Etiology Of Primary Ovarian Insufficiency Research Articles

Non-targeted metabolomics revealed novel links between serum metabolites and primary ovarian insufficiency: a Mendelian randomization study.

Primary ovarian insufficiency (POI) is a common clinical endocrine disorder with a high heterogeneity in both endocrine hormones and etiological phenotypes. However, the etiology of POI remains unclear. Herein, we unraveled the causality of genetically determined metabolites (GDMs) on POI through Mendelian randomization (MR) study with the overarching goal of disclosing underlying mechanisms. Genetic links with 486 metabolites were retrieved from GWAS data of 7824 European participants as exposures, while GWAS data concerning POI were utilized as the outcome. Via MR analysis, we selected inverse-variance weighted (IVW) method for primary analysis and several additional MR methods (MR-Egger, weighted median, and MR-PRESSO) for sensitivity analyses. MR-Egger intercept and Cochran's Q statistical analysis were conducted to assess potential heterogeneity and pleiotropy. In addition, genetic variations in the key target metabolite were scrutinized further. We conducted replication, meta-analysis, and linkage disequilibrium score regression (LDSC) to reinforce our findings. The MR Steiger test and reverse MR analysis were utilized to assess the robustness of genetic directionality. Furthermore, to deeply explore causality, we performed colocalization analysis and metabolic pathway analysis. Via IVW methods, our study identified 33 metabolites that might exert a causal effect on POI development. X-11437 showed a robustly significant relationship with POI in four MR analysis methods (P IVW=0.0119; P weighted-median =0.0145; PMR-Egger =0.0499; PMR-PRESSO =0.0248). Among the identified metabolites, N-acetylalanine emerged as the most significant in the primary MR analysis using IVW method, reinforcing its pivotal status as a serum biomarker indicative of an elevated POI risk with the most notable P-value (P IVW=0.0007; PMR-PRESSO =0.0022). Multiple analyses were implemented to further demonstrate the reliability and stability of our deduction of causality. Reverse MR analysis did not provide evidence for the causal effects of POI on 33 metabolites. Colocalization analysis revealed that some causal associations between metabolites and POI might be driven by shared genetic variants. By incorporating genomics with metabolomics, this study sought to offer a comprehensive analysis in causal impact of serum metabolome phenotypes on risks of POI with implications for underlying mechanisms, disease screening and prevention.

The relationship between primary ovarian insufficiency and gene variations: a prospective case-control study

ABSTRACT Around 70 percent of cases of Primary Ovarian Insufficiency (POI) etiology remain unexplained. The aim of our study is to contribute to the etiology and genetic background of POI. A total of 37 POI patients and 30 women in the reproductive period were included in this prospective, case-control study between August 2020 and December 2021. The women were examined for 36 genes with next-generation sequencing (NGS) panel. Gene variations were detected in 59.5 percent of the patients in the case group. FSHR p.S680N (rs6166, c.2039 G>A) and FSHR p.A307T (rs6165, c.919 G>A) gene variants, which are most frequently located in exon 10 of the FSHR gene, were detected in both groups. Although it was not found that these gene variants were significantly different between the groups, it was also found that they were significantly different in POI patients under 30 years of age and in those with a family history of POI. Variations were detected in 12 genes in POI patients. Two gene variants (FGFR1 [c.386A>C, rs765615419] and KISS1 [c.58 G>A, rs12998]) were detected in both groups, and the remaining gene variants were detected only in POI patients. No differences were detected between the groups in terms of gene variations. However, the gene variations detected only in POI patients may play a role in the etiology of POI.

Association of two single nucleotide polymorphisms rs10407022 and rs3741664 with the risk of primary ovarian insufficiency in a sample of Iraqi women.

Primary ovarian insufficiency (POI) can be a devastating disease impacting women below the age of forty. This involves a major decrease in the amount and quality of oocytes, or ovarian reserve in a woman. The distribution of single-nucleotide polymorphisms, rs10407022 and rs3741664, in Iraqi people and its association with primary ovarian insufficiency is the main objective of this study. The mean of FSH and LH levels of patients with POI was higher than control, while the mean of AMH levels of patients was lower compared to control. For rs10407022, the GT and TT genotypes were positively associated with the risk of POI. For the rs3741664, the AG genotype was negatively associated with the risk of POI. The results lead to the main conclusion that rs10407022 and rs3741664 polymorphisms may significantly affected the serum levels of AMH and FSH and thus affect POI etiology.

A critical analysis of the impact of endocrine disruptors as a possible etiology of primary ovarian insufficiency.

Primary ovarian insufficiency is a cause of infertility that affects about 1% of women under 40 years old, and is considered as idiopathic in 75% of cases. This review aims to carry out a critical synthesis of the knowledge of the chemical agents likely to affect follicular stock in humans and / or animals, by direct toxicity to follicles, or by increasing their recruitments. For the majority of toxic agents, only experimental data are currently available. We propose a strategy to encourage progress in identifying occupational factors responsible for premature ovarian failure.

BRCA2 deficiency is a potential driver for human primary ovarian insufficiency

Reproductive problem has been one of the top issues for women health worldwide in recent decades. As a typical female disease, primary ovarian insufficiency (POI) results in a loss of ovarian follicles and oocytes that thus destroys women fertility. However, due to the complex of POI etiology and rare resource of human POI oocytes, few biomarkers have been identified in clinics and no effective strategy could be applied to treat POI patients. In the search of possible association between DNA damage and POI by Smart-Seq2 and RT2 profiler PCR array, we find that BRCA2, a core DNA repair gene for homologous recombination shows significantly lower expression in two POI patient oocytes. In line with this, we generated oocyte-specific knockout mouse model driven by Gdf9-Cre. The Brca2-deficient mice are infertile because of the arrested follicle development and defective oocyte quality caused by the accumulation of DNA damage. Notably, ectopic expression of Brca2 in Brca2-deficient oocytes could partially restore the oocyte maturation and chromosome stability. Collectively, our data assign a definite deficiency to BRCA2 as a POI driver during follicle development and oocyte maturation, and provide a potential fertility treatment strategy for POI patients induced by BRCA2 deficiency.

MON-235 Bone Morphogenic Protein Receptor Variants: A New Cause of Primary Ovarian Insufficiency

Primary ovarian insufficiency (POI) is a major cause of infertility. This disease is characterized by amenorrhea with an increase in gonadotropin levels and affects 1% of women before the age of 40. POI may be the result of a broad spectrum of disorders caused by two main mechanisms: abnormal follicular development and follicle depletion due to a defect in their formation or an aberrantly rapid depletion of the stock. Although the majority of cases are idiopathic, POI can be trigged by autoimmune disease, infectious agents, iatrogenic effects, or genetic causes. It may also be part of syndromic diseases such as Turner, Fragile-X or Blepharophimosis Ptosis Epicanthus Inversus syndrome. However, in the majority of cases, the cause of POI is unknown suggesting that new causative genes are yet to be discovered. We conducted a Whole Exome Sequencing on 69 Caucasian women with sporadic POI and performed a bioinformatics analysis on a specific subset of 420 coherent candidate genes1. We identified variations in about fifty genes potentially linked to POI, including new genes never described to be associated with the diseases aetiology, such as AuTophagy related Genes (ATG)2, KHDRBS1 gene encoding an RNA-binding protein3, NOTCH2 gene4... We also found variants in genes encoding Bone Morphogenetic Protein Receptors (BMPR1A and BMPR1B) in three patients. These receptors bind ligands of TGFβ superfamily. Mutations of members of this family (e.g. BMP15, GDF9) are known to be involved in the etiology of POI. BMPR encode transmembrane receptors with serine-threonine kinase activity expressed in the granulosa cells of growing follicles. Missense variations, located in the kinase domain of both receptors 1A and 1B, are predicted to be deleterious in silico. We studied the signaling pathway of these receptors: SMAD proteins phosphorylation, measurement of their transcriptional activity and expression of specific target genes and showed that they are deleterious. Bmpr1a -/- and Bmpr1b-/- mouse models develop infertility due to a reduced spontaneous ovulation and compromised cumulus expansion respectively, indicating that both genes play a crucial role in fertility. Altogether, our study describes the first BMPR1A and 1B mutations associated with POI and increases the number of genes formally implicated as being responsible for this condition. 1Patiño LC, Beau I, Carlosama C, Buitrago JC, González R, Suárez CF, Patarroyo MA, Delemer B, Young J, Binart N, Laissue P. Hum Reprod. 2017; 32(7):1512-1520. 2Delcour C, Amazit L, Patino L, Magnin F, Fagart J, Delemer B, Young J, Laissue P, Binart N, Beau I. Genet Med. 2018 (in press) 3Carlosama C, Patiño L, Beau I, Morel A, Delemer B, Young J, Binart N, Laissue P. Clin Endocrinol (Oxf). 2018 (in press) 4Patiño LC, Beau I, Morel A, Delemer B, Young J, Binart N, Laissue P. Hum Mutat. 2018 (in press)

Functional evidence implicating NOTCH2 missense mutations in primary ovarian insufficiency etiology.

Primary ovarian insufficiency (POI) is a frequently occurring disease affecting women under 40 years old. Recently, we have analyzed unrelated POI women via whole exome sequencing (WES) and identified NOTCH2 mutations underlying possible functional effects. The present study involved reanalyzing of WES assays. We used in the KGN granulosa-like cell model, a synthetic gene reporter construct driving luciferase gene expression to assess the functional effects of five NOTCH2 mutations identified in POI patients. We found that NOTCH2-p.Ser1804Leu, p.Ala2316Val, and p.Pro2359Ala mutations had a functional impact on the protein's transcriptional activity. The results have demonstrated for the first time that NOTCH2 mutations contribute to POI etiology. We therefore recommend sequencing NOTCH2's open reading frame in large panels of POI patients to establish an accurate genotype-phenotype correlation. We cannot rule out the fact that patients affected by Alagille syndrome carrying NOTCH2 mutations may suffer ovarian dysfunction.

Two rare loss-of-function variants in the STAG3 gene leading to primary ovarian insufficiency

Background/AimPrimary ovarian insufficiency (POI) is characterized by primary or secondary amenorrhea, infertility, low estradiol levels, and increased gonadotropin levels. Most cases of POI remain unsolved even after exhaustive investigation. Here, we performed a targeted massively parallel sequencing to identify the genetic diagnosis of primary ovarian insufficiency (POI) in a Brazilian patient. Patient and methodsAn adopted 21-year-old Brazilian woman with isolated POI was selected. A custom SureSelectXT DNA target enrichment panel was designed and sequenced on an Illumina NextSeq 500 sequencer. The variants were confirmed using Sanger sequencing. ResultsTwo rare heterozygous pathogenic variants in the STAG3 gene were identified in our patient. An unpublished 1-bp duplication c.291dupC (p.Asn98Glnfs*2) and one stop codon variant c.1950C > A (p.Tyr650*) were identified in the STAG3 gene. Both undescribed heterozygous variants were absent in the public databases [1000Genomes, Exome Aggregation Consortium (ExAC), National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI/EVS), database of Single Nucleotide Polymorphisms (dbSNP), Genome Aggregation Database (gnomAD)], and Online Archive of Brazilian Mutations (ABraOM) databases. Moreover, neither heterozygous variants were found in 400 alleles from fertile Brazilian women screened by Sanger sequencing. The parents' DNA was not available to segregate these variants. ConclusionOur results suggested that POI is caused by pathogenic compound heterozygous variants in the STAG3 gene, supporting the key role of the STAG3 gene in the etiology of primary ovarian insufficiency.

"Evaluation of four genes associated with primary ovarian insufficiency in a cohort of Mexican women".

Primary ovarian insufficiency (POI) is a clinical condition observed in women younger than 40years of age, characterized by amenorrhea, hypoestrogenism, high levels of follicle-stimulating hormone (FSH), and infertility. Mutations in some master regulators of the development, maturation, and maintenance of ovarian follicles such as BMP15, FSHR, FOXL2, and GDF9 have been suggested as etiological factors in the development of POI. The aim of this study, the first in the Mexican population, is to evaluate the presence of mutations or polymorphisms in these four candidate genes. In a sample of 20 Mexican patients with idiopathic POI, we looked for and analyzed genetic variants in BMP15, FSHR, FOXL2, and GDF9 genes. We observed two polymorphisms: a coding change, c.919G>A (p.Ala307Thr), in the FSHR gene and a synonymous variant, c.447C>T (p.Thr149Thr), in the GDF9 gene. These two variants have been reported previously as polymorphisms (rs6165 and rs254286, respectively). We observed no significant difference associated with POI in the patients when compared with a healthy control group (p > 0.05). Also, no exonic variants were found for the genes BMP15 and FOXL2 in the individuals tested. The lack of association of the evaluated genes in this sample of Mexican women is consistent with the complex genetic etiology of POI that is observed across cohorts studied thus far.

Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency.

Primary ovarian insufficiency (POI) is characterized by amenorrhea and loss or dysfunction of ovarian follicles prior to the age of 40. POI has been associated with autosomal recessive mutations in genes involving hormonal signaling and folliculogenesis, however, the genetic etiology of POI most often remains unknown. Here we report MRPS22 homozygous missense variants c.404G>A (p.R135Q) and c.605G>A (p.R202H) identified in four females from two independent consanguineous families as a novel genetic cause of POI in adolescents. Both missense mutations identified in MRPS22 are rare, occurred in highly evolutionarily conserved residues, and are predicted to be deleterious to protein function. In contrast to prior reports of mutations in MRPS22 associated with severe mitochondrial disease, the POI phenotype is far less severe. Consistent with this genotype-phenotype correlation, mitochondrial defects in oxidative phosphorylation or rRNA levels were not detected in fibroblasts derived from the POI patients, suggesting a non-bioenergetic or tissue-specific mitochondrial defect. Furthermore, we demonstrate in a Drosophila model that mRpS22 deficiency specifically in somatic cells of the ovary had no effect on fertility, whereas flies with mRpS22 deficiency specifically in germ cells were infertile and agametic, demonstrating a cell autonomous requirement for mRpS22 in germ cell development. These findings collectively identify that MRPS22, a component of the small mitochondrial ribosome subunit, is critical for ovarian development and may therefore provide insight into the pathophysiology and treatment of ovarian dysfunction.

Evaluation and Management of Primary Ovarian Insufficiency in Adolescents and Young Adults

Study ObjectiveTo identify clinical features associated with primary ovarian insufficiency (POI) and collect data on the evaluation and treatment received. DesignRetrospective chart review. Data were abstracted on etiology of POI, history, laboratory evaluation, imaging results, return for clinical care, and treatment plans. SettingUrban children's hospital in Cincinnati, Ohio. ParticipantsFifty female patients, age 11-26 years, with initial presentation of POI between January 1, 2006 and December 31, 2015. Main Outcome MeasuresEtiology of POI, bone mineral density (BMD), laboratory evaluation, and services utilized at presentation. ResultsThree hundred thirty-one charts were reviewed, 71 with confirmed diagnosis of POI, and 50 with sufficient data for inclusion. Among the 50, 21 (42%) had Turner syndrome, 18 (36%) remained idiopathic, and 11 (22%) had another condition (eg, autoimmune polyglandular syndrome, galactosemia, etc). Thirty-six (72%) were karyotyped; in 14 (28%), 21-hydroxylase antibodies were measured; 32 (64%) underwent dual-energy x-ray absorptiometry BMD measures of lumbar spine. Eight of 50 patients (16%) reported fracture. Of these, at presentation, 4 (50%) had low BMD, and 2 (25%) had slightly low BMD. On initial spinal dual-energy x-ray absorptiometry, 9 of 32 (28%) had low BMD (Z-score ≤ −2.0) and 7 of 32 (22%) were slightly low (−1.0 to −1.9). All started estrogen therapy within 2 years of presentation. In follow-up, only 2 patients (4%) saw a mental health consultant for emotional support. ConclusionPOI is a model of estrogen deficiency with most cases due to Turner syndrome or idiopathic causes. At presentation, many had low BMD and few were seen for psychological support as part of multidisciplinary care.

New mutations in non-syndromic primary ovarian insufficiency patients identified via whole-exome sequencing.

Is it possible to identify new mutations potentially associated with non-syndromic primary ovarian insufficiency (POI) via whole-exome sequencing (WES)? WES is an efficient tool to study genetic causes of POI as we have identified new mutations, some of which lead to protein destablization potentially contributing to the disease etiology. POI is a frequently occurring complex pathology leading to infertility. Mutations in only few candidate genes, mainly identified by Sanger sequencing, have been definitively related to the pathogenesis of the disease. This is a retrospective cohort study performed on 69 women affected by POI. WES and an innovative bioinformatics analysis were used on non-synonymous sequence variants in a subset of 420 selected POI candidate genes. Mutations in BMPR1B and GREM1 were modeled by using fragment molecular orbital analysis. Fifty-five coding variants in 49 genes potentially related to POI were identified in 33 out of 69 patients (48%). These genes participate in key biological processes in the ovary, such as meiosis, follicular development, granulosa cell differentiation/proliferation and ovulation. The presence of at least two mutations in distinct genes in 42% of the patients argued in favor of a polygenic nature of POI. It is possible that regulatory regions, not analyzed in the present study, carry further variants related to POI. WES and the in silico analyses presented here represent an efficient approach for mapping variants associated with POI etiology. Sequence variants presented here represents potential future genetic biomarkers. This study was supported by the Universidad del Rosario and Colciencias (Grants CS/CIGGUR-ABN062-2016 and 672-2014). Colciencias supported Liliana Catherine Patiño´s work (Fellowship: 617, 2013). The authors declare no conflict of interest.

Primary Ovarian Insufficiency: Current Concepts.

A potential consequence of chemotherapy is the destruction of oocytes, resulting in primary ovarian insufficiency (POI) in young patients; this often results in secondary amenorrhea and necessitates hormone replacement therapy. Regardless of the etiology of POI, the chance of pregnancy is low in this patient population. Given the extent to which oocyte depletion or dysfunction is variable, there is the possibility of spontaneous ovulation on hormone replacement therapy and subsequent pregnancy, however. If pregnancy is not desired, contraception always should be discussed. In most patients, the etiology of POI will not be known, but the treatment for all patients includes estrogen and progesterone therapy, which ensures the development of secondary sex characteristics, acquisition of peak bone mass, and promotion of uterine growth and maturation. Early diagnosis, patient education, and emotional support are important to mitigate long-term sequelae.

POLR2C Mutations Are Associated With Primary Ovarian Insufficiency in Women.

Context:Primary ovarian insufficiency (POI) results from a premature loss of oocytes, causing infertility and early menopause. The etiology of POI remains unknown in a majority of cases.Objective:To identify candidate genes in families affected by POI.Design:This was a family-based genetic study.Setting:The study was performed at two academic institutions.Patients and Other Participants:A family with four generations of women affected by POI (n = 5). Four of these women, three with an associated autoimmune diagnosis, were studied. The controls (n = 387) were recruited for health in old age.Intervention:Whole-genome sequencing was performed.Main Outcome Measure:Candidate genes were identified by comparing gene mutations in three family members and 387 control subjects analyzed simultaneously using the pedigree Variant Annotation, Analysis and Search Tool. Data were also compared with that in publicly available databases.Results:We identified a heterozygous nonsense mutation in a subunit of RNA polymerase II (POLR2C) that synthesizes messenger RNA. A rare sequence variant in POLR2C was also identified in one of 96 women with sporadic POI. POLR2C expression was decreased in the proband compared with women with POI from another cause. Knockdown in an embryonic carcinoma cell line resulted in decreased protein production and impaired cell proliferation.Conclusions:These data support a role for RNA polymerase II mutations as candidates in the etiology of POI. The current data also support results from genome-wide association studies that hypothesize a role for RNA polymerase II subunits in age at menopause in the population.

Role of inflammation and oxidative stress in the etiology of primary ovarian insufficiency.

Objective:The aim of this study was to elucidate the etiology and treatment of primary ovarian insufficiency, which is of unknown cause in 95% of the cases.Materials and Methods:Thirty patients aged 18-40 years who presented to Dicle University Faculty of Medicine Clinic of Obstetrics and Gynecology between June 2012 and January 2014 and were diagnosed as having primary ovarian insufficiency based on their clinical and endocrinologic data, and 30 healthy controls were included in this study.Results:No significant differences were found between patients with primary ovarian insufficiency and control subjects in demographic data and lipid profile levels, thyroid- stimulating hormone, prolactin, and glucose. However, the neutrophil to lymphocyte ratio and levels of follicle-stimulating hormone, luteinizing hormone, total antioxidant status, total oxidant status, and oxidative stress index were significantly higher in patients with primary ovarian insufficiency than in control subjects. In the correlation analysis, follicle-stimulating hormone exhibited a positive correlation with total oxidant status, oxidative stress index, and the neutrophil to lymphocyte ratio (r=0.573** p<0.001, r=0.584** p<0.001, r=0.541 p<0.001, respectively) and correlated negatively with total antioxidant status (r=-0.437** p<0.001).Conclusion:The neutrophil to lymphocyte ratio, total oxidant status, and oxidative stress index levels are elevated in primary ovarian insufficiency. Therefore, anti-oxidative and anti-inflammatory treatment might be administered to patients in the early stage of primary ovarian insufficiency. However, larger studies are needed to clarify whether these elevated levels are a cause or a consequence of primary ovarian insufficiency.

Genetics of primary ovarian insufficiency: new developments and opportunities.

BACKGROUNDPrimary ovarian insufficiency (POI) is characterized by marked heterogeneity, but with a significant genetic contribution. Identifying exact causative genes has been challenging, with many discoveries not replicated. It is timely to take stock of the field, outlining the progress made, framing the controversies and anticipating future directions in elucidating the genetics of POI.METHODSA search for original articles published up to May 2015 was performed using PubMed and Google Scholar, identifying studies on the genetic etiology of POI. Studies were included if chromosomal analysis, candidate gene screening and a genome-wide study were conducted. Articles identified were restricted to English language full-text papers.RESULTSChromosomal abnormalities have long been recognized as a frequent cause of POI, with a currently estimated prevalence of 10–13%. Using the traditional karyotype methodology, monosomy X, mosaicism, X chromosome deletions and rearrangements, X-autosome translocations, and isochromosomes have been detected. Based on candidate gene studies, single gene perturbations unequivocally having a deleterious effect in at least one population include Bone morphogenetic protein 15 (BMP15), Progesterone receptor membrane component 1 (PGRMC1), and Fragile X mental retardation 1 (FMR1) premutation on the X chromosome; Growth differentiation factor 9 (GDF9), Folliculogenesis specific bHLH transcription factor (FIGLA), Newborn ovary homeobox gene (NOBOX), Nuclear receptor subfamily 5, group A, member 1 (NR5A1) and Nanos homolog 3 (NANOS3) seem likely as well, but mostly being found in no more than 1–2% of a single population studied. Whole genome approaches have utilized genome-wide association studies (GWAS) to reveal loci not predicted on the basis of a candidate gene, but it remains difficult to locate causative genes and susceptible loci were not always replicated. Cytogenomic methods (array CGH) have identified other regions of interest but studies have not shown consistent results, the resolution of arrays has varied and replication is uncommon. Whole-exome sequencing in non-syndromic POI kindreds has only recently begun, revealing mutations in the Stromal antigen 3 (STAG3), Synaptonemal complex central element 1 (SYCE1), minichromosome maintenance complex component 8 and 9 (MCM8, MCM9) and ATP-dependent DNA helicase homolog (HFM1) genes. Given the slow progress in candidate-gene analysis and relatively small sample sizes available for GWAS, family-based whole exome and whole genome sequencing appear to be the most promising approaches for detecting potential genes responsible for POI.CONCLUSIONTaken together, the cytogenetic, cytogenomic (array CGH) and exome sequencing approaches have revealed a genetic causation in ∼20–25% of POI cases. Uncovering the remainder of the causative genes will be facilitated not only by whole genome approaches involving larger cohorts in multiple populations but also incorporating environmental exposures and exploring signaling pathways in intragenic and intergenic regions that point to perturbations in regulatory genes and networks.

Etiology of primary ovarian insufficiency in a series young girls presenting at a pediatric endocrinology center.

The cause of the primary ovarian insufficiency (POI) remains unknown in the majority of cases. A retrospective study was carried out in 17 girls with POI and normal 46,XX karyotype evaluated before 20 years of age. The etiology of POI was determined in eight girls (group 1) and remained idiopathic in nine girls (group 2). In group 1, five patients had a medical history: cerebellar ataxia due to congenital disorder of glycosylation (CDG) 1 in three cases, mitochondrial disease in one case, and autoimmune deficiencies in one case. The diagnosis of POI was made on pubertal delay or primary amenorrhea in these five patients, whilst the others presented with clitoral hypertrophy at birth or short stature and pubertal delay in two cases with NR5A1 mutation or with short stature and learning difficulties in one case with mitochondrial disease. In group 2, associated diseases were arthrogryposis malformative, gut, and bladder malformations and kidney failure or parieto-occipital tumor. The genes tested (NR5A1, BMP15, GDF9, and NOBOX) showed no mutation. The frequency of defined etiologies (47%) is high. This is probably because of the recruitment of the cases at the pediatric center, where other somatic anomalies can lead to the accurate determination of the etiology.

Number of CGG repeats in the FMR1 gene of Japanese patients with primary ovarian insufficiency

To define the number of CGG repeats in the FMR1 gene of Japanese patients with primary ovarian insufficiency (POI) and normal controls. Retrospective, controlled cohort study. Outpatient department of an academic tertiary center. One hundred twenty-eight consecutive Japanese patients with sporadic, nonsyndromic POI and 98 controls with normal menstruation. Deoxyribonucleic acid was obtained from the plasma of each subject. Differences in the distribution of CGG repeat numbers between patients with POI and controls. Six alleles in the intermediate range and two in the premutation range were found in five and two patients with POI, respectively, but none were identified in normal controls. The prevalence of FMR1 premutation among Japanese POI patients was 1.56% (2 of 128). The prevalence of having >36 CGG repeats in the FMR1 gene was significantly higher in patients with POI than in controls, and age at the onset of amenorrhea was significantly lower in patients with >38 repeats. More than 36 CGG repeats in the FMR1 might intensify the etiology of POI, at least up to the premutation range.

Mechanisms and Models of Immune Tolerance Breakdown in the Ovary

Ovarian autoimmunity is increasingly implicated in the etiology of primary ovarian insufficiency (POI), previously termed PREMATURE OVARIAN FAILURE or PREMATURE MENOPAUSE. Links to autoimmunity in human POI have long been noted due to the close association of POI with several autoimmune diseases and syndromes such as Addison's disease and Autoimmune polyglandular syndrome 1. However, diagnosis of autoimmune-mediated POI (aPOI) remains challenging because of the lack of sensitive or specific markers of disease. Autoimmunity can arise from the breakdown of immunological tolerance in several ways. How then may we discern what constitutes a relevant target and what represents a downstream phenomenon? The answer lies in the study of pathogenic mechanisms in translational models of disease. From examples in humans and mice, we see that ovarian autoimmunity likely arises from a limited number of antigens targeted in the ovary that are organ specific. These antigens may be conserved but not limited to those seen in animal models of autoimmune ovarian disease. Recent advances in these areas have begun to define the relevant antigens and mechanisms of immune tolerance breakdown in the ovary. Work in translational models continues to provide insight into mechanisms of disease pathogenesis that will allow more accurate diagnosis and, ultimately, improved interventions for women with aPOI.

Bone Health in Primary Ovarian Insufficiency

The etiology of primary ovarian insufficiency (POI) may be genetic, autoimmune, or iatrogenic. Genetic conditions include 45,X, 46,XX and 46,XY POI, and POI associated with galactosemia and FMR premutations. Women with autoimmune polyglandular syndromes 1 and 2 may develop autoimmune POI, as may those who receive chemotherapy or radiotherapy. Hypogonadism in POI can result in reduced rates of bone mass accrual in adolescents and young women, and low bone density for age in older women. Measures to optimize bone density in women with POI include attention to lifestyle measures and hormone replacement. Resistance training and adequate calcium and vitamin D supplementation are essential, as is replacement of estrogen/progestin. Estrogen/progestin replacement may be problematic in women with estrogen-sensitive breast cancer who developed POI in the course of therapy for cancer. In these instances, bisphosphonates are an option. In particular, zoledronic acid has been used successfully in conjunction with chemotherapy, tamoxifen, and aromatase inhibitors.