menopause were diagnosed, respectively, five years and approximately four to six months later than the age of menstrual disturbances onset. Moreover, FSH (second confirmatory FSH measurement at 4-to-6-weeks interval) was greater in all POI patients than in early menopause women (55.4 ± 33.9 vs. 32.4 ± 19.4; < .05) whereas mean age of menarche was greater in early menopause women than in POI patients (13 ± 1.3 vs. 12 ± 2.2; < .05). Furthermore, FSH was increased in all POI and decreased in early menopause patients.
Prevalence of premature ovarian insufficiency and its determinants in Iranian populations: Tehran lipid and glucose study.
Rostami Dovom Marzieh,Bidhendi-Yarandi Razieh,Mohammad Kazem,Farahmand Maryam,Azizi Fereidoun,Ramezani Tehrani Fahimeh
BMC women's health
BACKGROUND:Premature ovarian insufficiency (POI) considered as a concerning health issue for women of reproductive age. In this study we aim to estimate the prevalence of POI and assessing the influential factors. METHODS:Data was obtained from Tehran lipid and glucose study (TLGS). All eligible post-menarcheal female participants of the TLGS, ages 20-65, were recruited (n = 6521). Participants were followed for the event of menopause, and age at menopause was recorded. Kaplan Meier analysis was applied to estimate mean and median for age at menopause. Weibull accelerated failure time survival regression model (AFT), was applied to assess influential determinants of POI. Conditional probability approach was used to provide estimation for prevalence of POI. RESULTS:In this population-based study, the prevalence of POI (menopause age < 40 years) and early menopause (menopause age < 45 years) were estimated 3.5% and 24.6%, respectively. AFT model showed that in comparison to normal weight women, time to menopause was decreased by - 0.09 year (95% CI - 0.27, - 0.01, p = 0.023) and - 0.03 year (95% CI - 0.05, - 0.02, p = 0.000) in underweight and overweight women, respectively. Moreover, time to natural menopause was increased by 0.12 year (95% CI 0.07 to 0.17, p = 0.000) in women used oral contraceptives for > 6 months. CONCLUSION:About one quartile of Iranian women experienced menopause at an age less than 45, especially the non-normal weight ones; this high prevalence is a critical public health concerns that needs to be addressed by health policy makers.
Perceptions and experiences of women with premature ovarian insufficiency about sexual health and reproductive health.
Moukhah Somayeh,Ghorbani Behzad,Behboodi-Moghadam Zahra,Zafardoust Simin
BMC women's health
BACKGROUND:Premature ovarian insufficiency (POI) is a condition with impaired ovarian function that occurred in women before the age of 40. Considering that women with POI are in reproductive age and their fertility and sexual life are afflicted by this disorder directly, the present study aimed to investigate perception and experience of women with POI of sexual and reproductive health (SRH). METHODS:This is a qualitative that was implemented based on the conventional content analysis approach. The data were collected using semi-structured in-depth interviews with 16 women having POI, based on purposeful sampling and continued until data saturation. The participants were women with POI that referred to the three infertility center in Tehran, Iran. The audio recorded data were transcribed verbatim and then analyzed using conventional content analysis based on the method proposed by Zhang and Wildmouth. RESULTS:After content analysis of the interviews with a focus on the perception and experience of women with POI of SRH, four main categories emerged i.e. endangerment of women's health, psychological agitation, disruption of social life and disturbance in sexual life. CONCLUSION:POI affects different aspects of women SRH (women physical, psychological, social and sexual heath). Therefore, knowledge of patients' concerns by health professionals is helpful to improve service delivery and increasing the effectiveness of treatment interventions by a comprehensive health care attitude.
The Potential Synergic Effect of a Complex Pattern of Multiple Inherited Genetic Variants as a Pathogenic Factor for Ovarian Dysgenesis: A Case Report.
Cattoni Alessandro,Spano Alice,Tulone Anna,Boneschi Annalisa,Masera Nicoletta,Maitz Silvia,Di Blasio Anna Maria,Persani Luca,Guizzardi Fabiana,Rossetti Raffaella
Frontiers in endocrinology
Non-syndromic primary ovarian insufficiency due to ovarian dysgenesis in 46,XX patients is an uncommon finding in the general population, even though several monogenic variants have been reported as causative factors. Here, we describe a 15-year-old patient diagnosed with gonadal dysgenesis possibly due to the interaction of three potentially pathogenic variants of genes involved in ovarian maturation, namely (), () and (). We also describe a different degree of residual ovarian function within the proband's family, whose female members carry one to three demonstrated variations in the aforementioned genes in a clinical potentially dependent on the number of alleles involved. Our results support the hypothesis that the severity of the clinical picture of the proband, resulting in complete ovarian dysgenesis, may be due to a synergic detrimental effect of inherited genetic variants.
Possible modification of BRSK1 on the risk of alkylating chemotherapy-related reduced ovarian function.
van der Kooi Anne-Lotte L F,van Dijk Marloes,Broer Linda,van den Berg Marleen H,Laven Joop S E,van Leeuwen Flora E,Lambalk Cornelis B,Overbeek Annelies,Loonen Jacqueline J,van der Pal Helena J,Tissing Wim J,Versluys Birgitta,Bresters Dorine,Beerendonk Catharina C M,Ronckers Cécile R,van der Heiden-van der Loo Margriet,Kaspers Gertjan L,de Vries Andrica C H,Robison Leslie L,Hudson Melissa M,Chemaitilly Wassim,Byrne Julianne,Berger Claire,Clemens Eva,Dirksen Uta,Falck Winther Jeanette,Fosså Sophie D,Grabow Desiree,Haupt Riccardo,Kaiser Melanie,Kepak Tomas,Kruseova Jarmila,Modan-Moses Dalit,Pluijm Saskia M F,Spix Claudia,Zolk Oliver,Kaatsch Peter,Krijthe Jesse H,Kremer Leontien C,Yasui Yutaka,Brooke Russell J,Uitterlinden André G,van den Heuvel-Eibrink Marry M,van Dulmen-den Broeder Eline
Human reproduction (Oxford, England)
STUDY QUESTION:Do genetic variations in the DNA damage response pathway modify the adverse effect of alkylating agents on ovarian function in female childhood cancer survivors (CCS)? SUMMARY ANSWER:Female CCS carrying a common BR serine/threonine kinase 1 (BRSK1) gene variant appear to be at 2.5-fold increased odds of reduced ovarian function after treatment with high doses of alkylating chemotherapy. WHAT IS KNOWN ALREADY:Female CCS show large inter-individual variability in the impact of DNA-damaging alkylating chemotherapy, given as treatment of childhood cancer, on adult ovarian function. Genetic variants in DNA repair genes affecting ovarian function might explain this variability. STUDY DESIGN, SIZE, DURATION:CCS for the discovery cohort were identified from the Dutch Childhood Oncology Group (DCOG) LATER VEVO-study, a multi-centre retrospective cohort study evaluating fertility, ovarian reserve and risk of premature menopause among adult female 5-year survivors of childhood cancer. Female 5-year CCS, diagnosed with cancer and treated with chemotherapy before the age of 25 years, and aged 18 years or older at time of study were enrolled in the current study. Results from the discovery Dutch DCOG-LATER VEVO cohort (n = 285) were validated in the pan-European PanCareLIFE (n = 465) and the USA-based St. Jude Lifetime Cohort (n = 391). PARTICIPANTS/MATERIALS, SETTING, METHODS:To evaluate ovarian function, anti-Müllerian hormone (AMH) levels were assessed in both the discovery cohort and the replication cohorts. Using additive genetic models in linear and logistic regression, five genetic variants involved in DNA damage response were analysed in relation to cyclophosphamide equivalent dose (CED) score and their impact on ovarian function. Results were then examined using fixed-effect meta-analysis. MAIN RESULTS AND THE ROLE OF CHANCE:Meta-analysis across the three independent cohorts showed a significant interaction effect (P = 3.0 × 10-4) between rs11668344 of BRSK1 (allele frequency = 0.34) among CCS treated with high-dose alkylating agents (CED score ≥8000 mg/m2), resulting in a 2.5-fold increased odds of a reduced ovarian function (lowest AMH tertile) for CCS carrying one G allele compared to CCS without this allele (odds ratio genotype AA: 2.01 vs AG: 5.00). LIMITATIONS, REASONS FOR CAUTION:While low AMH levels can also identify poor responders in assisted reproductive technology, it needs to be emphasized that AMH remains a surrogate marker of ovarian function. WIDER IMPLICATIONS OF THE FINDINGS:Further research, validating our findings and identifying additional risk-contributing genetic variants, may enable individualized counselling regarding treatment-related risks and necessity of fertility preservation procedures in girls with cancer. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by the PanCareLIFE project that has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602030. In addition, the DCOG-LATER VEVO study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20) and the St Jude Lifetime cohort study by NCI U01 CA195547. The authors declare no competing interests. TRIAL REGISTRATION NUMBER:N/A.
Revisiting the serum level of anti-Müllerian hormone in patients with functional hypothalamic anovulation.
Makolle Sarah,Catteau-Jonard Sophie,Robin Geoffroy,Dewailly Didier
Human reproduction (Oxford, England)
STUDY QUESTION:Are serum levels of anti-Müllerian hormone (AMH) normal in patients with functional hypothalamic anovulation (FHA)? SUMMARY ANSWER:Our study confirms that in the general FHA population, serum AMH levels are not decreased, but if patients with polycystic ovarian morphology (PCOM) are excluded, levels become significantly lower, as in other situations of gonadotropic insufficiency. WHAT IS KNOWN ALREADY:In most situations of low LH (physiological, pharmacological or pathological), serum AMH levels are low. However, paradoxically, many publications have reported normal or even increased serum AMH levels in FHA patients. STUDY DESIGN, SIZE, DURATION:Retrospective observational study conducted in an academic centre. The data concerning the study population was collected between 2006 and 2015 from a database including clinical, biological and ultrasound information. PARTICIPANTS/MATERIALS, SETTING, METHODS:A total of 45 FHA patients were compared to 37 controls matched based on age and body mass index (BMI). Serum LH, FSH, androstenedione, total testosterone, prolactin and AMH levels were measured by immunoassay. We defined PCOM with strict criteria: a follicle number per ovary (FNPO) ≥ 12 or ≥ 19 per ovary, depending on the date on which the assessment was carried out and the ultrasound device. An AMH level ≥ 35 pmol/l could be a substitute for an excess FNPO. Controls meeting these criteria were not included in this study. MAIN RESULTS AND THE ROLE OF CHANCE:There was no significant difference in the ranges of AMH levels between FHA and controls. Using strict criteria to define PCOM status, 46.7% of FHA patients had PCOM. After excluding these patients, the levels of AMH were significantly lower (P < 0.002) in FHA patients compared to controls. Within the FHA group, patients with PCOM had significantly higher ranks of AMH levels and BMI than those without PCOM. However, within the PCOM+ subgroup, the ranks of LH, FSH and A levels were still lower than in controls (P < 0.0001, <0.002 and <0.05, respectively). The positive correlation between AMH and LH was significant in the controls but not in the FHA group. However, in the FHA PCOM+, there was a strong positive correlation between BMI and LH. LIMITATIONS, REASONS FOR CAUTION:This is a retrospective study; our controls did not represent the general population as they were recruited in an ART centre; we used a modified classification for PCOM using follicle count and/or AMH level with in-house thresholds to define the follicle excess; the AMH assay used is no longer commercially available. WIDER IMPLICATIONS OF THE FINDINGS:Besides biasing the results of AMH assay in FHA patients, the presence of PCOM in FHA patients despite low gonadotropin and androgen levels raises the issue of epigenetically acquired amplification of androgen and/or FSH sensitivity within granulosa cells from polycystic ovaries. In terms of clinical practice, it seems important not to diagnose a low ovarian reserve in FHA patients too quickly on the basis of a decreased AMH level alone. On the contrary, a high AMH level in the context of a menstrual disorder and PCOM should not lead to a misdiagnosis of polycystic ovary syndrome (PCOS) if the basal LH is low. STUDY FUNDING/COMPETING INTEREST(S):None. TRIAL REGISTRATION NUMBER:N/A.
Rare missense variant in MSH4 associated with primary gonadal failure in both 46, XX and 46, XY individuals.
Akbari Arvand,Padidar Kimiya,Salehi Najmeh,Mashayekhi Mehri,Almadani Navid,Sadighi Gilani Mohammad Ali,Bashambou Anu,McElreavey Ken,Totonchi Mehdi
Human reproduction (Oxford, England)
STUDY QUESTION:Can whole-exome sequencing (WES) reveal a shared pathogenic variant responsible for primary gonadal failure in both male and female patients from a consanguineous family? SUMMARY ANSWER:Patients with primary ovarian insufficiency (POI) and non-obstructive azoospermia (NOA) were homozygous for the rare missense variant p. S754L located in the highly conserved MSH4 MutS signature motif of the ATPase domain. An oligozoospermic patient was heterozygous for the variant. WHAT IS KNOWN ALREADY:MSH4 is a meiosis-specific protein expressed at a certain level in the testes and ovaries. Along with its heterodimer partner MSH5, it is responsible for double-strand Holliday junction recognition and stabilization, to ensure accurate chromosome segregation during meiosis. Knockout male and female mice for Msh4 and Msh5 are reportedly infertile due to meiotic arrest. In humans, MSH4 is associated with male and female gonadal failure, with distinct variations in the MutS domain V. STUDY DESIGN, SIZE, DURATION:This was a retrospective genetics study of a consanguineous family with multiple cases of gonadal failure in both genders. The subject family was recruited in Iran, in 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS:The proband who is affected by POI, an NOA brother, a fertile sister and their parents were subjected to WES. The discovered variant was validated in these individuals, and the rest of the family was also genotyped by Sanger sequencing. The variant was not detected in 800 healthy Iranian individuals from the Iranome database nor in 30 sporadic NOA and 30 sporadic POI patients. Suggested effect in aberrant splicing was studied by RT-PCR. Moreover, protein homology modeling was used to further investigate the amino acid substitution in silico. MAIN RESULTS AND THE ROLE OF CHANCE:The discovered variant is very rare and has never been reported in the homozygous state. It occurs in the ATPase domain at Serine 754, the first residue within the highly conserved MutS signature motif, substituting it with a Leucine. All variant effect prediction tools indicated this variant as deleterious. Since the substitution occurs immediately before the Walker B motif at position 755, further investigations based on protein homology were conducted. Considering the modeling results, the nature of the substituted amino acid residue and the distances between p. S754L variation and the residues of the Walker B motif suggested the possibility of conformational changes affecting the ATPase activity of the protein. LARGE SCALE DATA:We have submitted dbSNP entry rs377712900 to ClinVar under SCV001169709, SCV001169708 and SCV001142647 for oligozoospermia, NOA and POI, respectively. LIMITATIONS, REASONS FOR CAUTION:Studies in model organisms can shed more light on the role of this variant as our results were obtained by variant effect prediction tools and protein homology modeling. WIDER IMPLICATIONS OF THE FINDINGS:Identification of variants in meiotic genes should improve genetic counseling for both male and female infertility. Also, as two of our NOA patients underwent testicular sperm extraction (TESE) with no success, ruling out the existence of pathogenic variants in meiotic genes in such patients prior to TESE could prove useful. STUDY FUNDING/COMPETING INTEREST(S):This study was financially supported by Royan Institute in Tehran, Iran, and Institut Pasteur in Paris, France. The authors declare no competing interests. TRIAL REGISTRATION NUMBER:N/A.
Novel variants in women with premature ovarian function decline identified via whole-exome sequencing.
Tang Ruiyi,Yu Qi
Journal of assisted reproduction and genetics
PURPOSE:To investigate the potential etiologies of premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR). METHODS:Fourteen women with sporadic POI and 6 women with DOR were enrolled. We used whole-exome sequencing (WES) and bioinformatics analysis to identify variants in a subset of 599 selected POI candidate genes. The identified genes were subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and protein-protein interaction (PPI) network analyses to uncover key genes and pathways. RESULTS:Among the 20 patients, 79 heterozygous variants were detected in 49 genes, which were classified as "likely pathogenic" or "variants of uncertain significance" according to the guidelines of the American College of Medical Genetics and Genomics. Most patients (17/20) carried two or more variants. Monoacylglycerol O-acyltransferase 1 mutations were found in six patients, and cytochrome P450 family 26 subfamily B member 1 and Bardet-Biedl syndrome 9 mutations were each found in four patients. Some variants were shared between DOR and POI. Enrichment analyses showed that the identified genes participate in key ovarian processes, such as follicular development, gonadal development, meiosis, Fanconi anemia, homologous recombination, and transforming growth factor β signaling. A PPI network revealed interactions between these proteins. CONCLUSION:Premature ovarian function decline may be polygenic, and overlap exists between the genetic backgrounds of DOR and POI. WES and in silico analyses may be a useful clinical tool for etiological diagnosis and risk prediction for high-risk women in the future.
Premature Ovarian Insufficiency: Past, Present, and Future.
Chon Seung Joo,Umair Zobia,Yoon Mee-Sup
Frontiers in cell and developmental biology
Premature ovarian insufficiency (POI) is the loss of normal ovarian function before the age of 40 years, a condition that affects approximately 1% of women under 40 years old and 0.1% of women under 30 years old. It is biochemically characterized by amenorrhea with hypoestrogenic and hypergonadotropic conditions, in some cases, causing loss of fertility. Heterogeneity of POI is registered by genetic and non-genetic causes, such as autoimmunity, environmental toxins, and chemicals. The identification of possible causative genes and selection of candidate genes for POI confirmation remain to be elucidated in cases of idiopathic POI. This review discusses the current understanding and future prospects of heterogeneous POI. We focus on the genetic basis of POI and the recent studies on non-coding RNA in POI pathogenesis as well as on animal models of POI pathogenesis, which help unravel POI mechanisms and potential targets. Despite the latest discoveries, the crosstalk among gene regulatory networks and the possible therapies targeting the same needs to explore in near future.
Molecular Pathways of Cellular Senescence and Placental Aging in Late Fetal Growth Restriction and Stillbirth.
Kajdy Anna,Modzelewski Jan,Cymbaluk-Płoska Aneta,Kwiatkowska Ewa,Bednarek-Jędrzejek Magdalena,Borowski Dariusz,Stefańska Katarzyna,Rabijewski Michał,Torbé Andrzej,Kwiatkowski Sebastian
International journal of molecular sciences
Abnormally accelerated, premature placental senescence plays a crucial role in the genesis of pregnancy pathologies. Abnormal growth in the third trimester can present as small for gestational age fetuses or fetal growth restriction. One differs from the other by the presence of signs of placental insufficiency and the risk of stillbirth. The majority of stillbirths occur in normally grown fetuses and are classified as "unexplained", which often leads to conclusions that they were unpreventable. The main characteristic of aging is a gradual decline in the function of cells, tissues, and organs. These changes result in the accumulation of senescent cells in mitotic tissues. These cells begin the aging process that disrupts tissues' normal functions by affecting neighboring cells, degrading the extracellular matrix, and reducing tissues' regeneration capacity. Different degrees of abnormal placentation result in the severity of fetal growth restriction and its sequelae, including fetal death. This review aims to present the current knowledge and identify future research directions to understand better placental aging in late fetal growth restriction and unexplained stillbirth. We hypothesized that the final diagnosis of placental insufficiency can be made only using markers of placental senescence.
Matrigel/Umbilical Cord-Derived Mesenchymal Stem Cells Promote Granulosa Cell Proliferation and Ovarian Vascularization in a Mouse Model of Premature Ovarian Failure.
Zhou Yao,Zhou Jinhua,Xu Xi,Du Fangzhou,Nie Mengting,Hu Lvzhong,Ma Yuhao,Liu Mengmeng,Yu Shuang,Zhang Jingzhong,Chen Youguo
Stem cells and development
In women of reproductive age, severe injuries to the ovary are often accompanied by premature ovarian failure (POF), which can result in amenorrhea or infertility. Hormone replacement therapy has been used to treat POF; however, it has limited therapeutic efficiency and may cause several side effects. In this study, we aimed to fabricate a Matrigel scaffold loaded with human umbilical cord-derived mesenchymal stem cells (MSCs) and explore its potential to restore ovarian function and repair ovarian structures in vitro and in vivo. POF mouse models were established by injecting mice with cyclophosphamide for 15 consecutive days. Then, MSC/Matrigel was transplanted into the ovaries of the mice. Five weeks later, the morphology of the ovaries and follicles was observed by hematoxylin/eosin staining, and the tissue fibrosis ratio was measured using Masson's trichrome staining. The number of blood vessels was evaluated by α-smooth muscle actin and CD31 immunofluorescence, and Ki67 expression was used to determine the proliferation of granulosa cells. The expression of vascular endothelial growth factor (VEGF)-A was assessed by western blotting. The Matrigel scaffold regulated the expression of VEGF-A in vitro. Moreover, it promoted MSC survival and proliferation and prevented MSC apoptosis in vivo. After the transplantation of the MSC/Matrigel, the number of follicles was significantly increased in the mice with POF, and the tissue fibrosis ratio was reduced. Furthermore, the MSC/Matrigel significantly improved the proliferation rate of granulosa cells, increased the number of blood vessels, and upregulated the expression of VEGF-A. These findings demonstrate that MSC/Matrigel may support follicular development and help restore ovarian structures in vivo.
Danggui Buxue Tang Rescues Folliculogenesis and Ovarian Cell Apoptosis in Rats with Premature Ovarian Insufficiency.
Wang Lingdi,Liu Jian,Nie Guangning,Li Yang,Yang Hongyan
Evidence-based complementary and alternative medicine : eCAM
Premature ovarian insufficiency (POI) is a common female endocrine disease that is closely linked to ovarian function. Danggui Buxue Tang (DBT) is a classic prescription of traditional Chinese medicine that is helpful for rescuing ovarian function. However, the mechanism by which DBT rescues ovarian function remains unclear. This study explored the molecular mechanism of DBT with respect to apoptosis and related signals in ovarian cells. The quality control of DBT was performed by HPLC. After DBT intervention in the POI rat model, serum AMH/FSH/LH/E levels were detected by ELISA, follicles at various developmental stages were observed by HE staining, apoptosis was detected by TUNEL, and the expression profiles of Bcl-2 family proteins and key proteins in the Jak2/Foxo3a signaling pathway were evaluated by western blot. The results demonstrated that DBT could encourage the development of primary/secondary/antral follicles and increase the secretion of AMH. Moreover, DBT might inhibit Foxo3a by upregulating Jak2, thereby mediating Bcl-2 family activities and inhibiting apoptosis in ovarian cells. In conclusion, DBT promotes follicular development and rescues ovarian function by regulating Bcl-2 family proteins to inhibit cell apoptosis, which could be related to the Jak2/Foxo3a signaling pathway.
Early ovarian ageing: is a low number of oocytes harvested in young women associated with an earlier and increased risk of age-related diseases?
Christensen M W,Kesmodel U S,Christensen K,Kirkegaard K,Ingerslev H J
Human reproduction (Oxford, England)
STUDY QUESTION:Do young women with early ovarian ageing (EOA), defined as unexplained, and repeatedly few oocytes harvested in ART have an increased risk of age-related events? SUMMARY ANSWER:At follow-up, women with idiopathic EOA had an increased risk of age-related events compared to women with normal ovarian ageing (NOA). WHAT IS KNOWN ALREADY:Early and premature menopause is associated with an increased risk of cardiovascular diseases (CVDs), osteoporosis and death. In young women, repeated harvest of few oocytes in well-stimulated ART cycles is a likely predictor of advanced menopausal age and may thus serve as an early marker of accelerated general ageing. STUDY DESIGN, SIZE, DURATION:A register-based national, historical cohort study. Young women (≤37 years) having their first ART treatment in a public or private fertility clinic during the period 1995-2014 were divided into two groups depending on ovarian reserve status: EOA (n = 1222) and NOA (n = 16 385). Several national registers were applied to assess morbidity and mortality. PARTICIPANTS/MATERIALS, SETTING, METHODS:EOA was defined as ≤5 oocytes harvested in a minimum of two FSH-stimulated cycles and NOA as ≥8 oocytes in at least one cycle. Cases with known causes influencing the ovarian reserve (endometriosis, ovarian surgery, polycystic ovary syndrome, chemotherapy etc.) were excluded. To investigate for early signs of ageing, primary outcome was an overall risk of ageing-related events, defined as a diagnosis of either CVD, osteoporosis, type 2 diabetes, cancer, cataract, Alzheimer's or Parkinson's disease, by death of any-cause as well as a Charlson comorbidity index score of ≥1 or by registration of early retirement benefit. Cox regression models were used to assess the risk of these events. Exposure status was defined 1 year after the first ART cycle to assure reliable classification, and time-to-event was measured from that time point. MAIN RESULTS AND THE ROLE OF CHANCE:Median follow-up time from baseline to first event was 4.9 years (10/90 percentile 0.7/11.8) and 6.4 years (1.1/13.3) in the EOA and NOA group, respectively. Women with EOA had an increased risk of ageing-related events when compared to women with a normal oocyte yield (adjusted hazard ratio 1.24, 95% CI 1.08 to 1.43). Stratifying on categories, the EOA group had a significantly increased risk for CVD (1.44, 1.19 to 1.75) and osteoporosis (2.45, 1.59 to 3.90). Charlson comorbidity index (1.15, 0.93 to 1.41) and early retirement benefit (1.21, 0.80 to 1.83) was also increased, although not reaching statistical significance. LIMITATIONS, REASONS FOR CAUTION:Cycles never reaching oocyte aspiration were left out of account in the inclusion process and we may therefore have missed women with the most severe forms of EOA. We had no information on the total doses of gonadotrophin administered in each cycle. WIDER IMPLICATIONS OF THE FINDINGS:These findings indicate that oocyte yield may serve as marker of later accelerated ageing when, unexpectedly, repeatedly few oocytes are harvested in young women. Counselling on life-style factors as a prophylactic effort against cardiovascular and other age-related diseases may be essential for this group of women. STUDY FUNDING/COMPETING INTEREST(S):No external funding was received for this study. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER:N/A.
Diminished Ovarian Reserve in Girls and Adolescents with Trisomy X Syndrome.
Davis Shanlee M,Soares Katelyn,Howell Susan,Cree-Green Melanie,Buyers Eliza,Johnson Joshua,Tartaglia Nicole R
Reproductive sciences (Thousand Oaks, Calif.)
An extra X chromosome occurs in ~ 1 in 1000 females, resulting in a karyotype 47,XXX also known as trisomy X syndrome (TXS). Women with TXS appear to be at increased risk for premature ovarian insufficiency; however, very little research on this relationship has been conducted. The objective of this case-control study is to compare ovarian function, as measured by anti-mullerian hormone (AMH) levels, between girls with TXS and controls. Serum AMH concentrations were compared between 15 females with TXS (median age 13.4 years) and 26 controls (median age 15.1 years). Females with TXS had significantly lower serum AMH compared to controls (0.7 ng/mL (IQR 0.2-1.7) vs 2.7 (IQR 1.3-4.8), p < 0.001). Additionally, girls with TXS were much more likely to have an AMH below the 2.5th percentile for age with 67% of them meeting these criteria (OR 11, 95% CI 2.3-42). Lower AMH concentrations in females with TXS may represent an increased risk for primary ovarian insufficiency in these patients and potentially a narrow window of opportunity to pursue fertility preservation options. Additional research is needed to understand the natural history of low AMH concentrations and future risk of premature ovarian insufficiency in girls with TXS.
Human Umbilical Cord Mesenchymal Stem Cells Improve Ovarian Function in Chemotherapy-Induced Premature Ovarian Failure Mice Through Inhibiting Apoptosis and Inflammation via a Paracrine Mechanism.
Deng Taoran,He Jing,Yao Qingyun,Wu Linjing,Xue Liru,Wu Mingfu,Wu Dongcheng,Li Changyong,Li Yufeng
Reproductive sciences (Thousand Oaks, Calif.)
Human umbilical cord mesenchymal stem cell (UC-MSC) application is a promising arising therapy for the treatment of premature ovarian failure (POF). However, little is known about the inflammation regulatory effects of human umbilical cord MSCs (UC-MSCs) on chemotherapy-induced ovarian damage, regardless of in vivo or in vitro. This study was designed to investigate the therapeutic effects of UC-MSC transplantation and underlying mechanisms regarding both apoptosis and inflammation in POF mice. The chemotherapy-induced POF models were induced by intraperitoneal injection of cyclophosphamide. Ovarian function parameters, granulosa cell (GC) apoptosis, and inflammation were examined. Morphological staining showed that UC-MSC treatment increased the ovary size, and the numbers of primary and secondary follicles, but decreased the number of atretic follicles. Estradiol levels in the UC-MSC-treated group were increased while follicle-stimulating hormone levels were reduced compared to those in the POF group. UC-MSCs inhibited cyclophosphamide-induced GC apoptosis and inflammation. Meanwhile, phosphorylation of AKT and P38 was elevated after UC-MSC treatment. Tracking of UC-MSCs in vivo indicated that transplanted UC-MSCs were only located in the interstitium of ovaries rather than in follicles. Importantly, UC-MSC-derived extracellular vesicles protected GCs from alkylating agent-induced apoptosis and inflammation in vitro. Our results suggest that UC-MSC transplantation can reduce ovary injury and improve ovarian function in chemotherapy-induced POF mice through anti-apoptotic and anti-inflammatory effects via a paracrine mechanism.
Human Mesenchymal Stem Cell Therapy and Other Novel Treatment Approaches for Premature Ovarian Insufficiency.
Ulin Mara,Cetin Esra,Hobeika Elie,Chugh Rishi Man,Park Hang-Soo,Esfandyari Sahar,Al-Hendy Ayman
Reproductive sciences (Thousand Oaks, Calif.)
Premature ovarian insufficiency (POI) is a condition characterized by amenorrhea, hypergonadotropic hypogonadism, estrogen deficiency, and reduced follicle counts leading to infertility under the age of 40. POI occurs in approximately 1-3% of women in the general population. Evaluation is warranted when the diagnosis of POI is made to rule out underlying etiologies, which could be multifactorial. This review serves to cover the novel treatment approaches reported in the literature.
Metabolic profile of women with premature ovarian insufficiency compared with that of age-matched healthy controls.
Huang Yizhou,Lv Yifei,Qi Tongyun,Luo Zhou,Meng Xingjun,Ying Qian,Li Die,Li Chunming,Lan Yibing,Chu Ketan,Fu Dongxia,Chen Peiqiong,Xu Wenxian,Jia Yingxian,Li Saisai,Cen Xiaoping,Li Li,Xu Ling,Ma Linjuan,Zhou Jianhong
OBJECTIVE:. To compare the metabolic profile of women with spontaneous premature ovarian insufficiency (POI) with that of age-matched healthy controls. STUDY DESIGN:. A cross-sectional case-control study was conducted using 1:1 matching by age. Women below the age of 40 with spontaneous POI who did not receive any medication (n = 303) and age-matched healthy women (n = 303) were included in this study. MAIN OUTCOME MEASURES:. Metabolic profiles, including serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), glucose, uric acid, urea and creatinine, were compared between women with POI and controls. For women with POI, factors associated with the metabolic profile were analyzed. RESULTS:. Women with POI were more likely to exhibit increased serum levels of TG (β, 0.155; 95% CI, 0.086, 0.223) and glucose (0.067; 0.052, 0.083), decreased levels of HDL-C (-0.087; -0.123, -0.051), LDL-C (-0.047; -0.091, -0.003) and uric acid (-0.053; -0.090, -0.015), and impaired kidney function (urea [0.070; 0.033, 0.107]; creatinine [0.277; 0.256, 0.299]; eGFR [-0.234; -0.252, -0.216]) compared with controls after adjusting for age and BMI. BMI, parity, gravidity, FSH and E2 levels were independent factors associated with the metabolic profile of women with POI. CONCLUSION:. Women with POI exhibited abnormalities in lipid metabolism, glucose metabolism, and a decrease in kidney function. In women with POI, early detection and lifelong management of metabolic abnormalities are needed.
The clinical outcomes of fresh versus frozen embryos transfer in women ≥40 years with poor ovarian response.
Liu Conghui,Li Yu,Jiang Hong,Liu Yingchun,Song Xiaomin
Obstetrics & gynecology science
OBJECTIVE:To compare the clinical outcomes of fresh embryo transfers (ETs) and frozen-thawed embryo transfers (FETs) after a freeze-all cycle in women ≥40 years old with poor ovarian response (POR). METHODS:We performed a single-center, retrospective, case-control study of patients who underwent in vitro fertilization between January 2014 and June 2019. We included a total of 192 patients aged 40 years or older from whom 3 or fewer oocytes had been retrieved and who were receiving cleavage-stage ET in this study. Of these patients, 101 and 91 patients underwent fresh ET and FET, respectively. The primary outcome was the live birth rate (LBR) after the first ET. Logistic regression analysis was used to compare the IVF outcomes and neonatal characteristics between the fresh ET and FET groups, adjusting for maternal age, body mass index, luteinizing hormone, and the number of good quality embryos transferred. RESULTS:The mean maternal ages and number of oocytes retrieved (43.2 years and 2.3 in both groups, P=0.902 and P=0.927, respectively) were similar in the fresh ET and FET groups. No significant difference was observed between the LBRs of the fresh ET and FET groups (adjusted odds ratio, 1.28; 95% confidence interval, 0.29-5.70). The clinical pregnancy and miscarriage rates, and neonatal characteristics (birth weights and premature infant rates) were similar between the 2 groups. CONCLUSION:s FET after the freeze-all strategy had no beneficial impact on the clinical outcomes of women ≥40 years with POR.
Local application of low level laser therapy in mice ameliorates ovarian damage induced by cyclophosphamide.
Oubiña Gonzalo,Pascuali Natalia,Scotti Leopoldina,Bianchi Silvia,May María,Martínez Jorge Esteban,Marchese Ragona Clariana,Higuera Javier,Abramovich Dalhia,Parborell Fernanda
Molecular and cellular endocrinology
The aim of the present study is to assess whether low level laser therapy (LLLT) can protect ovaries from chemotherapy-induced gonadotoxicity using a mice model of premature ovarian failure induced by cyclophosphamide (CTX). LLLT (64 J/cm) increased the number of antral follicles whilst decreasing the number of atretic follicles compared to CTX alone. LLLT increased the number of primordial follicles compared with those in the CTX group but they did not differ from those in the control group. LLLT treatment increased the number of AMH-positive follicles compared to CTX alone. LLLT application increased ovarian weight, serum progesterone concentration and P450scc protein levels compared to CTX alone. LLLT reduced the apoptosis in antral follicles and the BAX/BCL-2 ratio compared to CTX alone. Vascular morphology, analysed by CD31 and α-SMA immunostaining, was restored in LLLT-treated ovaries compared to CTX alone. In conclusion, application of LLLT prior to CTX might serve as a promising and novel protocol to preserve female fertility in cancer survivors.
Viral infection of the ovaries compromises pregnancy and reveals innate immune mechanisms protecting fertility.
Tomac Jelena,Mazor Marija,Lisnić Berislav,Golemac Mijo,Kveštak Daria,Bralić Marina,Bilić Zulle Lidija,Brinkmann Melanie M,Dölken Lars,Reinert Line S,Paludan Soren R,Krmpotić Astrid,Jonjić Stipan,Juranić Lisnić Vanda
Viral infections during pregnancy are a considerable cause of adverse outcomes and birth defects, and the underlying mechanisms are poorly understood. Among those, cytomegalovirus (CMV) infection stands out as the most common intrauterine infection in humans, putatively causing early pregnancy loss. We employed murine CMV as a model to study the consequences of viral infection on pregnancy outcome and fertility maintenance. Even though pregnant mice successfully controlled CMV infection, we observed highly selective, strong infection of corpus luteum (CL) cells in their ovaries. High infection densities indicated complete failure of immune control in CL cells, resulting in progesterone insufficiency and pregnancy loss. An abundance of gap junctions, absence of vasculature, strong type I interferon (IFN) responses, and interaction of innate immune cells fully protected the ovarian follicles from viral infection. Our work provides fundamental insights into the effect of CMV infection on pregnancy loss and mechanisms protecting fertility.
Receptor tyrosine kinases-instructed release of its inhibitor from hydrogel to delay ovarian aging.
Shi Zhonghua,Li Xiaoyan,Wei Mengxing,Chen Peiyao,Zhang Ting,Ling Xiufeng,Zhang Junqiang,Zhao Chun,Wang Fuqiang,Liang Gaolin
Premature ovarian failure (POF) is the most frequently occurred disease in ovary. Direct inhibition of mammalian target of rapamycin (mTOR) activity can treat woman POF but brings adverse effects to women. Herein, by rational design of a hydrogelator Nap-Phe-Phe-Asp-Arg-Leu-Tyr-OH (Y) and co-assembling Y with an inhibitor of receptor tyrosine kinase (RTK, an upstream kinase of mTOR), Ala-Glu-Ala-Ala-Leu-Tyr-Lys-Asn-Leu-Leu-His-Ser-OH (Inh), to form hydrogel Gel Y + Inh, we develop a "smart" strategy of RTK-responsive disassembly of the hydrogel to release Inh. Release of Inh moderately inhibits the activity of mTOR and therefore delays ovarian aging. Oocyte and zygote experiments show that Gel Y + Inh improves both meiotic maturation of the oocytes and early embryonic development of the zygotes. In vivo animal experiments indicate that Gel Y + Inh effectively delays ovarian aging in aged mice by down regulation of mTOR activity, stimulation of ovaries to secrete estrogen and progesterone, and development of more antral follicles for reproduction. We expect that our new hydrogel Gel Y + Inh could be applied to treat woman POF, as well as delay ovarian aging, in clinic in the near future.
Is climacterium by the mid-40s associated with thyroid dysfunction or autoimmunity? A population-based study.
Savukoski Susanna M,Niinimäki Maarit J,Pesonen Paula R O,Auvinen Juha P,Männistö Tuija,Puukka Katri S,Ebeling Tapani,Suvanto Eila T J
Menopause (New York, N.Y.)
OBJECTIVE:We investigated whether more advanced climacteric stage in the mid-40s is associated with thyroid autoimmunity and dysfunction. METHODS:This cross-sectional cohort study included 2,569 46-year-old women. Thyroid hormone, thyroid peroxidase antibodies, and follicle-stimulating hormone levels were determined. Using menstrual history and follicle-stimulating hormone levels, the participants were divided into climacteric (n = 340) and preclimacteric (n = 2,229) groups. Women diagnosed with premature ovarian insufficiency (menopause by 40 y of age) were excluded. The use of thyroid medication was evaluated from the medication reimbursement register. The prevalence of thyroid medication use, laboratory-based thyroid dysfunction, and thyroid peroxidase antibody positivity was compared between the two groups. The association between climacteric status and thyroid disorders was investigated using a logistic regression model including smoking and thyroid antibody status. RESULTS:At 46 years old, climacteric women used thyroid medication more often than preclimacteric women (9.1% vs 6.1%; P = 0.04). There was no difference in the prevalence of subclinical or clinical hypothyroidism and hyperthyroidism in nonmedicated participants (5.5% vs 5.0%; P = 0.7) or thyroid peroxidase antibody positivity (14.0% vs 15.0%, P = 0.7). In the regression model, being climacteric (OR = 1.6; 95% CI 1.1-2.3; P = 0.02) and antibody positivity (OR 4.9; 95% CI 3.6-6.6; P < 0.001) were associated with a higher prevalence of thyroid dysfunction. CONCLUSIONS:More advanced climacteric stage in the mid-40s was slightly associated with thyroid dysfunction but not thyroid autoimmunity.
Identifying susceptibility genes for primary ovarian insufficiency on the high-risk genetic background of a fragile X premutation.
Trevino Cristina E,Rounds J Christopher,Charen Krista,Shubeck Lisa,Hipp Heather S,Spencer Jessica B,Johnston H Richard,Cutler Dave J,Zwick Michael E,Epstein Michael P,Murray Anna,Macpherson James N,Mila Montserrat,Rodriguez-Revenga Laia,Berry-Kravis Elizabeth,Hall Deborah A,Leehey Maureen A,Liu Ying,Welt Corrine,Warren Stephen T,Sherman Stephanie L,Jin Peng,Allen Emily G
Fertility and sterility
OBJECTIVE:To identify modifying genes that explains the risk of fragile X-associated primary ovarian insufficiency (FXPOI). DESIGN:Gene-based, case/control association study, followed by a functional screen of highly ranked genes using a Drosophila model. SETTING:Participants were recruited from academic and clinical settings. PATIENT(S):Women with a premutation (PM) who experienced FXPOI at the age of 35 years or younger (n = 63) and women with a PM who experienced menopause at the age of 50 years or older (n = 51) provided clinical information and a deoxyribonucleic acid sample for whole genome sequencing. The functional screen was on the basis of Drosophila TRiP lines. INTERVENTION(S):Clinical information and a DNA sample were collected for whole genome sequencing. MAIN OUTCOME MEASURES:A polygenic risk score derived from common variants associated with natural age at menopause was calculated and associated with the risk of FXPOI. Genes associated with the risk of FXPOI were identified on the basis of the P-value from gene-based association test and an altered level of fecundity when knocked down in the Drosophila PM model. RESULTS:The polygenic risk score on the basis of common variants associated with natural age at menopause explained approximately 8% of the variance in the risk of FXPOI. Further, SUMO1 and KRR1 were identified as possible modifying genes associated with the risk of FXPOI on the basis of an untargeted gene analysis of rare variants. CONCLUSIONS:In addition to the large genetic effect of a PM on ovarian function, the additive effects of common variants associated with natural age at menopause and the effect of rare modifying variants appear to play a role in FXPOI risk.
The association between primary ovarian insufficiency and osteoporosis in the Canadian Longitudinal Study on Aging.
Shea Alison K,Buwembo Alice,Mayhew Alexandra,Sohel Nazmul,Griffith Lauren E,Raina Parminder
Menopause (New York, N.Y.)
OBJECTIVE:The objective of this study is to describe the association of premature ovarian insufficiency (POI) and early menopause on bone mineral density (BMD) and osteoporosis in a large cohort of women living in Canada. METHODS:Cross-sectional baseline data from a deeply characterized cohort (female participants) of the Canadian Longitudinal Study on Aging was used. Additional bio-psycho-social characteristics that may influence bone health and the development of osteoporosis were explored. RESULTS:The mean age of women at the time of baseline assessment was 65 years (N = 12,339). When comparing women with POI to those with early and normal age of menopause, there was no difference in hip BMD between groups, but women in the POI group were more likely to have a higher rate of self-reported osteoporosis (21.9% vs 16.7%) and have used osteoporosis drugs (11.39% vs 7.63%). After adjustment, POI was found to increase the odds of osteoporosis, as diagnosed using BMD. Current cigarette smoking was found to influence this association. Protective factors included obesity and current hormone therapy use, but not the duration of hormone therapy use. Women in the POI group were more likely to be obese, have decreased physical activity, and were more likely to be current smokers. CONCLUSION:These results confirm findings from smaller cohorts illustrating that POI is associated with osteoporosis. Increasing understanding of the sequelae associated with an earlier loss of ovarian function will aid in targeting earlier screening and intervention strategies for women in Canada and abroad.
Regulation of primordial follicle formation, dormancy, and activation in mice.
The Journal of reproduction and development
In female reproduction, the oocyte number is limited after birth. To achieve a continuous ovulatory cycle, oocytes are stored in primordial follicles. Therefore, the regulation of primordial follicle dormancy and activation is important for reproductive sustainability, and its collapse leads to premature ovarian insufficiency. In this review, we summarize primordial follicle development and the molecular mechanisms underlying primordial follicle maintenance and activation in mice. We also overview the mechanisms discovered through in vitro culture of functional oocytes, including the establishment of primordial follicle induction by environmental factors, which revealed the importance of hypoxia and compression by the extra cellular matrix (ECM) for primordial follicle maintenance in vivo.
Evaluation of serum anti-Müllerian hormone levels in women with Hashimoto thyroiditis in the reproductive age
Öztürk Ünsal İlknur,Hepşen Sema,Akhanlı Pınar,Çalapkulu Murat,Sencar Muhammed Erkam,Yalçındağ Ali,Çakal Erman
Turkish journal of medical sciences
Background/aim:Autoimmune thyroid disease in women is associated with subfertility and early pregnancy loss, and patients with primary ovarian insufficiency have a high prevalence of thyroid autoimmune disorders. The aim of this study was to investigate the association between Hashimoto thyroiditis (HT) and ovarian reserve. Materials and methods:Levels of serum thyroid stimulating hormones, thyroid autoantibodies, and anti-Müllerian hormone (AMH) were measured in women with HT and a healthy control group between 2018 and 2019. Results:Evaluation was made of 108 premenopausal women with HT, and a control group of 172 healthy females with normal antithyroid antibody levels and thyroid function. Serum AMH levels were determined to be significantly lower in the HT group compared to the control group. Conclusion:Ovarian reserve evaluated by serum AMH concentration is affected by thyroid autoimmunity independently of antithyroid antibodies type or titers.
Methods of Ovarian Tissue Cryopreservation: Is Vitrification Superior to Slow Freezing?-Ovarian Tissue Freezing Methods.
Kometas Marisa,Christman Gregory M,Kramer Joseph,Rhoton-Vlasak Alice
Reproductive sciences (Thousand Oaks, Calif.)
After cancer treatment, female survivors often develop ovarian insufficiency or failure. Oocyte and embryo freezing are well-established fertility preservation options, but cannot be applied in pre-pubescent girls, in women with hormone-sensitive malignancies, or when gonadotoxic treatment cannot be delayed. Although ovarian tissue cryopreservation (OTC) has been used to restore fertility and endocrine function, the relative efficacy of its two major protocols, slow freezing and vitrification, remains controversial. This literature review evaluates clinical and lab-based studies published between January 2012 and June 2020 to determine whether vitrification, the optimal technique for oocyte and embryo cryopreservation, preserves ovarian tissue more effectively than slow freezing. Due to limited clinical data involving ovarian tissue vitrification, most clinical studies focus on slow freezing. Only 9 biochemical studies that directly compare the effects of slow freezing and vitrification of human ovarian tissue were noted. Most studies report no significant difference in follicular morphology and distribution between cryopreservation methods, but these findings must be interpreted in the context of high methodological variability. Discrepant findings regarding the effects of cryopreservation method on follicle viability, gene expression, and hormone production require further evaluation. Early clinical outcomes appear favorable for vitrification, but additional studies and longer term follow-up are needed to establish its efficacy. Sharing data through national or international registries would expedite this analysis. However, even if research corroborates conclusions of no clinical or biochemical difference between cryopreservation methods, the decreased costs and increased efficiency associated with vitrification make this method more accessible and cost-effective.
Loss of ESRP1 blocks mouse oocyte development and leads to female infertility.
Yu Luping,Zhang Huiru,Guan Xuebing,Qin Dongdong,Zhou Jian,Wu Xin
Development (Cambridge, England)
Alternative splicing (AS) contributes to gene diversification, but AS program during germline development remains largely undefined. Here, we interrupted pre-mRNA splicing events controlled by epithelial splicing regulatory protein 1 (ESRP1) and found that it induced female infertility in mice. Esrp1 deletion perturbed spindle organization, chromosome alignment, and metaphase-to-anaphase transformation in oocytes. The first polar body extrusion (PBE) was blocked during oocyte meiosis due to abnormal activation of spindle assembly checkpoint (SAC) and insufficiency of anaphase-promoting complex/cyclosome (APC/C) in Esrp1-knockout oocytes. Esrp1-knockout hampered follicular development and ovulation; eventually, premature ovarian failure (POF) occurred in six-month-old Esrp1-knockout mouse. Using single-cell RNA sequencing analysis, 528 aberrant AS events of maternal mRNA transcripts were revealed and were preferentially associated with microtubule cytoskeletal organization. Notably, we found that loss of ESRP1 disturbed a comprehensive set of gene-splicing sites-including those within Trb53bp1, Rac1, Bora, Kif2c, Kif23, Ndel1, Kif3a, Cenpa, and Lsm14b-that potentially caused abnormal spindle organization. Collectively, our findings provide the first report elucidating the ESRP1- mediated AS program of maternal mRNA transcripts, may contribute to oocyte meiosis and female fertility in mice.
Roles of the Notch Signaling Pathway in Ovarian Functioning.
Guo Shuhan,Quan Song,Zou Siyi
Reproductive sciences (Thousand Oaks, Calif.)
The Notch signaling pathway regulates cell invasion, adhesion, proliferation, apoptosis, and differentiation via cell-to-cell interactions and plays important physiological roles in the ovary. This review summarizes current knowledge about the Notch signaling pathway in relation to ovarian functions and reveals the potential underlying mechanisms. We conducted an in-depth review of relevant literature to determine the current status of research into the Notch signaling pathway in relation to ovarian functioning and reveal potential underlying mechanisms. The activation of different Notch receptors promotes the formation of primordial follicles and proliferation of granulosa cells and inhibits steroid secretion. Abnormal regulation of the Notch signaling pathway or direct mutations might lead to over-activation or under-activation of the receptors, resulting in Notch upregulation or downregulation. It can also disrupt the normal physiological functions of the ovary. The lncRNA HOTAIR and growth hormones improved premature ovarian failure (POF) and promoted follicle maturation in a mouse model of POF by upregulating Notch1 expression. They also stimulated the Notch1 signaling pathway, increased the level of plasma estradiol, and decreased the level of plasma follicle-stimulating hormone. Thus, Notch1 could serve as a novel therapeutic target for POF. Several studies have reported multiple roles of Notch in regulating female primordial follicle formation and follicle maturation. Direct mutations in Notch-related molecules or abnormal gene regulation in the signaling pathway can lead to ovarian dysfunction. However, the underlying mechanisms are not fully understood.
Successful live birth after maturation treatment in a patient with autoimmune premature ovarian failure: a case report and review of the literature.
Chansel-Debordeaux Lucie,Rault Elisabeth,Depuydt Chloé,Soula Volcy,Hocké Claude,Jimenez Clément,Creux Hélène,Papaxanthos-Roche Aline
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
OBJECTIVE:We report a successful live birth after oocytes maturation (IVM) and fresh embryo transfer in a patient with autoimmune premature ovarian failure (POF) and performed a review of the literature of livebirths obtained after oocytes IVM treatment in this indication. METHODS:The patient was a 24-year-old woman with autoimmune POF diagnosed post-partum, who developed autoimmune polyglandular syndrome with serum anti-ovarian and anti-21-hydroxylase antibodies. The patient had typical symptoms of POF: secondary amenorrhea with hypoestrogenism, elevated gonadotropins and infertility; however, the serum anti-Müllerian hormone level and total antral follicle count remained normal. IVM of immature oocytes was performed after the administration of 150 IU highly purified human menopausal gonadotropin for three consecutive days and an injection of 10,000 IU human chorionic gonadotropin to trigger ovulation. RESULTS:The six oocyte-cumulus complexes collected matured . After intracytoplasmic sperm injection (ICSI), five embryos were obtained. Pregnancy was achieved after the fresh transfer of two embryos and appropriate endometrial preparation. A normal female child was delivered following a 37-weeks pregnancy characterized by the onset of adrenal insufficiency and unstable diabetes. CONCLUSIONS:We report a successful livebirth after IVM treatment in a patient with autoimmune premature ovarian failure (POF). Management of reproductive age women with autoimmune pathology requires fertility counseling. Early diagnosis of autoimmune POF is important for early conception and oocyte preservation, because the only other option at present is ovum donation.
Prevalence and clinical associations with premature ovarian insufficiency, early menopause, and low ovarian reserve in systemic sclerosis.
Jutiviboonsuk Arporn,Salang Lingling,Eamudomkarn Nuntasiri,Mahakkanukrauh Ajanee,Suwannaroj Siraphop,Foocharoen Chingching
The low prevalence of pregnancy in women with systemic sclerosis (SSc) is due to multi-factorial causes, including premature ovarian insufficiency (POI). The study aimed to determine the prevalence of POI, early menopausal status, and any clinical associations of these among Thai female SSc patients. An analytical cross-sectional study was conducted among female SSc patients between 18 and 45 years of age. The eligible patients underwent blood testing for follicle stimulating hormone and anti-mullerian hormone levels, gynecologic examination, and transvaginal ultrasound for antral follicle count. We excluded patients having surgical amenorrhea, previous radiation, and history of hormonal contraception < 12 weeks and pregnancy. A total of 31 patients were included. The majority (67.7%) had diffuse cutaneous systemic sclerosis. Three patients were POI with a prevalence of 9.7%. The factors associated with POI were a high cumulative dose of cyclophosphamide (CYC) (p = 0.02) and the long duration of CYC used (p = 0.02). After excluding POI, early menopause was detected in 10 patients with a prevalence of 35.7%. The factors associated with early menopause were long disease duration (p = 0.02), high cumulative dose of CYC (p = 0.03), and high cumulative dose of prednisolone (p = 0.02). Low ovarian reserve according to POSEIDON definition was found in 28 patients with the prevalence of 90.3%. POI in Thai SSc was uncommon, whereas early menopause and low ovarian reserve were frequently revealed. A high cumulative dose of CYC was associated with both POI and early menopause. Physicians should be aware of reproductive outcomes and advise patients at risk. Key Points • POI is revealed in patients with SSc particularly in who received high cumulative dose of cyclophosphamide, while early menopause and low ovarian reserve were major reproductive problem among SSc. • Prescriptions for CYC for female SSc-both for young patients of reproductive age and premenopausal middle-aged women-should be concerned of the long-term effects on gonadal function.
Analysis of the MCL-1 gene in Chinese women with idiopathic premature ovarian insufficiency.
Cao J,He Y,Cai W,Zhou W,Cong J,Tan R,Ge H,Pu D,Wu J
Climacteric : the journal of the International Menopause Society
OBJECTIVE:Animal studies have demonstrated that myeloid cell leukemia-1 (Mcl-1) gene deficiency leads to premature ovarian failure and decreased reproductive ability in mice. This study investigated the relationship between MCL-1 gene variation and idiopathic premature ovarian insufficiency (POI) in Chinese women. METHODS:A total of 200 idiopathic POI patients and 100 healthy controls were recruited for this study, and peripheral blood was collected. First, genomic DNA was extracted from peripheral leukocytes. Then, the entire coding region and splice sites of the MCL-1 gene were amplified by polymerase chain reaction. Chi-squared tests were used to compare the genotype distribution and allele frequency of single nucleotide polymorphisms between the POI and control groups. RESULTS:Three mutations of the MCL-1 gene (c.-36C > T, c.-131C > T and c.78C > T) were identified. After data analysis, c.-36C > T and c.-131C > T in the 5'-untranslated region were both found in the POI group and the control group. No difference was found in the genotype distribution or allelic frequency of either variant between the POI group and the control group ( > 0.05). The synonymous variant (c.78C > T) in exon 1 was discovered in only one of the control subjects and did not result in a change in amino acid sequence (p.Gly26Gly). CONCLUSION:MCL-1 gene mutation may not be associated with idiopathic POI in Chinese women.
Effects of chronic unpredictable mild stress on ovarian reserve in female rats: Feasibility analysis of a rat model of premature ovarian failure.
Fu Xiao-Yan,Chen Hao-Hao,Zhang Ning,Ding Ming-Xing,Qiu Ying-Er,Pan Xiao-Ming,Fang Yuan-Shu,Lin Yi-Ping,Zheng Qun,Wang Wen-Qian
Molecular medicine reports
Premature ovarian failure (POF) results from a number of disorders. The POF model is primarily based on chemotherapeutic injury, and hence is not suitable for assessing the effects of chronic stress on ovarian function. Therefore, improved animal models are required to analyze the effects of chronic stress on ovarian reserve. The feasibility of the chronic unpredictable mild stress (CUMS) method for establishing a model of POF was examined. The depressive behavior exhibited by rats was evaluated with the open field and sucrose preference tests. Vaginal smears were obtained for assessment of the estrous cycle. The ovarian reserve of the animals was evaluated using the estrous cycle, ovarian histology and serum levels of gonadotropin releasing hormone (GnRH), follicle‑stimulating hormone (FSH), estradiol (E2), and anti‑Müllerian hormone (AMH). Compared with the control group, body weight, time spent in the center, horizontal movement, vertical frequency, consumption of sucrose, sucrose preference, number of small follicles from the rats, and serum E2, AMH and GnRH levels were significantly decreased in the CUMS group (all P<0.05). However, the estrous cycle was prolonged significantly (P<0.05) and serum FSH levels were increased significantly (P<0.01). These results suggested that the CUMS model rats exhibited depression‑like behaviors. CUMS may induce psychological stress and decrease ovarian reserve in female rats. Thus, the CUMS model may be used to assess the effects of chronic stress on female reproductive function.
Ovarian toxicity: from environmental exposure to chemotherapy.
Iorio Roberto,Castellucci Annalisa,Ventriglia Giovanni,Teoli Flavia,Cellini Valerio,Macchiarelli Guido,Cecconi Sandra
Current pharmaceutical design
Unlike men, who have continuous spermatogenesis throughout most of their lifetime, women are born with a fixed supply of follicles, and this number progressively declines with age until the menopause. Beside age, the speed of follicle depletion can be regulated by genetic, hormonal and environmental influences. In the course of their lives, women are exposed to multiple chemicals and radiation sources that can increase the chance of developing permanent infertility and premature ovarian failure (POF). A wealth of experimental data indicate that iatrogenic (chemotherapy, radiotherapy) and xenobiotic agents (e.g., chemicals, pharmaceuticals) are potent ovotoxicants capable of accelerating ovarian reserve depletion. In the present review we reported the negative effects exerted on mammalian ovary by some widely diffused environmental chemicals, as polycyclic aromatic hydrocarbons (PAHs) and dithiocarbamate mancozeb, and by 1-3 butadiene and 4-vinylcycloexene, two occupational chemicals known to be capable of inducing ovarian cancer and infertility. Furthermore, attention has been devoted to the consequences of chemo- and radiotherapy on the ovary, both known to affect reproductive lifespan. Our increasing understanding of metabolic alterations induced by these agents is fundamental to individuate new therapeutic strategies aimed to prevent ovarian dysfunction in fertile women.
The role of antimullerian hormone in assessing ovarian damage from chemotherapy, radiotherapy and surgery.
Wong Queenie Ho Yan,Anderson Richard A
Current opinion in endocrinology, diabetes, and obesity
PURPOSE OF REVIEW:Iatrogenic ovarian damage can occur after chemotherapy, radiotherapy and surgery for cancer as well as for non-malignant conditions. This review describes the effects of such treatment on antimullerian hormone (AMH) and the implications of the fall in AMH in relation to ovarian function and fertility, especially in the era of improved fertility preservation strategies. RECENT FINDINGS:The risk of gonadotoxicity differs between chemotherapy regimens. There is growing evidence that pretreatment AMH has prognostic significance for the degree of fall in AMH after treatment, the reversibility of ovarian damage and risk of premature ovarian insufficiency. The accuracy of prediction increases when age is coupled with AMH. The adverse effect of removal of endometriomas is increasingly clear, and AMH pre and post surgery useful is assessing the degree of damage to the ovary. The implications of low AMH after such treatment on natural fertility and reproductive lifespan are less clear. Apart from treatment effects, there are other coexisting conditions that can affect AMH which needs to be taken into consideration during interpretation of AMH before and after treatment. SUMMARY:A fall in AMH in women after gonadotoxic treatment has been consistently described, with variable recovery, the accurate interpretation and clinical application of post-treatment AMH level on reproductive lifespan and fertility prediction needs to be studied in future larger prospective studies with longer follow-up.
Genetics of primary ovarian insufficiency: a review.
Fortuño Cristina,Labarta Elena
Journal of assisted reproduction and genetics
Primary ovarian insufficiency is one of the main causes of female infertility owing to an abnormal ovarian reserve. Its relevance has increased in more recent years due to the fact that age of motherhood is being delayed in developed countries, with the risk of having either primary ovarian insufficiency or less chances of pregnancy when women consider the option of having their first baby. Several exogenous factors can lead to this event, such us viral infections, metabolomic dysfunction, autoimmune diseases, and environmental or iatrogenic factors, although in most cases the mechanism that leads to the disorder is unknown. Genetic factors represent the most commonly identified cause and the impact of sex chromosome abnormalities (e.g., Turner syndrome or X structural abnormalities), autosomal and X-linked mutations on the genesis of primary ovarian insufficiency has also been well described. Yet in most cases, the genetic origin remains unknown and there are multiple candidate genes. This review aims to collect all the genetic abnormalities and genes associated with syndromic and non syndromic primary ovarian insufficiency that have been published in the literature to date using the candidate-gene approach and a genome-wide analysis.
Primary ovarian insufficiency in an adolescent population: clinical phenotype and diagnostic approach.
Hoyos-Martinez Alfonso,Hoyos Luis R,Comkornruecha Metee,Diaz Alejandro
Journal of pediatric endocrinology & metabolism : JPEM
Background Primary ovarian insufficiency (POI) can be seen in adolescents secondary to genetic or autoimmune conditions, or gonadotoxic therapies. Often times, its underlying cause is not identified. It is a rare condition in pediatrics, but a thorough evaluation is required for a timely diagnosis and optimizing outcomes. Objectives We aim to describe the clinical phenotype of idiopathic POI in an adolescent population seen in a referral center, and evaluate its diagnostic approach. Methods All patients evaluated between 2012 and 2018 were identified using the diagnostic codes for POI. Medical records were manually reviewed and clinical information was extracted. Cases were excluded from the final sample if they were found to have incomplete diagnostic information, Turner syndrome, eating disorders, gonadal surgeries and/or a history of oncological conditions or treatments. Results Forty-eight patients with POI were identified, and only seven met the established criteria. Anti-ovarian and anti-thyroid antibodies were evaluated in 100% and 86%, respectively, while only 29% were tested for anti-adrenal autoimmunity. The karyotype was obtained consistently, while the fragile X mental retardation 1 (FMR1) gene expansion was only assessed in approximately a third of the patients. Finally, only 29% of patients received reproductive counseling or referral to a fertility specialist. Conclusions Diagnostic evaluation for POI appears to be challenging to pediatric providers. Anti-ovarian antibodies are frequently obtained despite the lack of their clinical significance in POI, while anti-adrenal antibodies, which are the preferred diagnostic test, are not commonly obtained. Reproductive orientation or referral is seldom provided to the adolescent population.
Autoimmune primary ovarian insufficiency.
Silva C A,Yamakami L Y S,Aikawa N E,Araujo D B,Carvalho J F,Bonfá E
Primary ovarian insufficiency (POI) is defined as sustained amenorrhea, increased follicle-stimulating hormone and low estrogen levels, whereas diminished ovarian reserve (DOR) is characterized as regular menses and alterations of ovarian reserve tests. POI of autoimmune origin may be associated with adrenal autoimmunity, non-adrenal autoimmunity or isolated. This autoimmune disease is characterized by serum ovarian, adrenocortical or steroidogenic cell autoantibodies. POI of adrenal autoimmune origin is the most frequent type observed in 60-80% of patients. Clinically, amenorrhea is the hallmark of POI, however before menstruation stops completely, irregular cycles occur. Infertility, hot flushes, vaginal atrophy, and dyspareunia are also common. Autoimmune oophoritis is characterized by mononuclear inflammatory cell infiltrate in the theca cells of growing follicles, with early stage follicles without lymphocytic infiltration. This infiltrate includes plasma, B and T-cells. A novel classification criterion for autoimmune POI/DOR is proposed subdividing in three distinct categories (possible, probable and confirmed) according to autoantibodies, autoimmune disease and ovarian histology. Unfortunately, up to date guidelines for the treatment of autoimmune oophoritis are not available. Strategies to POI treatment include hormone replacement and infertility therapy. Assisted conception with donated oocytes has been proven to achieve pregnancy by intra cytoplasmic sperm injection in POI women.
Air pollution and human fertility rates.
Nieuwenhuijsen Mark J,Basagaña Xavier,Dadvand Payam,Martinez David,Cirach Marta,Beelen Rob,Jacquemin Bénédicte
BACKGROUND:Some reports have suggested effects of air pollution on semen quality and success rates of in vitro fertilization (IVF) in humans and lower fertility rates in mice. However, no studies have evaluated the impact of air pollution on human fertility rates. AIMS:We assessed the association between traffic related air pollution and fertility rates in humans in Barcelona, Spain (2011-2012). We hypothesized that higher air pollution levels would be associated with lower fertility rates. METHODS:We calculated the general fertility rate which is the number of live births per 1000 women between the ages of 15 and 44 years per census tract. We used land use regression (LUR) modeling to estimate the air pollution concentrations (particulate matter, NO2/NOx) per census tract. We used Besag-York-Mollié models to quantify the relationship between air pollution and fertility rates with adjustment for a number of potential confounders such as maternal age and area level socio-economic status. RESULTS:We found a statistically significant reduction of fertility rates with an increase in traffic related air pollution levels, particularly for the coarse fraction of particulate matter (IRR=0.87 95% CI 0.82, 0.94 per IQR). CONCLUSION:This is the first study in humans to show an association between reduced fertility rates and higher traffic related air pollution levels.
Dehydroepiandrosterone supplementation improves ovarian reserve and pregnancy rates in poor responders.
Ozcil M D
European review for medical and pharmacological sciences
OBJECTIVE:We investigated whether DHEA supplementation had an impact on ovarian reserve parameters and pregnancy rates in patients with poor ovarian response (POR) and primary ovarian insufficiency (POI). PATIENTS AND METHODS:A total of 34 people, 6 patients with POI and 28 patients with POR, were included in the study. The patients in the POR group consisted of two different groups: diminished ovarian reserve (DOR) and premature ovarian failure (PMOF). Patients in the POI and POR group were given 50 mg DHEA supplementation daily for 5 months. The primary outcome was to determine spontaneous clinical pregnancy rates. The monthly changes in the serum hormone levels and AFC were recorded for five months. AMH levels were also measured before and after treatment. RESULTS:The total follow-up time was 152 cycles. The number of pregnancies during the follow-up period was 9. The ratio of pregnancies to the number of patients was 26.5% and the rate per cycle was 5.9%. While 8 of 9 pregnancies resulted in a live birth, one resulted in a miscarriage. The rate of abortion was 11.1%. The mean AFC was 0 to 5 before treatment. Following DHEA administration, a significant increase was detected in 30.8% of the patients. There was an increase in AMH levels after DHEA, but this was not significant. The live birth rate and pregnancy rate per cycle were significantly higher in POR patients than those in POF. Patients with POF had no pregnancy. Although the PMOF patients were younger than the DOR patients, the rate of pregnancy (36% vs. 29%), and pregnancy rates per cycle (8.5% vs. 6.35%) were higher in the DOR group. The rates of live birth were the same in the PMOF and DOR groups (29% vs. 29%). CONCLUSIONS:Oral DHEA supplementation improves both ovarian reserve and pregnancy rates in women with POR.
TMEM150B is dispensable for oocyte maturation and female fertility in mouse.
Liu Ran,Ke Hanni,Shao Tong,Qin Yingying,Zhao Shidou
Premature ovarian insufficiency (POI) refers to severe decline of ovary function in females which usually leads to infertility. It has been reported that the TMEM150B gene is mostly associated with age at natural menopause, early menopause and POI, but its role in female reproduction remains unknown. In this study, we found Tmem150b was highly expressed in mouse oocytes, but its deletion had no obvious effect on meiotic maturation of oocytes indicated by first polar body emission and spindle morphology. There were also no obvious differences in follicle development and corpus luteum formation between knockout and wild type mice. Finally, knockout of Tmem150b did not affect female fertility and sexual hormone levels. In summary, our results suggest that TMEM150B is not essential for female fertility in mice.
Senataxin: A New Guardian of the Female Germline Important for Delaying Ovarian Aging.
Homer Hayden A
Frontiers in genetics
Early decline in ovarian function known as premature ovarian aging (POA) occurs in around 10% of women and is characterized by a markedly reduced ovarian reserve. Premature ovarian insufficiency (POI) affects ~1% of women and refers to the severe end of the POA spectrum in which, accelerated ovarian aging leads to menopause before 40 years of age. Ovarian reserve refers to the total number of follicle-enclosed oocytes within both ovaries. Oocyte DNA integrity is a critical determinant of ovarian reserve since damage to DNA of oocytes within primordial-stage follicles triggers follicular apoptosis leading to accelerated follicle depletion. Despite the high prevalence of POA, very little is known regarding its genetic causation. Another little-investigated aspect of oocyte DNA damage involves low-grade damage that escapes apoptosis at the primordial follicle stage and persists throughout oocyte growth and later follicle development. Senataxin (SETX) is an RNA/DNA helicase involved in repair of oxidative stress-induced DNA damage and is well-known for its roles in preventing neurodegenerative disease. Recent findings uncover an important role for SETX in protecting oocyte DNA integrity against aging-induced increases in oxidative stress. Significantly, this newly identified SETX-mediated regulation of oocyte DNA integrity is critical for preventing POA and early-onset female infertility by preventing premature depletion of the ovarian follicular pool and reducing the burden of low-grade DNA damage both in primordial and fully-grown oocytes.
Mechanisms of ovarian aging.
Park Selena U,Walsh Leann,Berkowitz Karen M
Reproduction (Cambridge, England)
Ovarian aging in women correlates with the progressive loss of both the number and quality of oocytes. When these processes occur early or are accelerated, their clinical correlates are diminished ovarian reserve and/or premature ovarian insufficiency. Both these conditions have important consequences for the reproductive and general health of women, including infertility. Although there are many contributing factors, the molecular mechanisms underlying many of the processes associated with ovarian aging have not been fully elucidated. In this review, we highlight some of the most critical factors that impact oocyte quantity and quality with advancing age. We discuss chromosomal factors including cohesion deterioration and mis-segregation, errors in meiotic recombination, and decreased stringency of the spindle assembly checkpoint. DNA damage, telomere changes, reactive oxygen species and mitochondrial dysfunction as they relate to ovarian aging, and well-known gene mutations associated with primary ovarian insufficiency and diminished ovarian reserve are also discussed. Additionally, studies investigating recently acknowledged cytoplasmic factors associated with ovarian aging including protein metabolic dysregulation and microenvironmental alterations in the ovary are presented. We use both mouse and human studies to support the roles these factors play in physiologic and expedited ovarian aging, and we propose directions for future studies. A better understanding of the molecular basis of ovarian aging will ultimately lead to diagnostic and therapeutic advancements that would provide women with information to make earlier choices about their reproductive health.
Early menopause: A hazard to a woman's health.
Hernández-Angeles Claudio,Castelo-Branco Camil
The Indian journal of medical research
Early menopause or premature ovarian insufficiency (POI) is a common cause of infertility in women and affects about one per cent of young women. This disorder has significant psychological sequelae and major health implications. Its relevance has increased in recent years due to the fact that age of motherhood is being delayed in developed countries, with the risk of having either primary ovarian insufficiency or less possibilities of pregnancy. The main characteristics are absence of ovulation, amenorrhoea and high levels of serum gonadotropins (hypergonadotropic hypogonadism). Although the aetiology remains uncertain in most cases, several rare specific causes have been elucidated. Potential causes for POI are iatrogenic (ovarian surgery, radiotherapy or chemotherapy), environmental factors, viral infections, metabolic and autoimmune diseases, and genetic alterations. Because of the association with other autoimmune diseases, close follow up is recommended in patients with POI. The traditional indicators to evaluate ovarian ageing are age, serum hormonal levels, anti-Mullerian hormone, antral follicle count, and ultrasonography of ovaries. Hormone replacement therapy remains the mainstay of treatment, and the best chance of achieving a pregnancy is through oocyte donation. This article aims to present an overview of potential causes, clinical manifestations, and treatment options of POI.
Effect of primary ovarian insufficiency and early natural menopause on mortality: a meta-analysis.
Tao X-Y,Zuo A-Z,Wang J-Q,Tao F-B
Climacteric : the journal of the International Menopause Society
OBJECTIVE:The aim of this review was to systematically evaluate the associations of all-cause, cardiovascular and all-cancer mortality with primary ovarian insufficiency (POI) and early natural menopause (ENM). METHODS:Electronic databases for relevant studies were searched up to February 28, 2015. POI and ENM were usually defined as spontaneous menopause before age 40 years and at age 40-44 years, respectively. RESULTS:A total of nine articles were derived from seven prospective cohort studies. In all studies, age of menopause was self-reported. Our meta-analysis showed that POI women had a higher risk of death from all causes (pooled relative risk (RR) 1.39, 95% confidence interval (CI) 1.10-1.77) and ischemic heart disease (IHD) (pooled RR 1.48, 95% CI 1.02-2.16) when compared with women at normal age at natural menopause (ANM). No significant association was detected from stroke and all-cancer mortality between POI women and normal ANM women. Only a slightly higher risk of death from IHD (pooled RR 1.09, 95% CI 1.00-1.18) was found when ENM women were compared with normal ANM women. CONCLUSION:The results of our study demonstrated that POI was associated with a higher risk of IHD and all-cause mortality; ENM was only associated with a slightly higher risk of IHD mortality.
Premenopausal factors influencing premature ovarian failure and early menopause.
Chang Soung Hoon,Kim Chung-Sik,Lee Kun-Sei,Kim Hyeongsu,Yim Sung Vin,Lim Yun Jeong,Park Sue Kyung
OBJECTIVES:We conducted this study to examine premenopausal risk factors associated with premature ovarian failure (POF) and early menopause (EM) among Korean women. METHODS:A 73% of total women aged 30-69 at four districts in the KMCC (Korean Multi-center Cancer Cohort) was participated in this study during 2002-2003. We selected 137 POF and 281 EM cases who had menopause before age 40 and at age 40-44, respectively, and 1318 normal menopause (NM) controls that experienced menopause at age 45-60, and among them, selected idiopathic POF (n=84) and EM (n=261) after excluding surgical/medical menopause. We collected the information of premenopausal lifestyle and reproductive risk factors. Multivariate and polytomous logistic regression were used to estimate POF and EM risk and to differentiate POF and EM risk using ordinal and nominal scale. RESULTS:Cigarette smoking was associated with an increased risk of idiopathic POF (OR=1.82 [1.03-3.23]), whereas oral contraceptive use was associated with a reduced risk of natural EM (OR=0.62 [0.43-0.90]). Idiopathic POF risk by both factors differed from idiopathic EM risk (p-nominal<0.05). Factors related to ovulation, such as later menarche, irregular menstruation and longer breast feeding cumulatively reduced the risk of natural EM and POF (p-ordinal<0.05). In analysis including medical and surgical menopause, lung tuberculosis, hysterectomy, past cancers, and lower number of deliveries before menopause were associated with POF. CONCLUSIONS:Our findings indicate that etiology in POF development may partly differ from that in EM.
Vaginal epithelium and microflora characteristics in women with premature ovarian failure under hormone therapy compared to healthy women.
Benetti-Pinto Cristina Laguna,Giraldo Paulo Cesar,Pacello Poliana Cordeiro Cesar,Soares Patricia Magda,Yela Daniela Angerame
Archives of gynecology and obstetrics
PURPOSE:To evaluate some microbiological aspects of the vaginal flora and the vaginal trophism of women with premature ovarian failure (POF) in use of oral hormone therapy. METHODS:A cross-sectional study with 36 women with POF under the age of 40 years using oral hormonal therapy. They were age matched with 36 women with normal gonadal function (control group). The characteristics of the vaginal epithelium were assessed through the hormonal vaginal cytology, vaginal pH measurement and vaginal health index to identify vaginal disturbances. Vaginal microflora was evaluated by the amine test, bacterioscopy (Nugent score) and culture for fungi to identify vaginal abnormal microflora and fungi infections. RESULTS:Despite the fact that there were no statistical significant differences related to the cytological aspects and pH measurements, it was found that the vaginal health index was highly superior in the control group than in the POF group (23.4 ± 1.8 vs 20.8 ± 3.5), p < 0.0001 despite both groups had trophic scores. There were no statistical significance differences regarding to vaginal microflora types and fungi infection. CONCLUSION:Oral hormone therapy for young women with POF seems to be good enough to reestablish the epithelium cells, vaginal pH and microflora.
Premature ovarian failure in patients affected by systemic lupus erythematosus: a cross-sectional study.
Ceccarelli Fulvia,Orefice Valeria,Perrone Giuseppina,Pirone Carmelo,Perricone Carlo,Truglia Simona,Miranda Francesca,Pacucci Viviana Antonella,Spinelli Francesca Romana,Galoppi Paola,Alessandri Cristiano,Valesini Guido,Conti Fabrizio
Clinical and experimental rheumatology
OBJECTIVES:We evaluated age at natural menopause and the prevalence of premature ovarian failure (POF) in a monocentric Caucasian cohort of patients with systemic lupus erythematosus (SLE). METHODS:In this cross-sectional study, we enrolled women affected by SLE compared with healthy controls (HC) to investigate data about natural menopause (amenorrhoea for at least 12 months at ≥40 years) and POF (amenorrhoea for at least 12 months at <40 years). RESULTS:We enrolled 196 SLE (median age 47.0 years, IQR 16.7; median disease duration 132 months, IQR 180) and 90 HC (median age 49.9 years, IQR 15.0). Ninety-four SLE (48.0%) and 26 HC (23.4%) were menopausal: median age at onset was significantly lower in SLE than HC (47 years, IQR 8.0 vs. 50.5 years, IQR 4; p=0.0001). POF was registered in 17% of the SLE, and in none of the HC (p<0.0001). POF was significantly associated with anti-Sm (p=0.0004), anti-RNP (p=0.02), anti-cardiolipin (p=0.0008), lupus anticoagulant (p=0.0002), treatment with cyclophosphamide (p=0.0001), azathioprine (p=0.0001), mycophenolate mofetil (p=0.0001), cyclosporine A (p=0.007). CONCLUSIONS:SLE patients develop menopause at a younger age; moreover, a higher POF frequency was observed in SLE patients in comparison with HC. POF is associated with specific SLE-related autoantibodies and the use of immunosuppressant drugs, in particular cyclophosphamide.
Beyond Premature Ovarian Insufficiency: Staging Reproductive Aging in Adolescent and Young Adult Cancer Survivors.
Medica Alexa C O,Whitcomb Brian W,Shliakhsitsava Ksenya,Dietz Andrew C,Pinson Kelsey,Lam Christina,Romero Sally A D,Sluss Patrick,Sammel Mary D,Su H Irene
The Journal of clinical endocrinology and metabolism
CONTEXT:Although stages of reproductive aging for women in the general population are well described by STRAW+10 criteria, this is largely unknown for female adolescent and young adult cancer survivors (AYA survivors). OBJECTIVE:This work aimed to evaluate applying STRAW + 10 criteria in AYA survivors using bleeding patterns with and without endocrine biomarkers, and to assess how cancer treatment gonadotoxicity is related to reproductive aging stage. DESIGN:The sample (n = 338) included AYA survivors from the Reproductive Window Study cohort. Menstrual bleeding data and dried-blood spots for antimüllerian hormone (AMH) and follicle-stimulating hormone (FSH) measurements (Ansh DBS enzyme-linked immunosorbent assays) were used for reproductive aging stage assessment. Cancer treatment data were abstracted from medical records. RESULTS:Among participants, mean age 34.0 ± 4.5 years and at a mean of 6.9 ± 4.6 years since cancer treatment, the most common cancers were lymphomas (31%), breast (23%), and thyroid (17%). Twenty-nine percent were unclassifiable by STRAW + 10 criteria, occurring more frequently in the first 2 years from treatment. Most unclassifiable survivors exhibited bleeding patterns consistent with the menopausal transition, but had reproductive phase AMH and/or FSH levels. For classifiable survivors (48% peak reproductive, 30% late reproductive, 12% early transition, 3% late transition, and 7% postmenopause), endocrine biomarkers distinguished among peak, early, and late stages within the reproductive and transition phases. Gonadotoxic treatments were associated with more advanced stages. CONCLUSIONS:We demonstrate a novel association between gonadotoxic treatments and advanced stages of reproductive aging. Without endocrine biomarkers, bleeding pattern alone can misclassify AYA survivors into more or less advanced stages. Moreover, a large proportion of AYA survivors exhibited combinations of endocrine biomarkers and bleeding patterns that do not fit the STRAW + 10 criteria, suggesting the need for modified staging for this population.
Premature ovarian insufficiency - aetiopathology, epidemiology, and diagnostic evaluation.
Rudnicka Ewa,Kruszewska Jagoda,Klicka Klaudia,Kowalczyk Joanna,Grymowicz Monika,Skórska Jolanta,Pięta Wojciech,Smolarczyk Roman
Przeglad menopauzalny = Menopause review
Premature ovarian insufficiency (POI) is defined as a cessation of ovarian function before the age of 40 years. It is associated with hypoestrogenism and loss of residual follicles, both of which lead to menstrual abnormalities, pregnancy failures, and decreased health-related quality of life. The prevalence of POI is estimated at 1% in the general population. Current European Society of Human Reproduction and Embryology (ESHRE) diagnostic criteria include: amenorrhoea or oligomenorrhoea for at least four months and increased follicle-stimulating hormone (FSH) levels > 25 IU/l measured twice (with a four-week interval). The aetiopathogenesis of the disease in most cases remains unexplained. Nevertheless, in some patients with POI, genetic abnormalities, metabolic disorders, autoimmunity, iatrogenic procedures, infections, or environmental factors have been established as underlying causes of the syndrome.
Health-related quality-of-life among patients with premature ovarian insufficiency: a systematic review and meta-analysis.
Li X T,Li P Y,Liu Y,Yang H S,He L Y,Fang Y G,Liu J,Liu B Y,Chaplin J E
Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation
PURPOSE:To systematically review studies investigating health-related quality-of-life (HrQoL) in patients with premature ovarian insufficiency (POI), to examine questionnaires used and to conduct a meta-analysis of control studies with normal ovarian function. METHODS:Data sources: PubMed, Embase, Web of science, CNKI, and CQVIP, searched from inception until June 2018. The search strategy was a combination of medical (e.g. POI), subjective (e.g. well-being) and methodological (e.g. questionnaires) keywords. PRISMA guidelines were used to assess outcome data quality/validity by one reviewer, verified by a second reviewer. Risk of bias within studies was evaluated. A meta-analysis compared HrQoL in patients and non-patients. Due to measurement differences in the studies, the effect size was calculated as standard mean difference. RESULTS:We identified 6869 HrQoL studies. Nineteen geographically diverse studies met inclusion criteria, dated from 2006, using 23 questionnaires. The meta-analysis included six studies with 645 POI participants (age 33.3 ± 5.47) and 492 normal-ovarian control subjects (age 32.87 ± 5.61). Medium effect sizes were found for lower overall HrQoL (pooled SMD = - 0.73, 95% CI - 0.94, - 0.51; I = 54%) and physical function (pooled SMD = - 0.54, 95% CI - 0.69, - 0.39; I = 55%). Heterogeneity was investigated. Effect sizes varied for sexual function depending on the measure (SMD = - 0.27 to - 0.74), overall HrQoL (SF-36) had the largest effect size (- 0.93) in one study. The effect sizes for psychological and social HrQoL were small. CONCLUSION:POI is associated with low-to-medium effect size on HrQoL compared to normal ovarian controls. The greatest effects are found in general HrQoL and most sexual function areas. Condition-specific questionnaires and RCTs are recommended for further investigation.
Thyroid autoimmunity is associated with higher risk of premature ovarian insufficiency-a nationwide Health Insurance Research Database study.
Hsieh Yi-Ting,Ho Jason Y P
Human reproduction (Oxford, England)
STUDY QUESTION:Is thyroid autoimmunity associated with a higher risk of low ovarian reserve and POI? SUMMARY ANSWER:Thyroid autoimmunity significantly increases the risk of POI in women. WHAT IS KNOWN ALREADY:POI is closely related with autoimmune disease, and according to some studies, thyroid autoimmunity (TAI) may account for diminished ovarian reserve. However, no large-scale cohort study has demonstrated the association between TAI and POI. STUDY DESIGN, SIZE, DURATION:A longitudinal population-based retrospective cohort study on the National Health Insurance Research Database (NHIRD) was designed. Since 1 March 1995, the National Health Insurance (NHI) programme in Taiwan has included 99.9% of the 23 million population of Taiwan. Patients between 1 January 2000 and 31 December 2012 were eligible for recruitment, and 21 325 subjects were analysed in our study. PARTICIPANTS/MATERIALS, SETTING, METHODS:Two cohorts, Hashimoto's and Grave's disease, were composed of patients with autoimmune thyroid disease between 20 and 40 years of age. The comparison cohorts consisted of patients in the NHIRD without autoimmune thyroid disease matched by age at a ratio of 1:4 in subject numbers. MAIN RESULTS AND THE ROLE OF CHANCE:The Hashimoto's disease (HD) cohort, Grave's disease (GD) cohort and two comparison cohorts were followed up until a diagnosis of amenorrhoea, menopausal syndrome, other ovarian failure or infertility due to ovarian failure had been made. Compared statistically with the non-HD cohort, patients with HD exhibited an 89% higher risk of amenorrhoea (95% CI =1.36-2.61). The HD patients exhibited a 2.40-fold higher risk of infertility due to ovarian failure than the non-HD subjects (hazard ratio (HR)=2.40, 95% confidence interval (CI)=1.02-5.68). In comparison with the non-GD cohort, patients with GD exhibited a 68% higher risk of amenorrhoea (95% CI = 1.43-1.98) after adjustment. According to the Kaplan-Meier analysis, the cumulative incidence of amenorrhoea and menopausal syndrome was significantly higher in the TAI groups than in the control groups. LIMITATIONS, REASONS FOR CAUTION:This is a retrospective study using ICD-9 disease code analysis to determine the statistical association between two diseases. WIDER IMPLICATIONS OF THE FINDINGS:Given that autoimmune thyroid disease is highly associated with early diminished ovarian reserve or even premature ovarian failure or POI, the options for infertility treatment may be re-directed to more efficient methods in infertile patients diagnosed with the disease. If the ovarian reserve is normal at the time of diagnosis of thyroid autoimmune disease, close follow-up of ovarian reserve may be highly recommended. STUDY FUNDING/COMPETING INTEREST(S):This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center, Grant Number: MOHW109-TDU-B-212-114004. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER:N/A.
Cardiovascular disease risk in women with premature ovarian insufficiency: A systematic review and meta-analysis.
Roeters van Lennep Jeanine E,Heida Karst Y,Bots Michiel L,Hoek Annemieke,
European journal of preventive cardiology
AIMS:The purpose of this review was to assess the relationship between premature ovarian insufficiency (POI), defined as natural menopause <40 years, and risk of ischaemic heart disease (IHD), stroke and overall cardiovascular disease (CVD). METHODS AND RESULTS:We performed a systematic search in PubMed (1966-2012), EMBASE (1980-2012). Studies were included if they were prospective, follow-up>3 years, assessment of age menopause <40 years, and incident cases of fatal or nonfatal IHD, stroke, or overall CVD. Relative risks (RRs) and 95% confidence interval (CI) were pooled using a random-effect model. Overall, 10 observational studies were identified, comprising 190,588 women (follow-up 4-37 years) with 9440 events (2026 events for IHD (seven studies) and 6438 events for stroke (seven studies) and 976 for total CVD (two studies). POI was assessed by questionnaire and incident cases through certification and event registers. POI was related to an increased risk of developing or dying from IHD (hazard ratio (HR) 1.69, 95% CI 1.29-2.21, p = 0.0001) and total CVD (HR 1.61, 95% CI 1.22-2.12, p = 0.0007). No relation was found for stroke (HR 1.03, 0.88-1.19, p = 0.74). We found no evidence for heterogeneity. CONCLUSION:POI is an independent though modest risk factor of IHD and overall CVD but not of stroke. Because of the limited impact of POI on CVD risk compared to classical cardiovascular risk factors, it is unlikely that POI will be implemented as modifier of cardiovascular risk classification.
Spanish consensus on premature menopause.
Mendoza Nicolás,Juliá Ma Dolores,Galliano Daniela,Coronado Pluvio,Díaz Begoña,Fontes Juan,Gallo José Luis,García Ana,Guinot Misericordia,Munnamy Merixtell,Roca Beatriz,Sosa Manuel,Tomás Jordi,Llaneza Plácido,Sánchez-Borrego Rafael
INTRODUCTION:While we recognise that the term premature menopause is more accepted by most non-specialist health care providers and by the general population, 'primary ovarian insufficiency' (POI) is currently considered the most apposite term to explain the loss of ovarian function, because it better explains the variability of the clinical picture, does not specify definitive failure, and highlights the specific ovarian source. Its pathogenesis involves a congenital reduction in the number of primordial follicles, poor follicle recruitment, or accelerated follicular apoptosis. However, its cause is unknown in most cases. AIM:This guide analyses the factors associated with the diagnosis and treatment of POI and provides recommendations on the most appropriate diagnostic and therapeutic measures for women under 40 years of age who experience POI. METHODOLOGY:A panel of experts from various Spanish scientific societies related to POI (Spanish Menopause Society, Spanish Fertility Society, and Spanish Contraception Society) met to reach a consensus on these issues. RESULTS:Hormonal therapy (HT) is considered the treatment of choice to alleviate the symptoms of hypoestrogenism and to prevent long-term consequences. We suggest that HT should be continued until at least age 51, the average age at natural menopause. The best treatment to achieve pregnancy is oocyte/embryo donation. If a patient is to undergo treatment that will reduce her fertility, she should be informed of this issue and the available techniques to preserve ovarian function, mainly vitrification of oocytes.
Aggregation of autoimmunity in extended families of people with autoimmune Addison's disease.
Fichna Marta,Małecki Piotr P,Gębarski Bolesław,Gębarska Helena,Ruchała Marek
Internal medicine journal
BACKGROUND:Autoimmunity accounts for 90% of cases of primary adrenal insufficiency (Addison's disease, AD). Affected persons present a significant co-occurrence of autoimmune conditions, hence, clustering of autoimmunity is also predicted among their relatives. AIMS:The aim of our study was to evaluate the burden of autoimmunity in families of people with AD. METHODS:116 individuals with AD were surveyed about the occurrence of 23 autoimmune diseases among their relatives. RESULTS:74.1% of persons with AD reported at least one relative with an autoimmune disorder - 257 cases were diagnosed in 221 relatives. Hashimoto's thyroiditis was found in 100 individuals, followed by Graves' disease and vitiligo - in 25 and 24 relatives, respectively. Type 1 diabetes was diagnosed in 23 relatives, psoriasis in 15, rheumatoid arthritis in 12, pernicious anaemia in 11, multiple sclerosis in 8, while premature menopause in 8 women. AD was found in 7 relatives, alopecia in 6, and celiac disease in 5. Other conditions were rare. Significant correlation was noticed between the number of autoimmune conditions in AD proband and the number of affected relatives (p = 0.031). 66.4% of people with AD had a first-degree relative suffering from autoimmunity. Autoimmune conditions were more frequent among females: sisters (p < 0.001), mothers (p = 0.002) and grandmothers (p = 0.002). CONCLUSIONS:Considerable prevalence of autoimmune conditions in relatives of persons with AD confirms substantial risk of autoimmunity, especially in females and relatives of patients affected by multiplex autoimmunity. Our data corroborate the recommendation of active screening for autoimmune disorders, particularly thyroid disease, among AD family members. This article is protected by copyright. All rights reserved.
New insights into the diagnosis and management of bone health in premature ovarian insufficiency.
Nguyen H H,Milat F,Vincent A J
Climacteric : the journal of the International Menopause Society
Premature ovarian insufficiency (POI), defined as a loss of ovarian function before the age of 40 years, is a life-changing diagnosis that has numerous long-term consequences. Musculoskeletal complications, including osteoporosis and fractures, are a key concern for women with POI. The risk of bone loss is influenced by the underlying etiology of POI, and the degree and duration of estrogen deficiency. A decline in muscle mass as a result of estrogen and androgen deficiency may contribute to skeletal fragility, but has not been examined in women with POI. This article aims to review musculoskeletal health in POI; summarize the traditional and novel modalities available to screen for skeletal fragility and muscle dysfunction; and provide updated evidence for available management strategies.
Age-independent anti-Müllerian hormone (AMH) standard deviation scores to estimate ovarian function.
Helden Josef van,Weiskirchen Ralf
European journal of obstetrics, gynecology, and reproductive biology
OBJECTIVIES:To determine single year age-specific anti-Müllerian hormone (AMH) standard deviation scores (SDS) for women associated to normal ovarian function and different ovarian disorders resulting in sub- or infertility. DESIGN AND METHODS:Determination of particular year median and mean AMH values with standard deviations (SD), calculation of age-independent cut off SDS for the discrimination between normal ovarian function and ovarian disorders. RESULTS:Single-year-specific median, mean, and SD values have been evaluated for the Beckman Access AMH immunoassay. While the decrease of both median and mean AMH values is strongly correlated with increasing age, calculated SDS values have been shown to be age independent with the differentiation between normal ovarian function measured as occurred ovulation with sufficient luteal activity compared with hyperandrogenemic cycle disorders or anovulation associated with high AMH values and reduced ovarian activity or insufficiency associated with low AMH, respectively. CONCLUSION:These results will be helpful for the treatment of patients and the ventilation of the different reproductive options.
Long-term outcome of ovarian function in women with intermittent premature ovarian insufficiency.
Bachelot Anne,Nicolas Carole,Bidet Maud,Dulon Jérôme,Leban Monique,Golmard Jean Louis,Polak Michel,Touraine Philippe
CONTEXT:Spontaneous resumption of ovarian function is not a rare phenomenon in patients with premature ovarian insufficiency (POI). The outcome of this resumption is not known. OBJECTIVE:To describe the outcome following the resumption of ovarian function in POI patients. DESIGN:Cross-sectional study. SETTING:University medical centre. PATIENTS AND MAIN OUTCOME MEASURES:Cumulative incidence of ovarian function resumption and risk factors arresting this resumption during follow-up were determined in a large cohort of POI women. RESULTS:Five hundred and seven patients were included in the study, with a follow-up of 3·44 ± 4·05 years (0-29). Of these, 117 (23%) had features of ovarian function resumption. The cumulative incidence of pregnancy was 3·5% among the whole cohort and 15·3% among patients with resumption of ovarian function. Fifty-five patients (47%) experienced an arrest of their resumption during the follow-up period. In univariate analysis, high FSH and DHEA levels at initial evaluation were risk factors for the arrest of the resumption of ovarian function. In multivariate analysis, high FSH levels at the initial evaluation [1·89 (1·10-3·23), P = 0·03] and older age at diagnosis [1·53 (1·01-2·33), P = 0·04] were risk factors for the arrest of this resumption. CONCLUSION:Resumption of ovarian function is not a rare or brief phenomenon in POI women. The identification of predictive factors of this resumption, as well as its duration, increases our knowledge of the natural history of POI, and will improve the medical management, especially infertility counselling of these patients.
Female exposure to endocrine disrupting chemicals and fecundity: a review.
Mínguez-Alarcón Lidia,Gaskins Audrey J
Current opinion in obstetrics & gynecology
PURPOSE OF REVIEW:Endocrine disrupting chemicals (EDCs) have been known for their ability to interfere with aspects of hormone action resulting in adverse health consequences among animals and humans; however, the effects of EDCs on human fecundity have shown inconsistent findings. This review summarizes the most recent epidemiologic literature from humans on the potential effects of female exposure to nonpersistent EDCs, specifically bisphenol A (BPA), phthalates, parabens, and triclosan, on fecundity, measured by markers of reproductive hormones, markers of ovulation or ovarian reserve, IVF outcomes, and time-to-pregnancy. RECENT FINDINGS:Although the epidemiologic literature on this topic is growing, the evidence supporting an association between female urinary concentrations of BPA, phthalates, parabens and triclosan, and fecundity remains unclear. The heterogeneous results could be due to methodological differences in recruitment populations (fertile vs. subfertile), study designs (prospective vs. retrospective), assessment of exposure (including differences in the number and timing of urine samples and differences in the analytical methods used to assess the urinary concentrations), residual confounding due to diet or other lifestyle factors, and coexposures to other chemicals. SUMMARY:At present, there is limited evidence to conclude that female exposure to nonpersistent EDCs affect fecundity in humans. Further studies focusing on exposure to mixtures of EDCs are needed.
Sleep quality and fatigue in women with premature ovarian insufficiency receiving hormone therapy: a comparative study.
Benetti-Pinto Cristina Laguna,Menezes Camila,Yela Daniela Angerame,Cardoso Tania Moc
Menopause (New York, N.Y.)
OBJECTIVE:To compare sleep quality and fatigue between women with premature ovarian insufficiency (POI) receiving hormone therapy (HT) and women of the same age with preserved ovarian function. METHODS:This was a cross-sectional study of 61 women with POI receiving HT (POI group) and 61 women with preserved ovarian function (control group) who were matched by age (±2 years). The Pittsburgh Sleep Quality Index (PSQI) and Chalder Fatigue Scale were used to assess sleep quality and fatigue. Apart from correlation analysis, the Mann-Whitney, chi-square, or Fisher test was used to compare the groups. RESULTS:Women from the POI and control groups were 35.03 ± 7.68 and 34.49 ± 7.55 years of age, respectively (P = 0.63). In the PSQI evaluation, the scores were 7.69 ± 4.18 and 8.03 ± 4.53, respectively (P = 0.79), showing no difference between the POI and control groups. However, the POI group had higher and therefore worse scores for the sleep latency component (1.74 ± 0.66 and 1.18 ± 0.87, respectively; P < 0.001) and use of medication to sleep (1.28 ± 0.88 and 0. 85 ± 0.8; P = 0.008). The POI group had a higher fatigue index than that of the control group (5.25 ± 2.78 and 3.49 ± 1.78, respectively; P < 0.001), with sleep quality being classified as poor in 69% and fatigue present in 59% of patients. CONCLUSIONS:Women with POI receiving HT have poor sleep quality. They take longer to fall asleep and have a higher fatigue index.
Investigation and treatment of premature ovarian insufficiency: A multi-disciplinary review of practice.
Richardson A,Haridass S A,Ward E,Ayres J,Baskind N E
Post reproductive health
Objectives:To assess compliance with the European Society for Human Reproduction and Embryology (ESHRE) guidelines on the investigation and management of women with premature ovarian insufficiency at the Leeds Teaching Hospitals NHS Trust (LTHT) and to determine whether this varies depending on the clinical setting in which the women present. Study design:A retrospective review of all females diagnosed with premature ovarian insufficiency between 1 July 2016 and 30 June 2017, presenting to one of the following clinics: reproductive medicine, specialist menopause, general gynaecology, oncology long-term follow-up, general endocrinology or paediatric endocrinology. Main outcome measures:Proportion of patients who had the necessary investigations performed and relevant treatment options discussed. Results:103 women were included in the study. Overall, 40.6% had a karyotype. Screening for the Fragile-X pre-mutation, thyroid peroxidase and 21-hydroxylase antibodies occurred in 7.4%, 11.1% and 13.6% of women, respectively. Only 35.9% had their bone mineral density measured. There was significant variation in the performance of a karyotype (p < 0.001) and thyroid peroxidase antibodies (p < 0.01) between the different clinical settings. Overall, lifestyle advice was offered to 30.1%. Estrogen replacement, contraception, fertility options and bone protection were discussed with 76.0%, 38.4%, 59.0% and 75.0%, respectively. Psychological support was offered to 25.2%. There was significant variation for all apart from contraception. Conclusion:The investigation and treatment of women with premature ovarian insufficiency at the LTHT is not consistent with the ESHRE guidelines and requires improvement. Furthermore, there is significant variation in management depending on the department to which the patient initially presents.
Vascular remodeling by placenta-derived mesenchymal stem cells restores ovarian function in ovariectomized rat model via the VEGF pathway.
Cho Jinki,Kim Tae-Hee,Seok Jin,Jun Ji Hye,Park Hyeri,Kweon Minyeoung,Lim Ja-Yun,Kim Gi Jin
Laboratory investigation; a journal of technical methods and pathology
Angiogenesis plays an important role in damaged organ or tissue and cell regeneration and ovarian development and function. Primary ovarian insufficiency (POI) is a prevalent pathology in women under 40. Conventional treatment for POI involves hormone therapy. However, due to its side effects, an alternative approach is desirable. Human mesenchymal stem cells (MSCs) from various sources restore ovarian function; however, they have many limitations as stem cell sources. Therefore, it is desirable to study the efficacy of placenta-derived MSCs (PD-MSCs), which possess many advantages over other MSCs, in a rat model of ovarian dysfunction. Here, we investigated the restorative effect of PD-MSCs on injured ovaries in ovariectomized (OVX) rats and the ability of intravenous transplantation (Tx) of PD-MSCs (5 × 10) to enhance ovarian vasculature and follicular development. ELISA analysis of serum revealed that compared to the non-transplantation (NTx) group, the Tx group showed significantly increased levels of anti-Müllerian hormone, follicle stimulating hormone, and estradiol (E2) (*P < 0.05). In addition, histological analysis showed more mature follicles and less atresia and restoration of expanded blood vessels in the ovaries of the OVX PD-MSC Tx group than those of the NTx group (*P < 0.05). Furthermore, folliculogenesis-related gene expression was also significantly increased in the PD-MSC Tx group (*P < 0.05). Vascular endothelial growth factor (VEGF) and VEGF receptor 2 expressions were increased in the ovaries of the OVX PD-MSC Tx group compared to the NTx group through PI3K/AKT/mTOR and GSK3β/β-catenin pathway activation. Interestingly, ex vivo cocultivation of damaged ovaries and PD-MSCs or treatment with recombinant VEGF (50 ng/ml) increased folliculogenic factors and VEGF signaling pathways. Notably, compared to recombinant VEGF, PD-MSCs significantly increased folliculogenesis and angiogenesis (*P < 0.05). These findings suggest that VEGF secreted by PD-MSCs promotes follicular development and ovarian function after OVX through vascular remodeling. Therefore, these results provide fundamental data for understanding the therapeutic effects and mechanism of stem cell therapy based on PD-MSCs and provide a theoretical foundation for their application for obstetrical and gynecological diseases, including infertility and menopause.
Inflammatory cytokines as key players of apoptosis induced by environmental estrogens in the ovary.
Zhang Fa-Li,Kong Li,Zhao Ai-Hong,Ge Wei,Yan Zi-Hui,Li Lan,De Felici Massimo,Shen Wei
Natural and synthetic environmental estrogens (EEs), interfering with the physiological functions of the body's estrogens, are widespread and are rising much concern for their possible deleterious effects on human and animal health, in particular on reproduction. In fact, increasing evidence indicate that EEs can be responsible for a variety of disfunctions of the reproductive system especially in females such as premature ovarian insufficiency (POI). Because of their great structural diversity, the modes of action of EEs are controversial. One important way through which EEs exert their effects on reproduction is the induction of apoptosis in the ovary. In general, EEs can exert pro-and anti-apoptotic effects by agonizing or antagonizing numerous estrogen-dependent signaling pathways. In the present work, results concerning apoptotic pathways and diseases induced by representative EEs (such as zearalenone, bisphenol A and di-2-ethylhexyl phthalate), in ovaries throughout development are presented into an integrated network. By reviewing and elaborating these studies, we propose inflammatory factors, centered on the production of tumor necrosis factor (TNF), as a major cause of the induction of apoptosis by EEs in the mammalian ovary. As a consequence, potential strategies to prevent such EE effect are suggested.
A 15q25.2 microdeletion phenotype for premature ovarian failure in a Chinese girl: a case report and review of literature.
Chen Zhen,Chen Hong,Yuan Ke,Wang Chunlin
BMC medical genomics
BACKGROUND:Proximal microdeletions on chromosome 15q25.2 are very rare, and are associated with neurodevelopmental delay, inguinal hernia, chest deformities, and anemia. The minimum length missed so far is 1.4 Mb. However, there were no cases reported till date on microdeletions at position q25.2 on chromosome 15 with premature ovarian failure (POF). CASE PRESENTATION:We herein reported a POF case characterized by short stature with only 0.447 Mb deletion on chromosome 15q25.2. The clinical and molecular characteristics in our patient showed the slightest clinical manifestations, with no clinical signs of neurodevelopmental delay, inguinal hernia, chest deformities, and anemia when compared to the previously reported cases. The microdeletions in our case included only 7 genes (HOMER2, FAM103A1, C15orf40, BTBD1, TM6SF1, HDGFRP3 and BNC1), and excluded the CPEB1 gene. Among these, the BNC1 gene is the only one that is known to be involved in reproduction. We hypothesized that the deletion of BNC1 gene in this patient led to haploinsufficiency, and consequently to POF. CONCLUSIONS:The study of this case increased the knowledge on the molecular and phenotypic consequences of interstitial 15q25.2 deletion, emphasizing that BNC1 gene deletion in this region might contribute to POF.
Urinary cadmium concentrations and risk of primary ovarian insufficiency in women: a case-control study.
Pan Wuye,Ye Xiaoqing,Zhu Zheying,Li Chunming,Zhou Jianhong,Liu Jing
Environmental geochemistry and health
Cadmium, a toxic heavy metal that occurs in the environment in large quantities through human activities, has been shown to have adverse effects on female reproductive health. However, the association between cadmium exposure and primary ovarian insufficiency (POI), one of the most prevalent ovarian diseases in women, has not been examined yet. This case-control study involving 169 POI cases and 209 healthy controls was conducted in Zhejiang Province, China. The urinary concentrations of cadmium were determined by inductively coupled plasma mass spectrometry (ICP-MS). In addition, serum levels of reproductive hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH) and estradiol, were measured. The median concentration of urinary cadmium in POI cases (0.43 μg/L, 0.58 μg/g for creatinine adjustment) was significantly higher than that of controls (0.29 μg/L, 0.43 μg/g for creatinine adjustment). The results of binary logistic regression models showed that the concentrations of urinary cadmium were positively significantly correlated with the odds ratio (ORs) of POI before the adjustment of confounders. After the adjustment, a significantly positive association was still present between the increased concentrations of cadmium and the ORs of POI (2.50, 95% CIs: 1.34-4.65 for the third tertile, p for trend = 0.001). The serum levels of FSH and LH were positively associated with urinary cadmium, while AMH and estradiol levels were inversely correlated. To the best of our knowledge, this is the first reported positive association of cadmium exposure with the risk of POI in women.
Follicular Activation and Stem Cell Therapy as a Novel Treatment Strategies in Diminished Ovarian Reserve and Primary Ovarian Insufficiency.
Fàbregues Francesc,Ferreri Janisse,Méndez Marta,Calafell Josep María,Otero Jordi,Farré Ramon
Frontiers in endocrinology
Usually poor ovarian response (POR) to gonadotropins reflects a diminished ovarian reserve (DOR) that gives place to few recruitable follicles despite aggressive stimulation. The reduction in the quantity and quality of the oocytes with advanced age is physiological. However, some women experience DOR much earlier and become prematurely infertile, producing an accelerated follicular depletion towards primary ovarian insufficiency (POI). Up to now, egg donation has been commonly used to treat their infertility. In the last thirty years, specialists in assisted reproduction have focused their attention on the final stages of folliculogenesis, those that depend on the action of gonadotrophins. Nevertheless, recently novel aspects have been known to act in the initial phases, with activating and inhibiting elements. activation (IVA) combining the stimulation of the ovarian Akt signaling pathway in ovarian cortex fragments with a method named Hippo-signaling disruption. Later, a simplification of the technique designated Drug-Free IVA have shown encouraging results in patients with POI. Another innovative therapeutic option in these patients is the infusion of bone marrow-derived stem cells (BMDSC) in order to supply an adequate ovarian niche to maintain and/or promote follicular rescue in patients with impaired or aged ovarian reserves. In this review, for the first time, both therapeutic options are addressed together in a common clinical setting. The aim of this review is to analyze the physiological aspects on which these innovative techniques are based; the preliminary results obtained up to now; and the possible therapeutic role that they may have in the future with DOR and POI patients.
Stem Cell Paracrine Signaling for Treatment of Premature Ovarian Insufficiency.
Polonio Alba M,García-Velasco Juan A,Herraiz Sonia
Frontiers in endocrinology
Premature ovarian insufficiency is a common disorder affecting young women and represents the worst-case ovarian scenario due to the substantial impact on the reproductive lifespan of these patients. Due to the complexity of this condition, which is not fully understood, non-effective treatments have yet been established for these patients. Different experimental approaches are being explored and strategies based on stem cells deserve special attention. The regenerative and immunomodulatory properties of stem cells have been successfully tested in different tissues, including ovary. Numerous works point out to the efficacy of stem cells in POI treatment, and a wide range of clinical trials have been developed in order to prove safety and effectiveness of stem cells therapy-in diminished ovarian reserve and POI women. The main purpose of this review is to describe the state of the art of the treatment of POI involving stem cells, especially those that use mobilization of stem cells or paracrine signaling.
What Are Models of Care? A Systematic Search and Narrative Review to Guide Development of Care Models for Premature Ovarian Insufficiency.
Jones Alicia R,Tay Chau T,Melder Angela,Vincent Amanda J,Teede Helena
Seminars in reproductive medicine
No specific model of care (MoC) is recommended for premature ovarian insufficiency (POI), despite awareness that POI is associated with comorbidities requiring multidisciplinary care. This article aims to explore the definitions and central components of MoC in health settings, so that care models for POI can be developed. A systematic search was performed on Ovid Medline and Embase, and including gray literature. Unique definitions of MoC were identified, and thematic analysis was used to summarize the key component of MoC. Of 2,477 articles identified, 8 provided unique definitions of MoC, and 11 described components of MoC. Definitions differ in scope, focusing on disease, service, or system level, but a key feature is that MoC is operational, describing how care is delivered, as well as what that care is. Thematic analysis identified 42 components of MoC, summarized into 6 themes-stakeholder engagement, supporting integrated care, evidence-based care, defined outcomes and evaluation, behavior change methodology, and adaptability. Stakeholder engagement was central to all other themes. MoCs operationalize how best practice care can be delivered at a disease, service, or systems level. Specific MoC should be developed for POI, to improve clinical and process outcomes, translate evidence into practice, and use resources more efficiently.
Use of Hormone Therapy in Women with Early Menopause and Premature Ovarian Insufficiency.
Lersten Ivy,Clain Elizabeth,Santoro Nanette
Seminars in reproductive medicine
Women with early menopause or primary ovarian insufficiency (POI) experience a menopausal state a decade or more earlier than their peers. The health consequences for POI are vast and varied with detrimental effects seen on neurological, psychological, bone, and cardiovascular systems. The risk profile of POI patients requires special attention, as they differ from a typical menopausal population. This review will explore the health risks associated with POI and examine the various treatment options and also the risks associated with hormone therapy. Given the risks and benefits, POI patients should be strongly encouraged to start hormone therapy until the median age of menopause.
Musculoskeletal Health in Premature Ovarian Insufficiency. Part Two: Bone.
Samad Navira,Nguyen Hanh H,Ebeling Peter R,Milat Frances
Seminars in reproductive medicine
Accelerated bone loss and muscle loss coexist in women with premature ovarian insufficiency (POI), but there are significant gaps in our understanding of musculoskeletal health in POI. This review describes estrogen signaling in bone and its role in skeletal health and disease. Possible mechanisms contributing to bone loss in different forms of POI and current evidence regarding the utility of available diagnostic tests and therapeutic options are also discussed. A literature review from January 2000 to March 2020 was conducted to identify relevant studies. Women with POI experience significant deterioration in musculoskeletal health due to the loss of protective effects of estrogen. In bone, loss of bone mineral density (BMD) and compromised bone quality result in increased fracture risk; however, tools to assess bone quality such as trabecular bone score (TBS) need to be validated in this population. Timely initiation of HRT is recommended to minimize the deleterious effects of estrogen deficiency on bone in the absence of contraindications; however, the ideal estrogen replacement regimen remains unknown. POI is associated with compromised bone health, regardless of the etiology. Ongoing research is warranted to refine our management strategies to preserve bone health in women with POI.
Musculoskeletal Health in Premature Ovarian Insufficiency. Part One: Muscle.
Samad Navira,Nguyen Hanh H,Scott David,Ebeling Peter R,Milat Frances
Seminars in reproductive medicine
Accelerated bone loss and muscle decline coexist in women with premature ovarian insufficiency (POI), but there are significant gaps in our understanding of musculoskeletal health in POI. This article is the first of a two-part review which describes estrogen signaling in muscle and its role in musculoskeletal health and disease. Current evidence regarding the utility of available diagnostic tests and therapeutic options is also discussed. A literature review from January 2000 to March 2020 was conducted to identify relevant studies. Women with POI experience significant deterioration in musculoskeletal health due to the loss of protective effects of estrogen. In addition to bone loss, muscle decay and dysfunction is now increasingly recognized. Nevertheless, there is a paucity of validated tools to assess muscle parameters. There is a growing need to acknowledge bone-muscle codependence to design new therapies which target both muscle and bone, resulting in improved physical performance and reduced morbidity and mortality. More high-quality research and international collaborations are needed to address the deficiencies in our understanding and management of musculoskeletal health in women with POI.
Consequences of -Thalassemia or Sickle Cell Disease for Ovarian Follicle Number and Morphology in Girls Who Had Ovarian Tissue Cryopreserved.
Mamsen Linn Salto,Kristensen Stine Gry,Pors Susanne Elisabeth,Bøtkjær Jane Alrø,Ernst Erik,Macklon Kirsten Tryde,Gook Debra,Kumar Ajay,Kalra Bhanu,Andersen Claus Yding
Frontiers in endocrinology
Women with -thalassemia (BT) and sickle cell disease (SCD) have a high risk of infertility and premature ovarian insufficiency. Different fertility preserving strategies, including ovarian tissue cryopreservation (OTC) and oocyte cryopreservation has been considered, and healthy babies have been born after successful OTC and transplantation. We evaluated follicle number and follicle health in ovarian tissue from a cohort of BT and SCD patients who underwent OTC before the age of 18 years. Patients undergoing OTC from 2002 to 2019 were included. A total of 14 girls and adolescents with BT and four with SCD, aged 2.8-17.4 years at OTC were included together with a reference group of 43 girls and adolescents with non-anemia diseases considered to have normal ovaries aged 0.6-17.9 years at OTC. Ovarian follicle density was measured in cortex biopsies and compared to the reference group. Expression of proteins associated with follicular health was evaluated using immunohistochemistry. Follicles were detected in the ovarian cortex biopsies from all patients with BT and SCD. The follicle densities were within the 95% prediction interval of the reference group in all cases. A similar expression of six proteins essential for follicular health was detected using immunohistochemistry in BT, SCD, and references. OTC should be considered an option for young girls and adolescents with BT and SCD.
Refining the risk for fragile X-associated primary ovarian insufficiency (FXPOI) by FMR1 CGG repeat size.
Allen Emily Graves,Charen Krista,Hipp Heather S,Shubeck Lisa,Amin Ashima,He Weiya,Nolin Sarah L,Glicksman Anne,Tortora Nicole,McKinnon Bonnie,Shelly Katharine E,Sherman Stephanie L
Genetics in medicine : official journal of the American College of Medical Genetics
PURPOSE:Approximately 20-30% of women with an FMR1 premutation experience fragile X-associated primary ovarian insufficiency (FXPOI); however, current risk estimates based on repeat size only identify women with the midrange of repeats to be at the highest risk. METHODS:To better understand the risk by repeat size, we collected self-reported reproductive histories on 1,668 women and divided them into high-resolution repeat size bins of ~5 CGG repeats to determine a more accurate risk for FXPOI in relation to CGG repeat length. RESULTS:As previously reported, women with 70-100 CGG repeats were at the highest risk for FXPOI using various statistical models to compare average age at menopause and risk of FXPOI, with women with 85-89 repeats being at the highest risk. Importantly, women with <65 repeats or >120 repeats did not have a significantly increased risk for FXPOI compared to women with <45 repeats. CONCLUSION:Using a large cross-section study on 1,668 women, we have provided more personalized risk assessment for FXPOI using high-resolution repeat size bins. Understanding the variability in risk has important implications for family planning and overall health among women with a premutation.
Premature ovarian failure after childhood cancer and risk of metabolic syndrome: a cross-sectional analysis.
Netterlid Axel,Mörse Helena,Giwercman Aleksander,Henic Emir,Åkesson Kristina E,Erfurth Eva-Marie,Elfving Maria
European journal of endocrinology
Objective:Female childhood cancer survivors (CCS) are at risk of several late effects, such as metabolic syndrome (MetS) and premature ovarian insufficiency (POI). The objective is to study if POI is associated with risk of MetS and increased cardiovascular risk in CSS. Design:A cross-sectional study with a median time since the cancer diagnosis of 25 (12-41) years. Patients and controls were recruited from the South Medical Region of Sweden. Methods:The study included 167 female CCS, median age 34 (19-57) years, diagnosed with childhood cancer at median age 8.4 (0.1-17.9) years together with 164 controls, matched for age, sex, ethnicity, residence, and smoking habits. All subjects were examined with fasting glucose, insulin, HbA1c, and lipid profile. Fat mass was calculated with dual-energy X-ray absorptiometry (DXA), and questionnaires for medication were obtained. Detailed information of cancer treatment was available. Results:POI was present in 13% (22/167) among CCS (hypothalamic/pituitary cause excluded) and in none among controls. MetS was present in 14% (24/167) among all CCS (P = 0.001), in 23% (5/22) of those with POI (P < 0.001), compared with 4% (6/164) among controls. OR for MetS in all CCS compared with controls was 4.4 (95% CI: 1.8, 11.1) (P = 0.002) and among CCS with POI the OR was 7.7 (CI: 2.1, 28.1) (P = 0.002). Conclusion:The prevalence of MetS was higher in females treated for childhood cancer compared with controls, and the presence of POI significantly increased the risk of developing MetS.
Premature ovarian insufficiency: the need for evidence on the effectiveness of hormonal therapy.
Upton C E,Daniels J P,Davies M C
Climacteric : the journal of the International Menopause Society
Premature ovarian insufficiency (POI) - the loss of ovarian function before the age of 40 years, a decade before natural menopause - is a life-changing diagnosis for women. POI causes significant short-term and long-term morbidity related to estrogen deficiency. The condition is managed by providing exogenous estrogen replacement, usually as the oral contraceptive pill or hormone therapy. These preparations have different estrogen formulations and may have differing benefits and risks. At present, there are no robust data to inform clinical recommendations and women's decision-making about treatment that they may be taking for many years. The POISE study (Premature Ovarian Insufficiency Study of Effectiveness of hormonal therapy) has been designed to determine whether hormone therapy is superior to combined oral contraceptives on important clinical outcomes and patient-reported symptoms, based on the hypothesis that hormone therapy provides more physiological continuous hormone supplementation with natural estrogens. The study is an open and pragmatic, parallel, randomized controlled trial. The primary outcome is absolute bone mineral density assessed by dual-energy X-ray absorptiometry of the lumbar spine after 2 years of treatment. The study will also investigate cardiovascular markers, symptom relief and acceptability of treatment, and will continue to collect long-term data on fractures and cardiovascular events. Results will inform future guidance on management of POI.
Ongoing pregnancy and healthy live births following very short ovarian stimulation of incidentally observed big antral follicles in oligoamenorrheic patients with extremely decreased ovarian reserve.
Turan Volkan,Sonmezer Meltem,Sonmezer Murat
JBRA assisted reproduction
In the present case series our aim is to present seven patients with extremely decreased ovarian reserve and oligomenorrhea, conceived with in vitro fertilization following a very short ovarian stimulation of incidentally detected big antral follicles. The study included women pursuing in vitro fertilization due to premature ovarian failure risk. When an incidental growing antral follicle was detected under ultrasound, immediate ovarian stimulation was initiated if the blood estradiol, luteinizing hormone and progesterone levels were correlated. Serum anti-Mullerian hormone measurements of all patients were consistent with extremely diminished ovarian reserve (ranged between 0.01 and 0.09ng/ml) and FSH levels varied between 13-104IU/l. The mean stimulation length ranged between 2-4 days. A total of 8 oocytes were retrieved; 6 MII, 1 GV and 1 degenerated. All 6 MII oocytes were fertilized with intracytoplasmic sperm injection. Two patients conceived after fresh embryo transfer, whereas the one conceived following frozen thawed embryo transfer. The ongoing pregnancy rate was 50% per transfer, and two of them resulted in a healthy live birth. In conclusion, close monitoring of oligoamenorrheic infertile patients who are at high risk of imminent ovarian failure using ultrasound and blood hormone levels is very important. Albeit low, the possibility of having a healthy pregnancy following "a very short ovarian stimulation" in such a specific patient group is emphasized.
Premature or early bilateral oophorectomy: a 2021 update.
Rocca W A,Mielke M M,Gazzuola Rocca L,Stewart E A
Climacteric : the journal of the International Menopause Society
In this invited review, we discuss some unresolved and controversial issues concerning premature (<40 years) or early (40-45 years) bilateral oophorectomy. First, we clarify the terminology. Second, we summarize the long-term harmful consequences of bilateral oophorectomy. Third, we discuss the restrictive indications for bilateral oophorectomy in premenopausal women to prevent ovarian cancer that are justified by the current scientific evidence. Fourth, we explain the importance of estrogen replacement therapy when bilateral oophorectomy is performed. Hormone replacement therapy is indicated after bilateral oophorectomy until the age of expected natural menopause like in premature or early primary ovarian insufficiency. Fifth, we discuss the relationship between adverse childhood experiences, adverse adult experiences, mental health, gynecologic symptoms and bilateral oophorectomy. The acceptance and popularity of bilateral oophorectomy over several decades, and its persistence even in the absence of supporting scientific evidence, suggest that non-medical factors related to sex, gender, reproduction, cultural beliefs and socioeconomic structure are involved. We discuss some of these non-medical factors and the need for more research in this area.
Long-term outcome of ovarian function after drug-free in vitro activation (IVA) in primary ovarian insufficiency patient.
Ferreri Janisse,Méndez Marta,Calafell José Maria,Fábregues Francesc
JBRA assisted reproduction
Drug-Free IVA has been recently introduced as a therapeutic option for patients with Primary Ovarian Insufficiency (POI). Despite the existing limited results, it can be considered as a promising option for these patients to achieve their own offspring. Here we report the case of a 35-year-old woman diagnosed with POI at 30 years of age. Drug-Free IVA was performed at age 33 and pregnancy was achieved by IVF 10 months after grafting. Unfortunately, she had a preterm delivery with neonatal death due to prematurity complications. After delivery, she recovered spontaneous ovarian function and one mature oocyte was retrieved 20 months after Drug-Free IVA. Following IVF, one embryo was transferred, and she is currently 33 weeks pregnant, suggesting that Drug-free IVA could lead to long-term ovarian function.
Genetic etiologic analysis in 74 Chinese Han women with idiopathic premature ovarian insufficiency by combined molecular genetic testing.
Shen Jiandong,Qu Dianyun,Gao Yan,Sun Fangxi,Xie Jiazi,Sun Xueping,Wang Daowu,Ma Xiang,Cui Yugui,Liu Jiayin,Diao Feiyang
Journal of assisted reproduction and genetics
PURPOSE:To identify the disease-causing genes of Chinese Han women with idiopathic premature ovarian insufficiency (POI). METHODS:Seventy-four Chinese Han women with idiopathic POI were collected to analyze the genetic etiology. Triplet repeat-primed polymerase chain reaction (TP-PCR) was performed to screen the FMR1 (CGG)n premutation, and then 60 POI-related genes were sequenced by targeted next-generation sequencing (NGS) in POI patients with normal FMR1. RESULTS:A total of one patient (1/74) with FMR1 premutation was identified. Targeted NGS revealed that 15.07% (11/73) patients had pathogenic or likely pathogenic variants of Mendelian genes (FOXL2, EIF2B2, CYP17A1, CLPP, MCM9, GDF9, MSH5, ERCC6, POLG). Ten novel variants in six Mendelian genes were identified, such as CLPP c.355A>C (p.I119L) and c.688A>C (p.M230L), MCM9 c.1157C>T (p.T386M) and c.1291A>G (p.M431V), GDF9 c. 238C>T (p.Q80X), MSH5 c.604G>C (p.G202R) and c.2063T>C (p.I688T), ERCC6 c.C1769C>T (p.P590L), POLG c.2832G>C (p.E944D), and c.2821A>G (p.I941V). CONCLUSION:This study suggested targeted NGS was an efficient etiologic test for idiopathic POI patients without FMR1 premutation and enriched the variant spectrum of POI-related genes.
Fertility preservation for genetic diseases leading to premature ovarian insufficiency (POI).
La Marca Antonio,Mastellari Elisa
Journal of assisted reproduction and genetics
PURPOSE:The current review aims to summarize the data available concerning the applicability of fertility preservation techniques to genetic conditions at risk of premature ovarian insufficiency (POI). METHODS:A literature review through the PubMed Database was carried out. RESULTS:About 10% of cases of POI is related to genetic diseases. The most frequent conditions associated with POI are Turner syndrome and fragile X pre-mutation; mutation of BRCA 1-2 genes and several other mutations and genetic syndromes have recently been highlighted, although they rarely occur. If a diagnosis is issued before POI onset, counseling on currently available fertility preservation techniques is advisable. In case of spontaneous menarche (this can occur variably depending on the mutation) established techniques like embryo or oocyte cryopreservation can be proposed, even if, in some cases, their effectiveness may be reduced by ovarian alterations connected to the mutation. Ovarian tissue cryopreservation has recently been defined as an established medical procedure for fertility preservation in young cancer patients and may be an option for prepubertal patients. However, it is still experimental in special populations with genetic diseases causing POI. New innovative experimental techniques, like in vitro maturation of immature oocytes (IVM) and vitro activation (IVA) of immature follicles on ovarian tissue, have shown limited but encouraging data and they will be probably available in the near future. For a correct risk-benefit evaluation, the following aspects should be considered: actual knowledge about the pathology-specific efficacy of the various techniques, the average age of onset of POI, the possible risks associated with the procedure in relation to the underlying pathology, the probability of spontaneous conception, as well as the health implications of a possible future pregnancy.. CONCLUSIONS:Fertility preservation techniques represent a crucial opportunity for patients with genetic risk of POI. Early diagnosis increases the chances to apply these techniques. No specific recommendations concerning fertility preservation for each genetic pathology are available, and clinicians should first counsel the patient and her relatives about known risks and benefits of the available techniques, both those established and those considered as experimental.
Novel approaches to fertility restoration in women with premature ovarian insufficiency.
Rosario R,Anderson R A
Climacteric : the journal of the International Menopause Society
The diagnosis of premature ovarian insufficiency (POI) brings with it the loss of fertility, an immediate concern for many affected women, and a future one for many others. While there is a low natural conception rate, for most the choice is between oocyte donation and alternative methods of family building such as adoption. There is, however, a lot of research into novel methods for increasing or restoring the fertility of women with POI, which are discussed in this review. Many approaches involve the use of mesenchymal stem cells, from a variety of sources including bone marrow, placenta and umbilical cord, and menstrual blood. These seem to have efficacy in animal models of POI, although through unclear mechanisms. Activation of remaining primordial follicles is also being explored, through physical or chemical manipulation of key regulatory pathways, notably the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and Hippo pathways. Much of the clinical data are uncontrolled, and mostly in women with a reduced ovarian reserve rather than POI, as are the results thus far for administration of platelet-rich plasma. Clinical studies with appropriate controls are needed to substantiate the preliminary claims of effectiveness of these approaches.
Current Understanding of the Etiology, Symptomatology, and Treatment Options in Premature Ovarian Insufficiency (POI).
Frontiers in endocrinology
Premature ovarian insufficiency (POI) occurs in at least 1% of all women and causes life-long health problems and psychological stress. Infertility caused by POI used to be considered absolute, with infertility treatment having little or no value. Generally, it has been thought that medicine can provide little service to these patients. The etiology of POI has been found to be genetic, chromosomal, and autoimmune. In addition, the increasing numbers of cancer survivors are candidates for iatrogenic POI, along with patients who have undergone ovarian surgery, especially laparoscopic surgery. Over 50 genes are known to be causally related to POI, and the disease course of some cases has been clarified, but in most cases, the genetic background remains unexplained, suggesting that more genes associated with the etiology of POI need to be discovered. Thus, in most cases, the genetic background of POI has not been clarified. Monosomy X is well known to manifest as Turner's syndrome and is associated with primary amenorrhea, but recent studies have shown that some women with numerical abnormalities of the X chromosome can have spontaneous menstruation up to their twenties and thirties, and some even conceive. Hormone replacement therapy (HRT) is recommended for women with POI from many perspectives. It alleviates vasomotor and genitourinary symptoms and prevents bone loss and cardiovascular disease. POI has been reported to reduce quality of life and life expectancy, and HRT may help improve both. Most of the problems that may occur with HRT in postmenopausal women do not apply to women with POI; thus, in POI, HRT should be considered physiological replacement of estrogen (+progesterone). This review describes some new approaches to infertility treatment in POI patients that may lead to new treatments for POI, along with the development of more sensitive markers of secondary/preantral follicles and genetic diagnosis.
Prediction of premature ovarian insufficiency: foolish fallacy or feasible foresight?
Nelson S M,Anderson R A
Climacteric : the journal of the International Menopause Society
Prediction of premature ovarian insufficiency (POI) would be of substantial individual benefit, but being a heterogeneous and fluctuating condition, with an extensive range of complex etiologies and arbitrary diagnostic criteria, might make this seem foolhardy. However, contemporary and complementary genetic strategies assessing consanguineous and large POI pedigrees and cohorts with age at natural menopause have shown strong enrichment in genes regulating DNA damage repair, homologous recombination, and meiosis, processes that are critical to oogenesis and folliculogenesis. Recognition of the molecular architecture of POI and its contribution to baseline genotypic risk may enable these estimates to be refined further by estimation of the residual ovarian reserve. Increasing data derived from spontaneous and gonadotoxic-induced POI cohorts demonstrate the utility of anti-Müllerian hormone (AMH) to predict POI. This review presents current understanding of how genetics in combination with AMH may facilitate the prediction of POI.
Premature ovarian insufficiency: a toolkit for the primary care physician.
Lambrinoudaki I,Paschou S A,Lumsden M A,Faubion S,Makrakis E,Kalantaridou S,Panay N
Climacteric : the journal of the International Menopause Society
Premature ovarian insufficiency (POI) refers to the loss of ovarian activity before the age of 40 years, which leads to hypoestrogenism and amenorrhea. The diagnosis of POI in a young woman has potentially life-changing physical and emotional consequences for both the patient and her family. Therefore, it is very important that the diagnosis is correct and that it is made in a timely manner. Unfortunately, the diagnosis and therefore the effective treatment of POI are often delayed, which underlines the need for education of the broad medical community on the issue. A panel of menopause experts reviewed and critically appraised the literature, and present: (1) the diagnostic approach to POI, (2) the investigation of the etiology of this condition, (3) the therapeutic strategy regarding both hormone replacement therapy and fertility, and (4) the long-term follow-up and management for ensuring quality of life, as well as urogenital, cardiovascular, bone and mental health. The ultimate goal of this article is to provide a complete toolkit for the primary care physician to have easy access to all the information needed for the optimal management of women with POI, in the context of evidence-based and personalized medicine.HIGHLIGHTSPremature ovarian insufficiency occurs in 1% of the female population of reproductive age, yet the diagnosis is often delayed, with severe physical and emotional consequences for the patient.Primary care physicians should be aware of the possibility of premature ovarian insufficiency in young women presenting with menstrual irregularity.Prompt initiation of hormone replacement therapy ensures quality of life and prevents osteoporosis and cardiovascular disease.Women seeking fertility should be referred to specialists to discuss assisted reproduction options.
Diminished ovarian reserve in recurrent pregnancy loss: a systematic review and meta-analysis.
Bunnewell Sarah J,Honess Emma R,Karia Amar M,Keay Stephen D,Al Wattar Bassel H,Quenby Siobhan
Fertility and sterility
OBJECTIVE:To evaluate the association between diminished ovarian reserve (DOR) in women at risk of recurrent pregnancy loss (RPL) using ovarian reserve tests. DESIGN:Systematic review and meta-analysis. SETTING:University medical schools. PATIENT(S):Women with a history of RPL. INTERVENTION(S):Systematic reviews of major electronic databases (MEDLINE, EMBASE, Web of Science, and Scopus) for studies that evaluated the incidence of DOR in women with RPL. MAIN OUTCOME MEASURE(S):Association between RPL and DOR. RESULT(S):In studies up to May 2019 we assessed quality using the Newcastle-Ottawa Scale and meta-analyzed data using a random-effect model. We included 15 studies (n = 3,082 women) reporting on six ovarian reserve tests: antimüllerian hormone [AMH], antral follicle count, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and FSH:LH ratio. More women with RPL seemed to have DOR compared with women who did not have RPL as measured by low AMH levels (odds ratio [OR] 2.77; 95% confidence interval [CI], 1.41-5.46) and AFC (OR 2.45; 95% CI, 1.16-5.19). Women with unexplained RPL also seemed to have a higher association with DOR compared with women whose RPL had a known etiology, as measured by low AMH levels (OR 3.23; 95% CI, 1.81-5.76). No statistically significant differences were found in the levels of any of the remaining ovarian reserve tests between those groups of women. CONCLUSION(S):There is an apparent association between DOR and RPL. Low AMH and AFC levels could predict higher odds for pregnancy loss, but more studies are needed to evaluate their prognostic value in the management of women with RPL. SYSTEMATIC REVIEW REGISTRATION NUMBER:Prospero CRD42018114673.
Anti-Müllerian Hormone in the Diagnosis and Prediction of Premature Ovarian Insufficiency.
Anderson Richard A,Nelson Scott M
Seminars in reproductive medicine
The menopause and its pathological version, premature ovarian insufficiency (POI), are characterized by the cessation of follicle growth in the ovary, with consequent lack of estrogen production and amenorrhea. The measurement of a specific product of ovarian follicles would therefore be expected to be a valuable biomarker in women with POI, and to be of likely clinical value in the diagnosis and perhaps prediction of POI. Anti-Müllerian hormone (AMH) is produced by the granulosa cells of growing follicles and is therefore likely to be of value in this context. Current data indicate that measurement of AMH is an accurate indicator of POI in many situations and has diagnostic validity and may facilitate more timely diagnosis. AMH seems to be of limited value in predicting age at natural menopause, even with multiple measurements, and there are scarce data regarding prediction of POI, other than when it is imminent, and in some contexts where there is an immediate iatrogenic threat to ovarian function. AMH therefore appears to have considerable value as a diagnostic test for POI, but apart from highlighting broadly those at increased risk, it has inadequate precision to be able to predict accurately the timing of onset of impending POI.
Assessment of premature menopause on the sexual function and quality of life in women.
Javadpour Shohreh,Sharifi Nader,Mosallanezhad Zahra,Rasekhjahromi Athar,Jamali Safieh
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
INTRODUCTION:Premature Ovarian Insufficiency (POI) is characterized by ending menstruation in women under 40 years of age. It has a significant effect on women's sexuality and mental health and quality of life. This study aimed to evaluate the sexual function and quality of life of premature menopausal women. METHODS:This study was a case-control study on 132 people (66 women with a diagnosis of POF and 66 women of reproductive age with normal ovarian function) who were matched in terms of the age, presenting to Women's Clinic in Jahrom in 2019. The WHOQOL-BREF questionnaire and the Female Sexual Function Index (FSFI) questionnaire were used to collect data. < .05 was considered statistically significant. RESULTS:The mean score of sexual function in premature menopausal women was 21.35 ± 4.82 and in non-menopausal women was 25.4 ± 6.61 (OR = 0.11, 95% CI = 0.04-0.28). All areas of sexual function; desires disorder (OR = 0.21 95% CI = 0.07-0.56), Arousal disorder(OR = 0.28, 95% CI = 0.08-0.93), orgasm disorder (OR = 0.36 95% CI = 0.16-0.80), lubrication disorder (OR = 0.21 95% CI= 0.05-0.78), satisfaction disorder (OR = 0.11, 95% CI = 0.04-0.28) and quality of life domains: physical health (OR = 0.4 95%CI = 0.06-0.3), mental health (OR = 0.28 95% CI = 0.06-0.1), environmental health (OR = 0.22 95%CI = 0.04-0.6) and social health (OR = 0.28 95%CI = 0.01-0.2) saw a decrease in the premature menopausal women group compared to the control group. CONCLUSION:The results demonstrated that premature menopausal women are found to be weaker than the control group in all areas of sexual function and quality of life. Among the areas of sexual function, such as libido, arousal, satisfaction, and pain have the most impact on quality of life. Therefore, based on the results from improving sexual function, this issue can improve the quality of life.
Menopausal symptoms in women with premature ovarian insufficiency: prevalence, severity, and associated factors.
Huang Yizhou,Qi Tongyun,Ma Linjuan,Li Die,Li Chunming,Lan Yibing,Chu Ketan,Chen Peiqiong,Xu Wenxian,Cao Yina,Ying Qian,Xu Ling,Zhou Jianhong
Menopause (New York, N.Y.)
OBJECTIVE:To comprehensively investigate and evaluate the prevalence, severity, and associated factors of menopausal symptoms in women with premature ovarian insufficiency (POI). In this study, the specific symptomatology experienced by women with POI and women with natural menopause was also compared. METHODS:In this cross-sectional study, 293 Chinese women with POI from an outpatient clinic were recruited between June 2014 and January 2019. The prevalence and severity of menopausal symptoms were assessed with modified Kupperman Menopausal Index. Participants completed a structured questionnaire, including medical history, menstrual characteristics, and sociodemographic data. Serum levels of reproductive hormones were measured. RESULTS:Among 293 women with POI (33.76 ± 5.47 y), the most prevalent symptoms were mood swings (73.4%), insomnia (58.7%), sexual problems (58.7%), and fatigue (57.3%). Moderate-to-severe mood swings were most frequently reported (23.9%), followed by formication (17.4%) and hot flashes/sweating (17.1%). Compared with women with natural menopause, women with POI exhibited significantly higher risks for fatigue (odds ratio = 1.42; 95% confidence interval, 1.04-1.94), melancholia (3.12; 1.94-5.01), mood swings (3.57; 2.33-5.45), insomnia (1.41; 1.02-1.96), and significantly lower risks for moderate-to-severe sexual problems (0.40; 0.23-0.69), any and moderate-to-severe muscle/joint pain (0.41; 0.27-0.62 and 0.45; 0.25-0.78, respectively). Living in urban areas and higher gravidity were independently associated with menopausal symptoms in women with POI. CONCLUSIONS:Women with POI experienced a high prevalence of menopausal symptoms, particularly related to psychological and sexual domains. Furthermore, women with POI tended to have more distressing menopausal symptoms compared with women with natural menopause.
Serum biomarker analysis in patients with premature ovarian insufficiency.
Liu Jian,Huang Xunchun,Cao Xiaojing,Feng Xuan,Wang Xiaoyun
Premature ovarian insufficiency (POI) is a primary ovarian defect characterized by premature depletion of ovarian follicles before 40 years of age. The disorder has been attributed to various causes, but the study of altered proteins in serum levels as the cause is rare. Additionally, identifying novel biomarkers can contribute to more accurate diagnosis or prognosis of POI. In the present study, a solid-phase antibody array simultaneously detecting multiple proteins was used to analyze POI serum with menopausal and healthy fertile subjects as control groups. As a result, compared to the menopause and healthy fertile groups, eleven proteins, including Neurturin, Frizzled-5, Serpin D1, MMP-7, ICAM-3, IL-17F, IFN-gamma R1, IL-29, IL-17R, IL-17C and Soggy-1, were uniquely down-regulated, and Afamin was particularly up-regulated in POI serum. More importantly, all of these factors were firstly found to be associated with POI in this study, suggesting that these proteins may participate in the pathogenesis of POI and may be novel serum biomarkers for POI.
Autoimmunological serum parameters and bone mass density in premature ovarian insufficiency: a retrospective cohort study.
Beitl Klara,Rosta Klara,Poetsch Nina,Seifried Manuel,Mayrhofer Daniel,Soliman Barbara,Marculescu Rodrig,Ott Johannes
Archives of gynecology and obstetrics
PURPOSE:It is still not clear whether to screen women with primary premature ovarian insufficiency for autoimmunity. Moreover, a possible association of autoimmunity with decreased bone mass density in premature ovarian insufficiency patients has not been evaluated. Thus, the objectives of this study were to review our experience with the use of an autoimmune screening panel in premature ovarian insufficiency women and to focus on bone mass density. METHODS:In a retrospective cohort study, 76 chromosomally normal women with primary premature ovarian insufficiency were included. The main outcome parameters were the results of an autoimmune screening panel and of dual-energy X-ray absorptiometry. RESULTS:Median age was 33 years. Sixty percent of premature ovarian insufficiency patients revealed abnormal dual-energy X-ray absorptiometry results (minimal T-score < -1.0). Any signs of autoimmunity were found in 21 women (36.2%). The most frequent abnormal results were increased thyroperoxidase antibodies (24.1%) and thyroglobulin antibodies (20.7%). A longer duration of amenorrhea (β = -0.015; p = 0.007), any abnormality during autoimmune screening (β = -0.940; p = 0.010), and a lower body mass index (β = -0.057; p = 0.036) were associated with a lower minimal T-score. CONCLUSION:In chromosomally normal women with primary premature ovarian insufficiency, the prevalence of autoimmunity and decreased bone mass density seem high. Our data highlight the association between autoimmune abnormalities and decreased dual-energy X-ray absorptiometry results.
Knowledge of iatrogenic premature ovarian insufficiency among Chinese obstetricians and gynaecologists: a national questionnaire survey.
Wang Yanfang,Zou Ying,Wang Wei,Zheng Qingmei,Feng Ying,Dong Han,Tan Zhangyun,Zeng Xiaoqin,Zhao Yinqing,Peng Danhong,Yang Xiaomin,Sun Aijun
Journal of ovarian research
BACKGROUND:With increasing cases of iatrogenic premature ovarian insufficiency (POI), more clinicians are required to counsel patients regarding the gonadotoxic effects of iatrogenic treatments. This survey aimed to explore obstetricians and gynaecologists' knowledge regarding iatrogenic POI. A national online questionnaire survey was conducted across China. Respondents were asked to select the iatrogenic condition(s) that can cause POI based on their experience and knowledge. RESULTS:Of the 5523 returned questionnaires, 4995 were analysed. Among tumour therapies causing POI, most respondents agreed that radiotherapy (73.5% of respondents) and chemotherapy (64.1%) are risk factors for POI. While only 6.5 and 7.8% of the gynaecological oncologists believed that tumour immunotherapy and tumour-targeting therapy, respectively, may cause ovarian impairment, 31.8 and 22.2% of the non-gynaecologic oncologists believed that these therapies could affect ovarian health. Most respondents believed that ovarian cystectomy (54.4%) was a risk factor for POI. In contrast, only a few respondents believed that hysterectomy with bilateral salpingectomy (39.6%) and uterine artery embolisation (33.5%) could cause ovarian impairment. Only 30.5% of respondents believed that immunosuppressants (ISs) increased the risk of POI. Views differed with experience and hospital setting. CONCLUSIONS:The knowledge of gonadal toxicity due to traditional tumour treatments is generally high among Chinese obstetricians and gynaecologists. A misunderstanding may exist in primary care hospitals and general gynaecologists regarding a link between novel tumour treatments and POI, owing to the lack of convincing evidence. Knowledge of POI caused by hysterectomy and ISs should be improved.
Occult form of premature ovarian insufficiency.
Shestakova I G,Radzinsky V E,Khamoshina M B
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
Premature ovarian insufficiency (POI) is a life-changing diagnosis, with profound physical and psychological consequences. Despite the description of different genetic, immune and iatrogenic factors of POI, the etiology of most cases of this disease are unexplained, and optimal management strategies are still unclear. Recent data showed that POI may have a long period of oligomenorrhea before the fully developed form (complete ovarian failure stage), with the occurrence of amenorrhea and climacteric symptoms. The main problem in the recognition of early stages of POI is the lack of proper diagnostic criteria. Patients with an undiagnosed occult form of POI may present with menstrual irregularities, unexplained infertility or repeated IVF failures. We evaluated 23 patients with unexplained oligomenorrhea and/or infertility. After a proper evaluation of these patients, a low ovarian reserve was identified, and an occult form of POI was diagnosed.
Prevalence and Risk Factors of Premature Ovarian Insufficiency/Early Menopause.
Giri Rinky,Vincent Amanda J
Seminars in reproductive medicine
Premature ovarian insufficiency (POI) and early menopause, defined as loss of ovarian activity prior to 40 years or menopause between the ages of 40 and 45 years, respectively, is associated with significant adverse health impacts. Recent data indicate that the prevalence of POI and early menopause is greater than was previously thought, affecting more than 10% of women. Biopsychosocial risk factors including genetic, autoimmune, reproductive, lifestyle, early-life, social/environmental, and iatrogenic have been associated with POI/early menopause or earlier age at menopause. However, establishing a causal role and the underlying mechanisms remains elusive. Understanding and clarification of these risk factors will facilitate prevention and risk minimization strategies to optimize women's health.
Management of bone health in women with premature ovarian insufficiency: Systematic appraisal of clinical practice guidelines and algorithm development.
Kiriakova Velislava,Cooray Shamil D,Yeganeh Ladan,Somarajah Gowri,Milat Frances,Vincent Amanda J
BACKGROUND:Osteoporosis is a key concern of women with premature ovarian insufficiency (POI) but there are gaps in clinicians' knowledge of bone health. OBJECTIVES:1) To systematically evaluate the quality of clinical practice guidelines (CPGs) related to POI and bone health; 2) to formulate a management algorithm. METHODS:Systematic search for English-language clinical practice guidelines (CPGs) from August 2012 to August 2017 (PROSPERO registration number CRD42017075143). Four reviewers independently evaluated the methodological quality of included CPGs using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument (comprising 23 items across 6 domains) using the My AGREE PLUS platform. Inter-rater reliability was assessed using the intraclass correlation coefficient (ICC). Individual domain and total percentage scores were calculated for each CPG. Data from high-scoring CPGs were extracted and summarised to develop the algorithm, with subsequent refinement via expert and end-user clinician feedback. RESULTS:The systematic search yielded 16 CPGs for appraisal. ICC values were 0.71 (good) to 0.95 (very good). The quality of the CPGs was appraised as "high" in 4 cases, "average" in 8 and "low" in 4. High-quality CPGs had mean total scores of 82-96%. Recommendations from high-quality CPGs were summarised into 6 categories: screening; risk factors; initial assessment; diagnosis; subsequent assessment; and management. Only "management" had recommendations (moderate-quality to low-quality evidence) from all four high-quality CPGs. Limitations are reflected in the algorithm. CONCLUSIONS:Most CPGs regarding bone health and POI are of average to poor quality. High-quality CPGs have evidence limitations and recommendation gaps indicating the need for further research.
Premature ovarian insufficiency: an International Menopause Society White Paper.
Panay N,Anderson R A,Nappi R E,Vincent A J,Vujovic S,Webber L,Wolfman W
Climacteric : the journal of the International Menopause Society
The aim of this International Menopause Society White Paper on premature ovarian insufficiency (POI) is to provide the latest information regarding this distressing condition. The impact of POI has far-reaching consequences due to its impact on general, psychological, and sexual quality of life, fertility prospects, and long-term bone, cardiovascular, and cognitive health. Progress in fully understanding the etiology, diagnosis, and optimal management options has been slow thus far due to the complexity of the condition and fragmented research. Recent advances in epidemiological and genetic research have improved our understanding of this condition and randomized prospective trials are being planned to determine the intervention strategies, which will optimize quality of life and long-term well-being. The International Menopause Society has commissioned a number of experts at the forefront of their specialty to define the state of the art in the understanding of this condition, to advise on practical management strategies, and to propose future research strategies. It is hoped that a global task force will subsequently be convened in order to formulate a consensus statement across key societies, to accelerate date collection and analysis of a global POI registry, and to facilitate progress in the key defined areas of research.
Premature Ovarian Insufficiency and Long-Term Health Consequences.
Tsiligiannis Sophia,Panay Nick,Stevenson John C
Current vascular pharmacology
Premature ovarian insufficiency (POI) is defined as the cessation of ovarian function before the age of 40 years. The trio of amenorrhea, elevated gonadotropins and oestrogen deficiency is associated with long-term health consequences including increased cardiovascular disease (CVD), decreased bone mineral density (BMD), significantly reduced fertility, psychological distress, vulvovaginal atrophy, neurological effects and overall reduced life expectancy. There are deficits in our understanding of this condition and subsequently the long-term health consequences. The underlying aetiology of POI and the optimal management strategies are also poorly understood. Our knowledge of long-term cardiovascular consequences specifically relating to women with POI is limited as most data on the subject are derived from studies involving women who experienced menopause at the natural age (after 40 years with an average age of 51).
The cardiovascular risk profile of middle age women previously diagnosed with premature ovarian insufficiency: A case-control study.
Gunning Marlise N,Meun Cindy,van Rijn Bas B,Daan Nadine M P,Roeters van Lennep Jeanine E,Appelman Yolande,Boersma Eric,Hofstra Leonard,Fauser Clemens G K M,Rueda-Ochoa Oscar L,Ikram Mohammad A,Kavousi Maryam,Lambalk Cornelis B,Eijkemans Marinus J C,Laven Joop S E,Fauser Bart C J M,
BACKGROUND:Cardiovascular disease (CVD) is the leading cause of death in women worldwide. The cardiovascular risk profile deteriorates after women enter menopause. By definition, women diagnosed with premature ovarian insufficiency (POI) experience menopause before 40 years of age, which may render these women even more susceptible to develop CVD later in life. However, prospective long-term follow up data of well phenotyped women with POI are scarce. In the current study we compare the CVD profile and risk of middle aged women previously diagnosed with POI, to a population based reference group matched for age and BMI. METHODS AND FINDINGS:We compared 123 women (age 49.0 (± 4.3) years) and diagnosed with POI 8.1 (IQR: 6.8-9.6) years earlier, with 123 population controls (age 49.4 (± 3.9) years). All women underwent an extensive standardized cardiovascular screening. We assessed CVD risk factors including waist circumference, BMI, blood pressure, lipid profile, pulse wave velocity (PWV), and the prevalence of diabetes mellitus, metabolic syndrome (MetS) and carotid intima media thickness (cIMT), in both women with POI and controls. We calculated the 10-year CVD Framingham Risk Score (FRS) and the American Heart Association's suggested cardiovascular health score (CHS). Waist circumference (90.0 (IQR: 83.0-98.0) versus 80.7 (IQR: 75.1-86.8), p < 0.01), waist-to-hip ratio (0.90 (IQR: 0.85-0.93) versus 0.79 (IQR: 0.75-0.83), p < 0.01), systolic blood pressure (124 (IQR 112-135) versus 120 (IQR109-131), p < 0.04) and diastolic blood pressure (81 (IQR: 76-89) versus 78 (IQR: 71-86), p < 0.01), prevalence of hypertension (45 (37%) versus 21 (17%), p < 0.01) and MetS (19 (16%) versus 4 (3%), p < 0.01) were all significantly increased in women with POI compared to healthy controls. Other risk factors, however, such as lipids, glucose levels and prevalence of diabetes were similar comparing women with POI versus controls. The arterial stiffness assessed by PWV was also similar in both populations (8.1 (IQR: 7.1-9.4) versus 7.9 (IQR: 7.1-8.4), p = 0.21). In addition, cIMT was lower in women with POI compared to controls (550 μm (500-615) versus 684 μm (618-737), p < 0.01). The calculated 10-year CVD risk was 5.9% (IQR: 3.7-10.6) versus 6.0% (IQR: 3.9-9.0) (p = 0.31) and current CHS was 6.1 (1.9) versus 6.5 (1.6) (p = 0.07), respectively in POI versus controls. CONCLUSIONS:Middle age women with POI presented with more unfavorable cardiovascular risk factors (increased waist circumference and a higher prevalence of hypertension and MetS) compared to age and BMI matched population controls. In contrast, the current study reveals a lower cIMT and similar 10-year cardiovascular disease risk and cardiovascular health score. In summary, neither signs of premature atherosclerosis nor a worse cardiovascular disease risk or health score were observed among middle age women with POI compared to population controls. Longer-term follow-up studies of women of more advanced age are warranted to establish whether women with POI are truly at increased risk of developing CVD events later in life. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02616510.
Serum androgen profiles in women with premature ovarian insufficiency: a systematic review and meta-analysis.
Soman Midhun,Huang Li-Cong,Cai Wen-Hui,Xu Jun-Bi,Chen Jun-Yao,He Ren-Ke,Ruan Heng-Chao,Xu Xiang-Rong,Qian Zhi-Da,Zhu Xiao-Ming
Menopause (New York, N.Y.)
OBJECTIVE:This meta-analysis aims to investigate serum androgen profiles (testosterone, dehydroepiandrosterone sulfate, androstenedione, and sex hormone-binding globulin) in women with premature ovarian failure and to establish if there is evidence of diminished androgen levels in these women. METHODS:Various Internet sources of PubMed, Cochrane library, and Medline were searched systematically until February, 2018. Out of a pool of 2,461 studies, after applying the inclusion/exclusion criterion, 14, 8, 10, and 9 studies were chosen for testosterone, dehydroepiandrosterone sulfate, androstenedione, and sex hormone-binding globulin, respectively, for this meta-analysis. The effect measure was the standardized mean difference with 95% confidence interval (95% CI) in a random-effects model. RESULTS:The testosterone concentrations in premature ovarian insufficiency were compared with fertile controls: stamdard mean difference (IV, random, 95% CI) -0.73 [-0.99, -0.46], P value < 0.05. The dehydroepiandrosterone sulfate concentrations in premature ovarian insufficiency compared to fertile controls: standard mean difference (IV, random, 95% CI) -0.65 [-0.92, -0.37], P value < 0.05. Androstenedione in premature ovarian insufficiency were compared with fertile controls: standard mean difference (IV, random, 95% CI) -1.09 [-1.71, -0.48], P value < 0.05. Sex hormone-binding globulin levels did not show statistical significance. The dehydroepiandrosterone sulfate levels were reduced in premature ovarian insufficiency cases, but still showed a higher level than in postmenopausal women. CONCLUSIONS:Women with premature ovarian insufficiency are at risk for decreased concentrations of testosterone, dehydroepiandrosterone sulfate, and androstenedione. Dehydroepiandrosterone sulfate levels were more reduced in postmenopausal controls when compared with premature ovarian insufficiency cases.
Identifying and addressing osteoporosis knowledge gaps in women with premature ovarian insufficiency and early menopause: A mixed-methods study.
Goh Maylyn,Nguyen Hanh H,Khan Nadia N,Milat Frances,Boyle Jacqueline A,Vincent Amanda J
OBJECTIVE:Osteoporosis associated with premature ovarian insufficiency (POI) and early menopause (EM) is a major concern for women. We aimed to (a) identify information and knowledge gaps and behaviours regarding bone health in women with POI/EM and (b) co-design an osteoporosis fact sheet. DESIGN:Mixed-methods study: survey of women and online resource appraisals to develop and refine, using semi-structured interviews, an osteoporosis fact sheet. PATIENTS:Women with POI/EM (menopause before ages 40 and 45 years respectively). MEASUREMENTS:Demographics, comorbidities, information needs, calcium intake, exercise, osteoporosis knowledge (OKAT), beliefs and self-efficacy, DISCERN appraisal (validated scales). ANALYSIS:descriptive statistics, logistic regression and thematic analysis of interviews. RESULTS:Median age of survey respondents (n = 316) was 54(IQR47-63) years, median age of menopause was 40(IQR38-43) years, and osteoporosis diagnosis was reported in 19%. Most reported inadequate dietary calcium intake (99%) and exercise (65%). Median OKAT score 8 [IQR6-10]/19 indicated knowledge gaps regarding risk factors and treatment options. Adjusting for age and education, OKAT predicted calcium intake (OR 1.126 [CI 1.035-1.225]; P = 0.006) and screening (OR 1.186 [CI 1.077-1.305]; P = 0.001); beliefs predicted screening (OR 1.027 [CI 1.004-1.050]; P = 0.019); and self-efficacy predicted calcium intake (OR1.040 (CI 1.013-1.069); P = 0.003] and exercise (OR 1.117 [CI 1.077-1.160]; P < 0.001). Current online resources have deficiencies. Five themes identified from two interview rounds (n = 10/ round) were as follows: content, emotional response, design, perceived usefulness and clinical considerations. The final fact sheet was considered acceptable and useful in addressing knowledge gaps, promoting information-seeking, impacting behaviours and facilitating healthcare discussions. CONCLUSION:A co-designed fact sheet is acceptable and addresses identified osteoporosis knowledge gaps in women with POI/EM.
Psychosocial Vulnerability, Resilience Resources, and Coping with Infertility: A Longitudinal Model of Adjustment to Primary Ovarian Insufficiency.
Driscoll Mary A,Davis Mary C,Aiken Leona S,Yeung Ellen W,Sterling Evelina Weidman,Vanderhoof Vien,Calis Karim Anton,Popat Vaishali,Covington Sharon N,Nelson Lawrence M
Annals of behavioral medicine : a publication of the Society of Behavioral Medicine
BACKGROUND:The infertility associated with primary ovarian insufficiency (POI) presents significant emotional challenges requiring psychosocial adjustment. Few investigations have explored the longitudinal process of adaptation to POI. PURPOSE:This longitudinal investigation tests a model of adjustment to POI that includes separate psychosocial vulnerability and resilience resource factors. METHODS:Among 102 women with POI, personal attributes reflective of vulnerability and resilience were assessed at baseline. Coping strategies were assessed 4 months later and measures of distress and well-being 12 months later. RESULTS:As hypothesized, confirmatory factor analysis yielded separate, inversely correlated vulnerability and resilience resource factors at baseline, and distress and well-being factors at 12 months. Contrary to predictions, maladaptive and adaptive coping strategies were not bi-factorial. Moreover, a single stand-alone strategy, avoidance (i.e., refusing to acknowledge stress), mediated the association between baseline vulnerability and 12-month distress. CONCLUSIONS:For women with POI, interventional studies targeted to reduce avoidance are indicated.
Long-term health consequences of premature or early menopause and considerations for management.
Faubion S S,Kuhle C L,Shuster L T,Rocca W A
Climacteric : the journal of the International Menopause Society
AIM:To review the current evidence concerning the long-term harmful effects of premature or early menopause, and to discuss some of the clinical implications. MATERIAL AND METHODS:Narrative review of the literature. RESULTS:Women undergoing premature or early menopause, either following bilateral salpingo-oophorectomy or because of primary ovarian insufficiency, experience the early loss of estrogen and other ovarian hormones. The long-term consequences of premature or early menopause include adverse effects on cognition, mood, cardiovascular, bone, and sexual health, as well as an increased risk of early mortality. The use of hormone therapy has been shown to lessen some, although not all of these risks. Therefore, multiple medical societies recommend providing hormone therapy at least until the natural age of menopause. It is important to individualize hormone therapy for women with early estrogen deficiency, and higher dosages may be needed to approximate physiological concentrations found in premenopausal women. It is also important to address the psychological impact of early menopause and to review the options for fertility and the potential need for contraception, if the ovaries are intact. CONCLUSIONS:Women who undergo premature or early menopause should receive individualized hormone therapy and counseling.
The Role of Premature Ovarian Failure Awareness in Female Sexual Functions and Distress.
Aydin Serdar,Ateş Seda,Arioğlu Aydin Çağri,Batmaz Gonca
Journal of sex & marital therapy
The diagnosis of premature ovarian failure is traumatic to women, with loss of gonadal functions having been associated with distress and anxiety. The aim of this study is to evaluate the sexual function and distress of women with premature ovarian failure before the diagnosis. Women with premature ovarian failure and age-matched controls were evaluated through the Female Sexual Function Index and the Female Sexual Distress Scale-Revised, and their androgen levels were compared. The major finding of this study is the lack of difference between sexual function in women who are unaware that they have premature ovarian failure and age-matched women with normal gonadal function.
Impact of a premature menopause on cognitive function in later life.
Ryan J,Scali J,Carrière I,Amieva H,Rouaud O,Berr C,Ritchie K,Ancelin M-L
BJOG : an international journal of obstetrics and gynaecology
OBJECTIVE:To determine whether premature menopause (≤40 years) can have long-lasting effects on later-life cognition and investigate whether this association varies depending on the type of menopause and use of hormone treatment (HT). DESIGN:Population-based cohort study. SETTING:The French Three-City Study. POPULATION:Four thousand eight hundred and sixty-eight women aged at least 65 years. METHODS:Multivariable-adjusted logistic regression models were used to determine the association between age at menopause, type of menopause (surgical, natural), and the use of menopausal HT and later-life cognitive function. MAIN OUTCOME MEASURES:Performance on a cognitive test battery (at baseline and over 7 years) and clinical dementia diagnosis. RESULTS:Menopause at or before the age of 40 years, both premature bilateral ovariectomy and premature ovarian failure (non-surgical loss of ovarian function), was associated with worse verbal fluency (OR 1.56, 95%CI 1.12-1.87, P=0.004) and visual memory (OR 1.39, 95%CI 1.09-1.77, P=0.007) in later life. HT at the time of premature menopause appeared beneficial for later-life visual memory but increased the risk of poor verbal fluency. Type of menopause was not significantly associated with cognitive function. Premature menopause was associated with a 30% increased risk of decline in psychomotor speed and global cognitive function over 7 years. CONCLUSION:Both premature surgical menopause and premature ovarian failure were associated with long-term negative effects on cognitive function, which are not entirely offset by menopausal HT. In terms of surgical menopause, these results suggest that the potential long-term effects on cognitive function should form part of the risk/benefit ratio when considering ovariectomy in younger women.