Cases Of Premature Ovarian Insufficiency Research Articles

Penetrance of Pathogenic Genetic Variants Associated With Premature Ovarian Insufficiency

(Abstracted from Nat Med 2023;29:1692–1699) Premature ovarian insufficiency (POI), defined as the loss of ovarian activity and permanent cessation of menstruation occurring before age 40 years, affects 1% of women and is a leading cause of infertility. Up to 90% of POI cases are idiopathic, with up to 30% of those having some familial association, suggesting a genetic basis.

Single-cell RNA-seq identified novel genes involved in primordial follicle formation.

The number of primordial follicles (PFs) in mammals determines the ovarian reserve, and impairment of primordial follicle formation (PFF) will cause premature ovarian insufficiency (POI). By analyzing public single-cell RNA sequencing performed during PFF on mice and human ovaries, we identified novel functional genes and novel ligand-receptor interaction during PFF. Based on immunofluorescence and in vitro ovarian culture, we confirmed mechanisms of genes and ligand-receptor interaction in PFF. We also applied whole exome sequencing (WES) in 93 cases with POI and whole genome sequencing (WGS) in 465 controls. Variants in POI patients were further investigated by in silico analysis and functional verification. We revealed ANXA7 (annexin A7) and GTF2F1 (general transcription factor IIF subunit 1) in germ cells to be novel potentially genes in promoting PFF. Ligand Mdk (midkine) in germ cells and its receptor Sdc1 (syndecan 1) in granulosa cells are novel interaction crucial for PFF. Based on immunofluorescence, we confirmed significant up-regulation of ANXA7 in PFs compared with germline cysts, and uniform expression of GTF2F1, MDK and SDC1 during PFF, in 25 weeks human fetal ovary. In vitro investigation indicated that Anxa7 and Gtf2f1 are vital for mice PFF by regulating Jak/Stat3 and Jnk signaling pathways, respectively. Ligand-receptor (Mdk-Sdc1) are crucial for PFF by regulating Pi3k-akt signaling pathway. Two heterozygous variants in GTF2F1, and one heterozygous variants in SDC1 were identified in cases, but no variant were identified in controls. The protein level of GTF2F1 or SDC1 in POI cases are significantly lower than that of controls, indicating the pathogenic effects of the two genes on ovarian function were dosage dependent. Our study identified novel genes and novel ligand-receptor interaction during PFF, and further expanding the genetic architecture of POI.

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

Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency.

Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P = 1.59 × 10-6) and SOHLH2 (3.48 years earlier menopause, P = 1.03 × 10-4). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI.

Association of genetic disorders and congenital malformations with premature ovarian insufficiency: a nationwide register-based study.

Are genetic disorders and congenital malformations associated with premature ovarian insufficiency (POI)? A wide range of genetic disorder and congenital malformation diagnoses are associated with POI, especially early onset POI. POI is known to be associated with some genetic disorders, such as Turner syndrome and Fragile X premutation. Multiple genetic syndromes, such as ataxia teleangiectasia and galactosemia, have also been associated with an increased risk of POI, and many of these genetic syndromes manifest with various congenital malformations. In previous studies, a genetic aetiology has been found for 7-15% of POI cases. This population-based study included 5011 women diagnosed with POI in 1988-2017. The data were collected from various national registries and covers women with POI nationwide. We identified 5011 women diagnosed with POI from 1988 to 2017 from the drug reimbursement registry of the Social Insurance Institution of Finland. Women with surgical POI (bilateral oophorectomy for benign indications) were not included. We selected four population controls per woman with POI matched by month and year of birth and municipality of residence. Diagnostic codes for genetic disorders and congenital malformations (GD/CM) for the cases and controls were searched from the Hospital Discharge Register. Binary logistic regression was used to compare the odds for GD/CM among cases and controls. To minimize bias, for the statistical analyses, we excluded diagnoses which were reported <2 years prior to the index date. Of the women with POI, 15.9% (n = 797) had at least one diagnostic code for GD or CM. The odds ratio (OR) for Turner syndrome was 275 (95% CI 68.1-1110), and for other sex chromosome abnormalities, it was 12.7 (95% CI 4.1-39.1). For autosomal single gene disorders, the OR was 16.5 (95% CI 6.2-43.7). Women with POI had a higher odds of having a GD/CM diagnosis in all categories. The OR for GD/CM diagnoses was highest among the youngest POI patients (10-14 years old, OR 24.1, 95% CI 15.1-38.2). The odds of having POI were higher the more GD or CM diagnoses a woman had. Some women with POI might not have sought help for their symptoms and therefore remain undiagnosed. Due to the register-based nature of our study, we did not have access to more specific genetic diagnoses than international classification of diseases offers. GD/CM diagnoses were strongly associated with POI, especially when POI was diagnosed at a young age. The risk of POI was highest in women with multiple GD/CM diagnoses. Early onset POI can be a sign of underlying genetic disorder or congenital anomaly, and this should serve as a reminder for clinicians to consider further examinations. To avoid unnecessary delay in the diagnosis of POI and starting relevant hormone replacement therapy treatment, clinicians should be aware of these associations. Oulu University Hospital financially supported this work. H.S. has received personal grants from the Finnish Menopause Society, Oulu Medical Research Foundation, and Finnish Research Foundation of Gynaecology and Obstetrics. S.S. has received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. None of the authors have any competing interests to declare. N/A.

Characterizing the Adolescent Premature Ovarian Insufficiency Phenotype: A Case Control Study

To characterize the skeletal, cardiometabolic, cognitive, and mental health phenotype of adolescents with idiopathic premature ovarian insufficiency (POI) DESIGN: Case control SETTING: Pediatric tertiary referral center in Cincinnati, Ohio PARTICIPANTS: Nine adolescents (ages 11-18.99 years) with newly diagnosed POI and 9 normally menstruating controls, matched by age and body mass index MAIN OUTCOME MEASURES: Between-group comparisons of bone characteristics assessed by dual energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), psychosocial health (anxiety, depression, and quality of life), and cognition and memory by questionnaire RESULTS: Adolescents with POI had lower bone density Z-scores by DXA (lumbar spine -1.93vs 0.80; whole body less head -2.05vs 0.00; total hip -1.03vs 0.83; and femoral neck -1.23vs 0.91; all P < .001), as well as lower trabecular volumetric bone mineral density (tibia 3% site 226vs 288mg/mm3, P < .001; radius 3% site 200vs 251, P=.001), smaller cortical area (tibia 66% site 251vs 292 mm2, P=.028), and thickness (tibia 66% site 3.56vs 4.30mm, P=.001) than controls. No abnormalities in cardiometabolic biomarkers were detected in POI cases. Adolescents with POI were also more likely to report low energy (78% vs 22%, P=.02). Estrogen deficiency adversely affects bone health in adolescents with POI. However, we did not find associations with cardiometabolic, mental health, or cognitive outcomes in this small sample.

O-147 Genomic analyses in 101,127 UK women show that previously reported monogenic genes are not common causes of premature ovarian insufficiency

Abstract Study question What is the penetrance of variants in previously reported genes for premature ovarian insufficiency (POI) in the general population? Summary answer Heterozygous genetic variants in previously reported monogenic genes are not a common, highly penetrant cause of POI. What is known already Premature ovarian insufficiency (POI), defined as menopause before 40, has been associated with variants in over 70 genes. However, the evidence to support the causality of individual genetic variants varies between studies. As genomic data becomes more accessible, it is essential to ascertain the penetrance of variants in the absence of family history information. We identified 75 genes associated with POI from the literature, including family segregation studies, consanguineous pedigrees and cohort analyses of whole-exome/targeted sequencing data. Functional evaluation was also available for many of the genes. Study design, size, duration We used data from 101,127 females of European ancestry in the UK Biobank, to study the role of previously reported monogenic causal genes on ovarian function. We tested the association of 301 previously reported variants with POI and ANM, plus more than 2.5 million rare variants which were annotated and had not been implicated in POI previously. Genomic variants were tested individually and also combined into a gene burden test. Participants/materials, setting, methods Age at natural menopause (ANM) was derived from self-reported questionnaire data from the age at last menstrual period, excluding those with surgical menopause or taking hormone replacement therapy. POI cases were classified as women with ANM under 40 years (N = 2,213). Linked primary care records were used to identify a clinical cohort of POI cases, including primary amenorrhea (N = 113). Main results and the role of chance All of the previously reported individual variants we identified in our POI cases were also detected in the control group. Moreover, the gene burden tests were not associated with POI or ANM as a quantitative trait. Our results indicate that autosomal dominant causes of POI are rare; a single predicted loss-of-function (LOF) or non-synonymous genetic variant in one of the previously reported genes is generally not pathogenic. Limitations, reasons for caution The penetrance of monogenic disease-causing variants is likely to be lower in population-based cohorts such as UK Biobank than in clinically-ascertained cohorts. Wider implications of the findings Heterozygous LOF or non-synonymous variants in previously reported POI genes should be interpreted with caution and are unlikely to cause POI. The findings have implications for clinicians diagnosing causes of POI. Trial registration number Not applicable

Cases Study on the Management of Diminished Ovarian Reserve (DOR) and Premature Ovarian Insufficiency (POI) with Traditional Chinese Medicine (TCM)

Diminished Ovarian Reserve (DOR) is one of the main causes of female infertility and is common in women under of 40s. The definition and diagnosis are pragmatic and the treatment in mainstream medicine is not promising as many of the sufferers have to choose IVF as the last resort. DOR could be the reduced ability of producing quality egg or the poor quality of eggs produced. Premature Ovarian Insufficiency (POI) belongs to its aggravate stage. Traditional Chinese medicine has long been employed in treating female infertility, and a large proportion of the cases in the records now could be classified as DOR or POI. Some clinical reports have demonstrated great potential in treating DOR &amp; POI. The authors have treated many cases of DOR and POI, and great achievements have been recorded. The protocol used in the treatment is a whole system approach which combines acupuncture, Chinese herbal medicine and lifestyle advice into an organic composition to maximize the effects. The cases reported here are of good details and could demonstrate the application of the TCM diagnosis of syndrome pattern which logically leads to the whole-system treatment implementation.

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.

Incidence and familial risk of premature ovarian insufficiency in the Finnish female population.

STUDY QUESTIONWhat is the incidence of premature ovarian insufficiency (POI), has the incidence of POI changed over time, and what is the risk of POI among relatives of POI women?SUMMARY ANSWERThe incidence of POI increased among females aged 15–19 years from 2007 onwards and decreased in older age groups, and among relatives of women with POI the risk of POI is significantly increased.WHAT IS KNOWN ALREADYSo far, there has been no good quality, nationwide studies of the incidence of POI. Early menopause has been associated with the elevated risk of early menopause among relatives, but the knowledge of the familial risk of POI is scarce. Lower socioeconomic status has been associated with lower age at natural menopause.STUDY DESIGN, SIZE, DURATIONPopulation-based study with 5011 women diagnosed with POI in 1988–2017. The data were collected from national registries and covers POI subjects in entire Finland.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen with hormone replacement therapy reimbursement for POI were identified from Social Insurance Institution (SII). We calculated POI incidence in different age groups and studied the changes in the incidence rate over time in 5-year segments. Four population-based controls were selected from the Digital and Population Data Services Agency (DVV) for each POI woman. Family members of the POI cases and controls were identified from the DVV and linked to SII reimbursement data to identify POI diagnoses among them. The familial risk of POI was estimated with a logistical regression model.MAIN RESULTS AND THE ROLE OF CHANCEThe incidence was highest in the 35–39 age group, ranging from 73.8/100 000 women-years in 1993–1997 to 39.9/100 000 women-years in 2013–2017. From 2007, the incidence among 15- to 19-year-olds rose from 7.0 to 10.0/100 000 women-years in 2015–2017. Cumulative incidence of POI for women under 40 years in 1988–2017 was 478/100 000 women. The relative risk of POI among relatives of women with POI was 4.6 (95% CI 3.3–6.5) compared to relatives of women without POI. POI women tended to have slightly lower socioeconomic status and level of education compared to controls.LIMITATIONS, REASONS FOR CAUTIONFor some women with POI, diagnosis or reimbursement may be lacking. However, we presume that these women represent a minority due to the nature of the disease and the economic benefits of reimbursement. Some changes in the incidence of POI can reflect changes in clinical practice and changing treatments and reimbursement criteria.WIDER IMPLICATIONS OF THE FINDINGSThe risk of developing POI is significantly higher in women who have first-degree relatives diagnosed with POI. Raising awareness of the increased risk might lead to earlier diagnosis and initiation of hormonal replacement therapy, possibly preventing adverse effects of low oestrogen levels, such as osteoporosis.STUDY FUNDING/COMPETING INTEREST(S)This work was financially supported by the Oulu University Hospital. H.S. received a grant from Finnish Menopause Society. S.M.S. received a grant from the Finnish Menopause Society, the Finnish Medical Foundation and the Juho Vainio Foundation. The authors do not have any competing interests to declare.TRIAL REGISTRATION NUMBERN/A.

Whole exome sequencing in a cohort of familial premature ovarian insufficiency cases reveals a broad array of pathogenic or likely pathogenic variants in 50% of families

To study the diagnostic yield, including variants in genes yet to be incriminated, of whole exome sequencing (WES) in familial cases of premature ovarian insufficiency (POI). Cross-sectional study. Endocrinology and reproductive medicine teaching hospital departments. Familial POI cases were recruited as part of a nationwide multicentric cohort. A total of 36 index cases in 36 different families were studied. Fifty-two relatives were available, including 25 with POI and 27 affected who were nonaffected. Karyotype analysis, FMR1 screening, single nucleotide polymorphism array analysis, and WES were performed in all subjects. None. The primary outcome was a molecular etiology, as diagnosed by karyotype, FMR1 screening, single nucleotide polymorphism array, and WES. A likely molecular etiology (pathogenic or likely pathogenic variant) was identified in 18 of 36 index cases (50% diagnostic yield). In 12 families, we found a pathogenic or likely pathogenic variant in a gene previously incriminated in POI, and in 6 families, we found a pathogenic or likely pathogenic variant in new candidate genes. Most of the variants identified were located in genes involved in cell division and meiosis (n = 11) or DNA repair (n = 4). The genetic etiologic diagnosis in POI allows for genetic familial counseling, anticipated pregnancy planning, and ovarian tissue preservation or oocyte preservation. Identifying new genes may lead to future development of therapeutics in reproduction based on disrupted molecular pathways. NCT01177891.

AACE2021-A-1026: Premature Ovarian Insufficiency: Epidemiology, Aetiopathology, and Diagnostic Evaluation at Sultan Qaboos University Hospital

Premature ovarian insufficiency (POI) affects women younger than 40 years and is described by the loss of ovarian functions. This study aim is to identify the incidence of POI, describe the epidemiological characteristic of patients and their presenting symptoms, determine biochemical features, identify radiological features of POI, and describe the treatment option in patients of POI at Sultan Qaboos Hospital (SQUH). A retrospective observational study was designed to identify the incidence of POI at SQU in the period between January 2015 and January 2020 on women with POI who aged between 13 and 40 years old and came with amenorrhea, infertility, low estrogen levels, and with or without small ovaries under pelvis ultrasound radiography. Data were obtained from the Hospital Information System by TrakCare system which includes demographic, clinical, biochemical, radiological features and medications which were described at SQUH to women with POI. SPSS was used for data analysis. 143 patients were collected from a database with POI in 5 years. The median age was 33 years, the mean of ages was 30.8 ± 7.07 years, and the range of ages was between 16-39 years. Most of the patients who were diagnosed with POI at SQUH were from Muscat governorate. 79% of patients came with amenorrhea whereas 21% came with menstrual irregularity. The most common cause within patients was post-BMT and chemotherapy by 45% of patients. As a radiological feature, pelvis ultrasound (US) was shown the abnormal size of ovaries in 41% of patients. Oral contraceptive (OCP) drugs were described in 53% of patients. The majority of cases had POI due to chemotherapy and bone marrow transplantation (BMT) and presented with amenorrhea. Almost all cases of POI suffer from infertility. Hormone replacement therapy (HRT) is a treatment that is used in most cases of POI.

Prevalence of cytogenetic abnormalities and FMR1 gene premutation in a Portuguese population with premature ovarian insufficiency.

Chromosome abnormalities contribute to about 10% of cases of premature ovarian insufficiency. Most are associated with X chromosome. Fragile mental retardation 1 (FMR1) gene premutation has an estimated prevalence of 1% - 7% in sporadic cases and up to 13% in familial cases. Our aim was to describe the clinical characteristics, cytogenetic and FMR1 testing of a Portuguese population with premature ovarian insufficiency. Women diagnosed with premature ovarian insufficiency in a Portuguese tertiary centre were retrospectivelyanalysed. Data were retrieved from electronic medical records including clinical characteristics, cytogenetic and FMR1 testing. The main outcome measures were the prevalence of chromosome abnormalities and FMR1 premutation in a Portuguese population withpremature ovarian insufficiency. Ninety-four patients were included, with a median age at menopause of 36 years. The prevalence of chromosome abnormalities was 16.5% (14/85) and most were X chromosome related (78.6%). The prevalence of FMR1 premutation was 6.7% (6/90). The prevalence of karyotypic abnormalities or FMR1 premutation did not differ significantly between familial and sporadic cases. Neither chromosome abnormalities nor FMR1 premutation influenced age at menopause or follicle stimulating hormone levels at diagnosis in premature ovarian insufficiency patients. This is the first study describing the clinical characteristics and both cytogenetic and FMR1 testing in a Portuguese population with premature ovarian insufficiency. The rate of chromosome abnormalities in our sample was higher than in other populations, while the prevalence of FMR1 premutation was similar to previous reports. Our results underline the importance of genetic screening in premature ovarian insufficiency patients in both etiological study and genetic counselling.

O-177 Long-term follow up to assess criteria for ovarian tissue cryopreservation for fertility preservation in young women and girls with cancer

Abstract Study question Do the Edinburgh selection criteria correctly identify females, diagnosed with cancer under 18 years old, at high risk of future premature ovarian insufficiency (POI)? Summary answer Patient assessment using these criteria accurately identifies those at risk of POI. Ovarian tissue cryopreservation with future transplantation can be offered, providing future fertility options. What is known already Cancer treatments can be gonadotoxic and future fertility and reproductive health should be considered at the time of diagnosis and treatment planning. Correct identification of patients at high risk allows appropriate discussion of fertility preservation with ovarian tissue cryopreservation (OTC) and future transplantation. The Edinburgh selection criteria have been proposed as a tool to identify those patients at high risk. However, the surgical procedure is not without risk and reproductive outcomes remain uncertain in girls. Therefore, long-term follow up of reproductive function is crucial to ensure that this treatment strategy is offered appropriately. Study design, size, duration All females diagnosed with cancer less than 18 years old, in South East Scotland, between 01/01/96 and 30/10/20 were included. They were assessed using the Edinburgh selection criteria and offered OTC, if appropriate. Ongoing long-term follow up of reproductive outcomes has been undertaken for the whole patient cohort to detect those who develop POI. Participants/materials, setting, methods A total of 639 eligible patients were identified from the Cancer registry and their electronic records reviewed. Reproductive function was assessed by the presence of menstruation, pregnancy, hormonal measurements, evidence of puberty or diagnosis of POI. Patients on hormonal contraception (other than for the treatment of POI) were considered unsuitable for analysis. Data were analysed using the Kaplan Meier method, with POI as the event, and the Cox proportional hazards model to calculate hazard ratios. Main results and the role of chance Of the 639 patients diagnosed with cancer during the study period, those deceased before age 12 years old (n = 73) or under 12 years old (n = 134) at the date of analysis were excluded; also excluding those on hormonal contraception (n = 9) gave a study population of 423. Data were analysed including those with unknown reproductive outcomes (n = 143), assuming they did not have POI. A subgroup analysis excluding these patients was also performed. Mean age at diagnosis and analysis was 8.8 years and 22.5 years respectively. OTC was offered to 37 patients, 26 of whom underwent the procedure. Nine patients developed POI (24.3%). Of the 386 not offered OTC, 11 developed POI (2.85%). The hazard ratio for developing POI was 8.8 (CI 3.6-21). Excluding the patients with unknown outcomes (n = 143) left a study population of 280. Within this group, 9 of 29 offered OTC developed POI (31.0%) versus 11 of 251 not offered OTC (4.4%); hazard ratio 8.2 (CI 3.4-20). In the group offered OTC, all cases of POI developed after the primary treatment. In those not offered OTC, POI developed after secondary treatment for disease relapse in 5 patients (45.5%). Limitations, reasons for caution A significant number of patients had unknown reproductive outcomes; this is likely to reflect a lack of recording of normal menstrual function in oncology/haematology clinics but may have biased the analysis. The duration of follow up is also short for some patients, highlighting the need for further follow up. Wider implications of the findings The overall prevalence of POI after childhood cancer is low, but the Edinburgh selection criteria are a robust tool for selecting those at high risk at the time of diagnosis, who can be offered OTC. However, many patients had incomplete information on current reproductive status, which should be assessed routinely. Trial registration number N/A

A case-control study of thallium exposure with the risk of premature ovarian insufficiency in women

Thallium exposure has been associated with female reproductive health, but little is known about its potential association with premature ovarian insufficiency (POI). In this study, a total of 169 patients with POI and 209 healthy women were recruited from Zhejiang province, China. Urinary thallium concentrations were significantly positively associated with the risk of POI [adjusted odds ratio (OR) = 1.63, 95% CI: 1.25–2.13, p < 0.001], geometric mean values of which were significantly higher in POI cases (0.213 μg/L, 0.302 μg/g for creatinine adjustment) than those of controls (0.153 μg/L, 0.233 μg/g for creatinine adjustment). Furthermore, the serum levels of follicle-stimulating hormone and luteinizing hormone were positively associated with urinary thallium concentrations, whereas anti-Mullerian hormone and estradiol were negatively correlated with thallium. To the best of our knowledge, this is the first study to provide evidence that thallium exposure at currently environmental levels is the potential risk factor for POI in women.

Fertility preservation for genetic diseases leading to premature ovarian insufficiency (POI).

The current review aims to summarize the data available concerning the applicability of fertility preservation techniques to genetic conditions at risk of premature ovarian insufficiency (POI). A literature review through the PubMed Database was carried out. About 10% of cases of POI is related to genetic diseases. The most frequent conditions associated with POI are Turner syndrome and fragile X pre-mutation; mutation of BRCA 1-2 genes and several other mutations and genetic syndromes have recently been highlighted, although they rarely occur. If a diagnosis is issued before POI onset, counseling on currently available fertility preservation techniques is advisable. In case of spontaneous menarche (this can occur variably depending on the mutation) established techniques like embryo or oocyte cryopreservation can be proposed, even if, in some cases, their effectiveness may be reduced by ovarian alterations connected to the mutation. Ovarian tissue cryopreservation has recently been defined as an established medical procedure for fertility preservation in young cancer patients and may be an option for prepubertal patients. However, it is still experimental in special populations with genetic diseases causing POI. New innovative experimental techniques, like in vitro maturation of immature oocytes (IVM) and vitro activation (IVA) of immature follicles on ovarian tissue, have shown limited but encouraging data and they will be probably available in the near future. For a correct risk-benefit evaluation, the following aspects should be considered: actual knowledge about the pathology-specific efficacy of the various techniques, the average age of onset of POI, the possible risks associated with the procedure in relation to the underlying pathology, the probability of spontaneous conception, as well as the health implications of a possible future pregnancy.. Fertility preservation techniques represent a crucial opportunity for patients with genetic risk of POI. Early diagnosis increases the chances to apply these techniques. No specific recommendations concerning fertility preservation for each genetic pathology are available, and clinicians should first counsel the patient and her relatives about known risks and benefits of the available techniques, both those established and those considered as experimental.

The Predictive Value of Serum Progesterone and Estrogen Recepters as Diagnostic Tool for Premature Ovarian Failure

Background: Premature ovarian insufficiency (POI) is a delicate medical problem in young women. Thiscondition is not unchangeable and permanent but is associated with intermittent and unpredictable ovarianactivity, resulting in low conception rate. Over the period of 8 years, the evaluation of secondary amenorrheawas conducted in 90 patients below the age of 40 who wished to restore fertility and is characterized byirregular or absent periods and reduced fertility. Symptoms include those associated with the naturalmenopause (night sweats and vaginal dryness), and with the long-term adverse effects of estrogen deficiency(osteoporosis and cardiovascular disease): The latter is believed to explain the shorter life expectancyassociated with POI.Aim: To illustrate the predictive value of progesterone receptors (PRs), estrogen receptors (ERs), progesterone(PRG), estradiol (E2), Lulilizing hormones (LH), Follicle stimulating hormones (FSH) and Anti mullerianhormones (AMH) serum levels as diagnostic approach for POI.Method: Sixty (60) women with idiopathic POF with thirty (30) women as control groups were includedin the study. Baseline investigation in all subjects included serum progesterone receptors(PRs), estrogenreceptors(ERs), progesterone (PRG), estradiol (E2), Lulilizing hormones (LH), Follicle stimulatinghormones (FSH) and Anti mullerian hormones (AMH) levels were estimated using appropriate assays inbiochemistry laboratory.Results: There was statistically significant differences in the serum progesterone receptors, estrogenreceptors, progesterone, estradiol, LH, FSH and AMH in POI cases when compared with healthy control(P=&lt;0.05).Conclusion: These results indicate that serum progesterone and estrogen receptors levels, is high in POI casesas a result of lack progesterone and estradiol hormones as a result of loss negative feedback inhibition,thisresult may be used to primary diagnosis of premature ovarian failure.

Effects of Environment and Lifestyle Factors on Premature Ovarian Failure.

Premature ovarian insufficiency (POI) or primary ovarian failure is defined as a cessation of the menstrual cycle in women younger than 40years old. It is strictly defined as more than 4months of oligomenorrhea or amenorrhea in a woman <40years old, associated with at least two follicle-stimulating hormone (FSH) levels >25U/L in the menopausal range, detected more than 4weeks apart. It is estimated that POI was affected 1 and 2% of women. Although 80% of POI cases are of unknown etiology, it is suggested that genetic disorder, autoimmune origin, toxins, and environmental factors, as well as personal lifestyles, may be risk factors of developing POI. In this section, we will discuss the influences of environmental and lifestyle factors on POI. Moreover updated basic research findings regarding how these environmental factors affect female ovarian function via epigenetic regulations will also be discussed.

Genetic conditions impairing female fertility.

Fertility represents a biological and psychological requirement for women. Some genetic diseases represent a rare cause of infertility, being responsible for 10% of cases of premature ovarian insufficiency. Among these, the most frequent and also those most studied by researchers are Turner Syndrome - due to a karyotype abnormality of the X chromosome pair - and the presence of fragile X premutation (FMR1). To exclude these conditions the diagnostic workup for non-iatrogenic premature ovarian insufficiency (POI) involves the performance of a karyotype analysis and the search for the FMR1 gene mutation, as well as the search for the presence of Y-chromosomal material. However, several other mutations and genetic syndromes associated with POI development have recently been highlighted, although they occur rarely, such as the GALT gene mutation in galactosemia or the FOXL2 gene mutation in BPES and many others, and further autosomal genetic testing are indicated if clinical suspicion is present. Mutations of BRCA 1 and 2 genes, make patients at genetically determined high risk of developing early ovarian or breast cancer and of getting POIs for the treatments they must undergo to prevent it (prophylactic bilateral oophorectomy) or treat it (chemotherapy). The management of impaired fertility is not less important than that of other syndromic manifestations for the quality of life of patients. Few data are available regarding the efficiency of cryopreservation of reproductive material (oocytes, embryos or ovarian tissue) in order to preserve fertility in this particular subgroup of patients, but certainly it represents a promising chance and a hope for the future.

Adverse Life Events as a Potential Cause of Premature Ovarian Insufficiency: A Novel, Mixed-Methods Study

Background: Premature ovarian insufficiency (POI) has serious physical and psychological consequences due to estrogen deprivation, leading to increased morbidity and mortality. Previous research has predominately focused on genetic, autoimmune, iatrogenic and infectious factors. However, the causes of most POI cases remain unknown. This is the first study to explore adverse life events as a potential cause of POI disease. Methods: A novel, mixed-methods study was conducted in an obstetric and gynecologic hospital located in Shanghai between 2018 and 2019. In the qualitative component, we recruited women newly- diagnosed with idiopathic POI (FSH levels >40 IU/L) in the hospital to participate in semi-structured interviews through convenience sampling. The main questions covered by the topic guide were designed to explore adverse life events prior to POI diagnosis. Data was audio recorded and transcribed verbatim before thematic analysis using QDA Miner Lite. Quantitatively, we then evaluated genome-wide patterns of DNA methylation in whole blood-derived DNA obtained from a sub-sample comprising the interview participants diagnosed with POI (n=20, mean age=34 years) and healthy women (comparison group) with regular menstrual cycles and a FSH level <8.8 IU/L (n=20, mean age= 34 years) using an Illumina850K microarray. Finally, a theoretical disease model was proposed by integrating findings of qualitative and quantitative studies. Findings: A total of 43 women (mean age=33·8 years) participated in the qualitative study. A number of stressful life events prior to POI diagnosis were discussed by them as important factors influencing their health and well-being. Three core themes emerged: 1) persistent exposure to workplace stress. 2) persistent exposure to family-related adverse life events, and 3) sleep problem/disturbance. In the quantitative study, we found that genome wide DNA-methylation profiles of patients with POI were different from women who experienced regular menses. Our analysis identified 5,582 differential methylated sites (DMSs), including 4,722 hypermethylated sites and 860 hypomethylated sites. Functional enrichment analysis identified differentially methylated sites (DMSs) were significantly associated with genes related to “stress response” and “circadian entrainment pathway”. An explanatory disease model was proposed to illustrate that long-term cumulative adverse experiences might interact with various genetic alterations and play a role in pathogenesis of POI. Interpretation: Persistent exposures to adverse life events related to work stress, family stress and sleep disturbance exist in idiopathic POI patients. The altered DNA methylation in POI patients who experienced adverse life events indicates that social adversity may affect ovarian function through a genetic process. Future research should investigate how social environmental factors influence POI disease risks, and whether provision of tailored interventions (i.e. preventing or mitigating impact of adverse life events) aimed at high-risk populations may help prevent new POI cases and improve conditions of existing POI patients. Funding Statement: This study was supported by National Key Research and Development Program of China (No.2018YFC1004800, 2018YFC1004802); The National Natural Science Foundation of China (No. 81971334); The Shanghai Municipal Education Commission—Gaofeng Clinical Medicine (No. 20152236). Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: Ethical approval was obtained from International Peace Maternity and Child Health Hospital (IPMCH) Ethic Committee.