Cases Of Premature Ovarian Insufficiency Research Articles

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

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

Effects of Environment and Lifestyle Factors on Premature Ovarian Failure.

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

Genetic conditions impairing female fertility.

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

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

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

Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause.

Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40years of age. Known genetic causes account for 25-30% of POI cases, demonstrating the high genetic heterogeneity of POI and the necessity for further genetic explorations. Here we conducted genetic analyses using whole-exome sequencing in a Chinese non-syndromic POI family with the affected mother and at least four affected daughters. Intriguingly, a rare missense variant of BUB1B c.273A>T (p.Gln91His) was shared by all the cases in this family. Furthermore, our replication study using targeted sequencing revealed a novel stop-gain variant of BUB1B c.1509T>A (p.Cys503*) in one of 200 sporadic POI cases. Both heterozygous BUB1B variants were evaluated to be deleterious by multiple in silico tools. BUB1B encodes BUBR1, a crucial spindle assembly checkpoint component involved in cell division. BUBR1 insufficiency may induce vulnerability to oxidative stress. Therefore, we generated a mouse model with a loss-of-function mutant of Bub1b, and also employed D-galactose-induced aging assays for functional investigations. Notably, Bub1b+/- female mice presented late-onset subfertility, and they were more sensitive to oxidative stress than wild-type female controls, mimicking the clinical phenotypes of POI cases affected by deleterious BUB1B variants. Our findings in human cases and mouse models consistently suggest, for the first time, that heterozygous deleterious variants of BUB1B are involved in late-onset POI and related disorders.

MiR-21 and Pellino-1 Expression Profiling in Autoimmune Premature Ovarian Insufficiency.

Background Premature ovarian insufficiency (POI) represents the hypergonadotropic hypoestrogenic symptoms that result in the loss of ovarian follicles. 5-30% POI cases are suggested to be involved in autoimmune etiology. MicroRNA-21 (miR-21) plays a vital role in ovarian folliculogenesis via regulating and interacting with multiple target genes. Here, we conduct the target prediction of miR-21, identify the expression and correlation of miR-21 and its putative target Pellino-1 (Peli1), and confirm their relationship with clinical characteristics in autoimmune POI. Methods Bioinformatic analysis was conducted to screen the miR-21 putative target gene. Autoimmune POI mouse models were established by ZP3 immunization. Serum miR-21, Peli1 mRNA of peripheral blood mononuclear cells (PBMCs) and regulatory T cells (Tregs), general status, spleen Tregs ratio, inflammatory factors, ovarian endocrine function, and ovarian structure were evaluated. For autoimmune POI patients, serum miR-21, PBMCs Peli1 mRNA levels, general data, immune parameters, hormone levels, and ultrasound examinations were obtained. The correlations of miR-21 with Peli1 and clinical characteristics in patients were analyzed. Results Peli1 was selected based on four microRNA prediction databases and literature retrieval. In mouse models, serum miR-21 level, PBMCs and Tregs Peli1 mRNA, and spleen Tregs ratio were 0.61 ± 0.09, 0.12 ± 0.12, 0.27±0.23 and 4.82 ± 0.58, respectively, lower than those in the control group. In patients, miR-21 level (0.60 ± 0.14) and Peli1 mRNA (0.30 ± 0.14) were lower than those in the control group (1.01 ± 0.07 and 1.63 ± 0.54); miR-21 was positively related with Peli1, AMH, E2, the size of the uterus, and ovarian volume and negatively related with FSH, LH, and the number of positive immune parameters (AOAb, EMAb, ACL, ANA, ds-DNA, ACA, IgG, IgA, IgM, IgE, C3, and C4). Conclusions Low expressions of miR-21 and Peli1 were detected in autoimmune POI mice and patients. Positive correlation between miR-21 and Peli1 was observed in autoimmune POI patients, suggesting that miR-21 and Peli1 might be associated with the pathogenesis of autoimmune POI.

CORRELATION BETWEEN PLASMA LEAD AND SERUM ANTI MULLERIAN HORMONE LEVELS IN WOMEN WITH PREMATURE OVARIAN FAILURE

Background: Lead is a highly toxic metal to humans, with the injurious effects on the hemopoietic, nervous and reproductive system. Lead crosses the placenta during pregnancy and has been associated with intrauterine death, prematurity and low birth weight. Objective: To collate between plasma lead and serum antimullerian hormone levels in women with premature ovarian failure, by estimation of level of Anti Mullerian Hormone (AMH), Follicular Stimulating Hormone (FSH), Estradiol (E2) and plasma Lead level. Subjects and Method: This study was conducted in Al Azhar University Hospital outpatient clinics after approval of the research and ethical committee during the period from December 2015 to December 2018. Study groups were: Group 1 included 50 normal candidate women under 40 years old has regular menstrual cycles (21-35 days), fertile (at least one natural pregnancy carried to term), and serum FSH was less than 10 mlU/ml, Group 2 included 50 patients with premature ovarian failure who aged under 40 years with absence of spontaneous menstrual bleeding for more than 12 months, serum estradiol level was less than 25pg/ml, serum FSH level more than 40 mlU/ml. AMH, plasma lead level in patients with premature ovarian failure diagnosed and correlated with level of serum FSH with the normal control group. Results: There was a statistically significant positive correlation between plasma lead levels with FSH among the study group. On the other hand, there was no statistically significant correlation between plasma lead level and AMH level. Conclusion: The anti mullerian hormone showed a significant difference between the cases of premature ovarian insufficiency and the control group. Moreover, AMH was a good marker for ovarian reserve and ovarian response for gonadotropins simulation. Chronic exposures to heavy metals, especially lead, affected the ovarian function and impairment in folliculogenesis which increased the incidence of Premature Ovarian Failure (POF) especially in rural area due to the low socioeconomic status.

CORRELATION BETWEEN PLASMA LEAD AND SERUM ANTI MULLERIAN HORMONE LEVELS IN WOMEN WITH PREMATURE OVARIAN FAILURE

Background: Lead is a highly toxic metal to humans, with the injurious effects on the hemopoietic, nervous and reproductive system. Lead crosses the placenta during pregnancy and has been associated with intrauterine death, prematurity and low birth weight. Objective: To collate between plasma lead and serum antimullerian hormone levels in women with premature ovarian failure, by estimation of level of Anti Mullerian Hormone (AMH), Follicular Stimulating Hormone (FSH), Estradiol (E2) and plasma Lead level. Subjects and Method: This study was conducted in Al Azhar University Hospital outpatient clinics after approval of the research and ethical committee during the period from December 2015 to December 2018. Study groups were: Group 1 included 50 normal candidate women under 40 years old has regular menstrual cycles (21-35 days), fertile (at least one natural pregnancy carried to term), and serum FSH was less than 10 mlU/ml, Group 2 included 50 patients with premature ovarian failure who aged under 40 years with absence of spontaneous menstrual bleeding for more than 12 months, serum estradiol level was less than 25pg/ml, serum FSH level more than 40 mlU/ml. AMH, plasma lead level in patients with premature ovarian failure diagnosed and correlated with level of serum FSH with the normal control group. Results: There was a statistically significant positive correlation between plasma lead levels with FSH among the study group. On the other hand, there was no statistically significant correlation between plasma lead level and AMH level. Conclusion: The anti mullerian hormone showed a significant difference between the cases of premature ovarian insufficiency and the control group. Moreover, AMH was a good marker for ovarian reserve and ovarian response for gonadotropins simulation. Chronic exposures to heavy metals, especially lead, affected the ovarian function and impairment in folliculogenesis which increased the incidence of Premature Ovarian Failure (POF) especially in rural area due to the low socioeconomic status.

Premature ovarian insufficiency (POI) and autoimmunity-an update appraisal

Primary ovarian insufficiency (POI) represents ovarian dysfunction related to very early aging of the ovaries. While the cause of POI in a majority of clinical cases remains undefined, autoimmunity is responsible for approximately 4-30% of POI cases. In the present paper, we aim to provide a critical appraisal and update review on the role of autoimmunity in POI patients. A literature review was conducted for all relevant articles reporting on POI and autoimmunity. PubMed/MEDLINE and the Cochrane library were searched for the best available evidence on this topic. Patients with POI and coexisting autoimmunity are indistinguishable from those with negative autoimmune screen with regard to age of onset, prevalence of primary amenorrhea, or their endocrine profiles. A specific noninvasive reliable diagnostic test for the diagnosis of an autoimmune etiology is lacking; therefore, patients should be screened for the most common autoantibodies, i.e., steroid cell antibodies, anti-ovarian antibodies, and anti-thyroid antibodies. Moreover, treatment strategies to POI infertility are lacking and controversial. Nowadays, guidelines for the treatment of autoimmune POI are not available. Moreover, since diagnostic and treatment strategies to POI infertility are still lacking and controversial, further large clinical studies are needed to investigate the true impact of autoimmunity on POI and to identify the selected groups of patients who are most likely to benefit from immunossuprresive treatment.

Novel FSHR mutations in Han Chinese women with sporadic premature ovarian insufficiency

Premature ovarian insufficiency (POI) is characterized by amenorrhea and elevated levels of follicle-stimulating hormone (FSH, usually > 25 IU/L) before 40 years of age. To identify the relationship between FSHR mutations and sporadic POI patients of Han Chinese descent, we performed Sanger sequencing of FSHR gene in 192 sporadic POI patients and 192 matched controls of Han Chinese descent. Two heterozygous missense variants, c.793A > G (p.M265V) and c.1789C > A (p.L597I), were identified exclusively in POI patients. Functional studies showed that both mutants were expressed on the cell surface, while p.L597I showed decreased membrane localization compared with wild-type FSHR. Moreover, FSH-induced cAMP production and ERK1/2 phosphorylation were reduced in the cells transfected with p.L597I mutant, but not in the cells transfected with p.M265V mutant. In addition, two single-nucleotide polymorphisms (SNPs), rs1394205 (c.-29G > A) and rs140106399 (c.*111 T > C), were identified in both POI group and control group with significantly different genotypic and allelic distributions. These results indicated that dysfunctional FSHR due to mutation or SNPs might explain a fraction of sporadic POI cases in Han Chinese population.

Clinical and Genetic Investigation of Premature Ovarian Insufficiency Cases from Turkey

ObjectivePremature ovarian insufficiency is a lack of ovarian functions in patients younger than 40 years old. Genetic causes leading to accelerated follicle depletion may result in premature ovarian insufficiency. We aimed to determine genetic etiology of nonsyndromic premature ovarian insufficiency cases from Turkey. Materials and methodsWe analyzed 86 nonsyndromic premature ovarian insufficiency cases and 26 matched control female participants. Participants have been investigated in cytogenetic analysis followed by FMR1 repeat size expansions and search of variants for nine premature ovarian insufficiency-associated genes. ResultsFour cases had a structural cytogenetic abnormality. Two cases revealed with premutation size FMR1 triplet repeat expansion. Four cases carried variants in which two were very rare in FSHR and PDPK1, and three were novel in NR5A1, PDPK1, and POF1B genes. Six novel variants have been identified in NOBOX, NR5A1, POF1B, and PDPK1 in control population assigned to be benign alterations. ConclusionMosaicism of sex chromosomes was responsible in 4.6% and FMR1 premutation in 2.4% of premature ovarian insufficiency cases, while the association of premature ovarian insufficiency-related genes was found very subtle. Novel variants in NR5A1, PDPK1, and POF1B may necessitate further evaluation for their association with premature ovarian insufficiency via functional studies.

Serum androgen profiles in women with premature ovarian insufficiency: a systematic review and meta-analysis.

This meta-analysis aims to investigate serum androgen profiles (testosterone, dehydroepiandrosterone sulfate, androstenedione, and sex hormone-binding globulin) in women with premature ovarian failure and to establish if there is evidence of diminished androgen levels in these women. Various Internet sources of PubMed, Cochrane library, and Medline were searched systematically until February, 2018. Out of a pool of 2,461 studies, after applying the inclusion/exclusion criterion, 14, 8, 10, and 9 studies were chosen for testosterone, dehydroepiandrosterone sulfate, androstenedione, and sex hormone-binding globulin, respectively, for this meta-analysis. The effect measure was the standardized mean difference with 95% confidence interval (95% CI) in a random-effects model. The testosterone concentrations in premature ovarian insufficiency were compared with fertile controls: stamdard mean difference (IV, random, 95% CI) -0.73 [-0.99, -0.46], P value < 0.05. The dehydroepiandrosterone sulfate concentrations in premature ovarian insufficiency compared to fertile controls: standard mean difference (IV, random, 95% CI) -0.65 [-0.92, -0.37], P value < 0.05. Androstenedione in premature ovarian insufficiency were compared with fertile controls: standard mean difference (IV, random, 95% CI) -1.09 [-1.71, -0.48], P value < 0.05. Sex hormone-binding globulin levels did not show statistical significance. The dehydroepiandrosterone sulfate levels were reduced in premature ovarian insufficiency cases, but still showed a higher level than in postmenopausal women. Women with premature ovarian insufficiency are at risk for decreased concentrations of testosterone, dehydroepiandrosterone sulfate, and androstenedione. Dehydroepiandrosterone sulfate levels were more reduced in postmenopausal controls when compared with premature ovarian insufficiency cases.

P68: Peripheral blood effector Treg cells decreased in premature ovarian insufficiency cases

American Journal of Reproductive ImmunologyVolume 80, Issue S1 p. 86-86 ABSTRACTS P68: Peripheral blood effector Treg cells decreased in premature ovarian insufficiency cases First published: 26 June 2018 https://doi.org/10.1111/aji.67_12984Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume80, IssueS1Special Issue: American-Sino Joint Meeting of Reproductive Immunology (ASRI-CSI 2018), June 28-1 July, 2018 Shanghai, ChinaJune 2018Pages 86-86 RelatedInformation

O4: Peripheral blood effector Treg cells decreased in premature ovarian insufficiency cases

O4: Peripheral blood effector Treg cells decreased in premature ovarian insufficiency cases

Consequences of premature ovarian insufficiency on women's sexual health.

Premature ovarian insufficiency (POI) is defined by amenorrhoea and decreased serum levels of oestrogens associated with increased serum gonadotropins concentrations before the age of 40 years. Patients suffering from POI present with irregular menses, either secondary or (less common) primary amenorrhoea, and subfertility. POI affects approximately 1 in 100 women by the age 40 years and 0.1% by 30 years of age. Both spontaneous and iatrogenic causes may induce POI, although up to 90% of POI cases are idiopathic. Impairment of sexual function is a common problem affecting women suffering from POI. Premature loss of gonadal function is particularly traumatic in young women and affects many aspects of physical and social life. POI patients suffer from genital pain due to vaginal dryness and diminished sexual arousal. Additionally, POI patients report increased anxiety, depressed mood, and have impaired interactions with their peers, which leads to feeling less feminine and having decreased self-esteem. Moreover, they have significantly decreased physical and psychological well-being when compared to age-matched controls. Systemic hormonal replacement therapy and topical oestrogen therapy as well as vaginal moisturisers may be used in the treatment of POI patients’ sexual impairment.

Premature Ovarian Insufficiency: An Adolescent Series

Study ObjectiveTo study the presentation and causes of premature ovarian insufficiency (POI) in adolescents. DesignRetrospective notes review. SettingTertiary referral outpatient clinic for pediatric and adolescent gynecology. ParticipantsAdolescents with POI. InterventionsStandard POI evaluation. Main Outcome MeasuresAge and clinical symptoms at presentation, causative factors for POI, if identified. ResultsWe identified 22 girls with POI, with a mean age of 15.6 years. Eight of them presented with delayed puberty, 3 with primary amenorrhea, and the remainder presented with either irregular bleeding (n = 9) or secondary amenorrhea (n = 2). For those who presented with delayed puberty, only 3 were found to have a sex chromosome abnormality. A clear cause for the POI was identified in 3 further cases. ConclusionAlthough POI in adolescents traditionally is associated with primary amenorrhea and delayed puberty, a proportion of girls will present with irregular bleeding that might be mistaken for expected menstrual disturbances of puberty, thus delaying the diagnosis. We identified a clear cause for POI in 6 cases. Although there were no familial cases of POI, it remains a possibility that genetic reasons might be involved in the pathogenesis.

Evaluation of serum heavy metal levels on primary ovarian insufficiency

In this study we aimed to investigate the level of exposure to these toxic heavy metals such as Aluminum (Al), Arsenic (As), Mercury (Hg) ,Manganese (Mn) and Lead (Pb) among Premature Ovarian Insufficiency (POI) patients. This cross-sectional study was performed in 23 women with normal reproductive hormones (control) and 23 women with POI (case). Risk factors evaluated were; age,body mass index(BMI), gravidity and blood serum metal levels (Al,As,Hg,Mn,Pb). Risk factors were compared between groups. Women with history of pelvic surgery, any cancer or autoimmune disease treatment, endometriosis and other chronic systemic diseases were excluded from the study. The Age, BMI and Gravidity were similar between the case and control group (p > 0.05). And also the aluminum, arsenic, manganese, mercury and lead serum levels were smilar between the case and control group (p > 0.05). Etiology of most POI cases remains undetermined. Early recognition of predisposing factors of POI may help to make prevention about ovarian failure and would offer this patient population the opportunity to preserve fertility. Identifying people with elevated blood heavy metal levels will give chance of avoiding oncoming destructive health effects of heavy metals.

Deletion of CPEB1 Gene: A Rare but Recurrent Cause of Premature Ovarian Insufficiency.

Premature ovarian insufficiency (POI) may be secondary to chemotherapy, radiotherapy, or environmental factors. Genetic causes are identified in 20-25% of cases, but most POI cases remain idiopathic. This study aimed to identify new genes involved in POI and to characterize the implication of CPEB1 gene in POI. This was a case report and cohort study replicate conducted in academic medical centers. A deletion including CPEB1 gene was first identified in a patient with primary amenorrhea. Secondly, 191 sporadic POI cases and 68 familial POI cases were included. For each patient, karyotype was normal and FMR1 premutation was excluded. Search for CPEB1 deletions was performed by quantitative multiplex PCR of short fluorescent fragments or DNA microarray analysis. Gene sequencing of CPEB1 was performed for 95 patients. We identified three patients carrying a microdeletion in band 15q25.2. The proximal breakpoint, for the three patients, falls within a low-copy repeat region disrupting the CPEB1 gene, which represents a strong candidate gene for POI as it is known to be implicated in oocyte meiosis. No mutation was identified by sequencing CPEB1 gene. Therefore, heterozygous deletion of CPEB1 gene leading to haploinsufficiency could be responsible for POI in humans. Microdeletions of CPEB1 were identified in 1.3% of patients with POI, whereas no mutation was identified. This microdeletion is rare but recurrent as it is mediated by nonallelic homologous recombination due to the existence of low-copy repeats in the region. This result demonstrates the importance of DNA microarray analysis in etiological evaluation and counseling of patients with POI.

AMH mutations with reduced in vitro bioactivity are related to premature ovarian insufficiency.

Could anti-Müllerian hormone (AMH) mutations be implicated in the development of idiopathic premature ovarian insufficiency (POI)? Three rare or unknown missense variants of the AMH gene were identified in a cohort of 55 POI patients; all three variants showed a drastically reduced in vitro bioactivity. Genetic factors are implicated in 5-15% of cases of POI. However, only a few genes have been shown to be involved in its development. AMH inhibits the recruitment of primordial follicles in the ovary and defective or absent AMH leads to premature depletion of the primordial follicle pool in AMH null mice. The whole coding sequence and the exon-intron junction of the AMH gene was sequenced in a cohort of 55 POI patients recruited over a period of 8 years. The studied variants were also sequenced in 197 ethnically matched controls. POI was defined as amenorrhea of more than 4 months with increased FSH before the age of 40. Patients with POI resulting from radio- or chemotherapy, surgery, chromosomal anomalies or FMR1 gene pre-mutation were excluded from the study. Recombinant human wild-type (wt) and mutated AMH proteins were produced in HEK293 T cells. KK-1 cells transfected with the AMH receptor type 2 (AMHR2) and a BMP responsive element coupled to a luciferase reporter vector were stimulated with different concentrations of wt AMH and the three tested variants. The whole coding sequence of the AMH gene could be performed and analyzed for 50 POI patients: 16 variants were found, including 6 missense variants from which 1 was unknown (R444H) and 2 were very rare (G264R and D288E). The variant D288E was also found in one of the patient's mother who also underwent POI at 32 years old. The stimulation of the AMHR2 assessed by the luciferase activity was drastically reduced for the three variants when compared with the wt AMH. The study is limited by a relatively small number of patients in the POI cohort. This is the first time that the bioactivity of AMH variants related to POI patients is tested in vitro. The functional study showed a drastic reduction of the protein activity for the three variants, supporting their contribution to the development of the ovarian insufficiency. The familial segregation further supports the implication of AMH in the development of POI. The study was performed thanks to funding from the 'Fondation Erasme'. No conflicts of interest are declared.

Elevated LH levels draw a stronger distinction than AMH in premature ovarian insufficiency

Objectives A significant number of individuals have high serum follicle stimulating hormone (FSH) levels but do not meet the criteria for diagnosis of premature ovarian insufficiency (POI) due to ongoing menstruation. We compared a group of women with elevated FSH levels and POI with a control group in terms of biochemical markers.Methods In this cross-sectional retrospective study, 38 POI cases and 48 cases of elevated FSH were compared to 89 individuals in a control arm in terms of biochemical markers. The receiver operating characteristics curve was calculated to assess the utility of anti-Müllerian hormone (AMH) levels to discriminate women with elevated FSH levels accompanied by POI from those women with elevated FSH levels but not defineable as having POI.Results A multiple regression analysis revealed that only the AMH level was significantly different for the discrimination between the control and elevated FSH groups. AMH and estradiol levels were found to be statistically significant for the discrimination between control and POI cases. However, only luteinizing hormone (LH) was found to be significant for distinguishing between women with elevated FSH and POI, interestingly excluding the serum AMH level in this context.Conclusions AMH was the most important and superior marker to differentiate both POI cases and patients with an elevated FSH level from the controls; however, it did not show the same resolution for differentiating POI cases from those with elevated FSH. Moreover, we conclude that the serum LH level is the most useful marker for differentiating POI cases from women with elevated FSH levels.