Pathogenesis Of Premature Ovarian Insufficiency Research Articles

Treg deficiency-mediated TH 1 response causes human premature ovarian insufficiency through apoptosis and steroidogenesis dysfunction of granulosa cells.

Immune dysregulation has long been proposed as a component of premature ovarian insufficiency (POI), but the underlying mediators and mechanisms remain largely unknown. Here we showed that patients with POI had augmented T helper 1 (TH1) responses and regulatory T (Treg) cell deficiency in both the periphery and the ovary compared to the control women. The increased ratio of TH1:Treg cells was strongly correlated with the severity of POI. In mouse models of POI, the increased infiltration of TH1 cells in the ovary resulted in follicle atresia and ovarian insufficiency, which could be prevented and reversed by Treg cells. Importantly, interferon (IFN) ‐γ and tumor necrosis factor (TNF) ‐α cooperatively promoted the apoptosis of granulosa cells and suppressed their steroidogenesis by modulating CTGF and CYP19A1. We have thus revealed a previously unrecognized Treg cell deficiency‐mediated TH1 response in the pathogenesis of POI, which should have implications for therapeutic interventions in patients with POI.

Premature Ovarian Insufficiency: Past, Present, and Future.

Premature ovarian insufficiency (POI) is the loss of normal ovarian function before the age of 40 years, a condition that affects approximately 1% of women under 40 years old and 0.1% of women under 30 years old. It is biochemically characterized by amenorrhea with hypoestrogenic and hypergonadotropic conditions, in some cases, causing loss of fertility. Heterogeneity of POI is registered by genetic and non-genetic causes, such as autoimmunity, environmental toxins, and chemicals. The identification of possible causative genes and selection of candidate genes for POI confirmation remain to be elucidated in cases of idiopathic POI. This review discusses the current understanding and future prospects of heterogeneous POI. We focus on the genetic basis of POI and the recent studies on non-coding RNA in POI pathogenesis as well as on animal models of POI pathogenesis, which help unravel POI mechanisms and potential targets. Despite the latest discoveries, the crosstalk among gene regulatory networks and the possible therapies targeting the same needs to explore in near future.

Meiotic Recombination Defects and Premature Ovarian Insufficiency.

Premature ovarian insufficiency (POI) is the depletion of ovarian function before 40 years of age due to insufficient oocyte formation or accelerated follicle atresia. Approximately 1–5% of women below 40 years old are affected by POI. The etiology of POI is heterogeneous, including genetic disorders, autoimmune diseases, infection, iatrogenic factors, and environmental toxins. Genetic factors account for 20–25% of patients. However, more than half of the patients were idiopathic. With the widespread application of next-generation sequencing (NGS), the genetic spectrum of POI has been expanded, especially the latest identification in meiosis and DNA repair-related genes. During meiotic prophase I, the key processes include DNA double-strand break (DSB) formation and subsequent homologous recombination (HR), which are essential for chromosome segregation at the first meiotic division and genome diversity of oocytes. Many animal models with defective meiotic recombination present with meiotic arrest, DSB accumulation, and oocyte apoptosis, which are similar to human POI phenotype. In the article, based on different stages of meiotic recombination, including DSB formation, DSB end processing, single-strand invasion, intermediate processing, recombination, and resolution and essential proteins involved in synaptonemal complex (SC), cohesion complex, and fanconi anemia (FA) pathway, we reviewed the individual gene mutations identified in POI patients and the potential candidate genes for POI pathogenesis, which will shed new light on the genetic architecture of POI and facilitate risk prediction, ovarian protection, and early intervention for POI women.

LncRNA GCAT1 is involved in premature ovarian insufficiency by regulating p27 translation in GCs via competitive binding to PTBP1

Dysfunction of granulosa cells (GCs) leading to follicle atresia has been extensively studied as a major cause of premature ovarian insufficiency (POI), but the regulatory role of long non-coding RNAs (lncRNAs) in this process is still poorly understood. Here, we show that the lncRNA LINC02690 or GCAT1 (granulosa cell-associated transcript 1) is downregulated in GCs from patients with biochemical POI (bPOI), and we show a significant correlation between downregulated GCAT1 and serum levels of follicle-stimulating hormone and anti-Müllerian hormone. Downregulation of GCAT1 inhibited G1/S cell cycle progression and thus inhibited the proliferation of GCs. Mechanistically, we show that GCAT1 competes with cyclin-dependent kinase inhibitor 1B (CDKN1B) mRNA for polypyrimidine tract-binding protein 1 (PTBP1) binding, and thus decreased GCAT1 might promote PTBP1 binding to CDKN1B mRNA and thereby initiate CDKN1B protein (p27) translation. Together, our results suggest that downregulation of GCAT1 under conditions of bPOI inhibits the proliferation of GCs through PTBP1-dependent p27 regulation, thus suggesting a novel form of lncRNA-mediated epigenetic regulation of GC function that contributes to the pathogenesis of POI.

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.

New theca-cell marker insulin-like factor 3 is associated with premature ovarian insufficiency

To characterize circulating insulin-like factor 3 (INSL3) in different stages of ovarian insufficiency and its role in the evaluation of premature ovarian insufficiency (POI). Retrospective cohort study. University-based center for reproductive medicine. A total of 145 women, including 48 patients with POI (25 IU/L < follicle-stimulating hormone [FSH] ≤40 IU/L), 49 with biochemical POI (bPOI) (10 IU/L < FSH ≤25 IU/L) and 48 age-matched control women with normal ovarian reserve (FSH <10 IU/L), retrospectively included from the reproductive hospital affiliated with Shandong University between 2017 and2019. Levels of INSL3 in the serum and follicular fluid assayed with a commercial radioimmunoassay. Level of INSL3 in serum and follicular fluid among control women and patients with bPOI and POI, its association with different ovarian reserve markers, and its predictive value for bPOI and POI. The serum INSL3 level continuously declined with the progress of ovarian insufficiency. It showed strong negative association with FSH (-0.655) and luteinizing hormone (-0.433), but positively correlated with antimüllerian hormone (0.617), inhibin B (0.400), antral follicle count (0.630), and testosterone (0.180). Additionally, the circulating INSL3 served as a good predictor for bPOI and POI. No statistically significant difference of INSL3 levels in follicular fluid was observed between bPOI patients and control women. For the first time our study has revealed an INSL3 deficiency in women with POI, indicating that circulating INSL3 could serve as a promising theca-cell specific marker for POI. Future research on the role of INSL3 in modulating follicular development, steroidogenesis, and POI pathogenesis is warranted.

Genetics of premature ovarian insufficiency and the association with X-autosome translocations.

Premature ovarian insufficiency (POI) is the cessation of menstruation before the age of 40 and can result from different etiologies, including genetic, autoimmune, and iatrogenic. Of the genetic causes, single-gene mutations and cytogenetic alterations, such as X-chromosome aneuploidies and chromosome rearrangements, can be associated with POI. In this review, we summarize the genetic factors linked to POI and list the main candidate genes. We discuss the association of these genes with the ovarian development, the functional consequences of different mutational mechanisms and biological processes that are frequently disrupted during POI pathogenesis. Additionally, we focus on the high prevalence of X-autosome translocations involving the critical regions in Xq, known as POI1 and POI2, and ddiscuss in depth the main hypotheses proposed to explain this association. Although the incorrect pairing of chromosomes during meiosis could lead to oocyte apoptosis, the reason for the prevalence of X-chromosome breakpoints at specific regions remains unclear. In most cases, studies on genes disrupted by balanced structural rearrangements cannot explain the ovarian failure. Thus, the position effect has emerged as a putative explanation for genetic mechanisms as translocations possibly result in changes in overall chromatin topology due to chromosome repositioning. Given the tremendous impact of POI on women's quality of life, we highlight the value of investigations in to the interplay between ovarian function and gene regulation to deepen our understanding of the molecular mechanisms related to this disease, with the ultimate goal of improving patients' care and assistance.

New insights into the genetic basis of premature ovarian insufficiency: Novel causative variants and candidate genes revealed by genomic sequencing

Ovarian deficiency, including premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR), represents one of the main causes of female infertility. POI is a genetically heterogeneous condition but current understanding of its genetic basis is far from complete, with the cause remaining unknown in the majority of patients. The genes that regulate DOR have been reported but the genetic basis of DOR has not been explored in depth. Both conditions are likely to lie along a continuum of degrees of decrease in ovarian reserve. We performed genomic analysis via whole exome sequencing (WES) followed by in silico analyses and functional experiments to investigate the genetic cause of ovarian deficiency in ten affected women. We achieved diagnoses for three of them, including the identification of novel variants in STAG3, GDF9, and FANCM. We identified potentially causative FSHR variants in another patient. This is the second report of biallelic GDF9 and FANCM variants, and, combined with functional support, validates these genes as bone fide autosomal recessive “POI genes”. We also identified new candidate genes, NRIP1, XPO1, and MACF1. These genes have been linked to ovarian function in mouse, pig, and zebrafish respectively, but never in humans. In the case of NRIP1, we provide functional support for the deleterious nature of the variant via SUMOylation and luciferase/β-galactosidase reporter assays. Our study provides multiple insights into the genetic basis of POI/DOR. We have further elucidated the involvement of GDF9, FANCM, STAG3 and FSHR in POI pathogenesis, and propose new candidate genes, NRIP1, XPO1, and MACF1, which should be the focus of future studies.

Long noncoding RNA HCP5 participates in premature ovarian insufficiency by transcriptionally regulating MSH5 and DNA damage repair via YB1.

The genetic etiology of premature ovarian insufficiency (POI) has been well established to date, however, the role of long noncoding RNAs (lncRNAs) in POI is largely unknown. In this study, we identified a down-expressed lncRNA HCP5 in granulosa cells (GCs) from biochemical POI (bPOI) patients, which impaired DNA damage repair and promoted apoptosis of GCs. Mechanistically, we discovered that HCP5 stabilized the interaction between YB1 and its partner ILF2, which could mediate YB1 transferring into the nucleus of GCs. HCP5 silencing affected the localization of YB1 into nucleus and reduced the binding of YB1 to the promoter of MSH5 gene, thereby diminishing MSH5 expression. Taken together, we identified that the decreased expression of HCP5 in bPOI contributed to dysfunctional GCs by regulating MSH5 transcription and DNA damage repair via the interaction with YB1, providing a novel epigenetic mechanism for POI pathogenesis.

Serum biomarker analysis in patients with premature ovarian insufficiency

Premature ovarian insufficiency (POI) is a primary ovarian defect characterized by premature depletion of ovarian follicles before 40 years of age. The disorder has been attributed to various causes, but the study of altered proteins in serum levels as the cause is rare. Additionally, identifying novel biomarkers can contribute to more accurate diagnosis or prognosis of POI. In the present study, a solid-phase antibody array simultaneously detecting multiple proteins was used to analyze POI serum with menopausal and healthy fertile subjects as control groups. As a result, compared to the menopause and healthy fertile groups, eleven proteins, including Neurturin, Frizzled-5, Serpin D1, MMP-7, ICAM-3, IL-17F, IFN-gamma R1, IL-29, IL-17R, IL-17C and Soggy-1, were uniquely down-regulated, and Afamin was particularly up-regulated in POI serum. More importantly, all of these factors were firstly found to be associated with POI in this study, suggesting that these proteins may participate in the pathogenesis of POI and may be novel serum biomarkers for POI.

Variation analysis of tousled like kinase 1 gene in patients with sporadic premature ovarian insufficiency

Tousled like kinase 1 (TLK1), a member of DNA repair family, participates in the regulation of chromatin assembly and is associated with early menopause and premature ovarian insufficiency (POI) in European women. However, whether the sequence variant in the TLK1 gene was causative for POI is still elusive. Here we performed direct sequencing of the TLK1 gene in 192 patients with sporadic POI. All exons and exon–intron boundaries of TLK1 were amplified and sequenced. Six known single-nucleotide polymorphisms were identified in POI, including rs149844334, rs11553951, rs757600673, rs2277339, rs113416007 and rs17283147. No novel variant was identified, which indicates that sequence variants in the coding region of TLK1 might be uncommon in Chinese women with POI. The role of TLK1 in POI pathogenesis needs to be further explored in larger cohorts from Chinese and other ethnic populations.

Inflamm-Aging: A New Mechanism Affecting Premature Ovarian Insufficiency.

The normal function of ovaries, along with the secretion of sex hormones, is among the most important endocrine factors that maintain the female sexual characteristics and promote follicular development and ovulation. Premature ovarian insufficiency (POI) is a common cause in the etiology of female infertility. It is defined as the loss of ovarian function before the age of 40. The characteristics of POI are menstrual disorders, including amenorrhea and delayed menstruation, accompanied by a raised gonadotrophin level and decreased estradiol level. Inflammatory aging is a new concept in the research field of aging. It refers to a chronic and low-degree proinflammatory state which occurs with increasing age. Inflammatory aging is closely associated with multiple diseases, as excessive inflammation can induce the inflammatory lesions in certain organs of the body. In recent years, studies have shown that inflammatory aging plays a significant role in the pathogenesis of POI. This paper begins with the pathogenesis of inflammatory aging and summarizes the relationship between inflammatory aging and premature ovarian insufficiency in a comprehensive way, as well as discussing the new diagnostic and therapeutic methods of POI.

Whole-exome sequencing reveals SALL4 variants in premature ovarian insufficiency: an update on genotype-phenotype correlations.

Premature ovarian insufficiency (POI) is a severe female disorder characterized by primary or secondary amenorrhea before 40years of age. Genetic factors have been implicated in the pathogenesis of POI, but known POI-associated genes account for only a small fraction of heritability. Here, we performed whole-exome sequencing (WES) to explore pathogenic genes in Han Chinese subjects with POI. Intriguingly, we identified novel or rare heterozygous missense variants of SALL4 (spalt-like transcription factor 4) in 3 (6%) of 50 POI subjects. The SALL4 c.541G>A and c.2279C>T variants were paternally inherited, while c.1790A>G was inherited from an affected mother with early menopause. SALL4 encodes a transcription factor that is highly expressed in oocytes and early embryos. Our in vitro functional assays suggested that all of these SALL4 missense variants had significantly increased SALL4 protein expression with enhanced regulatory activity in regard to its downstream target POU5F1 compared to that of wild-type SALL4. Notably, previous studies demonstrated the genetic involvement of SALL4 loss-of-function variants in Okihiro syndrome and related syndromic developmental disorders. Through our analysis of genotype-phenotype correlations, we suggest that different variation types of SALL4 might have different effects on SALL4 activity, resulting in phenotypic variability. Our findings highlight the genetic contribution of SALL4 missense variants with enhanced regulatory activities to POI and underscore the importance of variant classification and evaluation for molecular diagnosis and genetic counseling.

Variation analysis of theTMEM150B gene in Chinese women with premature ovarian insufficiency

The TMEM150B gene, which promotes cell survival under stress conditions by modulating autophagy, is closely associated with age at natural menopause, early menopause and premature ovarian insufficiency (POI) in European women. However, whether gene variants of TMEM150B contribute to the pathogenesis of POI needs to be determined. A case-control genetic study in 408 Han Chinese women with non-syndromic POI, in which all exons and exon-intron boundaries of the TMEM150B gene were screened by Sanger sequencing; the results were analysed by statistics and bioinformatics. Two novel variants located in the 3' untranslated region of the TMEM150B gene were identified, but bioinformation analyses showed that neither was potentially disease-causing. Six known single-nucleotide polymorphisms (SNP) were found, and they were not potentially causative for POI. The intronic SNP rs11668344 was also detected in the POI patients; no significant differences were found in either genotype or allele frequencies compared with the control population. The results suggest that the perturbations in the TMEM150B gene are not a common explanation for POI in Chinese women. The role of autophagy in the pathogenic mechanism of POI needs further exploration.

Premature ovarian insufficiency may be associated with the mutations in mitochondrial tRNA genes.

Premature ovarian insufficiency (POI) is a common endocrine disorder featured by the triad constituting of amenorrhea for at least four months, to date, the molecular pathogenesis of POI is largely undetermined. Despite several investigations have reported an increase in reactive oxygen species (ROS) content in idiopathic POI, the role of mitochondrial DNA (mtDNA) mutations/variants in the progression of POI has not been widely investigated. The current study aimed to explore the association between mt-tRNA mutations/variants and POI; we first used the PCR-Sanger sequencing to detect the mutations/variants in mt-tRNA genes from 50 POI patients and 30 healthy subjects. In addition, we evaluated the mitochondrial functions by using trans-mitochondrial cybrid cells containing these potential pathogenic mt-tRNA mutations. Consequently, five mutations: tRNALeu(UUR) C3303T, tRNAMet A4435G, tRNAGln T4363C, tRNACys G5821A and tRNAThr A15951G were identified. Notably, these mutations occurred at the extremely conserved nucleotides of the corresponding mt-tRNAs and may result the failure in mt-tRNA metabolism and subsequently lead to the impairment in mitochondrial protein synthesis. Furthermore, biochemical and molecular analyses of the cybrid cells containing these mutations showed a significantly lower level of ATP production when compared with the controls, whereas the ROS levels were much higher in POI patients carrying these mt-tRNA mutations, strongly indicated that these mt-tRNA mutations may cause the mitochondrial dysfunction, and play active roles in the progression and pathogensis of POI. Together, this study shaded additional light on the molecular mechanism of POI that was manifestated by mt-tRNA mutations.

CAV1 regulates primordial follicle formation via the Notch2 signalling pathway and is associated with premature ovarian insufficiency in humans.

What is the function of CAV1 in folliculogenesis and female reproduction? CAV1 regulates germline cyst breakdown and primordial follicle (PF) formation in mice, and CAV1 mutation may be related to premature ovarian insufficiency (POI). Pre-granulosa cells are essential for the establishment of the PF pool, which determines female fertility and reproductive lifespan. Cav1 participates in vascularization in fetal mouse ovaries. However, the role of CAV1 in early folliculogenesis and POI pathogenesis remains unclear. Cav1 function was investigated in mice and Human Embryonic Kidney 293 cells. Ovaries (six per group) were randomly assigned to Cav1-vivo-morpholino, control and control-morpholino groups, and all experiments were repeated at least three times. To investigate CAV1 mutations in women, 200 Chinese women with POI and 200 control individuals with regular menstrual cycles and normal endocrine profiles were recruited from the Center for Reproductive Medicine of Shandong University between September 2012 and December 2013. Wild-type CD1 mice, Lgr5-EGFP-ires-CreERT2 (Lgr5-KI) reporter mice and Human Embryonic Kidney 293 cells were used for these experiments. Protein expression was detected by Western blot, and quantitative RT-PCR was used to detect gene expression. The expression pattern of CAV1 in mouse ovaries and the phenotype of Cav1 deficiency in mice were detected by immunofluorescence. Pre-granulosa cell proliferation in ovaries was detected by bromodeoxyuridine (BrdU) assay and immunofluorescence. The coding region of the CAV1 gene was sequenced in 200 women with POI and 200 controls. The functional effect of the novel mutation c.142 G > C (p.Glu48Gln) was investigated by Cell Counting Kit-8 (CCK8) assays and Western blot. We confirmed that Cav1 deficiency in mouse ovary induced by CAV1-vivo-morpholino resulted in more multi-oocyte follicles than in the control and control-morpholino groups (P < 0.01). Suppression of Cav1 decreased Leucine rich repeat containing G protein coupled receptor 5 (Lgr5)-positive cell proliferation (P < 0.01) and reduced the number of Lgr5 and Forkhead box L2 (Foxl2) double-positive cells (P < 0.01). Furthermore, suppression of Cav1 inhibited ovarian epithelial Lgr5-positive cell proliferation and differentiation through the Notch2 signalling pathway. Two of the POI women carried novel CAV1 mutations (c.45 C > G synonymous and c.142 G > C [Glu48Gln]). The deleterious effect of p.Glu48Gln was corroborated by showing that it adversely affected the function of CAV1 in cell proliferation and NOTCH2 expression in HEK293FT cells. N/A. The novel Glu48Gln mutation was only detected in one of 200 POI patients and we were unable to investigate its effects in the ovary. The identification of CAV1 as a potentially causative gene for POI provides a theoretical basis to devise treatments for POI in women. This work was supported by the National Basic Research Program of China (973 Programs: 2012CB944700; 2013CB945501; 2013CB911400; 2014CB943202), the National Key Research and Development Program of China (2016YFC1000604, 2017YFC1001301), the State Key Program of National Natural Science Foundation of China (81430029), and the National Natural Science Foundation of China (31571540, 81522018, 81471509, 81601245, 81701406, 81571406). The authors declare no competing financial interests.

Clinical Study: Role of Bmp-15 Gene in the Pathogenesis of Premature Ovarian Insufficiency (POI)

Premature Ovarian Insufficiency (POI) is a heterogeneous syndrome from an etiological point of view, as different causes work to determine this kind of hormonal disorder. Although many typologies have been recognized, currently for most cases the real causes are uncertain; therefore we come up against forms defined as Idiopathic. Nevertheless, other literature has described the different alterations of most candidate genes responsible for this disorder including the BMP-15 gene. In this study, we will specifically examine the BMP-15 gene, which belongs to the Transforming Growth Factor-β Superfamily or TGF- β, to which the Growth Differentiation Factors (GDFs) also belong. This study examines a sample of Sicilian women affected by POI, especially selected according to their young age, because in these specific cases, the genetic factor truly has a major impact. Identifying a mutant gene that causes the ovarian failure can be important for making a diagnosis that foresees the possible future development of the disease. The result of the studies does not show mutations on the gene in question, but this fact can be a direct consequence of the limited number of women on which the study in question has been done; This hypothesis can be disproved by increasing the number of patients.

Primary ovarian insufficiency: autoimmune causes

To review the pathogenesis of premature ovarian insufficiency due to steroid cell autoimmunity (SCA-POI). Autoimmune oophoritis is characterized by a selective mononuclear cell infiltration into the theca layer of large, antral follicles, with earlier stage follicles consistently free of lymphocytic infiltration. SCA-POI is caused by the selective autoimmune destruction of theca cells with preservation of granulosa cells that produce low amounts of estradiol because of lack of substrates. Typically, serum concentrations of inhibins are increased in women with SCA-POI, as compared to both healthy fertile women and women with other forms of ovarian insufficiency. Normal serum antimüllerian hormone (AMH) concentrations were detected in two-thirds of women with recently diagnosed SCA-POI, which demonstrates that this form of ovarian insufficiency is associated with a preserved pool of functioning follicles. The combined measurement of autoantibodies and markers of ovarian reserve (as inhibin B and AMH) may permit to identify women with POI due to steroid cell autoimmunity with a preserved proportion of primordial and primary follicles. In the future the development of techniques of in-vitro folliculogenesis may permit new treatment strategies for women with SCA-POI-related infertility.