Ovarian Insufficiency Research Articles

MGA loss-of-function variants cause premature ovarian insufficiency.

Although premature ovarian insufficiency (POI), a common cause of female infertility and subfertility, has a well-established hereditary component, the genetic factors currently implicated in POI account for only a limited proportion of cases. Here, using an exome-wide, gene-based case-control analysis in a discovery cohort comprising 1,027 POI cases and 2,733 ethnically matched women controls from China, we found that heterozygous loss-of-function (LoF) variants of MAX dimerization protein (MGA) were significantly enriched in the discovery cohort, accounting for 2.6% of POI cases, while no MGA LoF variants were found in the matched control females. Further exome screening was conducted in 4 additional POI cohorts (2 from China and 2 from the United States) for replication studies, and we identified heterozygous MGA LoF variants in 1.0%, 1.4%, 1.0%, and 1.0% of POI cases, respectively. Overall, a total of 37 distinct heterozygous MGA LoF variants were discovered in 38 POI cases, accounting for approximately 2.0% of the total 1,910 POI cases analyzed in this study. Accordingly, Mga+/- female mice were subfertile, exhibiting shorter reproductive lifespan and decreased follicle number compared with WT, mimicking the observed phenotype in humans. Our findings highlight the essential role of MGA deficiency for impaired female reproductive ability.

Defects in meiosis I contribute to the genesis of androgenetic hydatidiform moles.

To identify novel genes responsible for recurrent hydatidiform moles (HMs), we performed exome sequencing on 75 unrelated patients who were negative for mutations in the known genes. We identified biallelic deleterious variants in 6 genes, FOXL2, MAJIN, KASH5, SYCP2, MEIOB, and HFM1, in patients with androgenetic HMs, including a familial case of 3 affected members. Five of these genes are essential for meiosis I, and their deficiencies lead to premature ovarian insufficiency. Advanced maternal age is the strongest risk factor for sporadic androgenetic HM, which affects 1 in every 600 pregnancies. We studied Hfm1-/- female mice and found that these mice lost all their oocytes before puberty but retained some at younger ages. Oocytes from Hfm1-/- mice initiated meiotic maturation and extruded the first polar bodies in culture; however, their meiotic spindles were often positioned parallel, instead of perpendicular, to the ooplasmic membrane at telophase I, and some oocytes extruded the entire spindle with all the chromosomes into the polar bodies at metaphase II, a mechanism we previously reported in Mei1-/- oocytes. The occurrence of a common mechanism in two mouse models argues in favor of its plausibility at the origin of androgenetic HM formation in humans.

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles harboring IGF-1 improve ovarian function of mice with premature ovarian insufficiency through the Nrf2/HO-1 pathway.

Premature ovarian insufficiency (POI) is a disease with medical, psychological and reproductive implications, but its common therapies have limited efficacy and a likelihood of complications. This study delves into the therapeutic role of human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSCs-EVs) in POI mice through the insulin-like growth factor 1 (IGF-1)/nuclear factor E2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/autophagy pathway. hUC-MSCs were transfected with lentiviral short hairpin RNA of IGF-1 before EV extraction. Cyclophosphamide (CTX)-induced POI mouse models were administrated with hUC-MSCs-EVs. Mouse ovarian granulosa cells (GCs) were induced with CTX, then treated with hUC-MSCs-EVs and ML385. Ovarian histopathological changes were observed, changes in follicle number at all levels were counted and serum sex hormones were evaluated, as well as LC3II/I and Beclin-1 expression. GCs were subject to detection of proliferation, deaths, oxidative stress, and Nrf2 nuclear translocation. After CTX exposure, mice showed thinner GCs layer in the ovary, reduced number of GCs and follicles at all levels, disturbed serum sex hormones, enhanced oxidative stress and autophagy, and downregulated ovarian IGF-1; whereas, hUC-MSCs-EVs upregulated IGF-1 to improve the ovarian function. hUC-MSCs-EVs carrying IGF-1 activated Nrf2/HO-1 signaling to inhibit CTX-induced excessive autophagy of GCs, but this ameliorative effect was partially weakened by inhibiting Nrf2/HO-1 signaling. hUC-MSCs-EVs inhibited excessive autophagy of GCs and improved ovarian function of CTX-induced mice through IGF-1/Nrf2/HO-1 pathway. hUC-MSCs-EVs activate the Nrf2/HO-1 signaling by carrying IGF-1, which in turn inhibits excessive autophagy and damage of GCs, thus improving ovarian function in POI mice.

Examining suicidality in relation to the menopause: A systematic review

Suicide is one of the leading causes of deaths worldwide, with an estimated 1 in 100 deaths being attributable to suicide. Whilst rates of suicide are higher in men, evidence suggests that suicide attempts are more frequent in women. Suicidality data indicates that deaths by suicide in women are highest in those in midlife, warranting investigation into the relationship between the menopause and suicidality. The current study aimed to review the existing literature examining the relationship between suicidality and the menopause using a systematic review approach. A systematic literature search of MEDLINE, Cochrane Library, Scopus Web of Science, PsycINFO, and Embase databases was conducted in October 2023. Two authors independently screened the titles and abstracts of identified articles against the eligibility criteria. Any inconsistencies were discussed and resolved. This process was subsequently repeated with the articles’ full-text. Risk of bias was assessed using the Quality Assessment Tool for Studies with Diverse Designs (QATSDD). Relevant data were extracted and summarised in both a tabulated and narrative form. A total of 28 studies met the inclusion criteria, with the findings revealing a complex relationship between the menopause and suicidality. Several studies highlighted that the perimenopause period shows a higher prevalence of suicidal thoughts compared to pre-menopausal and post-menopausal stages. Conversely, some studies indicated increased suicidality during the post-menopausal phase, while others noted elevated suicidality in pre-menopausal individuals and those with primary ovarian insufficiency. Critically, several studies found no link between hormonal status and suicidality. The quality of the studies also varied, with a lack of involvement from individuals with relevant lived experience being a consistent methodological flaw across all the included studies. Overall, the current evidence on menopause and suicidality is mixed. Further research is needed to unravel the relationship between menopause and suicidality.

Reproductive and Metabolic Health Following Exposure to Environmental Chemicals: Mechanistic Insights from Mammalian Models.

The decline in human reproductive and metabolic health over the past 50years is associated with exposure to complex mixtures of anthropogenic environmental chemicals (ECs). Real-life EC exposure has varied over time and differs across geographical locations. Health-related issues include declining sperm quality, advanced puberty onset, premature ovarian insufficiency, cancer, obesity, and metabolic syndrome. Prospective animal studies with individual and limited EC mixtures support these observations and provide a means to investigate underlying physiological and molecular mechanisms. The greatest impacts of EC exposure are through programming of the developing embryo and/or fetus, with additional placental effects reported in eutherian mammals. Single-chemical effects and mechanistic studies, including transgenerational epigenetic inheritance, have been undertaken in rodents. Important translational models of human exposure are provided by companion animals, due to a shared environment, and sheep exposed to anthropogenic chemical mixtures present in pastures treated with sewage sludge (biosolids). Future animal research should prioritize EC mixtures that extend beyond a single developmental stage and/or generation. This would provide a more representative platform to investigate genetic and underlying mechanisms that explain sexually dimorphic and individual effects that could facilitate mitigation strategies.

MSCs-derived EVs protect against chemotherapy-induced ovarian toxicity: role of PI3K/AKT/mTOR axis.

Chemotherapy detrimentally impacts fertility via depletion of follicular reserves in the ovaries leading to ovarian failure (OF) and development of estrogen deficiency-related complications. The currently proposed options to preserve fertility such as Oocyte or ovarian cortex cryopreservation are faced with many technical obstacles that limit their effective implementation. Therefore, developing new modalities to protect ovarian function remains a pending target. Exosomes are nano-sized cell-derived extracellular vesicles (EVs) with documented efficacy in the field of regenerative medicine. The current study sought to determine the potential beneficial effects of mesenchymal stem cells (MSCs)-derived EVs in experimentally induced OF. Female albino rats were randomly allocated to four groups: control, OF group, OF + MSCs-EVs group, OF + Rapamycin (mTOR inhibitor) group, and OF + Quercetin (PI3K/AKT inhibitor) group. Follicular development was assessed via histopathological and immunohistochemical examination, and ovarian function was evaluated by hormonal assay. PI3K/Akt/mTOR signaling pathway as a key modulator of ovarian follicular activation was also assessed. MSCs-EVs administration to OF rats resulted in restored serum hormonal levels, preserved primordial follicles and oocytes, suppressed ovarian PI3K/AKT axis and downstream effectors (mTOR and FOXO3), modulated miRNA that target this axis, decreased expression of ovarian apoptotic markers (BAX, BCl2) and increased expression of proliferation marker Ki67. The present study validated the effectiveness of MSCs-EVs therapy in preventing ovarian insufficiency induced by chemotherapy. Concomitant MSCs-EVs treatment during chemotherapy could significantly preserve ovarian function and fertility by suppressing the PI3K/Akt axis, preventing follicular overactivation, maintaining normal ovarian cellular proliferation, and inhibiting granulosa cell apoptosis.

Single-cell RNA sequencing reveals common interactions between follicle immune cells and granulosa cells in premature ovarian insufficiency patients.

To investigate the follicle microenvironment of individuals with premature ovarian insufficiency (POI), normal ovarian reserve (normal) and advanced maternal age (AMA), and identify potential therapeutic targets. A total of 9 women, including 3 POI, 3 normal and 3 AMA women, underwent in vitro fertilization or intracytoplasmic sperm injection were included in this study. For each participant, the first punctured follicle not containing cumulus cells were submitted to single-cell RNA sequencing to explore the characteristics of the follicle microenvironment of POI, normal and AMA individuals. A total of 87,323 cells were isolated and grouped into six clusters: T cells, B cells, neutrophils, basophils, mononuclear phagocytes, and granulosa cells. Further analysis demonstrated that the population of granulosa cells in cluster 6 was increased in AMA and POI patients, whereas the population of gamma delta T (GDT)-cells was decreased. We also found that the genes that were differentially expressed between GDT cells and monocytes were enriched in ribosome- and endoplasmic reticulum (ER)-related pathways. In addition, it showed that VEGFA-FLT1 interaction between the monocytes and granulosa cells may be lost in the AMA and POI patients as compared with the normal group. Loss of the VEGFA-FLT1 interaction in monocytes and granulosa cells, along with enriched ER- and ribosome-related pathways, may drive excess inflammation, accelerating granulosa cell senility and contributing to infertility. This study provides new insights into the pathogenesis of POI and aging and highlights the VEGFA/FLT1 interaction may be a potential therapeutic target for reducing inflammation and treating POI.

Huyang Yangkun formula regulates the mitochondria pathway of ovarian granulosa cell apoptosis through FTO/m6A-P53 pathway

BackgroundPremature ovarian insufficiency (POI) presents a significant challenge to female reproductive health. The Huyang Yangkun Formula (HYF), a traditional Chinese medicinal formulation, has been utilized in clinical settings for the treatment of POI for over a decade. Nevertheless, the therapeutic application of HYF is considerably constrained by the lack of clarity regarding its underlying mechanism of action.MethodsThe experimental procedures entailed administering VCD to female Sprague-Dawley rats at a dosage of 160 mg/kg/day over a period of 15 days, succeeded by a 100-day treatment with HYF. Blood serum samples were collected and analyzed using ELISA to quantify the concentrations of Anti-Müllerian Hormone (AMH), Follicle-Stimulating Hormone (FSH), and Estradiol (E2). The levels of N6-methyladenosine (m6A) were assessed through Dot blot analysis and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Western blotting was employed to validate the differential expression of m6A-related catalytic enzymes and apoptosis-related regulators, including BCL-2, BCL-XL, and MCL-1, which may be implicated in the effects of HYF. Certain shRNA-COV434 cell line was constructed for the exploration of molecular mechanism, and then the potential targets were finally verified by MeRIP-qPCR.ResultsHYF has been identified as having a significant influence on the development of residual ovarian follicles in rats with POI, especially during the initial stages. It was observed that HYF facilitates the progression of escaping antral follicles to full maturation. Additionally, HYF exhibited the capacity to enhance the proliferation of COV434, a human ovarian granulosa cell line, while concurrently inhibiting apoptosis within these cells. Notably, HYF treatment resulted in the downregulation of apoptotic proteins, including BCL-XL, cleaved-caspase 9, cleaved-caspase 3, and Bcl-2. Concurrently, m6A modification is implicated in the regulation of HYF. Both in vitro and in vivo studies indicate that FTO may play a role in the anti-apoptotic mechanisms mediated by m6A in ovarian granulosa cells influenced by HYF. Moreover, employing qPCR and MeRIP-qPCR techniques, P53 has been identified as the target gene for m6A modification mediated by FTO.ConclusionThese findings suggest that HYF holds promise as a potential treatment for POI and provide a more comprehensive understanding of the mechanism by which HYF operates, specifically its ability to prevent the BCL-2 mitochondrial apoptosis pathway mediated by P53 in ovarian granulosa cells of POI rats by regulating FTO/m6A-Tp53.

Service evaluation: HRT regimens prescribed for complex menopausal patient cases

Abstract Introduction With government and NHS drivers, there has been an increase in menopause awareness and management. The NHS Business Services Authority reported a 29% increase in hormone replacement therapy (HRT) prescribing between 2022-2023, with expectation that this would rise further with introduction of the new HRT prepayment certificate in April 20231. Partly due to celebrity sway and supported by national guidance2,3 there is patient expectation towards transdermal oestrogen with natural progesterone HRT. Older women, some years since undergoing natural menopause, are also seeking advice on HRT use (3) with referrals accepted by specialist menopause clinics. Aims This service evaluation project was undertaken to evaluate the prescribing of HRT regimens in complex patient cases seen within a specialist menopause clinic and included assessment of those advised to use natural progesterone as part of their HRT regimen, for endometrial protection2,3. Method 366 specialist menopause clinic appointments over 6 months (05.01.23-22.06.23) were retrospectively evaluated, with patients seen by a multidisciplinary team within an outpatient secondary care setting. Exclusion criteria included appointments not attended, those that were incorrectly booked or patients with inaccessible records. Data was collected using electronic patient records with results analysed using Microsoft Excel. Results Of 327 (89%) appointments evaluated, the patient age ranged between 30-84 years (median age 53). HRT was recommended for 288 (88%) patients. HRT was not recommended in cases such as antiphospholipid syndrome, breast cancer without genitourinary symptoms, in those of advanced age or in line with patient choice with patient decision not to take HRT after an individualised risk benefit evaluation. For 26 (9%) patients, only topical oestrogen treatment for localised genitourinary syndrome symptoms was advised. 171 (52%) patients were postmenopausal, 61 (19%) perimenopausal, 46 (14%) with premature ovarian insufficiency and 20 (6%) with surgical menopause. For 22 patients (7%) with Mirena intra-uterine system in situ, their menopause phase could not be accurately defined. 243 (88%) of those recommended HRT were advised a combined regime; 154 (53%) continuous combined; 67 (23%) sequential combined and 22 (9%) oestrogen with Mirena coil. For patients accepting combined HRT, one third (81) were recommended natural progesterone, with the other patients using progestogens for endometrial protection. Of these 81 patients, 77 (95%) were recommended transdermal oestrogen in combination with natural progesterone. For patients recommended natural progesterone, 68 (84%) were for doses in line with licensing and current British Menopause Society guidance. For 10 patients the off-label recommendation involved doubled doses of natural progesterone to help with control of unfavourable bleeding. Discussion For prescribing of natural progesterone, we assumed that our recommendations to the GP were enacted. With retrospective evaluation of patient letters as a limitation, this project identified that within our specialist clinic complex patient population, a recommendation for natural progesterone was made for one third of patients suitable for combined HRT use. When not prescribed in line with licensing, this was due to issues with vaginal bleeding. Acknowledgments Biranavi Kirupakaran, Sahil Misri, Hernani Almeida, Medical Students, Imperial College London for data collection.

P300 Maintains Primordial Follicle Activation by Repressing VEGFA Transcription.

During the reproductive life, most primordial follicles remain dormant for years or decades, while some are progressively activated for development. Misactivation of primordial follicles can cause ovarian diseases, for example, premature ovarian insufficiency (POI). Our results show that p300 expression increased with primordial follicle activation. Using a p300 inhibitor resulted in premature activation of primordial follicles in cultured mouse ovaries. Conversely, the ratio of primordial follicle activation was markedly decreased upon culturing with the p300 agonist. Furthermore, p300 regulated primordial follicle activation by inhibiting Vegfa transcription in granulosa cells. Additionally, this study was extended to potential clinical applications, showing that short-term treatment with a p300 inhibitor in vitro significantly increased primordial follicle activation in newborn mouse ovaries after dorsal kidney membrane transplantation in female NSG mice. Our results revealed that p300 controls the activation of primordial follicles in mammalian ovaries.

Genetic Landscape of a Cohort of 120 Patients with Diminished Ovarian Reserve: Correlation with Infertility

Diminished ovarian reserve (DOR) and primary ovarian insufficiency (POI) are major causes of female infertility. We recently found a monogenic etiology in 29.3% of POI, leading to personalized medicine. The genetic landscape of DOR is unknown. A prospective study (2018–2023) of an international cohort of 120 patients with unexplained DOR was performed using a large custom targeted next-generation sequencing panel including all known POI-causing genes. The diagnostic yield, based on the American College of Medical Genetics, was 24, 2%. Genes belong to different pathways: metabolism and mitochondria (29.7%), follicular growth (24.3%), DNA repair/meiosis (18.9%), aging (16.2%), ovarian development (8.1%), and autophagy (2.7%). Five genes were recurrently found: LMNA, ERCC6, SOX8, POLG, and BMPR1B. Six genes identified in single families with POI were involved in DOR, GNAS, TGFBR3, XPNPEP2, EXO1, BNC1, ATG, highlighting their role in maintaining ovarian reserve. In our cohort, 26 pregnancies were recorded, but no pregnancy was observed when meiosis/DNA repair genes were involved, suggesting severely impaired oocyte quality. Additional studies should confirm these preliminary results. This study with a large NGS panel defines the genetic landscape of a large cohort of DOR. It supports routine genetic diagnosis. Genetics could be a biomarker predicting infertility and progression to POI.

Cardio-metabolic Disorders Affected by Genetic Polymorphisms Related to Premature Menopause.

Premature menopause (PM) is defined as the end of ovulation before the age of 40 years, a condition commonly referred to as primary ovarian insufficiency. It has been shown there is an association between early menopause and a high risk of cardiovascular disease. This study aimed to evaluate the effect of genetic polymorphisms related to premature menopause on cardio-metabolic disorders Objective: We aimed to investigate the single nucleotide polymorphisms associated with PM and the risk of cardio-metabolic disorders in the MASHAD cohort study. In this cross-sectional study, a total of 117 women with PM were recruited and compared with 183 healthy women. All participants were assessed for anthropometric indices and genotyped for eight selected polymorphisms within seven different genes. A significant difference was observed in physical activity level (PAL) between the groups. Individuals with rs4806660 CC genotype had a 3.63-fold increased risk of metabolic syndrome. Moreover, individuals with a TT genotype of the rs2303369 polymorphism had a 3.11-- fold increased risk of obesity. Our findings showed that genetic variations are risk factors related to cardio- metabolic disorders in women with premature menopause.

Uptake of gonadotrophin-releasing hormone agonists for prevention of premature ovarian insufficiency in women undergoing chemotherapy: an Australian single-centre study.

Treatment-related premature ovarian insufficiency (POI) can result in early-onset menopause and infertility. To assess the prevalence of goserelin use for POI prevention in women with cancer since it was listed by the Australian Pharmaceutical Benefits Scheme in 2018 for this indication. This retrospective study included women aged 18-45 years who received curative-intent alkylating chemotherapy for a malignancy between August 2020 and December 2022 at the Peter MacCallum Cancer Centre. The co-primary end-points were (i) documentation of a discussion with the patient regarding goserelin for POI prevention and (ii) prescription of goserelin for POI prevention prior to chemotherapy commencement. Sixty-six patients were eligible. Fifty patients (76%) had a documented discussion regarding goserelin for POI prevention and 53 patients (80%) were prescribed goserelin for POI prevention. Nulliparous women were more likely to have a discussion regarding goserelin (P = 0.004). Younger women, nulliparous women and those referred to a fertility service were more likely to have been prescribed goserelin for POI prevention (P = 0.003, P = 0.001 and P = 0.002 respectively). Twenty-one of 53 patients (40%) who received goserelin had the first dose administered ≥7 days before chemotherapy commencement. One-quarter of eligible patients did not have a documented discussion regarding goserelin, despite the negative consequences of POI. Efforts are needed to increase the discussion and use of goserelin in all premenopausal women regardless of their fertility interests and to ensure timely administration in those who choose to receive it.

Identification and Characterization of Novel FSHR Copy Number Variations Causing Premature Ovarian Insufficiency.

Follicle stimulating hormone (FSH) is a key pituitary gonadotropic hormone implicated in human fertility and is crucial for folliculogenesis and recruitment of new antral follicles. Variations in its receptor, FSHR, can lead to diverse reproductive phenotypes including ovarian hyperstimulation syndrome (OHSS) and premature ovarian insufficiency (POI). This study reports a novel case of FSHR-related ovarian insufficiency in a patient with primary amenorrhea, subnormal AMH levels, and delayed puberty. Genetic exploration revealed two compound heterozygous intragenic deletions of FSHR. Specifically, the patient inherited a maternally derived deletion spanning exons 5-10 and a paternally derived deletion involving exons 3-6. Through chromosomal microarray analysis (CMA), exome sequencing, long-range PCR, and Sanger sequencing, we characterized the breakpoints and confirmed the compound heterozygous deletions. The findings reveal a complete loss of function of both FSHR alleles, contributing to the patient's POI phenotype. This case emphasizes the complexity of genotype-phenotype correlations in FSHR-related disorders and the role of CNVs in POI phenotypes. Although these events are rare, our results advocate for the inclusion of CNV detection in the diagnostic workup of POI to ensure accurate diagnosis and better patient management.

Melatonin protects against particulate matter-induced ovarian dysfunction by activating the Nrf2 signaling pathway to alleviate ferroptosis

Accumulating evidence suggests that exposure to ambient airborne PM2.5 increases the risk of primary ovarian insufficiency (POI). However, whether ferroptosis, a newly discovered type of cell death involved in PM2.5-induced lung injury and fibrosis, is involved in PM2.5-induced POI has not been determined. This study aimed to verify the involvement of PM2.5-induced ferroptosis in ovarian dysfunction and further demonstrate that melatonin inhibits ferroptosis by activating the Nrf2 signaling pathway to ameliorate POI in vivo and in vitro. In our study, PM2.5 promoted iron accumulation and induced lipid peroxidation, thus contributing to ferroptosis in KGN cells and ovaries. However, these effects were eliminated and enhanced in Nrf2-overexpressing and Nrf2-knockdown cells, respectively. In addition, melatonin and ferrostatin-1 (Fer-1) inhibited ferroptosis by activating the NRF2 signaling pathway, as evidenced by the silencing of Nrf2 in vivo and in vitro. Mechanistically, Nrf2-knockout mice were more susceptible to ferroptosis and PM2.5-induced POI than control mice. Moreover, melatonin suppressed changes in morphological and biochemical indicators related to ferroptosis, such as MDA and GSH depletion and GPX4 and XCT downregulation, by enhancing Nrf2 signaling. Here, we first reported that PM2.5 triggered ferroptosis by increasing ROS levels, lipid peroxidation and glutathione depletion. Notably, melatonin significantly decreased ferroptosis levels and improved ovarian function by activating the NRF2 signaling pathway in vivo and in vitro.

Novel Loss-of-function Variants of ZP3 Associated with Premature Ovarian Insufficiency.

Premature ovarian insufficiency (POI) is one of the leading causes of female infertility. To date, the genetic etiology of POI has been elucidated in approximately 20-25% of the total cases. The human zona pellucida (ZP) plays an important role in the organization and differentiation of granulosa cells, follicle formation, and sperm recognition. Mutations in ZP1, ZP2, and ZP3 have been reported to cause female infertility due to oocyte degeneration, empty follicle, or in vitro fertilization failure. In this study, we identified three novel missense mutations in ZP3 (NM_001110354.2): c.643G > A (p.Asp215Asn), c.215C > T (p.Thr72Ile), and c.152T > C (p.Leu51Pro) in three sporadic Han Chinese POI patients through whole-exome sequencing. These variants are absent from population databases and were predicted to be deleterious by multiple in silico tools. Structure prediction analysis showed that the affected amino acid altered the ZP3 protein structure. Western blot further confirmed that these ZP3 variants reduced the expression and secretion of ZP components. In summary, this study reports three novel deleterious variants in ZP3 associated with POI, thereby broadening the mutation spectrum of ZP3 in POI patients.

Genetic associations of miRNA variants (miR-10a, miR-30c, miR-181a, miR-499b) with primary ovarian insufficiency in Korean women

ObjectivesMicroRNAs (miRNAs) are pivotal in post-transcriptionally modulating gene expression in both animals and plants. This study investigates the relationship between microRNA polymorphisms and the occurrence of primary ovarian insufficiency in Korean women. Our hypothesis posits that polymorphisms in microRNAs—specifically miR-10aA > T, miR-30cA > G, miR-181aT > C, and miR-499bA > G—may be linked to primary ovarian insufficiency, influencing the risk of developing the condition. MethodsWe conducted a case-control study of 141 Korean women with primary ovarian insufficiency and 281 control individuals with at least one live birth and no history of pregnancy loss. ResultsOur findings indicate that various combinations of these four microRNA polymorphic sites are associated with an increased risk of primary ovarian insufficiency. The combination analysis indicated a significant decrease in the frequency of the miR-181a/miR-499b TC/AA allele combination in individuals with primary ovarian insufficiency (P < 0.05). Additionally, one-way analysis of variance of data from patients with primary ovarian insufficiency revealed that, in comparison with miR-181aTT, the miR-181aCC genotype was associated with significantly lower levels of both follicle-stimulating hormone and luteinizing hormone, suggesting potential protective effects. ConclusionsOur data suggest that dysregulation of the miR-10aA > T, miR-30cA > G, miR-181aT > C, and miR-499bA > G polymorphisms in these microRNAs contributes to the regulation of target genes related to primary ovarian insufficiency.

Society for endocrinology guideline for understanding, diagnosing and treating female hypogonadism.

Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are monospecialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo-pituitary disorders, whether organic or functional.

Clinical utility of anti-Müllerian hormone in female children and adolescents.

Anti-Müllerian hormone (AMH) is a dimeric glycoprotein that belongs to the transforming growth factor beta superfamily and plays essential roles in sexual differentiation and folliculogenesis. In the male embryo, AMH is produced by the Sertoli cells and induces the involution of the Müllerian ducts. In females, AMH is predominately produced by the granulosa cells of growing preantral and small antral follicles and regulates follicular maturation. Many recent studies have highlighted the significant role of this hormone in the diagnostic approach to female children and adolescents with various disorders that affect ovarian development and function. AMH is considered a valuable diagnostic tool in the management of female pediatric patients with conditions such as polycystic ovary syndrome, precocious puberty, ovarian tumors, differences in sex development, and premature ovarian insufficiency. Standardization of AMH assays, internationally approved reference values based on age and pubertal stage, and widespread availability of the test could further upgrade the clinical utility of AMH, rendering it a valuable tool in the armamentarium of physicians involved in the care of female children and adolescents, and promote future research.

Investigation of an MCM8 gene variant in women with premature ovarian insufficiency

Investigation of an MCM8 gene variant in women with premature ovarian insufficiency