Depletion Of Ovarian Follicles Research Articles

TAF4b promotes mouse primordial follicle assembly and oocyte survival

Primary ovarian insufficiency (POI) affects 1% of women under the age of 40 and is associated with premature ovarian follicle depletion. TAF4b deficiency in adult female mouse models results in hallmarks of POI including stereotyped gonadotropin alterations indicative of early menopause, poor oocyte quality, and infertility. However, the precise developmental mechanisms underlying these adult deficits remain unknown. Here we show that TAF4b is required for the initial establishment of the primordial follicle reserve at birth. Ovaries derived from TAF4b-deficient mice at birth exhibit delayed germ cell cyst breakdown and a significant increase in Activated Caspase 3 staining compared to control ovaries. Culturing neonatal TAF4b-deficient ovaries with the pan-caspase inhibitor ZVAD-FMK suppresses the excessive loss of these oocytes around the time of birth. These data reveal a novel TAF4b function in orchestrating the correct timing of germ cell cyst breakdown and establishment of the primordial follicle reserve during a critical window of development.

Linkage analysis coupled with exome sequencing identified defects in gene ‘X’ causing premature ovarian insufficiency

Background Premature ovarian insufficiency (POI) is defined as a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 (secondary amenorrhea) with hypergonadotropism and hypoestrogenism. POI results in infertility and lifelong steroid deficiency, and is potentially associated with accelerated health risks such as cardiovascular and neurodegenerative disorders and osteoporosis.

Serologic autoimmunologic parameters in women with primary ovarian insufficiency

BackgroundPrimary ovarian insufficiency (POI) is heterogeneous disease defined by amenorrhea or premature depletion of ovarian follicles before the age of 40 years. The etiology of POI is still unclear. The purpose of this study is to evaluate whether women with POI have an elevated serum levels of autoimmunologic parameters.MethodsThe serum from peripheral blood samples which come from 96 POI patients and 100 age-matched health women were analyzed for a series of autoimmune antibodies using protein microarray. The antibodies to double-stranded DNA (ds-DNA), histone (HIS), nuclear ribonucleoprotein (RNP), Sjogren’s syndrome A (SSA/Ro), Sjogren’s syndrome B (SSB/La) and Smith antigen, Jo-1, scleroderma-associated antigen (Scl-70) and centromere (CEN), zona pellucid (ZP), adrenocortical antibodies (ACA),Rheumatoid factor (RF), glomerular basement membrane (GBM), proliferating cell nuclear antigen (PCNA), myeloperoxidase (MPO), proteinase 3 (PR3), thyroid microsomal antibody and antinuclear antibody (ANA)were analyzed.ResultsAmong the 96 women with POI and 100 age-matched health controls, women with POI had significantly elevated circulation levels of Jo-1 and PR3 (p = 0.010 and p = 0.001) whereas circulation levels of ANAs, dsDNA, histone, RNP, Sm, Scl-70, SSA, SSB, CEN, ZP, ACA, RF, GBM, PCNA, MPO and TM antibodies were similar between the two groups.ConclusionsThis study shows that the autoimmune antibodies JO-1 and PR3 were significantly higher in POI women group which suggested that these antibodies may have played special role in POI, but the evaluation of the exact pathways of them remains to be determined.

Validation of the power model of ovarian nongrowing follicle depletion associated with aging in women

To validate recently proposed models of ovarian nongrowing follicle (NGF) decay associated with aging within the context of an independent data set. Prospective investigation. Academic medical center. Normal appearing ovaries collected from 52 women (age 28-51 years) undergoing oophorectomy for benign gynecologic indications. Determining ovarian NGF counts with systematic random sampling rules and a validated fractionator/optical disector technique. The goodness-of-fit of predicted NGF counts based on the power and double Gaussian models and those observed in the validation set was assessed with the calculation of the Akaike information criterion and R(2) values. The goodness-of-fit between observed and expected ovarian NGF counts. The power model was an excellent fit to the observed data. The average difference between the observed and expected NGF count was 0.161 (95% CI, -0.058, 0.327). In the present study population, the power model was a superior fit to the observed data compared with the double Gaussian model. This prospective investigation with an independent set of ovarian NGF counts validates the power model as an excellent characterization of the ovarian NGF decline associated with aging.

ACCELERATED FOLLICLE DEPLETION IN VITRO AND IN VIVO IN SPRAGUE-DAWLEY RATS USING THE COMBINATION OF 4-VINYLCYCLOHEXENE DIEPOXIDE AND TRIPTOLIDE

Rodent pests cause major damage to the world's agricultural crops and food stores. Rodenticides used since World War II did not lead to sustained reduction of rodent populations, and so fertility control is becoming attractive because rats reproduce with great efficiency. Chemical acceleration of ovarian failure via oral dosing also would improve management of rat pest populations. The chemical 4-vinylcyclohexene diepoxide (VCD) is orally efficacious, causing depletion of nonregenerating primordial ovarian follicles of Sprague-Dawley rats. However, to cause rapid reduction in pups in the first breeding cycle after dosing, all stages of ovarian follicle development must be targeted. To achieve this goal, the Chinese herb triptolide was tested because it can precipitate apoptosis and deplete growing follicles. The impact of triptolide was tested in cultured postnatal day 4 Sprague-Dawley rat pup ovaries. Triptolide at 5 nM caused 100% primordial, primary, and secondary follicle depletion after 8 days of culture, compared to 38% follicle depletion caused by VCD at 30 microM. Next, a palatable rat bait was developed, containing 1% VCD with increasing concentrations of triptolide at 25, 50, and 100 microg/kg body weight. Rats ate an average 3-6% of their body weight/day over 15 feeding days. Two days after the end of baiting, rats were euthanized to conduct necropsies and collect ovaries to count all follicular stages and corpora lutea. At 50 microg triptolide/kg body weight, there was significant reduction of all follicular stages; primordial follicles were 50% lower, secondary follicles were 64% lower, antral follicles were 80% lower, and there were no corpora lutea. These results suggest that combining VCD and triptolide in an oral bait leads to significantly compromised rat ovarian function and reduced ovulations, and is likely to reduce pup production.

Cyclooxygenase-1 Inhibition Prolongs Postnatal Ovarian Follicle Lifespan in Mice1

Menopause is the permanent cessation of menstruation that results from depletion of ovarian germ cells and follicles. Although most animals experience reproductive senescence, the mechanisms differ from that in women, who may live more than one-third of their lives after menopause and consequently face the risk of a number of menopause-associated health problems. Understanding factors that influence ovarian aging may provide strategies to delay or alleviate physiological alterations that take place in postmenopausal women. The germ cell-deficient Wv mice recapitulate follicle loss, prolong postreproductive lifespan, and model many physiological changes that take place in postmenopausal women. Here, using genetic and pharmacological approaches, we found that inhibition of cyclooxygenase-1 but not cyclooxygenase-2 in Wv mice delays germ cell depletion and preserves ovarian follicles. Cyclooxygenase-1 inhibition slows down follicle maturation at the conversion of primary to secondary follicles and prolongs postnatal ovarian follicle lifespan. The current study suggests that inhibition of cyclooxygenase-1 may be able to delay ovarian aging and modulate menopausal timing.

Validation of the power model of ovarian non-growing follicle depletion associated with aging

The primary determinant of reproductive aging in women is the progressive decline in ovarian non-growing follicles (NGFs). This pool of NGFs, inclusive of the ovarian primordial, intermediate and primary follicles, constitutes the ovarian reserve. Ultimately the depletion of the NGF pool results in menopause. We have previously characterized the decline in NGFs associated with aging, determining that a power model taking the form y = axb + c, where a, b, and c are constants and y = NGF count at age x, best characterizes the decline in the log-transformed NGF count associated with increasing age. This investigation was aimed at validating the power model of ovarian NGF decay within the context of an independent data set. Prospective cross-sectional study, university setting. Normal ovaries were collected from 55 women (age 28-52 years) undergoing oophorectomy for benign indications. Using systematic random sampling rules and a validated fractionator/optical disector technique, ovarian NGF counts were determined. The goodness-of-fit of predicted NGF counts based on the power model {Log (NGF count) = (-0.00019)*(age in years)2.452 + 5.717} and those observed in the validation set was assessed with a chi-square goodness of fit test, where a p-value > 0.05 is considered a good fit for the model. The power model was an excellent fit to the observed data (p = 0.97). The average difference between observed and expected NGF count was 0.17 (95% CI -0.02,0.345). This difference would translate into a discrepancy of ∼506 NGFs at the predicted menopause threshold of ∼758 NGFs. This investigation, with an independent set of ovarian NGF counts, validates the power model of ovarian NGF depletion associated with aging. These findings confirm the utility of the power model as the best available characterization of the decline in ovarian NGFs from birth to menopause.

Mutations ineIF4ENIF1Are Associated With Primary Ovarian Insufficiency

Primary ovarian insufficiency (POI), or premature ovarian failure, results from ovarian follicle depletion with a consequent elevation of FSH levels before age 40 years. We identified a family in which 9 women in 3 consecutive generations developed menopause at approximately age 30 years. We hypothesized a genetic cause with a dominant mode of inheritance. This was a family-based genetic study and a replicate group of women with POI. The study was conducted at an academic medical center. Seven affected women and an obligate carrier and 7 unaffected family members were genotyped. The genes of interest were also sequenced in 38 unrelated women with POI. The DNA from 7 family members was subjected to whole-exome sequencing. The genotypes of interest were confirmed and genotypes of additional family members and unrelated women with POI were determined using Sanger sequencing. A high-impact, deleterious variant that segregated appropriately with POI in the family was required. A heterozygous stop codon (Ser429X) was identified in the eukaryotic translation initiation factor 4E nuclear import factor 1 (eIF4ENIF1) in the proband and all affected women but not in the unaffected family members. The chance that such a high-impact, deleterious variant would segregate appropriately among the affected and unaffected relatives by chance is very low (P < .05). There were no additional mutations identified in eIF4ENIF1 or eIF4E in 38 unrelated women with POI. Data demonstrate a new gene associated with dominantly inherited POI. These results highlight the importance of translation initiation factors and their regulators in ovarian function.

Differentiation of rat iPS cells and ES cells into granulosa cell-like cells &amp;lt;italic&amp;gt;in vitro&amp;lt;/italic&amp;gt;

Premature ovarian failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles before 40 years of age, representing one major cause of female infertility. Stem cells provide the possibility of a potential treatment for POF. In this study, rat embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) were co-cultured with granulosa cells (GCs) to differentiate to GC-like cells. The level of estradiol (E2) analyzed by radioimmunoassay showed that the E2 concentration of the culture supernatant of co-cultured rat iPSCs and ESCs increased in a time-dependent manner, compared with the GCs group that has an opposite trend. The expression of follicle-stimulating hormone receptor (FSHR) was confirmed by immunostaining. These results indicated that rat iPSCs and ESCs were effectively induced to GC-like cells through indirect cell-to-cell contact. Real-time polymerase chain reaction was performed to analyze the expression level of marker genes in POF, including BMP15, FMR1, FSHR, INHA, AMH, NOBOX, FOXO3, EIF2B, FIGLA, and GDF9. The BMP15, FSHR, INHA, AMH, NOBOX, and GDF9 genes were significantly up-regulated in iPSCs and ESCs co-cultured with GCs in comparison with cells that were not co-cultured. Thus, here we demonstrated an available method to differentiate rat iPSCs and ESCs into GC-like cells in vitro for the possible cell therapy of POF.

Morpho-physiological features associated with menopause: recent knowledge and areas for future work.

Menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity which happens as a result of depletion of primary follicles which is basically an aging effect. Depletion of ovarian follicles is reflected as declined production of oestradiol which is currently known to be central to the morphologic and physiological changes that happen during the climacteric, menopause and post menopause periods. The cessation of oestradiol production is much more pronounced in tissues with oestrogen receptors such as bones, brain, blood vessels, central nervous system and the skin. But generally little is known on the subject and in particular the bioactive substances involved in the process such that there are some symptoms that menopause women experience which not only defy clinicians but also challenge the management of the condition. This article is presented to shade light to what is currently known, what is not known and stimulate future research which may reveal more understanding and advance our knowledge on management of women throughout the climacteric and menopausal periods.

Peripheral WBC Telomere Length as a Marker of Reproductive Age in Women

Reproductive aging is a continuous process that begins many years prior to menopause. The primary mechanism of reproductive aging is through the process of ovarian primordial follicle depletion, a process that exhibits considerable variation between women. The relationship between somatic and reproductive aging in women has been controversial, with some investigations suggesting a correlation between the two processes, whereas others have suggested no relationship. Peripheral lymphocyte telomere length is widely considered to be a marker of somatic aging.

An Unexpected Pregnancy in a 22-Year-Old Woman with History of Premature Ovarian Failure: A Case Report

Introduction Premature Ovarian Failure (POF) that leads to secondary amenorrhea is caused by early depletion of ovarian follicles. Therapeutic methods have been described for treating infertility in POF but even with these therapies the probability of pregnancy remains so low. However, some spontaneous gestations are reported in these patients. Case presentation In this report, we describe a young woman with diagnosed POF from two years earlier who referred to our emergency department with the possibility of acute appendicitis. Her chief complaint was periodic abdominal pain that had been started 4 hours before presenting to emergency room. During her staying in the emergency room for further investigations, the patient delivered a normal baby without even being aware of pregnancy throughout this period. The neonate was term and male. The Apgar score was 7 in the first minute after birth which rapidly improve to 10 in tenth minute after providing immediate suction, repositioning and stimulation the neonate. More evaluations of child didn’t show any abnormality in child or a significant morbidity in both mother and child. Discussion POF is a condition that leads to secondary amenorrhea in women younger than 40 years. In this case, the patient didn’t use any contraception due to POF diagnosis. It is important to consider the low possibility of getting pregnant, especially in patients who don’t desire pregnancy. The mechanisms of spontaneous pregnancy in POF and attributing factors in these mechanisms are issues that need further investigations.

Insight into the Genomics of Premature Ovarian Failure

Primary Ovarian Failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles. It causes infertility in ~1% of women <40 years of age and it has important health consequences for affected patients. POF is a heterogeneous disease, which can develop as a result of a broad variety of pathogenic mechanisms including genetic, autoimmune and iatrogenic causes. However, the mechanisms that cause ovarian dysfunction are poorly understood. Focus on genetic component of the disease has revealed the existence of several causal genetic defects, thus indicating that in addition to some monogenic forms, POF may frequently be a multifactorial disease involving several gene abnormalities and chromosome aberrations. Moreover, most recent studies have highlighted that epigenetic mechanisms may give an additional contribution to POF pathogenesis. This review gives a picture of the state of the art of the complex genetic and epigenetic defects associated with POF, being it clear that a deep comprehension of the molecular etiology of POF may in future early identify those women with higher risk of POF.

Clinical characteristics and genetic analysis in women with premature ovarian insufficiency

ObjectivePremature ovarian insufficiency (POI) is defined as a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 (secondary amenorrhea) with hypergonadotropism and hypoestrogenism. MethodsWe studied the clinical, biological, and genetic data related to 50 POI patients with a mean age of menopause of 29years (94% with secondary amenorrhea, 6% with primary amenorrhea and 15% with a family history of POI). Seventeen patients were affected by endocrine autoimmune diseases, antral follicles were observed in 31 patients by ultrasonography. ResultsKaryotype analysis did not show any abnormality of the X chromosome. No mutation in FSH receptor and GDF-9 genes was reported, while in one patient a variant of BMP-15 gene (A180T) was found. Four patients had fragile X mental retardation 1 gene (FMR1) premutation and one an intermediate sized CGG repeats of the same gene. Two patients with FMR1 premutation were sister and developed secondary amenorrhea at the age of 34 and 37years. The other two patients presented with oligoamenorrhea at the age of 39 and 34years. The patient harboured the intermediate sized CGG repeats developed secondary amenorrhea at the age of 33years. ConclusionsThe genetic analysis performed on a cohort of patients with POI revealed that 8% had FMR1 premutation and only one patient a previously known variant of BMP-15 gene. No alteration of the karyotype and FSH receptor and GDF-9 genes was evidenced.

Histological and immunohistochemical study on the protective effects of cetrorelix against chemotherapy-induced ovarian damage

Introduction Chemotherapy exerts several adverse effects on the ovaries and can lead to ovarian atrophy and infertility. Aim of the study This study was carried out to determine the possible protective effect of cetrorelix (a gonadotropine-releasing hormone antagonist) against the ovarian damage caused by a chemotherapeutic drug (cyclophosphamide). Materials and methods Thirty adult female albino rats were used in this study. They were classified into three main groups. Group I served as the control group. In group II, rats were injected intraperitoneally with cyclophosphamide. In group III, rats were injected intraperitoneally with cetrorelix in combination with cyclophosphamide. After 20 days, the rats were sacrificed and ovaries were excised and processed. Sections were stained with H&E, Masson's trichrome and immunohistochemical stains for Bcl2 (antiapoptotic gene) and FasL (proapoptotic factor). Results Cyclophosphamide injection resulted in ovarian damage in the form of depletion of ovarian follicles, apoptosis of granulosa cells (lining the follicular cavity) and cortical fibrosis. Bcl2 immunostaining was significantly decreased and FasL immunostaining significantly increased in granulosa cells in the rats of group II. Pretreatment with cyclophosphamide (group III) reversed these changes to a huge extent. Conclusion Cetrorelix reduced chemotherapy-induced ovarian damage by suppressing apoptosis.

White spotting variant mouse as an experimental model for ovarian aging and menopausal biology.

Menopause is a unique phenomenon in modern women, as most mammalian species possess a reproductive period comparable with their life span. Menopause is caused by the depletion of germ cell-containing ovarian follicles and in laboratory studies is usually modeled in animals in which the ovarian function is removed through ovariectomy or chemical poisoning of the germ cells. Our objective was to explore and characterize the white spotting variant (Wv) mice that have reduced ovarian germ cell abundance, a result of a point mutation in the c-kit gene that decreases kinase activity, as a genetic model for use in menopause studies. Physiological and morphological features associated with menopause were determined in female Wv/Wv mice compared with age-matched wildtype controls. Immunohistochemistry was used to evaluate the presence and number of follicles in paraffin-embedded ovaries. Bone density and body composition were evaluated using the PIXImus x-ray densitometer, and lipids, calcium, and hormone levels were determined in serum using antigen-specific enzyme immunoassays. Heart and body weight were measured, and cardiac function was evaluated using transthoracic echocardiography. The ovaries of the Wv/Wv females have a greatly reduced number of normal germ cells at birth compared with wildtype mice. The remaining follicles are depleted by around 2 months, and the ovaries develop benign epithelial lesions that resemble morphological changes that occur during ovarian aging, whereas a normal mouse ovary has numerous follicles at all stages of development and retains some follicles even in advanced age. Wv mice have elevated plasma gonadotropins and reduced estrogen and progesterone levels, a significant reduction in bone mass density, and elevated serum cholesterol and lipoprotein levels. Moreover, the Wv female mice have enlarged hearts and reduced cardiac function. The reduction of c-kit activity in Wv mice leads to a substantially diminished follicular endowment in newborn mice and premature depletion of follicles in young mice, although mutant females have a normal life span after cessation of ovarian function. The Wv female mice exhibit consistent physiological changes that resemble common features of postmenopausal women. These alterations include follicle depletion, morphological aging of the ovary, altered serum levels of cholesterol, gonadotropins and steroid hormones, decreased bone density, and reduced cardiac function. These changes were not observed in male mice, either age-matched male Wv/Wv or wildtype mice, and are improbably caused by global loss of c-kit function. The Wv mouse may be a genetic, intact-ovary model that mimics closely the phenotypes of human menopause to be used for further studies to understand the mechanisms of menopausal biology.

Xenobiotic effects on ovarian preantral follicles.

Women are born with a finite population of ovarian follicles, which are slowly depleted during their reproductive years until reproductive failure (menopause) occurs. The rate of loss of primordial follicles is determined by genetic and environmental influences, but certain toxic exposures can accelerate this process. Ionizing radiation reduces preantral follicle numbers in rodents and humans in a dose-dependent manner. Cigarette smoking is linked to menopause occurring 1-4 yr earlier than with nonsmokers, and components of smoke, polycyclic aromatic hydrocarbons, can cause follicle depletion in rodents or in ovaries in vitro. Chemotherapeutic agents, such as alkylating drugs and cisplatin, also cause loss of preantral ovarian follicles. Effects depend on dose, type, and reactivity of the drug, and the age of the individual. Evidence suggests DNA damage may underlie follicle loss induced by one common alkylating drug, cyclophosphamide. Occupational exposures have also been linked to ovarian damage. In an industrial setting, 2-bromopropane caused infertility in men and women, and it can induce ovarian follicle depletion in rats. Solvents, such as butadiene, 4-vinylcyclohexene, and their diepoxides, can also cause specific preantral follicle depletion. The mechanism(s) underlying effects of the latter compound may involve alterations in apoptosis, survival factors such as KIT/Kit Ligand, and/or the cellular signaling that maintains primordial follicle dormancy. Estrogenic endocrine disruptors may alter follicle formation/development and impair fertility or normal development of offspring. Thus, specific exposures are known or suspected of detrimentally impacting preantral ovarian follicles, leading to early ovarian failure.

Genetic defects of ovarian TGF-β-like factors and premature ovarian failure

Premature ovarian failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles; POF affects approximately 1-2% of women under the age of 40 yr, thus representing one major cause of female infertility. POF relevance is continuously growing because women tend to conceive always more frequently beyond 30 yr. Frequently, POF is the end-stage of an occult process [primary ovarian insufficiency (POI)]. POI is a heterogeneous disease caused by a variety of mechanisms. Though the underlying cause remains unexplained in the majority of cases, several data indicate that POI has a strong genetic component. These data include the existence of several causal genetic defects in human, experimental, and natural models, as well as the frequent familiarity. The candidate genes are numerous, but POF remains unexplained in most of the cases. Several recent evidences have driven the attention of researchers on the possible involvement of various elements belonging to the transforming growth factor β family, which includes bone morphogenetic proteins, growth/differentiation factors, and inhibins. These peptides are produced by either the oocyte or granulosa cells to constitute a complex paracrine network within the ovarian follicle. Here, we review the studies reporting the genetic alterations of these factors in human and animal defects of ovarian folliculogenesis which support the fundamental roles played by these signals in ovarian morphogenesis and function.

Tamoxifen decreases ovarian follicular loss from experimental toxicant DMBA and chemotherapy agents cyclophosphamide and doxorubicin in the rat

we serendipitously observed a protective effect of tamoxifen against depletion of ovarian follicles by 7,12-dimethylbenzanthracene (DMBA), a chemical carcinogen, during a cancer prevention study. Such ovarian protection is being sought as an alternative approach to fertility preservation in human cancer patients. rats received tamoxifen (0, 1 mg or 2.5 mg/kg/d) and DMBA (0, 1, 2 mg/kg/wk) or cyclophosphamide (0, 35, 50 mg/kg/wk). Ovarian follicles were quantified and effects on fertility and litter size were tested. Cultured oocytes were exposed to chemotherapy drug doxorubicin, with or without 4-hydroxytamoxifen (4HT). DMBA and cyclophosphamide decreased the number of primordial and total follicles, and this reduction was prevented by tamoxifen. Cyclophosphamide tended to reduce fertility and lessened neonatal survival. Tamoxifen reversed these defects. Doxorubicin caused oocyte fragmentation which was prevented by 4HT. tamoxifen decreases follicle loss and improves reproductive function following exposure to ovarian toxicants including chemotherapy drugs in the female rat.

Genes involved in human premature ovarian failure

Premature ovarian failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles before the age of 40 years, representing one major cause of female infertility. POF relevance is continuously growing because women tend to conceive ever more frequently in their thirties and forties. POF can present very early with a pubertal defect. More frequently, it is the end stage of an occult process (primary ovarian insufficiency, POI) affecting ∼ 1-2% of under-40 women. POI is a heterogeneous disease caused by a variety of mechanisms. Though the underlying cause remains unexplained in the majority of cases, various data indicate that POI has a strong genetic component. These data include the existence of several causal genetic defects in humans, experimental and natural models, as well as the frequent familiarity. The variable expressivity of POI defect in women of the same family may indicate that, in addition to some monogenic forms, POI may frequently be considered as a multifactorial defect resulting from the contribution of several predisposing alleles. The X chromosome-linked defects play a major role among the presently known causal defects. Here, we review the principal X-linked and autosomal genes involved in syndromic and nonsyndromic forms of POI with the wish that this list will soon become upgraded because of the discovery of novel contributing mechanisms. A better understanding of POI pathogenesis will indeed allow the construction of tests able to predict the age of menopause in women at higher risk of POI.