Idiopathic Premature Ovarian Insufficiency Research Articles

Effects of herbal medicine on ovulation in premature ovarian insufficiency patients during in vitro fertilization

Introduction: Premature ovarian insufficiency (POI) is a condition in which menopause occurs before the age of 40 and is known to be a relatively common disease that occurs in 1% of all women. The only way for patients diagnosed with POI to become pregnant is through oocyte donation, in which fertilized ovums are transplanted by receiving oocytes from donors.4 Can POI patients increase their chances of normal ovulation? POI patients were more likely to observe and collect follicles larger than the average 15 mm diameter when herbal medicine was administered. Methods: This study is a retrospective cohort study conducted on POI patients undergoing in vitro fertilization (IVF) who visited our hospital from 2020 to 2022. We would like to report the response rate to gonadotropin-releasing hormone (GnRH) during IVF in the hyperovulation induction low response group after herbal medicine treatment. Statistical analysis was performed using IBM’s SPSS Statistics to verify significance with a P-value<0.05. Results: In recovering ovarian POI patient's ovarian function, herbal medicine treatment increased the response rate to GnRH (the number of oocytes collected) during IVF, follicle-stimulating hormone (FSH) and cortisol levels decreased, and estradiol (E2) and luteinizing hormone (LH) levels increased. Conclusions: It was confirmed that herbal medicine treatment can increase the probability of normal ovulation in patients with idiopathic POI with high cortisol levels. Until now, it has been known that ovarian function cannot be recovered once irreversibly decreased, but by increasing the probability of ovulation through herbal medicine treatment, it is significant that it may be possible to suppress ovarian aging or preserve fertility.

Premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a cause of infertility and endocrine dysfunction in women, defined by loss of normal, predictable ovarian activity before the age of 40 years. POI is clinically characterized by amenorrhoea (primary or secondary) with raised circulating levels of follicle-stimulating hormone. This condition can occur due to medical interventions such as ovarian surgery or cytotoxic cancer therapy, metabolic and lysosomalstorage diseases, infections, chromosomal anomalies and autoimmune diseases. At least 1 in 100 women is affected by POI, including 1 in 1,000 before the age of 30 years. Substantial evidence suggests a genetic basis to POI. However, the cause of idiopathic POI remains unknown in most patients, indicating that gene variants associated with this condition remain to be discovered. Over the past 10years, tremendous progress has been made in our knowledge of genes involved in POI. Genetic approaches in diagnosis are important as they enable patients with familial POI to be identified, with the opportunity for oocyte preservation. Moreover, genetic approaches could provide a better understanding of disease mechanisms, which will ultimately aid the development of improved treatments.

Bone mineral density: Comparison between women under hormone replacement therapy with Turner syndrome or idiopathic premature ovarian insufficiency

ContextTurner syndrome (TS) is characterized by short stature and premature ovarian insufficiency (POI). The main long-term complication of POI is osteoporosis, which can be prevented by hormone replacement therapy (HRT). ObjectiveThe objective of our study was to compare initial bone mineral density (BMD) and progression between TS and idiopathic POI patients under HRT. MethodsA single-center retrospective study was conducted between 1998 and 2018. All women had undergone at least two bone densitometry assessments at least 2 years apart. ResultsSixty-eight TS patients and 67 idiopathic POI patients were included. Mean age at initial assessment was 27 years (IQR, 21–35.5 years) in TS patients and 31.5 years (IQR, 23–37 years) in idiopathic POI patients (P=0.1). Lumbar and femoral neck BMD were lower in the TS group than in the idiopathic POI group (respectively 0.89g/cm2 versus 0.95g/cm2, P=0.03; 0.70g/cm2 versus 0.77g/cm2, P<0.0001). Mosaic karyotype was associated with better BMD in TS patients while history of growth hormone treatment had no impact on BMD. Over time, a significant gain in vertebral BMD was observed in TS patients versus a loss of BMD in idiopathic POI patients (P=0.0009). ConclusionTS patients had a lower BMD at baseline than idiopathic POI patients, at both spinal and femoral levels. Over time, on HRT, a significant gain in vertebral BMD was observed in patients with TS, compared with a loss of BMD in patients with idiopathic POI. We hypothesized that earlier initiation and longer duration of HRT played an important role in this finding. Long-term prospective follow-up to assess the incidence of fractures in TS would be useful.

O-083 Sexual function in women with Premature Ovarian Insufficiency (POI): systematic review and meta-analysis

Abstract Study question What is the impact of idiopathic premature ovarian insufficiency (POI) on sexual function in women? Summary answer Women with POI exhibit significant reduced sexual function and a higher risk of sexual dysfunction than healthy control women. What is known already POI is a life-changing diagnosis with profound physical and psychological consequences. The impact of POI on sexual complaints, seems multifaceted. Many women report vaginal dryness, dyspareunia (painful intercourse), and diminished libido, but also psychosexual function could be impaired, with potential effects on sexual identity, sexual function, and sexual relationships. Furthermore, the POI diagnosis can have a significant impact on a woman's self-esteem and body image, which could result in problems with sexual function. The ESHRE Guideline emphasizes the importance of providing psychological support and counseling to address the emotional and psychosexual impact of POI. Study design, size, duration This systematic review and meta-analysis is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The following online databases were systematically searched: EMBASE, Medline(Ovid), Web of Science, Coachrane, PsychInfo and Google Scholar up to January 2023. Participants/materials, setting, methods A total of ten studies were included in the systematic review and five studies involving 352 women with POI were included in the meta-analysis. Random effects models were used for analyses, with data reported as Hedges’ g and 95% confidence interval, and the risk of heterogeneity was evaluated. Main results and the role of chance Eight of the ten studies concluded that women with POI have a reduced sexual function. An overall medium Hedges’ g effect size of −0.72 was found (ranging between −0.20 to −1.29) in favor of control women, with moderate heterogeneity (I2 = 64%). When we stratified studies in which women were using hormone replacement therapy (HRT) we calculated an even higher Hedges’ g effect size of −0.82 (95% CI −1.18, −0.47). Pooled data from the different FSFI domains, revealed that women with POI scored significantly lower on all domains. Especially the domain ‘dyspareunia’ exhibited the greatest dissimilarity (Hedges g of −0.63, 95%CI −0.86, −0.39) in women with POI compared to control. Limitations, reasons for caution We have reported a moderate heterogeneity which may be caused by differences in age, duration of diagnosis, infertility status, and socioeconomic background in the various studies. Additionally, limitations such as selection bias, data duplication, and questionnaire variation were identified. Wider implications of the findings The results show that women with POI have reduced sexual function, and HRT use did not improve sexual function. This suggest that oral HRT is less effective for sexual dysfunction. There could be an important role for psychological factors in improving sexual well-being among women with POI. Trial registration number CRD42023437203 (PROSPERO)

Novel compound heterozygous variants in FANCI cause premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a common reproductive aging disorder due to a dramatic decline of ovarian function before 40 years of age. Accumulating evidence reveals that genetic defects, particularly those related to DNA damage response, are a crucial contributing factor to POI. We have demonstrated that the functional Fanconi anemia (FA) pathway maintains the rapid proliferation of primordial germ cells to establish a sufficient reproductive reserve by counteracting replication stress, but the clinical implications of this function in human ovarian function remain to be established. Here, we screened the FANCI gene, which encodes a key component for FA pathway activation, in our whole-exome sequencing database of 1030 patients with idiopathic POI, and identified two pairs of novel compound heterozygous variants, c.[97C > T];[1865C > T] and c.[158-2A > G];[c.959A > G], in two POI patients, respectively. The missense variants did not alter FANCI protein expression and nuclear localization, apart from the variant c.158-2A > G causing abnormal splicing and leading to a truncated mutant p.(S54Pfs*5). Furthermore, the four variants all diminished FANCD2 ubiquitination levels and increased DNA damage under replication stress, suggesting that the FANCI variants impaired FA pathway activation and replication stress response. This study first links replication stress response defects with the pathogenesis of human POI, providing a new insight into the essential roles of the FA genes in ovarian function.

The impact of premature ovarian insufficiency on sexual function; which domain is mostly disrupted?

This study aimed to compare the sexual function (SF) and its domains between women with idiopathic premature ovarian insufficiency (POI) and healthy control. A cross-sectional study was conducted on 63 married women with idiopathic POI, referred to the reproductive endocrinology research center (Tehran, Iran), and 784 married women with regular menstrual cycles who visited for routine annual gynecological exams in 2021-2022. The Female Sexual Function Index (FSFI) questionnaire was used to assess the SF of participants. Linear regression and factor analysis were used to analyze the data. Characteristics were similar in both study groups except for body mass index, hip circumference, job status, and number of deliveries. The mean score (standard deviation) of FSFI in women with POI and control were 21.70 (9.0) and 24.30 (5.0), respectively (P < 0.001). All domains' scores of FSFI were significantly lower in POI women than in the control group (P < 0.05). After adjusting for potential confounders, these findings remained unchanged. Factor analysis demonstrated the arousal and lubrication domains as the most influential factors SF among POI women, while the desire domain played the lowest role. In addition to various health conditions threatening POI women's future lives, sexual disturbances must be addressed in their routine care.

Homozygous missense variant in MEIOSIN causes premature ovarian insufficiency.

Are variants of genes involved in meiosis initiation responsible for premature ovarian insufficiency (POI)? A MEIOSIN variant participates in the pathogenesis of human POI by impairing meiosis due to insufficient transcriptional activation of essential meiotic genes. Meiosis is the key event for the establishment of the ovarian reserve, and several gene defects impairing meiotic homologous recombination have been found to contribute to the pathogenesis of POI. Although STRA8 and MEIOISN variants have been found to associate with POI in a recent study, the condition of other meiosis initiation genes is unknown and direct evidence of variants participating in the pathogenesis of POI is still lacking. This was a retrospective genetic study. An in-house whole exome sequencing (WES) database of 1030 idiopathic POI patients was screened for variations of meiosis initiation genes. Homozygous or compound heterozygous variations of genes involved in meiosis initiation were screened in the in-house WES database. The pathogenicity of the variation was verified by in vitro experiments, including protein structure prediction and dual-luciferase reporter assay. The effect of the variant on ovarian function and meiosis was demonstrated through histological analyses in a point mutation mouse model. One homozygous variant in MEIOSIN (c.1735C>T, p.R579W) and one in STRA8 (c.258 + 1G>A), which initiates meiosis via the retinoic acid-dependent pathway, were identified in a patient with idiopathic POI respectively. The STRA8 variation has been reported in the recently published work. For the MEIOSIN variation, the dual-luciferase reporter assay revealed that the variant adversely affected the transcriptional function of MEIOSIN in upregulating meiotic genes. Furthermore, knock-in mice with the homologous mutation confirmed that the variation impacted the meiotic prophase I program and accelerated oocyte depletion. Moreover, the variant p.R579W localizing in the high-mobility group (HMG) box domain disrupted the nuclear localization of the MEIOSIN protein but was dispensable for the cell-cycle switch of oocytes, suggesting a unique role of the MEIOSIN HMG box domain in meiosis initiation. Further studies are needed to explore the role of other meiosis initiation genes in the pathogenesis of POI. The MEIOSIN variant was verified to cause POI by impaired transcriptional regulation of meiotic genes and was inherited by a recessive mode. The function of HMG box domain in MEIOSIN protein was also expanded by this study. Although causative variations in meiotic initiation genes are rare in POI, our study confirmed the pathogenicity of a MEIOSIN variant and elucidated another mechanism of human infertility. This work was supported by the National Key Research & Developmental Program of China (2022YFC2703800, 2022YFC2703000), National Natural Science Foundation for Distinguished Young Scholars (82125014), National Natural Science Foundation of China (32070847, 32170867, 82071609), Basic Science Center Program of NSFC (31988101), Natural Science Foundation of Shandong Province for Grand Basic Projects (ZR2021ZD33), Natural Science Foundation of Shandong Province for Excellent Young Scholars (ZR2022YQ69), Taishan Scholars Program for Young Experts of Shandong Province (tsqn202211371), and Qilu Young Scholars Program of Shandong University. The authors declare no conflict of interest. N/A.

Novel Tu translation elongation factor, mitochondrial (TUFM) homozygous variant in a consanguineous family with premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by cessation of menstruation occurring before the age of 40 years. The genetic causes of idiopathic POI remain unclear. Here we recruited a POI patient from a consanguineous family to screen for potential pathogenic variants associated with POI. Genetic variants of the pedigree were screened using whole-exome sequencing analysis and validated through direct Sanger sequencing. A homozygous variant in TUFM (c.524G>C: p.Gly175Ala) was identified in this family. TUFM (Tu translation elongation factor, mitochondrial) is a nuclear-encoded mitochondrial protein translation elongation factor that plays a critical role in maintaining normal mitochondrial function. The variant position was highly conserved among species and predicted to be disease causing. Our in vitro functional studies demonstrated that this variant causes decreased TUFM protein expression, leading to mitochondrial dysfunction and impaired autophagy activation. Moreover, we found that mice with targeted Tufm variant recapitulated the phenotypes of human POI. Thus, this is the first report of a homozygous pathogenic TUFM variant in POI. Our findings highlighted the essential role of mitochondrial genes in folliculogenesis and ovarian function maintenance.

P-705 Homozygous missense variant in MEIOSIN causes premature ovarian insufficiency

Abstract Study question Are the gene variants involved in meiosis initiation responsible for premature ovarian insufficiency (POI)? Summary answer MEIOSIN variant participates in the pathogenesis of human POI by impairing meiosis due to insufficient transcriptional activation of essential meiotic genes. What is known already Meiosis is the key event for the establishment of the ovarian reserve, and several gene defects impairing meiotic homologous recombination have been found to contribute to the pathogenesis of POI. However, the genes involved in meiosis initiation have not been associated with POI. Study design, size, duration Retrospective genetic study. An in-house whole exome sequencing (WES) database of 1,030 idiopathic POI patients was screened for variations of meiosis initiation genes. Participants/materials, setting, methods Gene variations involved in meiosis initiation were screened in the in-house WES database of 1,030 POI cases. The pathogenicity of the variation was verified by in vitro experiments, including protein structure prediction and dual-luciferase reporter assay. The effect of the variant on ovarian function and meiosis was demonstrated through histological analyses in a point mutation mouse model. Main results and the role of chance A homozygous variant of MEIOSIN that initiates meiosis via the retinoic acid dependent pathway was identified in a patient with idiopathic POI. The dual-luciferase reporter assay revealed that the variant adversely affected the transcriptional function of MEIOSIN in upregulating meiotic genes. Further knock-in mice with the homologous mutation confirmed that the variation impacted the meiotic prophase I program and accelerated oocyte depletion. Limitations, reasons for caution Further studies are needed to explore the role of other meiosis initiation genes in the pathogenesis of POI. Wider implications of the findings The present study firstly identified pathogenic MEIOSIN variants in patients with POI. Although the causative variation in meiotic initiation genes is rare in POI, our study expanded the spectrum of causative genes and elucidated the different mechanisms in human infertility. Trial registration number Not available

O-303 Contribution of targeted sequencing for genetic diagnosis of premature ovarian insufficiency in clinical practice

Abstract Study question What is the diagnostic yield of custom designed gene panel for patients with premature ovarian insufficiency (POI)? Summary answer The diagnostic yield of our POI gene panel (POIGP) is 7.3% What is known already POI is a specific female syndrome with a high clinical and genetic heterogeneity. It is characterized by a premature exhaustion of the ovarian function and infertility and affects approximately 1% of women. POI can be related to genetic factors which include chromosomal abnormalities, FMR1 premutation and rare variants in numerous genes. The advent of high throughput sequencing methods has led to the identification of an increasing number of variants implicated in the development of POI over the last decades. However, POI etiologies still remain undetermined in the majority of cases. Study design, size, duration An observational analytic cohort study of 150 patients presenting idiopathic POI (normal karyotype, absence of FMR1 premutation, absence of adrenal and/or ovarian antibodies) recruited prospectively at three Belgian academic and university hospitals between 2016 and 2021. Participants/materials, setting, methods Patients were included if they experienced POI, as defined by ESHRE guidelines on POI (2016). POI genes included in the panel were selected from PubMed using different key words mainly premature ovarian insufficiency, gonadal dysgenesis, hypergonadotropic hypogonadism, ovarian failure and genetics. The panel included 156 genes, variants were filtered based on allele frequency (≤1%) in latest available population databases and classified according to ACMG/AMP (American College of Medical Genetics/Association for Molecular Pathology) guidelines 2015. Main results and the role of chance Our analysis revealed a potential causative variant for 11 patients in the following genes: MEIOB, BMP4, CFTR, FANCA, FSHR, FANCG, MLH1, MRPS22 and STARD9. This means that the diagnostic yield of our POI gene panel (POIGP) is 7.3%. Patients were mainly Caucasian (63%), North African (17%) and sub-Saharan African (13%). They presented primary amenorrhea in 14.7% of cases. Consanguinity and/or a family history of POI or early menopause in 28% of cases. Mean patient’s age (years) at POI diagnosis was 28.9± 8.5 (mean ± SD). The overall mean coverage was 229X, and more than 95% of the target exome was represented with more than 30-fold coverage. Limitations, reasons for caution The present study was limited to monogenic etiologies of POI, potential oligogenic causes have not been searched. Functional studies and/or family segregation were not performed for the identified variants. Wider implications of the findings Our findings show the importance of targeted next generation sequencing in clinical practice and highlight the limit of our current genetic knowledge in the field of POI. A regular update of genes included in POIGP will improve its diagnostic yield. Trial registration number P2016/196/CCB B406201628264

Pathogenic bi-allelic variants of meiotic ZMM complex gene SPO16 in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a heterogeneous disease affecting the physical and mental health of millions of women worldwide. The contribution of genetic factors in the pathogenesis of POI has increased, with quite a few of causative genes involved in meiosis. ZMM proteins are a group of conserved proteins participating in meiotic synapsis and crossover maturation. Here, by screening the variations of ZMM genes in our in-house WES database of 1030 idiopathic POI patients, one novel homozygous variation in SPO16 (c.160 + 8A > G) was firstly identified in one patient. The variation was verified to disturb mRNA splicing by minigene assay, produced a non-functional SPO16 protein, and was classified as pathogenetic according to American College of Medical Genetics guideline. During meiotic prophase I, SHOC1 binds to branched DNA and recruits SPO16 and other ZMM proteins to facilitate crossover formation. Together with our recent identified bi-allelic variations of SHOC1 in a published work, this study highlighted the essential roles of ZMM genes in the maintenance of ovarian function and expanded the POI gene spectrum.

Sexual function and quality of life in women with idiopathic premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a disruptive diagnosis for women, with major consequences on fertility but also on quality of life and sexual functioning. The aim of this study was to evaluate the impact of vaginal symptoms from the genitourinary syndrome of menopause on the quality of life and sexual functioning of women with POI. This cross-sectional observational study involved 88 women who were investigated in a specialized setting at the University Hospital of Toulouse (France) between 2014 and 2019. All women completed the Day-to-Day Impact of Vaginal Aging (DIVA) questionnaire on well-being and quality of life and the Female Sexual Function Index (FSFI) on sexual functioning. Analysis of total scores and subdomains of the questionnaire was performed and compared according to use of hormone replacement therapy or local low-dose estrogen treatment, age at POI, and use of antidepressant therapy or current psychological support. Outcomes included the DIVA questionnaire and the FSFI. Among the 88 women who fulfilled the inclusion criteria, 66 (75%) answered the questionnaires. Mean ± SD age at POI diagnosis was 32.6 ± 6.9 years and mean age at questionnaire time was 41.6 ± 6.9 years. The highest mean scores on the DIVA questionnaire were found in the self-perception and body image domain (2.05 ± 1.36), followed by the sexual functioning domain (1.52 ± 1.28). The mean FSFI score was 23.08 (95% CI, 21.43-24.73), with 32 women (78% of sexually active women) having a score <26.55, which defines sexual dysfunction. There was no difference in the FSFI score and for all DIVA domains whether or not women were taking hormone replacement therapy or local hormone therapy. This should encourage practitioners to systematically discuss the impact of POI on sexuality and vulvovaginal symptoms to provide women with specific care and advice to improve their quality of life. This is the first French study that aimed to assess the impact of the genitourinary syndrome of menopause on the quality of life and sexual well-being in women with POI by using standardized validated questionnaires with a very good participation rate (75%). The sample size was limited, and we could not eliminate selection bias due to university hospital recruitment. POI can have a negative impact on sexual quality of life, which raises the needs for specific advice and care.

A prospective and comparative investigation of blood sFlt-1, P1GF, and niacin concentrations in women with premature ovarian insufficiency.

Endothelial dysfunction is an important component of preeclampsia like premature ovarian insufficiency (POI), and it is reported that placental growth factor (P1GF) and soluble fms-like tyrosine kinase receptor-1 (sFlt-1) levels are important in preeclampsia. Extra-placental sources for P1GF and sFlt-1 have also been identified, including various cell types. In animal models of POI, niacin treatment inhibited follicular apoptosis under hazardous conditions while significantly reducing cumulus cell apoptosis. The number of developing follicles also increased after niacin was given. This study was designed to determine blood sFlt-1, P1GF, and niacin concentrations in women with idiopathic POI (iPOI) compared with those of healthy women. The study comprised 45 women with iPOI and 45 healthy women. Blood was obtained and analyzed at the early follicular phase of the menstrual cycle and sFlt-1, P1GF, and niacin levels were measured using a commercially available enzyme-linked immunosorbent assay kit. No significant differences were observed in the two groups according to the gravidity numbers, parity, abortion, live births, and menarche ages (p ≥ 0.05). In the iPOI group, the mean anti-mullerian hormone value was 0.03 ± 0.04 (min-max, 0.00-0.21)ng/ml. sFlt-1, P1GF, niacin levels, and also the sFlt-1/P1GF ratio were lower in the iPOI group (p < 0.01). A significant discriminative role of sFlt-1, P1GF, niacin levels, and the sFlt-1/P1GF ratio for the presence of iPOI, with cut-off values of 5.13, 10.28, 37.17, and 0.61 ng/ml, respectively, were reported in the receiver operating characteristics curve analysis. Lower levels of P1GF, sFlt-1, niacin, and sFlt-1/P1GF ratios may be associated with the development of POI/iPOI. Further studies are required to better understand the etiopathogenesis of POI/iPOI. NCT04641624 (clinicaltrials.gov).

Pathogenic variants in TSC2 might cause premature ovarian insufficiency through activated mTOR induced hyperactivation of primordial follicles

To investigate the role of tuberous sclerosis complex (TSC) genes, including TSC1 and TSC2, in the pathogenesis of human premature ovarian insufficiency (POI). Genetic and functional study. University-based reproductive medical center. Six patients from a cohort of 1,030 cases with idiopathic POI. Variants in TSC1 and TSC2 were screened through the largest in-house database of whole exome sequencing performed in 1,030 patients with idiopathic POI. The pathogenic effects of the variants were further verified by functional studies. TSC1 or TSC2 variant and functional characteristics. Five pathogenic heterozygous variants in TSC2 were identified in 6 patients with POI. Functional studies showed these variants impaired the repressive effect of TSC2 on mammalian target of rapamycin (mTOR) pathway by disrupting the formation of TSC complex or its GTPase-activating protein activity. Furthermore, invitro ovarian culture assay showed that TSC2 p.R98Q led to hyperactivation of mTOR pathway thereby triggering primordial follicle activation. The present study identified pathogenic variants of TSC2 in patients with POI, firstly suggested defective TSC/mTOR pathway mediated hyperactivation of primordial follicle participating in the pathogenesis of POI, giving insights into new targets of genetic counseling and clinical prevention for POI. Considering the pivotal role of TSC2 variants in diagnosis of TSC syndrome, the present study also highlighted the importance of history collection and long-term follow-up for the TSC2 variants carriers.

Identification of new variants and candidate genes in women with familial premature ovarian insufficiency using whole-exome sequencing.

To identify candidate variants in genes possibly associated with premature ovarian insufficiency (POI). Fourteen women, from 7 families, affected by idiopathic POI were included. Additionally, 98 oocyte donors of the same ethnicity were enrolled as a control group. Whole-exome sequencing (WES) was performed in 14 women with POI to identify possibly pathogenic variants in genes potentially associated with the ovarian function. The candidate genes selected in POI patients were analysed within the exome results of oocyte donors. After the variant filtering in the WES analysis of 7 POI families, 23 possibly damaging genetic variants were identified in 22 genes related to POI or linked to ovarian physiology. All variants were heterozygous and five of the seven families carried two or more variants in different genes. We have described genes that have never been associated to POI pathology; however, they are involved in important biological processes for ovarian function. In the 98 oocyte donors of the control group, we found no potentially pathogenic variants among the 22 candidate genes. WES has previously shown as an efficient tool to identify causative genes for ovarian failure. Although some studies have focused on it, and many genes are identified, this study proposes new candidate genes and variants, having potentially moderate/strong functional effects, associated with POI, and argues for a polygenic etiology of POI in some cases.

The probability and possible influence factors of intermittent ovarian function recovery in patients with premature ovarian insufficiency

Research questionWhat are the probability and underlying influence factors of intermittent ovarian function recovery in patients with idiopathic premature ovarian insufficiency (POI)? DesignThis was a retrospective cohort study conducted in tertiary hospitals recruiting 162 patients diagnosed with POI based on European Society of Human Reproduction and Embryology criteria from June 2015 to March 2022. The incidence of intermittent ovarian function recovery was evaluated, and the possible influence factors were investigated by univariate and multivariate analysis. ResultsAmong 162 POI patients, 48 (29.63%) presented intermittent ovarian function recovery, and 11 (6.79%) were natural pregnancies; 114 (70.37%) patients failed to show ovarian function recovery. No association was found between initial clinical features and intermittent ovarian function recovery. In contrast, the variables of FSH, LH, oestradiol, anti-Müllerian hormone (AMH), ovarian volume, passive smoking and weekly exercise time after diagnosis were correlated with intermittent ovarian function recovery in patients with POI and further analysis indicated that FSH concentration at diagnosis (odds ratio [OR] 0.964, 95% confidence interval [CI] 0.934–0.995, P = 0.023), passive smoking (OR 0.369, 95% CI 0.141–0.963, P = 0.042) and weekly exercise time after diagnosis (OR 5.592, 95% CI 1.83–17.088, P = 0.003) were influence factors of intermittent ovarian function recovery in POI patients. ConclusionsThe incidence of intermittent ovarian function recovery in patients with idiopathic POI was 29.63%, and the natural pregnancy rate was 6.79%. Lower FSH concentration at diagnosis, no passive smoking and a weekly exercise time ≥1.5 h after the diagnosis may be beneficial for intermittent ovarian function recovery in POI patients.

Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest.

The genetic causes of idiopathic premature ovarian insufficiency (POI) and nonobstructive azoospermia (NOA) remain unclear. We performed whole-exome sequencing (WES) in members of a consanguineous family with two POI and two NOA patients to screen for potential pathogenic variants for familial POI and NOA. And a homozygous variant in SPATA22 (c.400C>T:p.R134X) was identified. Histological analysis and spermatocyte spreading assay demonstrated that the spermatogenesis was arrested at a zygotene-like stage in the proband with NOA. The candidate gene was further screened in the in-house WES database of idiopathic POI-affected patients. One additional compound heterozygous variant in SPATA22 (c.900+1G>A and c.31C>T:p.R11X) was found in one patient with sporadic POI and validated by minigene assay. Thus, this is the first report identifying SPATA22 as the causative gene for human POI. Combined with the observations in the familial patient with NOA, our findings highlighted the essential role of meiotic HR genes in gametogenesis and gonadal function maintenance.

Novel bone morphogenetic protein 15 (BMP15) gene variants implicated in premature ovarian insufficiency

BackgroundBone morphogenetic protein 15 (BMP15) is expressed in oocytes and plays a crucial role in the reproduction of mono-ovulating species. In humans, BMP15 gene mutations lead to imperfect protein function and premature ovarian insufficiency. Here we investigated the BMP15 gene variants in a population of Iranian women with premature ovarian insufficiency. We conducted predictive bioinformatics analysis to further study the outcomes of BMP15 gene alterations.MethodsTwenty-four well-diagnosed premature ovarian insufficiency cases with normal karyotype participated in this study. The entire coding sequence and exon-intron junctions of the BMP15 gene were analyzed by direct sequencing. In-silico analysis was applied using various pipelines integrated into the Ensembl Variant Effect Predictor online tool. The clinical interpretation was performed based on the approved guidelines.ResultsBy gene screening of BMP15, we discovered p.N103K, p.A180T, and p.M184T heterozygous variants in 3 unrelated patients. The p.N103K and p.M184T were not annotated on gnomAD, 1000 Genome and/or dbSNP. These mutations were not identified in 800 Iranians whole-exome sequencing that is recorded on Iranom database. We identified the p.N103K variant in a patient with secondary amenorrhea at the age of 17, elevated FSH and atrophic ovaries. The p.M184T was detected in a sporadic case with atrophic ovaries and very high FSH who developed secondary amenorrhea at the age of 31.ConclusionsHere we newly identified p.N103K and p.M184T mutation in the BMP15 gene associated with idiopathic premature ovarian insufficiency. Both mutations have occurred in the prodomain region of protein. Despite prodomain cleavage through dimerization, it is actively involved in the mature protein function. Further studies elucidating the roles of prodomain would lead to a better understanding of the disease pathogenesis.

Comparing estrogen-based hormonal contraceptives and hormone therapy on bone mineral density in women with premature ovarian insufficiency: a systematic review.

Premature ovarian insufficiency (POI) is a condition associated with estrogen deficiency which leads to decreased bone mineral density and an increased risk of osteoporosis and fractures. Estrogen-based hormone therapy is an integral component of treatment; however, to date the ideal hormone formulation for optimizing bone health has not been established. To assess the effects of estrogen-based oral contraceptives (OCP) versus hormone therapy (HT) on bone mineral density (BMD) in women with POI. A systematic review of Ovid MEDLINE, EMBASE, Cochrane Library, and Web of Science databases was conducted from conception until December 2020. Randomized controlled trials (RCTs) and observational studies that met inclusion criteria were included in the analysis. Risk of bias was assessed with the Newcastle-Ottawa Quality Assessment Scale for cohort studies and the Cochrane Risk of Bias for RCTs. The study protocol was registered with the International Prospective Register of Systematic Reviews and adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. Our search yielded 1,227 studies; 3 RCTs and 2 observational cohort studies met inclusion criteria and were included in our study. The largest subpopulation was Turner Syndrome (n = 625), followed by idiopathic POI (n = 146). Of the four studies that assessed changes in BMD, two studies reported a significant increase in lumbar spine BMD with HT compared with OCP (+0.050 g/cm2, P < 0.025; +0.019 g/cm2, P < 0.01), one study found similar improvement in lumbar spine BMD across treatments (HT -0.003 g/cm2, P = 0.824), and one study did not directly compare treatments. Effects on bone turnover markers were inconsistent across three studies that evaluated this outcome. This is the first systematic review to include studies that directly compared OCP and HT on bone outcomes in POI. While two studies reported increased lumbar spine BMD with HT, this result was not consistently found across studies. There were important differences in POI etiology, treatment regimens and formulations, and risk of bias was high in many of the studies. These results indicate future, larger-scale trials are needed to further understand the optimal hormone therapy for bone density in POI.

Successful Mestrual Regularity and Spontaneous Pregnancies with a Resveratrol-Based Multivitamin Supplement in Women with Idiopathic Premature Ovarian Insufficiency

Abstract Premature ovarian insufficiency (POI) is a clinical syndrome defined by loss of ovarian activity before the age of 40 years and is characterized by menstrual disturbance, follicle stimulating hormone (FSH) concentration above 40 IU/l and infertility. In some patients the best option is to conceive spontaneously since many treatment strategies remain unsuccessful or involve eggs donation. In this case report series, we describe the effects of a resveratrol-based multivitamin supplement containing trans-resveratrol, folic acid, vitamin B6, B12 and D, in six women with poor prognosis of pregnancy due to POI and evaluate the achievement of desired conception. These women, aged less then 40 years, suffered from menstrual irregularities, anovulation and infertility. They all had normal karyotype, and no history of ovarian surgery, radiation exposure or chemotherapy. Blood test showed at least two values of FSH above 40 IU/l. Four out of six patients with POI conceived after 3-6 months of a resveratrol-based multivitamin supplement, ultimately giving birth to a full-term baby. Regular menstrual cycle was restored in all patients after two to four months the start of treatment. In conclusion the treatment with a resveratrol-based supplement improved menstrual regularity and suggest a useful potential of this supplementation in some cases of POI.