Inhibition of luteal steroidogenesis by two LHRH antagonists (Nal-Glu and Nal-Arg antagonists) in the pregnant rat.
Srivastava R K,Sridaran R
Endocrine research
We have examined the effect of two LHRH antagonists (Nal-Glu and Nal-Arg antagonists) on the basal progesterone (P4), pregnenolone (P5) and 20 alpha-dihydroprogesterone (20 alpha-DHP) production by luteal cells obtained from day 8 pregnant rats. A dose of 0.1 mmol/l of Nal-Glu or Nal-Arg attenuated basal P4 production by luteal cells after 12, 24 or 48 h of incubation. P5, a precursor for P4 synthesis was also reduced by both doses of Nal-Glu or Nal-Arg (0.1 mmol or 0.1 mumol/l) after 24 h of incubation. A period of 12 h was not sufficient to inhibit P5 production by luteal cells incubated with both doses of Nal-Glu or with the lower dose of Nal-Arg. The higher dose of Nal-Glu and Nal-Arg remained effective in attenuating P5 production by luteal cells after 48 h of incubation. We measured the production of a metabolite of P4, i.e., 20 alpha-DHP to assess whether this suppression in P4 production is due to an enhancement in the P4 metabolism by increasing the activity of 20 alpha-hydroxydehydrogenase. However, instead, we observed (i) a decrease in the production of 20 alpha-DHP by the higher dose of Nal-Glu and Nal-Arg after 12, 24 or 48 h of incubation and (ii) a decrease or no change in the production of 20 alpha-DHP by the lower dose of Nal-Glu or Nal-Arg at all time periods of incubation. Based on these observations we conclude that LHRH antagonists exert a direct effect on the corpus luteum and suppress luteal steroidogenesis. This suppression in luteal steroidogenesis could be due to a decrease in the activity of any one of these enzymes of the steroidogenic pathway, viz., cholesterol side chain cleavage (P450scc), a rate limiting enzyme involved in the synthesis of P5 from cholesterol, or 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), which catalyzes the oxidation of P5 to P4 or due to a decrease in activity of both enzymes.
10.1080/07435809409030412
Pregnancy enables antibody protection against intracellular infection.
Nature
Adaptive immune components are thought to exert non-overlapping roles in antimicrobial host defence, with antibodies targeting pathogens in the extracellular environment and T cells eliminating infection inside cells. Reliance on antibodies for vertically transferred immunity from mothers to babies may explain neonatal susceptibility to intracellular infections. Here we show that pregnancy-induced post-translational antibody modification enables protection against the prototypical intracellular pathogen Listeria monocytogenes. Infection susceptibility was reversed in neonatal mice born to preconceptually primed mothers possessing L. monocytogenes-specific IgG or after passive transfer of antibodies from primed pregnant, but not virgin, mice. Although maternal B cells were essential for producing IgGs that mediate vertically transferred protection, they were dispensable for antibody acquisition of protective function, which instead required sialic acid acetyl esterase to deacetylate terminal sialic acid residues on IgG variable-region N-linked glycans. Deacetylated L. monocytogenes-specific IgG protected neonates through the sialic acid receptor CD22, which suppressed IL-10 production by B cells leading to antibody-mediated protection. Consideration of the maternal-fetal dyad as a joined immunological unit reveals protective roles for antibodies against intracellular infection and fine-tuned adaptations to enhance host defence during pregnancy and early life.
10.1038/s41586-022-04816-9
Uterine bleeding: how understanding endometrial physiology underpins menstrual health.
Nature reviews. Endocrinology
Menstruation is a physiological process that is typically uncomplicated. However, up to one third of women globally will be affected by abnormal uterine bleeding (AUB) at some point in their reproductive years. Menstruation (that is, endometrial shedding) is a fine balance between proliferation, decidualization, inflammation, hypoxia, apoptosis, haemostasis, vasoconstriction and, finally, repair and regeneration. An imbalance in any one of these processes can lead to the abnormal endometrial phenotype of AUB. Poor menstrual health has a negative impact on a person's physical, mental, social, emotional and financial well-being. On a global scale, iron deficiency and iron deficiency anaemia are closely linked with AUB, and are often under-reported and under-recognized. The International Federation of Gynecology and Obstetrics have produced standardized terminology and a classification system for the causes of AUB. This standardization will facilitate future research endeavours, diagnosis and clinical management. In a field where no new medications have been developed for over 20 years, emerging technologies are paving the way for a deeper understanding of the biology of the endometrium in health and disease, as well as opening up novel diagnostic and management avenues.
10.1038/s41574-021-00629-4
Evolution of gonadotropin signaling on gonad development: insights from gene knockout studies in zebrafish.
Li Jianzhen,Cheng Christopher H K
Biology of reproduction
Gonadal development is precisely regulated by the two gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Much progress on understanding the functions of LH and FSH signaling on gonad development has been achieved in the past decades, mostly from studies in mammals, especially genetic studies in both mouse and human. The functions of both LH and FSH signaling in nonmammalian species are still largely unknown. In recent years, using zebrafish, a teleost phylogenetically distant from mammals, we and others have genetically analyzed the functions of gonadotropins and their receptors through gene knockout studies. In this review, we will summarize the pertinent findings and discuss how the actions of gonadotropin signaling on gonad development have evolved during evolution from fish to mammals.
10.1093/biolre/ioy101
Effects of progestins on local estradiol biosynthesis and action in the Z-12 endometriotic epithelial cell line.
Beranič Nataša,Rižner Tea Lanišnik
The Journal of steroid biochemistry and molecular biology
Endometriosis is a common estrogen-dependent gynecological disease. In patients with endometriosis estradiol can be synthesized locally in the endometriotic lesions from inactive precursors of adrenal or ovarian origin, via the aromatase pathway. These increased estradiol levels stimulate proliferation of endometriotic tissue. The progestins have been used in the therapy of endometriosis for more than 40 years but their pharmacological action is still not understood in detail. In the present study we therefore aimed to evaluate the effects of three progestins most commonly used in the therapy of endometriosis; medroxyprogesterone acetate, dydrogesterone and dienogest on expression of all genes encoding enzymes of the aromatase pathway and estrogen receptors in the Z-12 model epithelial cell line of peritoneal endometriosis, by qPCR and Western blotting. Our results show that application of medroxyprogestrone acetate, dydrogesterone and dienogest significantly decreases HSD17B1 and CYP19A1 expression and significantly increases HSD17B2 expression. Dydrogesterone and dienogest also significantly suppress ESR1 and ESR2 transcription, whereas medroxyprogestrone acetate and dydrogesterone significantly reduce mRNA levels of GPER. Our results thus suggest that in peritoneal endometriosis the beneficial effects of these progestins can be explained by lower HSD17B1 and higher HSD17B2 mRNA and protein levels, which lead to reduced local E2 biosynthesis. Although progestins significantly decrease CYP19A1 mRNA levels, the protein itself was not detectable by Western blotting. As progestins down-regulate expression of ESR1, ESR2 and GPER, they might also prevent E2-mediated proliferation.
10.1016/j.jsbmb.2012.07.004
Association between exposure to ambient air pollutants and the outcomes of in vitro fertilization treatment: A multicenter retrospective study.
Wu Shanshan,Zhang Yunshan,Wu Xueqing,Hao Guimin,Ren Haiqin,Qiu Jiahui,Zhang Yinfeng,Bi Xingyu,Yang Aimin,Bai Lina,Tan Jichun
Environment international
BACKGROUND:Exposure to ambient air pollution has been reported to be inversely correlated with human reproductive health. However, the results of previous studies exploring the association between air pollution and in vitro fertilization (IVF) outcomes are conflicting, and further research is needed to clarify this association. OBJECTIVES:This study aimed to investigate the associations between exposure to air pollutants and IVF outcomes. METHODS:We conducted a multicenter retrospective cohort study involving 20,835 patients from four cities in Northern China, contributing to 11,787 fresh embryo transfer cycles, 9050 freeze-all cycles, and 17,676 frozen-thawed embryo transfer (FET) cycles during 2014-2018. We calculated the daily average concentrations of six criteria air pollutants (PM, PM, O, NO, CO, and SO) during different exposure windows in IVF treatment timeline using data from the air monitoring station nearest to the residential site as approximate individual exposure. Generalized estimation equation models were used to assess the association between air pollution exposure and IVF outcomes. RESULTS:Exposure to O, NO, and CO during most exposure windows in fresh embryo transfer cycles were correlated with lower possibilities of biochemical pregnancy, clinical pregnancy, and live birth. An inverse association of exposure to O and SO with pregnancy outcomes was observed in FET cycles. In addition, we found a significant association of exposure to air pollutants with a higher risk of ectopic pregnancy and lower oocyte yield. CONCLUSIONS:Our study provided large-scale human evidence of the association between air pollution and adverse human reproductive outcomes in the population opting for IVF. Thus, exposure to air pollutants in the population opting for IVF should be limited to improve treatment outcomes.
10.1016/j.envint.2021.106544
Organoid systems to study the human female reproductive tract and pregnancy.
Alzamil Lama,Nikolakopoulou Konstantina,Turco Margherita Y
Cell death and differentiation
Both the proper functioning of the female reproductive tract (FRT) and normal placental development are essential for women's health, wellbeing, and pregnancy outcome. The study of the FRT in humans has been challenging due to limitations in the in vitro and in vivo tools available. Recent developments in 3D organoid technology that model the different regions of the FRT include organoids of the ovaries, fallopian tubes, endometrium and cervix, as well as placental trophoblast. These models are opening up new avenues to investigate the normal biology and pathology of the FRT. In this review, we discuss the advances, potential, and limitations of organoid cultures of the human FRT.
10.1038/s41418-020-0565-5
Assisted reproductive technologies induce temporally specific placental defects and the preeclampsia risk marker sFLT1 in mouse.
Vrooman Lisa A,Rhon-Calderon Eric A,Chao Olivia Y,Nguyen Duy K,Narapareddy Laren,Dahiya Asha K,Putt Mary E,Schultz Richard M,Bartolomei Marisa S
Development (Cambridge, England)
Although widely used, assisted reproductive technologies (ARTs) are associated with adverse perinatal outcomes. To elucidate their underlying causes, we have conducted a longitudinal analysis of placental development and fetal growth using a mouse model to investigate the effects of individual ART procedures: hormone stimulation, fertilization (IVF), embryo culture and embryo transfer. We demonstrate that transfer of blastocysts naturally conceived without hormone stimulation and developed prior to transfer can impair early placentation and fetal growth, but this effect normalizes by term. In contrast, embryos cultured before transfer do not exhibit this compensation but rather display placental overgrowth, reduced fetal weight, reduced placental DNA methylation and increased levels of sFLT1, an anti-angiogenic protein implicated in causing the maternal symptoms of preeclampsia in humans. Increases in sFLT1 observed in this study suggest that IVF procedures could increase the risk for preeclampsia. Moreover, our results indicate that embryo culture is the major factor contributing to most placental abnormalities and should therefore be targeted for optimization.
10.1242/dev.186551
Induction of autophagy protects against extreme hypoxia-induced damage in porcine embryo.
Lee Mun-Hyeong,Jeong Pil-Soo,Sim Bo-Woong,Kang Hyo-Gu,Kim Min Ju,Lee Sanghoon,Yoon Seung-Bin,Kang Philyong,Park Young-Ho,Kim Ji-Su,Song Bong-Seok,Koo Deog-Bon,Kim Sun-Uk
Reproduction (Cambridge, England)
In the mammalian female reproductive tract, physiological oxygen tension is lower than that of the atmosphere. Therefore, to mimic in vivo conditions during in vitro culture (IVC) of mammalian early embryos, 5% oxygen has been extensively used instead of 20%. However, the potential effect of hypoxia on the yield of early embryos with high developmental competence remains unknown or controversial, especially in pigs. In the present study, we examined the effects of low oxygen tension under different oxygen tension levels on early developmental competence of parthenogenetically activated (PA) and in vitro-fertilized (IVF) porcine embryos. Unlike the 5% and 20% oxygen groups, exposure of PA embryos to 1% oxygen tension, especially in early-phase IVC (0-2 days), greatly decreased several developmental competence parameters including blastocyst formation rate, blastocyst size, total cell number, inner cell mass (ICM) to trophectoderm (TE) ratio, and cellular survival rate. In contrast, 1% oxygen tension did not affect developmental parameters during the middle (2-4 days) and late phases (4-6 days) of IVC. Interestingly, induction of autophagy by rapamycin treatment markedly restored the developmental parameters of PA and IVF embryos cultured with 1% oxygen tension during early-phase IVC, to meet the levels of the other groups. Together, these results suggest that the early development of porcine embryos depends on crosstalk between oxygen tension and autophagy. Future studies of this relationship should explore the developmental events governing early embryonic development to produce embryos with high developmental competence in vitro.
10.1530/REP-20-0311
Endocrine Requirements for Oocyte Maturation Following hCG, GnRH Agonist, and Kisspeptin During IVF Treatment.
Abbara Ali,Hunjan Tia,Ho Vu N A,Clarke Sophie A,Comninos Alexander N,Izzi-Engbeaya Chioma,Ho Tuong M,Trew Geoffrey H,Hramyka Artsiom,Kelsey Tom,Salim Rehan,Humaidan Peter,Vuong Lan N,Dhillo Waljit S
Frontiers in endocrinology
Objective:The maturation of oocytes to acquire competence for fertilization is critical to the success of fertilization (IVF) treatment. It requires LH-like exposure, provided by either human chorionic gonadotropin (hCG), or gonadotropin releasing hormone agonist (GnRHa). More recently, the hypothalamic stimulator, kisspeptin, was used to mature oocytes. Herein, we examine the relationship between the endocrine changes following these agents and oocyte maturation. Design:Retrospective cohort study. Methods:Prospectively collected hormonal data from 499 research IVF cycles triggered with either hCG, GnRHa, or kisspeptin were evaluated. Results:HCG-levels (121 iU/L) peaked at 24 h following hCG, whereas LH-levels peaked at ~4 h following GnRHa (140 iU/L), or kisspeptin (41 iU/L). HCG-levels were negatively associated with body-weight, whereas LH rises following GnRHa and kisspeptin were positively predicted by pre-trigger LH values. The odds of achieving the median mature oocyte yield for each trigger were increased by hCG/LH level. Progesterone rise during oocyte maturation occurred precipitously following each trigger and strongly predicted the number of mature oocytes retrieved. Progesterone rise was positively associated with the hCG-level following hCG trigger, but negatively with LH rise following all three triggers. The rise in progesterone per mature oocyte at 12 h was greater following GnRHa than following hCG or kisspeptin triggers. Conclusion:The endocrine response during oocyte maturation significantly differed by each trigger. Counter-intuitively, progesterone rise during oocyte maturation was negatively associated with LH rise, even when accounting for the number of mature oocytes retrieved. These data expand our understanding of the endocrine changes during oocyte maturation and inform the design of future precision-triggering protocols.
10.3389/fendo.2020.537205
hCG Improves Luteal Function and Promotes Progesterone Output through the Activation of JNK Pathway in the Luteal Granulosa Cells of the Stimulated IVF Cycles†.
Bildik Gamze,Akin Nazli,Esmaeilian Yashar,Hela Francesko,Yakin Kayhan,Onder Tamer,Urman Bulent,Oktem Ozgur
Biology of reproduction
Human chorionic gonadotropin (hCG) is a luteotropic hormone that promotes the survival and steroidogenic activity of corpus luteum (CL) by acting through luteinizing hormone receptors (LHRs) expressed on luteinized theca and granulosa cells (GCs). Therefore, it is used to support luteal phase in in vitro fertilization (IVF) cycles to improve clinical pregnancy rates and prevent miscarriage. However, the molecular mechanism underlying this action of hCG is not well characterized. To address this question, we designed an in vitro translational research study on the luteal GCs obtained from 58 IVF patients. hCG treatment at different concentrations and time points activated c-Jun N-terminal kinase (JNK) pathway and significantly increased its endogenous kinase activity along with upregulated expression of steroidogenic enzymes (steroidogenic acute regulatory protein (stAR), 3β-Hydroxysteroid dehydrogenase (3β-HSD)) in a dose-dependent manner in the luteal GCs. As a result, in vitro P production of the cells was significantly enhanced after hCG. When JNK pathway was inhibited pharmacologically or knocked-down with small interfering RNA luteal function was compromised, P4 production was declined along with the expression of stAR and 3β-HSD in the cells. Further, hCG treatment after JNK inhibition failed to correct the luteal defect and promote P4 output. Similar to hCG, luteinizing hormone (LH) treatment improved luteal function as well and this action of LH was associated with JNK activation in the luteal GCs. These findings could be important from the perspective of CL biology and luteal phase in human because we for the first time identify a critical role for JNK signaling pathway downstream LHR activation by hCG/LH in luteal GCs. SUMMARY SENTENCE:JNK signaling pathway plays a central role in the upregulated expression of the steroidogenic enzymes StAR and 3b-HSD and augmented progesterone production by hCG/LH in human luteal granulosa cells.
10.1093/biolre/ioaa034