Dyslipidemia in midlife women: Approach and considerations during the menopausal transition.
Maturitas
Dyslipidemia is an established risk factor for cardiovascular disease (CVD), which remains the leading cause of morbidity and mortality in women globally. The incidence of dyslipidemia increases over a woman's lifespan, with adverse changes around the time of menopause. Menopause, and the years leading up to the final menstrual period, is a time of estrogen fluctuation and ultimately estrogen deficiency, which has been associated with proatherogenic changes in the lipid profile. Independent of aging, menopausal status is associated with elevations in serum total cholesterol, LDL cholesterol, apolipoproteins, and triglycerides, and decreases in HDL cholesterol (HDL-C). Emerging research also suggests that after menopause there is a loss of functional HDL cardioprotective properties. Early initiation of menopausal hormone therapy (MHT) confers a favorable effect on lipid profile, though this does not translate into improved CVD outcomes and therefore guidelines do not indicate it for primary or secondary prevention of CVD. At the time of menopause, special consideration should be given to women with conditions more associated with CVD, including polycystic ovarian syndrome, premature menopause, early menopause, premature ovarian insufficiency, and familial hypercholesterolemia. Statins remain the mainstay of dyslipidemia therapy, though novel lipid-lowering agents are emerging. This review provides an overview of lipid alterations observed during the menopausal transition, summarizes the current evidence on the role of estrogen and progestogen on lipids, identifies special populations of women at especially high risk for lipid dysregulation at menopause, and describes approaches to the screening and treatment of midlife women.
10.1016/j.maturitas.2022.08.001
Perfluorooctanoic Acid Disrupts Ovarian Steroidogenesis and Folliculogenesis in Adult Mice.
Toxicological sciences : an official journal of the Society of Toxicology
Perfluorooctanoic acid (PFOA) is a synthetic fluorosurfactant used in the manufacturing of fluorotelomers. Although PFOA is no longer produced in the United States, it is environmentally persistent and found in imported food packaging, cookware, and textiles. Previous studies have identified developmental toxicity of PFOA, but little is known about the effects of PFOA on the adult ovary. Thus, this study examined the effects of PFOA on hormone levels, ovarian steroidogenic gene expression, and folliculogenesis in mice in vitro and in vivo. For the in vitro studies, antral follicles from adult female mice were cultured with vehicle control or 1, 10, or 100 μg/ml PFOA for 96 h. For the in vivo studies, adult CD-1 female mice were orally dosed with vehicle control or 1, 5, 10, or 20 mg/kg/day PFOA for 10 days. Gene expression of steroidogenic enzymes, levels of sex steroid hormones, and follicle counts were analyzed. In vitro, PFOA (100 μg/ml) significantly decreased follicle growth, estradiol and estrone levels, and gene expression of StaR, Cyp11a1, and Hsd3b1 compared with controls. In vivo, exposure to PFOA significantly decreased progesterone and pregnenolone levels (5 mg/kg), increased testosterone levels (1 mg/kg), and increased gene expression of Cyp19a1 (1 mg/kg) compared with controls. Exposure to PFOA also significantly altered follicle counts by decreasing primordial follicles and increasing preantral and antral follicles (5 and 10 mg/kg) compared with controls. Collectively, these data show that PFOA disrupts adult ovarian function in a nonmonotonic matter and may pose a risk for premature ovarian failure.
10.1093/toxsci/kfac005
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.
10.1111/jog.14659
Protective Effects of Platelet-rich plasma for in vitro Fertilization of Rats with Ovarian Failure Induced by Cyclophosphamide.
Revista brasileira de ginecologia e obstetricia : revista da Federacao Brasileira das Sociedades de Ginecologia e Obstetricia
OBJECTIVE: Premature ovarian insufficiency (POI) contributes significantly to female infertility. Cyclophosphamide (CYC has adverse effects on folliculogenesis. Platelet-rich plasma (PRP) is an autologous product rich in many growth factors. We evaluated the protective effect of PRP on in vitro fertilization in female rats with CYC-induced ovarian damage. METHODS: Twenty-eight adult female Sprague-Dawley rats were randomly divided into four groups. Group 1 (control-sodium chloride 0.9%; 1 mL/kg, single-dose intraperitoneal [IP] injection); group 2 (CYC), 75 mg/kg, single-dose IP injection and sodium chloride 0.9% (1 mL/kg, single-dose IP injection); group 3 CYC plus PRP, CYC (75 mg/kg, single-dose and PRP (200 μl, single-dose) IP injection); and group 4 (PRP, 200 μl, single-dose IP injection). RESULTS: In the comparisons in terms of M1 and M2 oocytes, it was observed that the CYC group presented a significantly lower amount than the control, CYC/PRP, and PRP groups. (for M1, = 0.000, = 0.029, = 0.025; for M2, = 0.009, = 0.004, = 0.000, respectively). The number of fertilized oocytes and two-celled good quality embryos was found to be statistically significant between the CYC and control groups, CYC + PRP and PRP groups ( = 0.009, = 0.001, = 0.000 for oocytes, respectively. For embryos; = 0.016, = 0.002, = 0.000). CONCLUSION: Platelet-rich plasma can protect the ovarian function against damage caused by CYC, and, in addition, it improves oocyte count and the development of embryos as a result of oocyte stimulation during the IVF procedure.
10.1055/s-0041-1741451
Can mesenchymal stem cells derived from adipose tissue and their conditioned medium improve ovarian functions? A mini-review.
Zygote (Cambridge, England)
Stable ovarian function is a key factor in the performance of the reproductive system. In contrast, some ovarian function-related diseases, such as polycystic ovarian syndrome, premature ovarian failure (POF), and ovarian cancer, are the main cause of infertility and death of women around the world. Despite multiple attempts, there are no effective tools against these conditions; however, mesenchymal stem cell-based therapy, especially using adipose tissue, has attracted much attention in medicine in light of its advantages such as easy isolation and accessibility. Conversely, it has been suggested that MSC-conditioned medium (CM) can restore injured tissues and has high immunocompatibility. So, here, we will summarize the effects of administration of MSCs and CM derived from adipose tissue on ovarian functions and related diseases.
10.1017/S0967199422000235
Evaluation of Serum AMH, INHB Combined with Basic FSH on Ovarian Reserve Function after Laparoscopic Ovarian Endometriosis Cystectomy.
Frontiers in surgery
Objective:The value of serum AMH, INHB, and bFSH levels in assessing postoperative ovarian reserve function was analyzed by measuring serum anti-Mullerian hormone (AMH), inhibin B (INHB), and basal follicle-stimulating hormone (bFSH) levels in patients after laparoscopic cystectomy for endometrioma. Methods:From June 2019 to December 2021, 124 patients underwent laparoscopic cystectomy for endometrioma in our hospital were selected, and the serum AMH, INHB, bFSH level, antral follicle count (AFC) of all patients before and after operation were detected and compared. According to the results of postoperative testing, all the patients were divided into normal group ( = 86), diminished ovarian reserve (DOR) group ( = 27), and premature ovarian failure (POF) group ( = 11). Pearson correlation model and subject operating characteristic curve (ROC) were used to analyze the correlation and diagnostic value of serum AMH, INHB and bFSH levels with postoperative ovarian reserve function, respectively. Results:After operation, the levels of serum AMH, INHB and AFC in the DOR group and POF group decreased compared with those before the operation, and the serum bFSH levels increased (< 0.05). After operation, the levels of serum AMH, INHB and AFC in DOR group and POF group were lower than those in normal group,and the serum bFSH levels were higher than the normal group; the levels of serum AMH, INHB and AFC in POF group were lower than those in DOR group, and the serum bFSH levels were higher than the DOR group (< 0.05). Pearson analysis showed that serum AMH and INHB levels were negatively correlated with bFSH, and positively correlated with the number of AFC, the serum bFSH level was negatively correlated with the number of AFC (< 0.05). The diagnostic values of serum AMH, bFSH, INHB and the combination of the three tests for postoperative abnormal ovarian reserve function were 0.866 (95% CI, 0.801-0.923), 0.810 (95% CI, 0.730-0.890), 0.774 (95% CI, 0.687-0.860) and 0.940 (95% CI, 0.900-0.981), respectively. Conclusion:Serum AMH and INHB levels decreased and bFSH levels increased in patients after laparoscopic cystectomy for endometrioma, both of which were closely related to postoperative ovarian reserve function, and both could evaluate ovarian reserve function after ovarian cyst debulking, and the combined test could significantly improve the detection rate.
10.3389/fsurg.2022.906020
The role of oxidative stress on subclinical atherosclerosis in premature ovarian insufficiency and relationship with carotid intima-media thickness.
Bozkaya Veciha Özlem,Yumusak Omer Hamid,Ozaksit Gulnur,Tenekecioğlu Erhan,Gül Ibrişim Ece,Alkan Mihriban,Oskovi-Kaplan Z Aslı,Erel Özcan
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology
We aimed to investigate the relationship between oxidative stress (OS) and subclinical atherosclerosis in patients with premature ovarian insufficiency (POI), by analyzing the dynamic thiol/disulfide homeostasis (TDH) parameters as an OS marker and carotid intima-media thickness (CIMT).: A total of 69 women, 34 with POI and 35 healthy controls were included in this prospective cross-sectional study. TDH parameters (plasma native thiol, total thiol, disulfide, disulfide/native thiol, native thiol/total thiol, and disulfide/total thiol ratios) and CIMT were measured and compared between the two groups. In primary ovarian insufficiency group, native thiol (=.009) and total thiol (=.010) levels were significantly decreased, and CIMT values were significantly increased (= <.001). CIMT values were negatively correlated with native thiol (=-0.553, =.001) and total thiol levels (=-0.565, =.001); and positively correlated with age ( = 0.457, =.007), BMI ( = 0.408, =.017), and total cholesterol ( = 0.605, <.001) in POI group. Decreased native thiol and total thiol levels demonstrate the defective anti-oxidant mechanism in POI. Negative correlation between native thiol, total thiol levels, and CIMT means the presence of abnormal anti-oxidant mechanisms may play a role in the development of subclinical atherosclerosis in patients with POI. This is a novel report on the mechanism of subclinical atherosclerosis in women with POI, which needs to be supported with further studies evaluating the pathophysiology of OS.
10.1080/09513590.2020.1766439
Serum biomarker analysis in patients with premature ovarian insufficiency.
Cytokine
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.
10.1016/j.cyto.2019.154876
Immunomodulatory effect of human amniotic epithelial cells on restoration of ovarian function in mice with autoimmune ovarian disease.
Zhang Qiuwan,Huang Yating,Sun Junyan,Gu Tingting,Shao Xiaoyan,Lai Dongmei
Acta biochimica et biophysica Sinica
Autoimmune ovarian disease (AOD) is considered to be a major cause of premature ovarian failure (POF). The immunomodulatory properties of human amniotic epithelial cells (hAECs) have been studied in many disease models. We previously reported that hAECs restored ovarian function in chemotherapy-induced POF mice, but the immunomodulatory mechanism of hAECs is still unclear. To investigate the effect of hAECs on recipient mice, especially on regulatory Treg cells, hAECs and hAEC-conditioned medium (hAEC-CM) were intravenously injected into AOD mice immunized with zona pellucida protein 3 peptides (pZP3). Ovarian function was evaluated through estrous cycle, hormone secretion, follicle development, and cell apoptosis analysis. Immune cells including CD3, CD4, CD8 and Treg cells in the spleens were tested by flow cytometry. To elucidate the effect of hAEC-CM on macrophage function, inflammation model in vitro was established in RAW264.7 cells induced by lipopolysaccharide (LPS). hAECs and hAEC-CM regulated estrous cycles, promoted follicle development, ameliorated cell apoptosis and fibrosis in ovaries of AOD mice. In addition, hAECs significantly reversed the decrease of pZP3-induced Treg cells in the spleens. In vitro, hAEC-CM significantly inhibited the inflammatory reaction induced by LPS in RAW264.7 cells via up-regulating the expression of M2 macrophage genes. Further study demonstrated that hAEC-secreted transforming growth factor-beta and macrophage inhibitory factor played important roles in the macrophage polarization and migration under inflammatory stimulation. Taken together, hAECs restored ovarian function by up-regulating Treg cells in the spleens and reduced the inflammatory reaction via modulating the activated macrophage function in a paracrine manner in the ovaries of AOD mice.
10.1093/abbs/gmz065
Early menopause and other gynecologic risk indicators for chronic fatigue syndrome in women.
Menopause (New York, N.Y.)
OBJECTIVE:This study aims to examine whether gynecologic conditions are associated with chronic fatigue syndrome (CFS). METHODS:This study includes a subset of 157 women from a population-based case-control study in Georgia, United States, conducted in 2004-2009. Gynecologic history was collected using a self-administered questionnaire. Crude odds ratios (ORs) with 95% CIs and ORs adjusted for body mass index and other covariates, where relevant, were estimated for gynecologic conditions between 84 CFS cases and 73 healthy controls. RESULTS:Cases and controls were of similar age. Women with CFS reported significantly more gynecologic conditions and surgical operations than controls: menopause status (61.9% vs 37.0%; OR, 2.37; 95% CI, 1.21-4.66), earlier mean age at menopause onset (37.6 vs 48.6 y; adjusted OR, 1.22; 95% CI, 1.09-1.36), excessive menstrual bleeding (73.8% vs 42.5%; adjusted OR, 3.33; 95% CI, 1.66-6.70), bleeding between periods (48.8% vs 23.3%; adjusted OR, 3.31; 95% CI, 1.60-6.86), endometriosis (29.8% vs 12.3%; adjusted OR, 3.67; 95% CI, 1.53-8.84), use of noncontraceptive hormonal preparations (57.1% vs 26.0%; adjusted OR, 2.95; 95% CI, 1.36-6.38), nonmenstrual pelvic pain (26.2% vs 2.7%; adjusted OR, 11.98; 95% CI, 2.57-55.81), and gynecologic surgical operation (65.5% vs 31.5%; adjusted OR, 3.33; 95% CI, 1.66-6.67), especially hysterectomy (54.8% vs 19.2%; adjusted OR, 3.23; 95% CI, 1.46-7.17). Hysterectomy and oophorectomy occurred at a significantly younger mean age in the CFS group than in controls and occurred before CFS onset in 71% of women with records of date of surgical operation and date of CFS onset. CONCLUSIONS:Menstrual abnormalities, endometriosis, pelvic pain, hysterectomy, and early/surgical menopause are all associated with CFS. Clinicians should be aware of the association between common gynecologic problems and CFS in women. Further work is warranted to determine whether these conditions contribute to the development and/or perpetuation of CFS in some women.
10.1097/GME.0000000000000411
Screening of follicle-stimulating hormone receptor gene in women with premature ovarian failure in southern Brazil and associations with phenotype.
Vilodre L C,Kohek M B F,Spritzer P M
Journal of endocrinological investigation
We investigated the presence of mutations/polymorphisms in the FSH receptor (FSHR) gene and their association with phenotype in women with premature ovarian failure (POF) in southern Brazil. Clinical and hormonal variables were determined in 36 46,XX women with primary or secondary amenorrhea before the age of 40 yr, FSH >40 IU/l and ovarian failure. DNA was isolated from peripheral leukocytes. Exons 6, 7, 9, and 10 of the FSHR gene were analyzed by PCR, restriction enzyme analysis, denaturing gradient gel electrophoresis, and direct sequencing. No inactivating mutations were found. Exon 10 had two polymorphisms, Ala307Thr and Ser680Asn (allelic frequency: 52.9 and 35.7%, respectively), which were not related to FSH, LH or estradiol serum levels. Ovarian size and small ovarian follicles on transvaginal sonography were not associated with FSHR genetic variants. In contrast, the last menstruation occurred significantly earlier in patients with the Ala307Thr polymorphism (A: age=33.3+/-7.1 yr vs T: 28.6+/-11.4 yr, p=0.04). In conclusion, we did not identify inactivating mutations in exons 6, 7, 9, and 10 of the FSHR gene. A high frequency of two polymorphisms that are in linkage disequilibrium was found in exon 10 of the FSHR gene. The presence of the Ala307Thr polymorphism may be associated with a more precocious onset of clinical disease.
10.1007/BF03346407
Utility of complete blood count parameters to detect premature ovarian insufficiency in cases with oligomenorrhea/amenorrhea.
Sanverdi Ilhan,Kilicci Cetin,Cogendez Ebru,Abide Yayla Cigdem,Ozkaya Enis
Journal of clinical laboratory analysis
BACKGROUND:There are very few biomarkers available to diagnose cases with premature ovarian failure. Some complete blood count parameters have been introduced to be diagnostic biomarkers for several disorders associated with inflammatory process. Due to the evidence that indicated chronic inflammatory process to be underlying pathophysiology in premature ovarian insufficiency (POI), we aimed to assess the predictive value of complete blood count parameters for POI diagnosis. METHOD:A total of 96 women diagnosed to have premature ovarian failure were compared with 110 otherwise healthy women in terms of some basal hormone levels and complete blood count parameters. RESULTS:Mean age was similar between groups. Neutrophil/lymphocyte and mean platelet volume/lymphocyte ratios were significantly higher in group with POI (P < .001, P < .003, respectively). In group with POI, there were significant correlations between anti-Mullerian hormone and follicle stimulating hormone (r = -.30, P <.05), anti-Mullerian hormone and white blood cell count (r = .23, P < .05). Mean platelet volume/lymphocyte ratio significantly predicted cases with POI (AUC = 0.607, %95 CI: 0.529-0.684; P < .001). CONCLUSIONS:Neutrophil/lymphocyte and mean platelet volume/lymphocyte ratios are elevated in POI. There have been some controversies about the value of neutrophil/lymphocyte in POI diagnosis. We suggest mean platelet volume/lymphocyte ratio as a new biomarker in early POI because it is cheap and easily accessible compared to anti-Mullerian hormone.
10.1002/jcla.22372
A prospective study of inflammatory biomarker levels and risk of early menopause.
Bertone-Johnson Elizabeth R,Manson JoAnn E,Purdue-Smithe Alexandra C,Hankinson Susan E,Rosner Bernard A,Whitcomb Brian W
Menopause (New York, N.Y.)
OBJECTIVE:Early menopause, the cessation of ovarian function before age 45, has consequences for fertility and cardiovascular health. Evidence from studies of women with autoimmune conditions and genetic studies supports a role for inflammation in early menopause, but the association of inflammatory markers and risk has not been directly evaluated. METHODS:We assessed the relation of the soluble fraction of tumor necrosis factor alpha receptor 2 (sTNFR2), C-reactive protein, interleukin-6 (IL6) levels with incident early menopause among Nurses' Health Study II participants who provided a premenopausal blood sample in 1996 to 1999. Cases (n = 328) were women reporting natural menopause between blood collection and age 45.Controls (n = 492) included (1) 328 women with menopause after age 47, matched 1:1 with cases on age at blood collection and other factors; and (2) 164 additional women with menopause after age 45. RESULTS:In multivariable models comparing cases and n = 492 controls, we observed a significant association of sTNFR2 levels and risk of early menopause (P = 0.002). Compared with women with the lowest sTNFR2 levels, odds ratios (95% CIs) for quartiles 2 to 4 were 0.60 (0.38-0.95), 0.93 (0.61-1.43), and 1.40 (0.93-2.11). Results further adjusting for antimüllerian hormone levels were similar in magnitude, as were results from sensitivity analyses of matched cases and controls (n = 328 pairs), nonsmokers, and leaner women. C-reactive protein and IL6 levels were unrelated to risk. CONCLUSIONS:The observation of lower risk of early menopause among women with moderate sTNFR2 levels compared with women with lower and higher levels warrants further prospective study.
10.1097/GME.0000000000001162
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.
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).
10.22074/IJFS.2020.134678
Association between premature ovarian insufficiency, early menopause, socioeconomic status in a nationally representative sample from Korea.
Lim Young-Mee,Jeong Kyungah,Lee Sa Ra,Chung Hye Won,Lee Wanhyung
Maturitas
OBJECTIVE:We investigated whether, in the Korean population, the risk of premature ovarian insufficiency (POI) and early menopause varies with a woman's socioeconomic status, evaluated in relation to income, education, and occupation. METHODS:This cross-sectional, population-based study involved 31,508 women aged >19 years registered in the Korea National Health and Nutrition Examination Survey (KNHANES) (2007-2016). Menopausal status and socioeconomic status were obtained from self-reported KNHANES data. A logistic regression model was applied to test whether POI and early menopause varied with socioeconomic status. RESULTS:The prevalence of POI was 2.41% and of early menopause was 5.89%. The annual incidence of POI during the investigation period plateaued, while that of early menopause showed a linear trend. The risk of POI was significantly higher among participants with lower household incomes (odds ratio [OR], 95% confidence interval [CI]; 1.44, 1.16-1.78) and lower levels of education (OR, 95% CI: 1.75, 1.16-2.65) after adjustment for age. CONCLUSION:The prevalence of POI in the Korean population was almost twice that reported in a previous study. Lower socioeconomic status was associated with an increased risk of POI and early menopause. Further studies are warranted to investigate this association.
10.1016/j.maturitas.2018.12.004
Risk of premature ovarian failure is associated to the PvuII polymorphism at estrogen receptor gene ESR1.
Cordts Emerson Barchi,Santos Aline Amaro,Peluso Carla,Bianco Bianca,Barbosa Caio Parente,Christofolini Denise Maria
Journal of assisted reproduction and genetics
PURPOSE:Estrogen plays an important role in the human reproductive system and it action is mediated mainly by two specific receptors: α (ERα) and β (ERβ). There were described polymorphic variants in ESR1 and ESR2 genes and studies showed controversial results regarding their association with premature ovarian failure. We aimed to determine the prevalence of ESR1 and ESR2 polymorphisms in Brazilian patients and controls. After associate the polymorphisms with premature ovarian failure (POF). METHODS:Genetic association study was performed with 70 women with POF and 73 normally menopaused controls. Detection of ESR1 (PvuII/and XbaI) and ESR2 (AluI and RsaI) gene polymorphisms were performed using TaqMan PCR. The single-nucleotide polymorphism (SNPs) and haplotype effects were analyzed by multivariate logistic regression and haplotype analysis and a p-value < 0.05 was considered significant. RESULTS:Individual SNP analysis revealed that PvuII polymorphism was statistically associated with POF (p = 0.034) under a recessive model. Regarding XbaI, AluI and RsaI SNPs, no statistical difference was observed between POF group and controls (p = 0.575, p = 0.258 and p = 0.483, respectively). Combined genotypes of ESR1 and ESR2 polymorphisms did not identify a risk haplotype associated with POF. CONCLUSION:In Brazilian population evaluated results have demonstrated that the genetic variation in ESR1 gene (PvuII polymorphism) is associated to POF risk.
10.1007/s10815-012-9884-x
Vaginal Microbiota Changes in Patients With Premature Ovarian Insufficiency and Its Correlation With Ovarian Function.
Frontiers in endocrinology
Objectives:To reveal the characteristics of vaginal microbiota in premature ovarian insufficiency (POI) patients and their relationship with ovarian function. Materials and Methods:In this case-control study, the vaginal bacterial composition of 30 POI patients and 26 healthy women of comparable age was assessed by 16S rRNA gene sequencing targeting the V3-V4 hypervariable regions. The metabolic functions of vaginal microflora were preliminarily predicted through the PICRUSt2 analysis. Redundancy analysis and Spearman's correlation analyzed the relationships between vaginal microbiota and ovarian function indicators. Results:, , and were significantly increased in POI patients. Their increments were significantly negatively correlated with anti-müllerian hormone (AMH) and inhibin B, and positively correlated with follicle-stimulating hormone (FSH) and luteinizing hormone (LH). While was significantly decreased in POI patients. Its relative abundance was significantly positively correlated with AMH and negatively correlated with FSH and LH. Then, POI patients included in this study were divided into POI (25 < FSH ≤ 40) ( = 9) and premature ovarian failure (POF) (FSH > 40) ( = 21) subgroups according to serum FSH levels. Compared with the controls, and were significantly decreased only in POF (FSH > 40) patients, while no difference was observed in POI (25 < FSH ≤ 40) patients. was negatively correlated with FSH. was significantly reduced and was significantly increased in POF (FSH > 40) patients compared with POI (25 < FSH ≤ 40) patients. The key bacterial taxa and showed potency in predicting POI. Conclusions:Here we demonstrated significant changes in the vaginal microbiota of POI patients, and these changes were significantly correlated with reduced ovarian reserve, endocrine disruption, and symptoms of perimenopausal syndrome. Differences in vaginal microbiota between POI (25 < FSH ≤ 40) and POF (FSH > 40) patients were also identified. These findings may provide new evidence for the relationship between vaginal microbiota and ovarian function.
10.3389/fendo.2022.824282
Ovarian failure risk in post-pubertal patients with cancer: a prognostic model.
Future oncology (London, England)
To develop a predictive model for ovarian failure (OF) after chemotherapy in young post-pubertal women with cancer. Retrospective, monocentric cohort study including 348 patients referring to the Oncofertility Unit of San Raffaele Hospital (Milan, Italy) from August 2011 to January 2020. A predictive model was constructed by multivariate logistic regression and receiver operating characteristic analysis. Data about menstrual function resumption were available for 184 patients. The best predictive model for OF was identified by the combination of age; number of chemotherapy lines; vincristine, adriamycin, ifosphamide/adriamycin, ifosphamide; capecitabine; adriamycin, bleomycine, vinblastine, doxorubicin (area under the curve = 0.906; CI 95% 0.858-0.954; p = 0.0001). The model predicts the probability of loss of ovarian function at cancer diagnosis and with every change of treatment.
10.2217/fon-2022-0078
The Use of Thiol/Disulfide as a Novel Marker in Premature Ovarian Failure.
Isik Hatice,Sahbaz Ahmet,Timur Hakan,Aynioglu Oner,Atalay Mert Sule,Balık Ahmet Rıfat,Erel Ozcan,Harma Muge
Gynecologic and obstetric investigation
The study aimed to compare the dynamic thiol/disulfide homeostasis between patients with premature ovarian failure (POF) and healthy women. A total of 77 women, 40 POF and 37 healthy controls, were recruited from a university hospital between December 2013 and June 2015. Blood samples were taken from patients to evaluate follicle stimulating hormone (FSH), luteinizing hormone, estradiol and thiol/disulfide levels. A new, fully automated method was used to measure plasma thiol, total thiol and disulfide levels. Disulfide levels, disulfide/native thiol and disulfide/total thiol ratios were significantly increased, native thiol/total thiol levels were significantly decreased in POF patients compared to controls (p < 0.001). FSH was negatively correlated with native thiol and native thiol/total thiol levels and positively with disulfide, disulfide/native thiol, and disulfide/total thiol levels. This is the first study demonstrating the thiol/disulfide homeostasis in women with POF and may help us understanding the pathophysiology.
10.1159/000445745
The association of premature ovarian failure with ventricular repolarization dynamics evaluated by QT dynamicity.
Canpolat Uğur,Tokgözoğlu Lale,Yorgun Hikmet,Bariş Kaya Ergün,Murat Gürses Kadri,Şahiner Levent,Bozdağ Gürkan,Kabakçi Giray,Oto Ali,Aytemir Kudret
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology
AIMS:The association between premature ovarian failure (POF) and cardiovascular diseases has been investigated in a few studies, but none have looked at ventricular repolarization abnormalities in these patients. In this study, we aimed to evaluate the ventricular repolarization by QT dynamicity in patients with POF. METHODS AND RESULTS:We enrolled 26 female patients (mean age 37.5 ± 10.1 years) with primary POF and 31 healthy female subjects (mean age 37.5 ± 9.0 years). The linear regression slopes of the QT interval measured to the apex and to the end of the T-wave plotted against RR intervals (QTapex/RR and QTend/RR slopes, respectively) were calculated from 24 h Holter recordings using a standard algorithm. QTapex/RR and QTend/RR slopes were more steeper in the POF patients in contrary to healthy control subjects (QTapex/RR = 0.184 ± 0.022 vs. 0.131 ± 0.019, P < 0.001; QTend/RR = 0.164 ± 0.021 vs. 0.128 ± 0.018, P < 0.001). Pearson's correlation analyses revealed a stronger negative correlation between oestradiol (E2) and QTapex/RR (r = -0.715, P < 0.001). There was also a moderate negative correlation between E2 and QTend/RR (r = -0.537, P < 0.001). Serum follicle-stimulating hormone level was positively correlated with QTapex/RR (r = 0.681, P < 0.001) and QTend/RR (r = 0.531, P < 0.001). CONCLUSIONS:Our study results suggest that QT dynamicity is impaired in patients with POF despite the absence of overt cardiovascular involvement. Further studies are needed to elucidate the prognostic significance and clinical implications of impaired ventricular repolarization in patients with POF.
10.1093/europace/eut093
Is there a link between premature ovarian failure and serum concentrations of vitamin D, zinc, and copper?
Kebapcilar Ayse Gul,Kulaksizoglu Mustafa,Kebapcilar Levent,Gonen Mustafa Sait,Unlü Ali,Topcu Ali,Demirci Fatih,Taner Cüneyt Eftal
Menopause (New York, N.Y.)
OBJECTIVE:The risk of primary ovarian insufficiency (POI) increases in association with autoimmune conditions. Adequate intake of vitamin D (vit D) and trace elements is required for the immune system to function efficiently. The aim of this study was to evaluate vit D, zinc, and copper blood levels in women with POI who had given birth to at least one child and in women with normal menstrual cycles. METHODS:This was a cross-sectional, case-control study involving 63 participants divided into two groups: the study group, which is composed of 35 women with POI, and the control group, which is composed of 28 women with normal menstrual cycles. Serum concentrations of zinc, vit D, and copper were determined for each participant. RESULTS:Women with POI had significantly higher serum copper levels and copper-to-zinc ratio but significantly lower serum vit D and zinc levels when compared with the healthy control group. Serum follicle-stimulating hormone levels were inversely correlated with zinc and vit D levels and positively correlated with the copper-to-zinc ratio and copper levels. Vit D levels were inversely correlated with follicle-stimulating hormone levels, copper-to-zinc ratio, and copper levels and positively correlated with zinc levels. CONCLUSIONS:Most women with POI are deficient in vit D. Zinc, copper, and vit D seem to correlate with hormonal status in the participants. The present study may generate hypotheses for future studies that will investigate the possible mechanisms behind alterations in trace elements and vit D deficiency in women with POI and whether these changes could be used to screen for the risk of developing POI.
10.1097/gme.0b013e31826015ca
Granulin levels in patients with idiopathic premature ovarian failure.
Ersoy Ali Ozgur,Oztas Efser,Ersoy Ebru,Ozler Sibel,Ergin Merve,Yilmaz Nafiye
European journal of obstetrics, gynecology, and reproductive biology
OBJECTIVE:With the prolongation of expected lifespan, premature ovarian failure (POF) has gained increased significance as a crucial female health problem. Here we aimed to investigate the diagnostic value of the levels of the growth factor Granulin, which has been associated with epithelial ovarian carcinoma, in the pathogenesis of POF. STUDY DESIGN:Thirty-one patients with POF and 57 patients as a control group were recruited for this study in a tertiary referral center in the capital of Turkey. Granulin levels and individual characteristics of the two groups were compared. RESULTS:Age and body mass indices were similar between the two groups. Granulin levels in patients with POF (2.94±1.91ng/mL) were significantly lower than in the control group (4.77±1.62ng/mL) (p<0.001). CONCLUSION:Future larger studies should focus on Granulin levels and its correlation with ovarian reserve markers, its clinical applicability, and its possible therapeutic value, thus providing further insight into the role of Granulin in the pathogenesis of POF.
10.1016/j.ejogrb.2015.07.015
MicroRNA-22-3p is down-regulated in the plasma of Han Chinese patients with premature ovarian failure.
Dang Yujie,Zhao Shidou,Qin Yingying,Han Ting,Li Weiping,Chen Zi-Jiang
Fertility and sterility
OBJECTIVE:To determine whether plasma microRNAs (miRNAs) are differentially expressed between women with and without premature ovarian failure (POF), and to uncover the association of miRNAs with risk of POF. DESIGN:Microarray with real-time polymerase chain reaction validation. SETTING:University hospital. PATIENT(S):A total of 140 individuals with premature ovarian failure (POF) and 140 age- and body mass index-matched control subjects of Han Chinese ancestry. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Relative miRNA expression levels in plasma of POF and control group. RESULT(S):Fifty-one differentially expressed miRNAs were identified by chip-based discovery stage between ten patients with POF and ten control subjects, among which nine miRNAs (let-7b-5p, let-7c, miR-15b-5p, miR-22-3p, miR-23a-3p, miR-23b-3p, miR-24-3p, miR-151a-5p, and miR-151b) were selected and validated. The relative expression level of miR-22-3p was significantly down-regulated in POF compared with control subjects. MiR-22-3p yielded a receiver operating characteristic (ROC) curve area of 0.668 (95% confidence interval 0.602-0.733) in discriminating POF from controls. In addition, logistic binary regression analysis and linear regression analysis showed the miR-22-3p to be a protective factor for POF (odds ratio 0.766, 95% CI 0.643-0.912) and negatively associated with serum FSH. Furthermore, bioinformatics analysis indicated that the target function of miR-22-3p was involved in apoptosis, endocytosis, and tumorigenesis. CONCLUSION(S):Mir-22-3p showed a lower expression level in POF and was modestly effective in distinguishing POF from control subjects. The decreased expression of miR-22-3p in plasma of POF may reflect the diminished ovarian reserve and be a consequence of the pathologic process of POF.
10.1016/j.fertnstert.2014.12.106
Analysis on the level of IL-6, IL-21, AMH in patients with auto-immunity premature ovarian failure and study of correlation.
Sun Shulan,Chen Hong,Zheng Xiaoxia,Ma Chuanyan,Yue Ruiqin
Experimental and therapeutic medicine
Expression of interleukin-6 (IL-6), interleukin-21 (IL-21) and anti-müllerian hormone (AMH) in premature ovarian failure (POF) patients were observed to explore the correlation of each indicator and its significance in POF. One hundred and forty-two patients diagnosed with POF in Binzhou City Center Hospital from June 2014 to December 2015 were selected as the observation group. At the same time, another 140 healthy women were selected as the control group. The serum levels of IL-6, IL-2l, AMH, follicle stimulating hormone (FSH) and luteinizing hormone (LH), estradiol (E2), testosterone (T) and basal antral follicle count (AFC), and mean ovarian volume (MOV) were determined and compared; correlation analysis of IL-6, IL-2l and AMH with other indicators was performed. Compared to the control group, the serum levels of IL-6, IL-21, FSH and LH in the observation group were significantly higher (P<0.05), while E2, T, AMH levels in the serum, AFC and MOV were significantly lower (P<0.05). Spearman's correlation analysis showed that IL-6, IL-21 was positively correlated with FSH and LH (P<0.05), but negatively correlated with E2, T and MOV (P<0.05). AMH was negatively correlated with FSH and LH, but positively correlated with E2, T and MOV. Our results showed that the expression of IL-6, IL-21 and AMH were related to the occurrence and development of POF, IL-6, IL-21 and AMH can be used as the primary screening indexes for POF patients.
10.3892/etm.2018.6592
Comparing the Diagnostic Accuracy of Anti-Müllerian Hormone and Follicle Stimulating Hormone in Detecting Premature Ovarian Failure in Iraqi Women by ROC Analysis.
Reports of biochemistry & molecular biology
BACKGROUND:In women premature ovarian failure (POF) is a devastating disease impacting women under the age of 40. This involves a significant decrease in a women's quantity and quality of oocytes, or ovarian reserve (OR). POF can result in long-term physical and psychological health consequences. The earlier treatment can occur to manage this disease, the less likely the individual is going to suffer from the potential consequences. Accurate diagnosis is a critical proponent to ensuring immediate care. A traditional diagnostic marker includes follicular stimulating hormone (FSH). This individual test cannot be used to make a diagnosis in isolation due to the large variability in FSH levels among different women, and throughout a women's menstrual cycle. Anti-Müllerian hormone (AMH) is an alternative diagnostic marker for determining a women's OR. Serum levels of AMH have been shown to be associated with the size of the resting primordial follicle pool. When the levels of AMH are low, this is generally considered to be an indicator of a decline in fertility. In this study, we examined the specificity, sensitivity and accuracy of the FSH assay, against the more recently emerged AMH assay for diagnosing and predicting POR via Receiver Operator Characteristic curve (ROC) analysis. METHODS:A total of 60 participants were enrolled in the study. The POF group included 30 infertile women with POF, the infertile control group included 13 women without POF, and the fertile control group included 17 healthy women. Participants were recruited from the Kamal Al-Samarray Hospital in Bagdad city from December 2017 to March 2018. The age of participants ranged from 19-39 years of age. On day 2 of the menstrual cycle, peripheral blood samples were collected from each participant and the serum levels of AMH and FSH were examined using ELISA. RESULTS:Statistical analysis examining the FSH and AMH assays indicate that measuring AMH levels leads to an increased sensitivity, specificity and accuracy in determining the presence or absence of POF among the control fertile and POF groups. However, when comparing the specificity, sensitivity, and accuracy of AMH to FSH among the POF group and infertile controls, there were no differences among sensitivity, furthermore there was a slight decrease in the accuracy and specificity of AMH compared to FSH. CONCLUSION:Our findings indicate that the serum levels of AMH have higher sensitivity, specificity and accuracy in detecting POR than FSH when comparing the POF patients to healthy fertile controls. As the AMH levels have minimal within-menstrual cycle variation they can therefore be assessed whenever necessary, opposed to FSH, in which the levels vary throughout the menstrual cycle. The role of AMH may therefore hold a more useful role in the early diagnosis of POF.
Polymorphisms within the FANCA gene associate with premature ovarian failure in Korean women.
Pyun Jung-A,Kim Sunshin,Cha Dong Hyun,Kwack KyuBum
Menopause (New York, N.Y.)
OBJECTIVE:This study investigated whether polymorphisms within the Fanconi anemia complementation group A (FANCA) gene contribute to the increased risk of premature ovarian failure (POF) in Korean women. METHODS:Ninety-eight women with POF and 218 controls participated in this study. Genomic DNA from peripheral blood was isolated, and GoldenGate genotyping assay was used to identify single nucleotide polymorphisms (SNPs) within the FANCA gene. RESULTS:Two significant SNPs (rs1006547 and rs2239359; P < 0.05) were identified by logistic regression analysis, but results were insignificant after Bonferroni correction. Six SNPs formed a linkage disequilibrium block, and three main haplotypes were found. Two of three haplotypes (AAAGAA and GGGAGG) distributed highly in the POF group, whereas the remaining haplotype (GGAAGG) distributed highly in the control group by logistic regression analysis (highest odds ratio, 2.515; 95% CI, 1.515-4.175; P = 0.00036). CONCLUSIONS:Our observations suggest that genetic variations in the FANCA gene may increase the risk for POF in Korean women.
10.1097/GME.0b013e3182a4323e
Exposure to polycyclic aromatic hydrocarbons and risk for premature ovarian failure and reproductive hormones imbalance.
Ye Xiaoqing,Pan Wuye,Li Chunming,Ma Xiaochen,Yin Shanshan,Zhou Jianhong,Liu Jing
Journal of environmental sciences (China)
Polycyclic aromatic hydrocarbons (PAHs) are a typical class of persistent organic pollutants that is ubiquitous worldwide. Previous animal studies suggested that PAHs had adverse effects on female reproduction. However, the human data regarding relationship of PAHs exposure with women reproductive health, such as ovarian dysfunction, are scarce. In this case-control study, the associations of serum levels of PAHs with the risk of premature ovarian failure (POF) and reproductive hormones in Chinese women were investigated, with recruiting 157 POF patients and 217 healthy women. The serum levels of 12 types of PAHs, as well as reproductive hormones, including follicle-stimulating hormone, luteinizing hormone and anti-mullerian hormone, were determined. In the logistic regression models, most individual PAH congeners showed significantly positive correlations with the risk of POF (p < 0.05), except for fluorine and pyrene. Benzo(a)pyrene (BaP), as the most carcinogenic PAH congener, was observed to be significantly positively associated with the risk of POF. After adjustment for age, body mass index, educational levels and household income, per one-unit increase in the log-transformed BaP concentration was significantly correlated with 2.191-fold increased risk of POF (OR = 2.191, 95%CI: 1.634-2.938, p < 0.05). To the best of our knowledge, this is the first study to report an association between internal exposure levels of PAHs and the increased risk of POF in women.
10.1016/j.jes.2019.12.015
Diagnosis of Idiopathic Premature Ovarian Failure by Color Doppler Ultrasound under the Intelligent Segmentation Algorithm.
Computational and mathematical methods in medicine
The aim of this study was to explore the application value of transvaginal color Doppler ultrasound based on the improved mean shift algorithm in the diagnosis of idiopathic premature ovarian failure (POF). In this study, 80 patients with idiopathic POF were selected and included in the experimental group, and 40 volunteers who underwent health examinations during the same period were selected and included in the control group, who underwent transvaginal Doppler ultrasound examination. At the same time, an improved mean shift algorithm was proposed based on artificial intelligence technology and applied to ultrasound image processing. In addition, the ovarian artery parameters of patients were compared in two groups, including peak systolic flow rate (PSV), diastolic flow rate (EDV), resistance index (RI), and pulsatile index (PI). The results showed that the relative difference degree (RDD) of the segmentation results of the algorithm in this study was significantly lower than that of Snake, Live_wire, and the traditional mean shift algorithm, while the relative overlap degree (ROD) and Dice coefficient were opposite, and the differences were significant (<0.05). The mediolateral diameter of control group was 2.87±0.31cm, and the anteroposterior diameter was 1.86±0.28 cm; while those were 2.11±0.36 cm and 1.13±0.34 cm, respectively, in the experimental group, showing significant differences between the groups (<0.05). Of the 80 patients in the experimental group, 132 cases with ovarian arteries were found; among 40 patients in the experimental group, 76 cases were found with ovarian arteries, and the hemodynamic detection rate of the experimental group was significantly lower than that of the control group (<0.05). The ovarian artery parameters PI, RI, and S/D of the experimental group were significantly higher than those of the control group, and the differences were statistically significant (<0.05). The results showed that the segmentation results of the improved algorithm in this study were more superior to the segmentation results of other algorithms. The regional information loss of the segmentation results was not serious, and the resolution was higher and the definition was higher. The transvaginal color Doppler ultrasound based on the artificial intelligence segmentation algorithm can clearly show the functional status and hemodynamics of the patient's ovaries. The ovarian artery parameters PI and RI can be used as specific indicators for evaluating the POF.
10.1155/2022/2645607
hPMSC transplantation restoring ovarian function in premature ovarian failure mice is associated with change of Th17/Tc17 and Th17/Treg cell ratios through the PI3K/Akt signal pathway.
Stem cell research & therapy
BACKGROUND:Human placenta-derived mesenchymal stem cell (hPMSC) transplantation has been demonstrated to be an effective way of recovering ovarian function in mice with autoimmune induced premature ovarian failure (POF). But the exact mechanism remains unclear. The goal of the present study is to investigate the role of immune factors (T-helper 17 (Th17), cytotoxic T (Tc17) and regulatory T (Treg) cells) in the recovery of ovarian function and whether the phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway is involved in the regulation. METHODS:The inhibitor of PI3K/Akt was administered to observe its effect on ovarian function recovery and immune regulation. Serum levels of estradiol (E), follicle stimulation hormone (FSH), luteinizing hormone (LH) and anti-Müllerian hormone (AMH)) and anti-Zona pellucida antibody (AZPAb) were measured by ELISA to evaluate ovarian function. The morphological changes of ovaries were observed by HE staining. Apoptosis of granular cells (GCs) was determined by detecting the expression of capase-3. Expression of p-Akt protein was detected by immunohistochemistry and western blot assay in ovarian tissues. The MTT assay was performed to assess GC proliferation. GC apoptosis was performed using flow cytometry analysis. Percentages of Th17, Tc17 and Treg cells were detected by flow cytometry. Expression of interleukin (IL)-17 in serum was measured by ELISA. RESULTS:LY294002 administration decreased serum levels of E and AMH, while the levels of FSH, LH and AZPAb in serum were increased compared with mice in the hPMSC transplantation group. The ovarian morphology presented as atrophy and fibrosis, with functional follicles exhausted. The expression of p-Akt in ovarian tissue was significantly decreased. Also, LY294002 administration significantly decreased proliferation and increased cell apoptosis in GCs, and for immune factors the ratios of Th17/Tc17 and Th17/Treg cells were significantly increased, as well as the serum levels of IL-17. CONCLUSIONS:Our data suggest that the PI3K/Akt signal pathway is involved in the recovery of ovarian function by changing the ratios of Th17/ Tc17 and Th17/Treg cells in POF mice following hPMSC transplantation.
10.1186/s13287-018-0772-x
Women with premature ovarian failure using hormone therapy do not experience increased levels of depression, anxiety and stress compared to controls.
Menezes Camila,Pravata Gabriela Rezende,Yela Daniela Angerame,Benetti-Pinto Cristina Laguna
Journal of affective disorders
OBJECTIVE:To evaluate anxiety, depression and stress of POI women using hormone therapy. METHODS:A quantitative cross-sectional study included 61 women diagnosed with POI receiving HT, and 61 women with preserved ovarian function, matched 1:1 for age (control group). Instruments used to evaluate depression, anxiety and stress were Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Lipp's Stress Symptom Inventory (LSSI). The chi-square or Fisher's exact tests, Mann-Whitney test, Spearman's correlation coefficient or logistic regression analysis with stepwise criteria were used for analysis. RESULTS:The mean age of POI women and control group was 35.03±7.68 and 34.49±7.55 years old (p = 0.63). POI group and control group had a mean of 0.44±0.92 and 1.28±1.38 children (p = 0,001); the total BDI, BAI and LSSI scores were 15.72±11.68 and 13.66±8.44 (p = 0.64); 17.54±13.16 and 17.25±11.05 (p = 0.90), 19.39±12.08 and 18.93±11.21 (p = 0.945). The majority of women did not have depression or presented mild depression, but approximately one-third had moderate-severe undiagnosed depressive or anxiety symptoms. In POI group, depression was positively correlated with the number of children and anxiety. Anxiety and stress were also positively correlated. It was observed that for each point in the BDI, the risk of stress above 20 increased 19.6%, while for each point in the BAI, the risk of greater stress increased 32.4%. LIMITATIONS:This is a cross-sectional study, which made it impossible to draw cause and effect conclusions CONCLUSION: Women with POI receiving HT have indexes of depression, anxiety and stress similar to the population of women with preserved ovarian function.
10.1016/j.jad.2020.05.105
Restoring Ovarian Function With Human Placenta-Derived Mesenchymal Stem Cells in Autoimmune-Induced Premature Ovarian Failure Mice Mediated by Treg Cells and Associated Cytokines.
Yin Na,Zhao Wei,Luo Qianqian,Yuan Wendan,Luan Xiying,Zhang Hongqin
Reproductive sciences (Thousand Oaks, Calif.)
Regulatory T (Treg) cells play a key role in the regulation of autoimmunity and transplantation. Human placenta-derived mesenchymal stem cell (hPMSC) transplantation has a potential to restore ovarian dysfunction associated with premature ovarian failure (POF), while the exact function of the Treg cells in the transplantation still needs to be further investigated. In this study, hPMSCs were intravenously injected into POF mice following zona pellucida glycoprotein 3 (pZP3) treatment. Ovarian function was measured by analyzing estrous cycle, folliculogenesis, and hormone secretion, also, with the detection of apoptotic granular cells (GCs) in ovarian tissues. To determine whether immune response is involved in the regulation of ovarian function change, the population of Treg cell populations and expression of associated cytokines, for example, transforming growth factor β (TGF-β) and interferon γ (IFN-γ) were measured. After hPMSCs transplantation, the injured ovarian function is significantly improved. Also, the pZP3-treatment-induced apoptotic GCs were significantly decreased as compared with the POF mice. The transplantation of hPMSCs significantly increased the population of Treg cells which was inhibited by pZP3 treatment. The decrease in TGF-β and increase in IFN-γ in serum caused by pZP3 treatment have been reversed following hPMSCs transplantation. These findings strongly suggest that the recovery of ovarian function in POF mice is mediated via the regulation of Treg cells and production of associated cytokines following hPMSCs transplantation.
10.1177/1933719117732156
Fisetin regulates gut microbiota to decrease CCR9/CXCR3/CD4 T-lymphocyte count and IL-12 secretion to alleviate premature ovarian failure in mice.
Lin Jiajia,Nie Xiaoli,Xiong Ying,Gong Zhangbin,Chen Jiulin,Chen Chuan,Huang Yongyi,Liu Te
American journal of translational research
Currently, there are no studies reporting the efficacy of fisetin in premature ovarian failure (POF). In this study, using mouse and models, we found that fisetin not only significantly reversed ovarian damage in POF mice, but also effectively increased lifespan and fertility. Subsequently, we carried out 16S rRNA v3+v4 sequencing using fresh feces samples from each group of mice. Results showed that although there was no significant difference in the number of gut microbiomes between the different groups of mice, fisetin affected the diversity and distribution of gut microbiota in POF mice. Alpha and beta diversity analyses showed that in the gut of POF mice in the fisetin group, the bacterial count of uncultured_bacterium_f_Lachnospiraceae was significantly increased, while that of was significantly decreased. Finally, flow cytometry analysis showed that the numbers of CCR9/CXCR3/CD4 T lymphocytes in the peripheral blood of POF mice in the fisetin group were significantly reduced, along with the number of CD4/interleukin (IL)-12 cells. Therefore, our data suggested that fisetin regulates the distribution and bacterial counts of and uncultured_bacterium_f_Lachnospiracea in POF mice, and reduces peripheral blood CCR9/CXCR3/CD4 T-lymphocyte count and IL-12 secretion to regulate the ovarian microenvironment and reduce inflammation, thus exerting therapeutic effects against POF.
Prediction of Lipoprotein-Associated Phospholipase A2 and Inflammatory Markers in Subclinical Atherosclerosis in Premature Ovarian Failure Patients.
Cekici Yusuf,Kilic Salih,Ovayolu Ali,Saracoglu Erhan,Duzen İrfan Veysel,Yilmaz Mucahid,Kaya Bedri Caner,Bozkurt Devrim
Acta Cardiologica Sinica
Background:Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been associated with the risk of clinical cardiovascular events. Objectives:In this study, we aimed to investigate whether the activity of Lp-PLA2 presents a risk for subclinical atherosclerosis in young patients with premature ovarian failure (POF). Methods:Consecutive patients with clinical and biochemical evidence of naïve POF (n = 66) in January and February 2018 and age-matched healthy controls (n = 73) were enrolled. Lp-PLA2 activity, fibrinogen concentrations, high- sensitivity C-reactive protein (Hs-CRP) levels, and carotid intima-media thickness (CIMT) were measured in all participants. Results:Plasma Lp-PLA2 activity (24.6 ± 3.2 nmol/mL vs. 18.6 ± 1.6 nmol/mL; p < 0.001), mean Hs-CRP (0.620 ± 0.26 mg/dL vs. 0.450 ± 0.28 mg/dL; p < 0.001) and fibrinogen (0.310 ± 0.12 g/dL vs. 0.24 ± 0.11 g/dL; p < 0.001) levels were significantly higher in the patients with POF than control subjects. Mean CIMT was significantly higher in the POF patients than in controls (0.499 ± 0.122 mm vs. 0.323 ± 0.079 mm; p < 0.001). There was a possitive and strong correlation between CIMT and Lp-PLA2 activity (r = 0.548; 95% CI 0.445-0.644; p < 0.001) and a weak correlation Hs-CRP (r = 0.228, 95% CI 0.060-0.398; p = 0.007). In multivariate analysis, Lp-PLA2 activity (B = 1.456, 95% CI 0.908-2.003; p < 0.001) and 17β-E2 (B = -0.077, 95% CI -0.131 - -0.023; p = 0.006) were found to be independently associated with CIMT (R = 0.46). Conclusions:The present study showed that mean CIMT and Lp-PLA2 activity were significantly higher in POF subjects than control subjects. Moreover, Lp-PLA2 activity and 17β-E2 levels were independently associated with CIMT in young POF patients.
10.6515/ACS.202101_37(1).20200730A
Menstrual blood derived mesenchymal stem cells combined with Bushen Tiaochong recipe improved chemotherapy-induced premature ovarian failure in mice by inhibiting GADD45b expression in the cell cycle pathway.
Guo Fengyi,Xia Tian,Zhang Yedan,Ma Xiaotong,Yan Zhongrui,Hao Shaohua,Han Yali,Ma Ruihong,Zhou Yuan,Du Xue
Reproductive biology and endocrinology : RB&E
BACKGROUND:To investigate the therapeutic effects of menstrual blood derived mesenchymal stem cells (MB-MSCs) combined with Bushen Tiaochong recipe (BSTCR) on epirubicin induced premature ovarian failure (POF) in mice. METHODS:Twenty-four female C57BL/6 mice of 6-8 weeks were intraperitoneally injected with epirubicin to induce POF, and then they were randomized into 4 groups of 6 mice each and treated with PBS, MB-MSCs, BSTCR, and MB-MSCs combined with BSTCR, respectively. Six mice of the same age were used as controls. Vaginal smear, TUNEL and hematoxylin-eosin staining were to observe estrous cycles, ovarian cell apoptosis and follicles. Enzyme-linked immunosorbent analysis determined serum estradiol, follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH) levels. RT-qPCR and Western Blot analysis were to determine GADD45b, CyclinB1, CDC2 and pCDC2 expressions. RESULTS:Epirubicin treatment resulted in a decrease in the number of primordial, primary, secondary and antral follicles, an increase in the number of atretic follicles and ovarian cell apoptosis, a decrease in estradiol and AMH levels, an increase in FSH levels, and estrous cycle arrest. However, MB-MSCs combined with BSTCR rescued epirubicin induced POF through down-regulating GADD45b and pCDC2 expressions, and up-regulating CyclinB1 and CDC2 expressions. The combined treatment showed better therapeutic efficacy than BSTCR or MB-MSCs alone. CONCLUSIONS:MB-MSCs combined with BSTCR improved the ovarian function of epirubicin induced POF mice, which might be related to the inhibition of GADD45b expression and the promotion of CyclinB1 and CDC2 expressions. The combined treatment had better therapeutic efficacy than BSTCR or MB-MSCs alone.
10.1186/s12958-019-0499-2
[Correlation Between Dietary Nutrition and Premature Ovarian Failure].
Chen Hui,Cheng Ran,Xu Liang-Zhi
Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition
OBJECTIVE:To explore the relationship between dietary nutrition and premature ovarian failure (POF). METHODS:A case control study was undertaken in 294 patients recruited from the reproductive endocrine clinic of our hospital over the period from November 2015 to January 2017. The POF group included women with premature ovarian failure , and women with normal menstruation were included as control group. The dietary and nutritional status of these patients were analyzed and compared. RESULTS:A total of 70 POF patients (POF group) and 224 controls participated in this study. No significant differences in age, sex, height, body mass and body mass index (BMI) existed between the two groups. Significant differences were found between the two groups in daily intakes of protein, carbohydrate and dietary fiber (<0.05). Low carbohydrate (=11.652, 95% : 3.864-35.135) and dietary fiber intake (=7.851, 95% : 2.272-27.137) were associated with higher odds of POF. CONCLUSION:Deficiencies of carbohydrate and dietary fiber are associated with premature ovarian failure.
Lipid profile of women with premature ovarian failure.
Knauff Erik A H,Westerveld Hendrika E,Goverde Angelique J,Eijkemans Marinus J,Valkenburg Olivier,van Santbrink Evert J P,Fauser Bart C J M,van der Schouw Yvonne T
Menopause (New York, N.Y.)
OBJECTIVE:Earlier menopause is associated with a higher incidence of cardiovascular events later in life. Concurrent with the ages of menopausal transition, a shift in lipid profile takes place. Premature ovarian failure (POF) or premature menopause allows us to study the effect of cessation of ovarian function on the lipid profile independent of effects of advanced chronological age. DESIGN:Fasting triglycerides (TGs), total high-density lipoprotein (HDL), and low-density lipoprotein cholesterol levels were measured in 90 women with POF not using any hormone therapy and 198 population controls of the same age range not using oral contraceptives. Correlations between lipids and ovarian function parameters were assessed. RESULTS:: After correction for age, body mass index, and smoking, women with POF presented with significantly higher TG levels (mean difference: 0.17 log mmol/L [95% CI: 0.06-0.29]). HDL cholesterol levels were borderline significantly lower in women with POF. No age-corrected correlation between triglycerides or other lipids and estradiol levels or time of estrogen deprivation could be identified. However, the free androgen index, sex hormone-binding globulin, and testosterone concentrations showed significant correlations with TGs and/or HDL cholesterol concentrations. CONCLUSIONS:Loss of ovarian function at a very young age (POF) coincides with subtle changes in the lipid profile (higher TG levels and marginally lower HDL). Androgens (increased free androgen index and testosterone and decreased sex hormone-binding globulin) are better markers for unfavorable lipid changes compared with estrogen levels or duration of estrogen deprivation in women with POF. Elevated TG levels in combination with increased (free) androgens may be an early manifestation of reduced insulin sensitivity.
10.1097/gme.0b013e31816b4509
Effects of single and multiple transplantations of human umbilical cord mesenchymal stem cells on the recovery of ovarian function in the treatment of premature ovarian failure in mice.
Lv Xiaodan,Guan Chunyi,Li Ying,Su Xing,Zhang Lu,Wang Xueqin,Xia Hong-Fei,Ma Xu
Journal of ovarian research
BACKGROUND:Currently, there is no effective treatment for premature ovarian failure (POF), and stem cell therapy is considered the most promising treatment. Human umbilical cord blood mesenchymal stem cells (hUC-MSCs) have shown good regenerative ability in various diseases, including POF; however, their underlying mechanism and dosage for POF treatment remain unclear. This study aimed to compare the effect of single and multiple injections of hUC-MSCs on ovarian function repair in chemotherapy-induced POF. METHODS:Female mice were intraperitoneally injected with 30 mg/kg busulfan and 120 mg/kg cyclophosphamide (CTX) to induce POF. In the single hUC-MSC injection group, hUC-MSCs were transplanted into mice D7 after CTX and busulfan administration, while in the multiple injection group, hUC-MSCs were transplanted on D7, D14, and D21 after CTX and busulfan administration. We evaluated the ovarian morphology, fertility, follicle-stimulating hormone and estradiol concentrations, follicle count, POF model, and cell transplantation results. In addition, real-time polymerase chain reaction, immunohistochemistry, and miRNA and mRNA chips were used to evaluate the effect of the cell therapy. RESULTS:Ovary size, number of follicle at all developmental stages, and fertility were significantly reduced in the POF group compared with the control. Under hUC-MSC treatment, the ovarian morphology and follicle count were significantly restored, and fertility was significantly increased. By comparing the single and multiple hUC-MSC injection groups, we found that the anti-Müllerian hormone and Ki-67 levels were significantly increased in the multiple hUC-MSC group on D60 after chemotherapy. The expression of stimulating hormone receptors, inhibin α, and inhibin β was significantly restored, and the therapeutic effect was superior to that of the single hUC-MSC injection group. CONCLUSION:These results indicate that hUC-MSCs can restore the structure of injured ovarian tissue and its function in chemotherapy-induced POF mice and ameliorate fertility. Multiple hUC-MSC transplantations have a better effect on the recovery of ovarian function than single hUC-MSC transplantation in POF.
10.1186/s13048-021-00871-4
Identification of serum biomarkers for premature ovarian failure.
Lee Da-Hye,Pei Chang-Zhu,Song Jae-Yun,Lee Kyung-Ju,Yun Bo-Seong,Kwack Kyu-Bum,Lee Eun-Il,Baek Kwang-Hyun
Biochimica et biophysica acta. Proteins and proteomics
Premature ovarian failure (POF) is defined when a female achieves menopause before the age of 40. Although many conditions are known to be causative for POF, the most common one is idiopathic. This study was undertaken to investigate the pathogenesis of POF using proteomic tools. Two-dimensional electrophoresis (2-DE) analysis was performed to screen for proteins differentially expressed in patients with POF. Using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), we identified 11 significant proteins differentially expressed in the serum of POF patients: 5 proteins with expression increased more than two folds, 5 proteins with expression decreased more than two folds, and 1 protein expressed specifically in the serum of patients with POF. The results of the 2-DE analysis were further validated by Western blotting and ELISA analyses, which 5 reproductive system-related proteins (Ceruloplasmin, Complement C3, Fibrinogen α, Fibrinogen β, and SHBG) were selected. The different expression levels for these proteins were confirmed and demonstrated the possibility of using them as biomarkers to screen POF. These pre-clinical data provide plausible translational implications for targeting the pathogenesis of POF for each protein.
10.1016/j.bbapap.2018.12.007
Prevalence of premature ovarian insufficiency and its determinants in Iranian populations: Tehran lipid and glucose study.
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.
10.1186/s12905-021-01228-1
[Ovarian reserve and premature ovarian failure in girls and adolescents after hematopoietic stem cell transplantation].
Andes pediatrica : revista Chilena de pediatria
INTRODUCTION:The increased survival of children and adolescents after Stem Cell Transplantation (SCT) has allowed us to gain a better understanding of the late effects that this procedure might have. OBJECTIVE:to measure ovarian function and reserve after SCT. PATIENTS AND METHOD:A descriptive, observatio nal, and cross-sectional study of girls and adolescents with SCT between 1999 and 2011. External gynecologic examination, hormone tests, and abdominal gynecologic ultrasound were performed, observing pubertal development pre-SCT. The following data from the clinical record were recorded: baseline pathology, type of conditioning, use of radiotherapy in conditioning, age at the time of SCT, and history of acute or chronic graft-versus-host disease (GVHD). Hormonal tests included follicle- stimulating hormone (FSH), luteinizing hormone (LH), estradiol, prolactin (PRL), thyroid-stimula ting hormone (TSH), free thyroxine, total testosterone, sex hormone-binding globulin (SHBG), and anti-Müllerian hormone (AMH). Statistical analysis included the chi-square or Fisher's Exact test with a p-value < 0.05. RESULTS:41 patients were evaluated. The median age at the time of SCT was 6.8 years (1.5-14.1) and the median age at evaluation was 14.8 years (range: 4-25.4 years). 93% of the transplants were in patients with oncological disease and with myeloablative conditioning regimens. All patients presented decreased ovarian reserve, and 72% showed Premature Ovarian Failure (POF). CONCLUSIONS:All patients had decreased ovarian reserve and most of them had a high prevalence of POF. Before SCT, a gynecological evaluation and subsequent follow-up for hormone monitoring and initiation of hormone replacement are essential.
10.32641/andespediatr.v93i1.3693
The prevalence and phenotypic characteristics of spontaneous premature ovarian failure: a general population registry-based study.
Haller-Kikkatalo K,Uibo R,Kurg A,Salumets A
Human reproduction (Oxford, England)
STUDY QUESTION:What is the measured prevalence and phenotype of spontaneous premature ovarian failure (POF) in the general population? SUMMARY ANSWER:Spontaneous POF occurs in ∼1% of the general population with unique phenotype of post-menopausal ageing distinct from surgically induced premature menopause. WHAT IS KNOWN ALREADY:POF is multifactorial ovarian quiescence before the age of 40. The clinical features of POF are diverse and the population prevalence of POF is still not known. STUDY DESIGN, SIZE, DURATION:This population-depictive registry-based case-cohort study included 34 041 women from the Estonian Genome Center registered between 2003 and 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS:Spontaneous POF was selected retrospectively by excluding other causes for premature menopause under the age of 40 (N = 310) and women with surgically induced premature menopause participated as a reference group (N = 242). MAIN RESULTS AND THE ROLE OF CHANCE:The prevalence of spontaneous POF was 0.91% (0.81-1.02%) among women of the general population in Estonia. In women with POF, menarche occurred a few months later than in the reference group and a significantly higher number of live births during their reproductive life was recorded. Women with POF also consumed less alcohol and had smaller waist-to-hip ratios than those in the reference group, although both groups of women were similar in body mass index a decade after menopause. The prevalence of concomitant diseases was similar between two groups of women by their fifties, but the pattern of onset of these diseases was different. Surgically induced premature menopause associated with faster development of osteoporosis, hypertension, and connective tissue diseases, but slower development of allergies, compared with spontaneous POF. The age of menopause was determined by irregular menstrual cycles, but not by the length of regular menstrual cycles, the age of menarche, the number of pregnancies or live births, smoking or alcohol consumption, or the use of oral contraceptives for some time during the reproductive period. LIMITATIONS, REASONS FOR CAUTION:POF is rarely stated in medical records and cannot be diagnosed retrospectively by standard procedures. Therefore the data on all cases of women with primary amenorrhea or premature menopause before the age of 40 were requested from the registry and spontaneous POF was predicted retrospectively by excluding other extraovarian causes for premature menopause. Since the current study is retrospective registry-based data analysis, no genetic evaluation concerning possible candidate genes and no blood analysis concerning immunologic disorders could be performed to describe etiopathogenesis of POF. WIDER IMPLICATION OF THE FINDINGS:Spontaneous POF most likely comprises several diseases with different etiopathologies and there may be a unique phenotype of post-menopausal ageing distinct from that in surgically induced premature menopause. Irregular menstrual cycles may be a prospective risk for developing spontaneous POF. Compared with spontaneous POF, surgically induced premature menopause associates with faster development of age-related diseases. The data point to new ideas and hypotheses for further studies on etiopathologies and treatment options for spontaneous POF. STUDY FUNDING/COMPETING INTERESTS:The study was funded by grant SF0180044s09, SF0180027s10 and IUT20-43 from the Estonian Ministry of Education and Research, Enterprise Estonia, grant no EU30020, Eureka's EUROSTARS programme grant (NOTED, EU41564). No competing interests are declared.
10.1093/humrep/dev021
Premature menopause and autoimmune primary ovarian insufficiency in two international multi-center cohorts.
Endocrine connections
Objective:To investigate markers of premature menopause (<40 years) and specifically the prevalence of autoimmune primary ovarian insufficiency (POI) in European women. Design:Postmenopausal women were categorized according to age at menopause and self-reported reason for menopause in a cross-sectional analysis of 6870 women. Methods:Variables associated with the timing of menopause and hormone measurements of 17β-estradiol and follicle-stimulating hormone were explored using multivariable logistic regression analysis. Specific immunoprecipitating assays of steroidogenic autoantibodies against 21-hydroxylase (21-OH), side-chain cleavage enzyme (anti-SCC) and 17alpha-hydroxylase (17 OH), as well as NACHT leucine-rich-repeat protein 5 were used to identify women with likely autoimmune POI. Results:Premature menopause was identified in 2.8% of women, and these women had higher frequencies of nulliparity (37.4% vs 19.7%), obesity (28.7% vs 21.4%), osteoporosis (17.1% vs 11.6%), hormone replacement therapy (59.1% vs 36.9%) and never smokers (60.1% vs 50.9%) (P < 0.05), compared to women with menopause ≥40 years. Iatrogenic causes were found in 91 (47%) and non-ovarian causes in 27 (14%) women, while 77 (39%) women were classified as POI of unknown cause, resulting in a 1.1% prevalence of idiopathic POI. After adjustments nulliparity was the only variable significantly associated with POI (odds ratio 2.46; 95% CI 1.63-3.42). Based on the presence of autoantibodies against 21 OH and SCC, 4.5% of POI cases were of likely autoimmune origin. Conclusion:Idiopathic POI affects 1.1% of all women and almost half of the women with premature menopause. Autoimmunity explains 4.5% of these cases judged by positive steroidogenic autoantibodies.
10.1530/EC-22-0024