Optimising health after early menopause.

The typical age at menopause is 50-51 years in high-income countries. However, early menopause is common, with around 8% of women in high-income countries and 12% of women globally experiencing menopause between the ages of 40 years and 44 years. Menopause before age 40 years (premature ovarian insufficiency) affects an additional 2-4% of women. Both early menopause and premature ovarian insufficiency can herald an increased risk of chronic disease, including osteoporosis and cardiovascular disease. People who enter menopause at younger ages might also experience distress and feel less supported than those who reach menopause at the average age. Clinical practice guidelines are available for the diagnosis and management of premature ovarian insufficiency, but there is a gap in clinical guidance for early menopause. We argue that instead of distinct age thresholds being applied, early menopause should be seen on a spectrum between premature ovarian insufficiency and menopause at the average age. This Series paper presents evidence for the short-term and long-term consequences of early menopause. We offer a practical framework for clinicians to guide diagnosis and management of early menopause, which considers the nature and severity of symptoms, age and medical history, and the individual's wishes and priorities to optimise their quality of life and short-term and long-term health. We conclude with recommendations for future research to address key gaps in the current evidence.

Improving diagnostic precision in primary ovarian insufficiency using comprehensive genetic and autoantibody testing.

STUDY QUESTION: Is it possible to find the cause of primary ovarian insufficiency (POI) in more women by extensive screening? SUMMARY ANSWER: Adding next generation sequencing techniques including a POI-associated gene panel, extended whole exome sequencing data, as well as specific autoantibody assays to the recommended diagnostic investigations increased the determination of a potential etiological diagnosis of POI from 11% to 41%. WHAT IS KNOWN ALREADY: POI affects ∼1% of women. Clinical presentations and pathogenic mechanisms are heterogeneous and include genetic, autoimmune, and environmental factors, but the underlying etiology remains unknown in the majority of cases. STUDY DESIGN, SIZE, DURATION: Prospective cross-sectional study of 100 women with newly diagnosed POI of unknown cause consecutively referred to Haukeland University Hospital, Bergen, Norway, January 2019 to December 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: In addition to standard recommended diagnostic investigations including screening for chromosomal anomalies and premutations in the fragile X mental retardation 1 gene (FMR1) we used whole exome sequencing, including targeted analysis of 103 ovarian-related genes, and assays of autoantibodies against steroid cell antigens. MAIN RESULTS AND THE ROLE OF CHANCE: We identified chromosomal aberrations in 8%, FMR1 premutations in 3%, genetic variants related to POI in 16%, and autoimmune POI in 3%. Furthermore in 11% we identified POI associated genetic Variants of unknown signifcance (VUS). A homozygous pathogenic variant in the ZSWIM7 gene (NM_001042697.2) was found in two women, corroborating this as a novel cause of monogenic POI. No associations between phenotypes and genotypes were found. LIMITATIONS, REASONS FOR CAUTION: Use of candidate genetic and autoimmune markers limit the possibility to discover new markers. To further investigate the genetic variants, family studies would have been useful. We found a relatively high proportion of genetic variants in women from Africa and lack of genetic diversity in the genomic databases can impact diagnostic accuracy. WIDER IMPLICATIONS OF THE FINDINGS: Since no specific clinical or biochemical markers predicted the underlying cause of POI discussion of which tests should be part of diagnostic screening in clinical practice remains open. New technology has altered the availability and effectiveness of genetic testing, and cost-effectiveness analyses are required to aid sustainable diagnostics. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by grants and fellowships from Stiftelsen Kristian Gerhard Jebsen, the Novonordisk Foundation, the Norwegian Research Council, University of Bergen, and the Regional Health Authorities of Western Norway. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT04082169.

Identification of energy metabolism anomalies and serum biomarkers in the progression of premature ovarian failure via extracellular vesicles' proteomic and metabolomic profiles.

BACKGROUND: Premature ovarian failure (POF) is a clinical condition characterized by the cessation of ovarian function, leading to infertility. The underlying molecular mechanisms remain unclear, and no predictable biomarkers have been identified. This study aimed to investigate the protein and metabolite contents of serum extracellular vesicles to investigate underlying molecular mechanisms and explore potential biomarkers. METHODS: This study was conducted on a cohort consisting of 14 POF patients and 16 healthy controls. The extracellular vesicles extracted from the serum of each group were subjected to label-free proteomic and unbiased metabolomic analysis. Differentially expressed proteins and metabolites were annotated. Pathway network clustering was conducted with further correlation analysis. The biomarkers were confirmed by ROC analysis and random forest machine learning. RESULTS: The proteomic and metabolomic profiles of POF patients and healthy controls were compared. Two subgroups of POF patients, Pre-POF and Pro-POF, were identified based on the proteomic profile, while all patients displayed a distinguishable metabolomic profile. Proteomic analysis suggested that inflammation serves as an early factor contributing to the infertility of POF patients. For the metabolomic analysis, despite the dysfunction of metabolism, oxidative stress and hormone imbalance were other key factors appearing in POF patients. Signaling pathway clustering of proteomic and metabolomic profiles revealed the progression of dysfunctional energy metabolism during the development of POF. Moreover, correlation analysis identified that differentially expressed proteins and metabolites were highly associated, with six of them being selected as potential biomarkers. ROC curve analysis, together with random forest machine learning, suggested that AFM combined with 2-oxoarginine was the best diagnostic biomarker for POF. CONCLUSIONS: Omics analysis revealed that inflammation, oxidative stress, and hormone imbalance are factors that damage ovarian tissue, but the progressive dysfunction of energy metabolism might be the critical pathogenic pathway contributing to the development of POF. AFM combined with 2-oxoarginine serves as a precise biomarker for clinical POF diagnosis.

ACBD5-related retinal dystrophy with leukodystrophy due to novel mutations in ACBD5 and with additional features including ovarian insufficiency.

Acyl-CoA-binding domain-containing protein 5-related retinal dystrophy with leukodystrophy (ACBD5) is a peroxisomal disorder due to deficiency of ACBD5. Presenting features include retinal dystrophy, progressive leukodystrophy, and ataxia. Only seven cases of ACBD5-related retinal dystrophy have been reported in the literature to date, including one other case diagnosed in adulthood. Here we report a case with novel compound heterozygous ACBD5 mutations, presenting with the common features of rod monochromatism and progressive leukodystrophy with spasticity and ataxia. Additional novel clinical features included head and neck tremor and ovarian insufficiency. The patient's symptoms were present since infancy, but a diagnosis was only reached in adulthood when whole exome sequencing was performed. This case, which reports two novel mutations and additional clinical manifestations, contributes to the emerging phenotype of ACBD5-related retinal dystrophy with leukodystrophy, and delineation of the natural history and disease progression.

Diagnostic Value of Autoantibodies against Steroidogenic Enzymes and Hormones in Infertile Women with Premature Ovarian Insufficiency.

The objective of the study was to evaluate the profile and diagnostic significance of serum autoantibodies in infertile patients with premature ovarian insufficiency (POI). The pilot study included 26 patients of reproductive age with POI and diminished ovarian reserve who received complex treatment using new surgical technologies (Group 1) and 18 patients without POI (Group 2). The profile of serum autoantibodies, including anti-ovarian antibodies, antibodies against thyroid peroxidase (TPO), steroidogenic enzymes, and steroid and gonadotropic hormones, was studied using modified ELISAs and human recombinant steroidogenic enzymes (CYP11A1, CYP19A1, CYP21A2). Patients in Group 1 had higher levels of IgG autoantibodies against steroidogenic enzymes, estradiol, progesterone, and TPO than those in Group 2. Tests for IgG antibodies against CYP11A1, CYP19A1, and CYP21A2 exhibited high sensitivity (65.4-76.9%), specificity (83.3-89.9%), and AUC values (0.842-0.910) for POI, the highest in the first test. Three-antibodies panel screening showed higher diagnostic accuracy (84.1% versus 75-79.6%). The levels of these antibodies correlated with menstrual irregularities and a decrease in the antral follicle count. Thus, antibodies against CYP11A1, CYP19A1, and CYP21A2 have a high diagnostic value for POI. Three-antibody panel screening may improve the accuracy of POI diagnosis and be useful for identifying high-risk groups, early stages of the disease, and predicting POI progression.

Development and validation of age-specific risk prediction models for primary ovarian insufficiency in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort.

BACKGROUND: Female survivors of childhood cancer are at risk for primary ovarian insufficiency (POI), defined as the cessation of gonadal function before the age of 40 years. We aimed to develop and validate models to predict age-specific POI risk among long-term survivors of childhood cancer. METHODS: To develop models to predict age-specific POI risk for the ages of 21-40 years, we used data from the Childhood Cancer Survivor Study (CCSS). Female survivors aged 18 years or older at their latest follow-up, with self-reported menstrual history information and free of subsequent malignant neoplasms within 5 years of diagnosis, were included. We evaluated models that used algorithms based on statistical or machine learning to consider all predictors, including cancer treatments. Cross-validated prediction performance metrics (eg, area under the receiver operating characteristic curve [AUROC]) were compared to select the best-performing models. For external validation of the models, we used data from 5-year survivors in the St Jude Lifetime Cohort (SJLIFE) with ovarian status clinically ascertained using hormone measurements (menopause defined by follicle stimulating hormone >30 mIU/mL and oestradiol <17 pg/mL) and medical chart or questionnaire review. We also evaluated an SJLIFE-based polygenic risk score for POI among 1985 CCSS survivors with genotype data available. FINDINGS: 7891 female CCSS survivors (922 with POI) were included in the development of the POI risk prediction model, and 1349 female SJLIFE survivors (101 with POI) were included in the validation study. Median follow-up from cancer diagnosis was 23·7 years (IQR 18·3-30·0) in CCSS and 15·1 years (10·4-22·9) in SJLIFE. Between the ages of 21 and 40 years, POI prevalence increased from 7·9% (95% CI 7·3-8·5) to 18·6% (17·3-20·0) in CCSS and 7·3% (5·8-8·9) to 14·9% (11·6-19·1) in SJLIFE. Age-specific logistic regression models considering ovarian radiation dosimetry or prescribed pelvic and abdominal radiation dose, along with individual chemotherapy predictors, performed well in CCSS. In the SJLIFE validation, the prescribed radiation dose model performed well (AUROC 0·88-0·95), as did a simpler model that considered any exposures to pelvic or abdominal radiotherapy or alkylators (0·82-0·90). Addition of the polygenic risk predictor significantly improved the average positive predictive value (from 0·76 [95% CI 0·63-0·89] to 0·87 [0·80-0·94]; p=0·029) among CCSS survivors treated with ovarian radiation and chemotherapy. INTERPRETATION: POI risk prediction models using treatment information showed robust prediction performance in adult survivors of childhood cancer. FUNDING: Canadian Institutes of Health Research, US National Cancer Institute.

Genetic screening in patients with ovarian dysfunction.

Ovarian dysfunction, including premature ovarian insufficiency and decreased ovarian reserve, affects the ovarian reserve and is one of the leading causes of female infertility. More and more cases of ovarian dysfunction are associated with genetic factors. Here, we identified eight potential variants in five genes (MSH4, HFM1, SYCE1, FSHR, and C14orf39) from six independent families by exome sequencing. The splice-site variants in SYCE1 and MSH4 affected canonical splicing isoforms, leading to missing protein domains or premature termination. Our findings expand the mutational spectrum of ovarian dysfunction and provide potential biomarkers for future genetic counseling and for more personalized treatments. Exome sequencing was shown to be a useful tool to better dissect the genetic basis for ovarian dysfunction and yielded a genetic diagnosis in about 5.0% (6/124) of cases in a cohort of 124 patients with ovarian dysfunction.

Gonadal function in pediatric Fanconi anemia patients treated with hematopoietic stem cell transplant.

Gonadal dysfunction and reduced fertility are clinical manifestations well described in patients with Fanconi anemia (FA) and following hematopoietic stem cell transplantation (HSCT). It is difficult to differentiate gonadal dysfunction from the primary disease itself or from HSCT procedures. Therefore, it is important to manage expectations about gonadal failure and infertility for all patients with FA, regardless of the HSCT status. We performed a retrospective analysis of 98 pediatric patients with FA who were transplanted between July 1990 and June 2020 to evaluate the incidence of gonadal dysfunction in female and male patients with FA. New-onset premature ovarian insufficiency (POI) was diagnosed in a total of 30 (52.6%) patients. Follicle-stimulating hormone and luteinizing hormone levels were increased in patients diagnosed with POI. Anti- Mullerian hormone levels declined in POI patients after HSCT (r2=0.21; P=0.001). Twenty (48.8%) male patients were diagnosed with testicular failure. Follicle-stimulating hormone levels increased after HSCT even in patients without testicular failure (r2=0.17; P=0.005). Inhibin B levels decreased over time after HSCT in patients with testicular failure (r2=0.14; P=0.001). These data indicate brisk decline in already impaired gonadal function in transplanted children with FA.

COVID-19-related premature ovarian insufficiency: case report and literature review.

OBJECTIVE: The aim of this study is to present the case report of a 36-year-old woman developing premature ovarian insufficiency (POI) after COVID-19 and review the literature referring to the possible impact of SARS-CoV-2 infection on female reproduction. METHODS: A 36-year-old nulligravida with normal menstrual cycles, non-smoker, with a normal body mass index and no pelvic surgery or oncological treatment in her medical history presented to the Infertility Center of the Institute of Mother and Child in Warsaw after a year of unsuccessful attempts to get pregnant. During diagnostic process she was affected by COVID-19 with a mild manifestation and thereafter she presented amenorrhea with intense hot flushes. Further diagnostic confirmed the diagnosis of POI. RESULTS: There is a strong molecular basis for a possible effect of SARS-CoV-2 infection on the female reproductive system; however, the results of available research are conflicting. All of these aspects are discussed in detail. CONCLUSIONS: SARS-CoV-2 infection may cause serious complications that cast a long shadow on a patient's future life and health. Further research is needed to assess the real impact of SARS-CoV-2 infection on female reproductive health, as well as potential preventive and therapeutic strategies for women affected with COVID-19.

RegEMR: a natural language processing system to automatically identify premature ovarian decline from Chinese electronic medical records.

BACKGROUND: The ovarian reserve is a reservoir for reproductive potential. In clinical practice, early detection and treatment of premature ovarian decline characterized by abnormal ovarian reserve tests is regarded as a critical measure to prevent infertility. However, the relevant data are typically stored in an unstructured format in a hospital's electronic medical record (EMR) system, and their retrieval requires tedious manual abstraction by domain experts. Computational tools are therefore needed to reduce the workload. METHODS: We presented RegEMR, an artificial intelligence tool composed of a rule-based natural language processing (NLP) extractor and a knowledge-based disease scoring model, to automatize the screening procedure of premature ovarian decline using Chinese reproductive EMRs. We used regular expressions (REs) as a text mining method and explored whether REs automatically synthesized by the genetic programming-based online platform RegexGenerator + + could be as effective as manually formulated REs. We also investigated how the representativeness of the learning corpus affected the performance of machine-generated REs. Additionally, we translated the clinical diagnostic criteria into a programmable disease diagnostic model for disease scoring and risk stratification. Four hundred outpatient medical records were collected from a Chinese fertility center. Manual review served as the gold standard, and fivefold cross-validation was used for evaluation. RESULTS: The overall F-score of manually built REs was 0.9444 (95% CI 0.9373 to 0.9515), with no significant difference (paired t test p > 0.05) compared with machine-generated REs that could be affected by training set sizes and annotation portions. The extractor performed effectively in automatically tracing the dynamic changes in hormone levels (F-score 0.9518-0.9884) and ultrasonographic measures (F-score 0.9472-0.9822). Applying the extracted information to the proposed diagnostic model, the program obtained an accuracy of 0.98 and a sensitivity of 0.93 in risk screening. For each specific disease, the automatic diagnosis in 76% of patients was consistent with that of the clinical diagnosis, and the kappa coefficient was 0.63. CONCLUSION: A Chinese NLP system named RegEMR was developed to automatically identify high risk of early ovarian aging and diagnose related diseases from Chinese reproductive EMRs. We hope that this system can aid EMR-based data collection and clinical decision support in fertility centers.

The diagnostic experience of women with fragile X-associated primary ovarian insufficiency (FXPOI).

PURPOSE: The fragile X premutation occurs when there are 55-200 CGG repeats in the 5' UTR of the FMR1 gene. An estimated 1 in 148 women carry a premutation, with 20-30% of these individuals at risk for fragile X-associated primary ovarian insufficiency (FXPOI). Diagnostic experiences of FXPOI have not previously been included in the literature, limiting insight on experiences surrounding the diagnosis. This study identifies barriers and facilitators to receiving a FXPOI diagnosis and follow-up care, which can inform care and possibly improve quality of life. METHODS: We conducted qualitative interviews with 24 women with FXPOI exploring how FMR1 screening, physician education, and supportive care impacted their experience. Three subgroups were compared: women diagnosed through family history who have biological children, women diagnosed through family history who do not have biological children, and women diagnosed through symptoms of POI. RESULTS: Themes from interviews included hopes for broader clinician awareness of FXPOI, clear guidelines for clinical treatment, and proper fertility workups to expand reproductive options prior to POI onset. Participants also spoke of difficulty finding centralized sources of care. CONCLUSIONS: Our results indicate a lack of optimal care of women with a premutation particularly with respect to FMR1 screening for molecular diagnosis, short- and long-term centralized treatment, and clinical and emotional support. The creation of a "FXPOI health navigator" could serve as a centralized resource for the premutation patient population, assisting in connection to optimal treatment and appropriate referrals, including genetic counseling, mental health resources, advocacy organizations, and better-informed physicians.

Genomic testing in premature ovarian insufficiency: proceed with caution.

Genomic testing has the potential to transform outcomes for women with infertility conditions, such as premature ovarian insufficiency (POI), with growing calls for widespread diagnostic use. The current research literature, however, often uses poor variant curation leading to inflated diagnostic claims and fails to address the complexities of genomic testing for this condition. Without careful execution of the transition from research to the clinic, there is danger of inaccurate diagnoses and poor appreciation of broader implications of testing. This Forum outlines the benefits of genomic testing for POI and raises often overlooked concerns.

A SPIDR homozygous nonsense pathogenic variant in isolated primary ovarian insufficiency with chromosomal instability.

Primary ovarian insufficiency (POI), affecting 1% of women under 40 years is a public health problem. Genes involved in meiosis/DNA repair were recently shown to be the leading family of associated causal genes, some of them also cause tumors/cancers. Here, using targeted next-generation sequencing in an Indian POI patient with primary amenorrhea and streak ovaries, we identified a novel homozygous nonsense variant in exon 7 of SPIDR (KIAA0146) c.814C > T, R272*, predicted to lead a nonsense-mediated mRNA decay. SPIDR was recently identified by in vitro assays as an auxiliary protein interacting with RAD51 and BLM, two major proteins involved in genome stability. Consistent with alteration of the RAD51 pathway, we observed a strong increase in mitomycin C-induced DNA breaks and aberrant metaphases in the patient's cells compared to a control. However, sister chromatid exchanges were normal in contrast to the sharp increase characteristic of the BLM pathway. This is the first evidence of chromosomal instability associated with a SPIDR molecular defect, which supports the role of SPIDR in double-stranded DNA damage repair in vivo in humans and its causal role in POI. Our study increases knowledge on the SPIDR function and has broad implications in the management of such patients.

Female fragile X premutation carriers are at increased risk for metabolic syndrome from early adulthood.

BACKGROUND AND AIMS: Women with primary ovarian insufficiency exhibit an unfavorable cardiovascular risk profile. A common cause for primary ovarian insufficiency is fragile X premutation (FXPC), and data on the cardiovascular risk factors in women with FXPC are scarce. We aimed to assess the prevalences of abnormal metabolic components among FXPC. METHODS AND RESULTS: Clinical, anthropometric and laboratory data were collected from 71 women with FXPC and compared to 78 women referred for counseling in an in-vitro fertilization clinic (control group). The mean ± SD ages of the FXPC and control groups were 33.5 ± 5.6 and 36.2 ± 5.3 years, respectively (p = 0.003). In a logistic regression analysis, the FXPC group had increased risks for hyperglycemia, hypertriglyceridemia, central obesity and low high-density lipoprotein cholesterol, of 21.8-fold (95% CI 2.7-175, p = 0.004), 6.9-fold (95% CI 2.5-18.7, p < 0.0001), 3.1-fold (95% CI 1.4-6.9, p = 0.005) and 2.4-fold (95% CI 1.1-5.2, p = 0.03), compared to the control group. The FXPC group had 2.7-fold higher prevalence of two abnormal metabolic components; 19% met the full criteria of MetS, compared to 3% of the control group. Neither CGG repeats nor ovarian reserve markers were associated with metabolic risk. CONCLUSIONS: Carriers of fragile X premutation are at increased metabolic risk from early adulthood; waist circumference, glucose and lipid levels are particularly elevated. We recommend metabolic screening for all women with FMR1 premutation, to enable early interventions for prevention of long-term cardiovascular comorbidities.

Two consecutive pregnancies in a patient with premature ovarian insufficiency in the course of classic galactosemia and a review of the literature.

AIM: To present a case report of a patient with classic galactosemia and the Q188R/K285N GALT mutation, who conceived spontaneously twice despite severe ovarian failure. A review of the literature is included. MATERIALS AND METHODS: A 20-year-old patient with classic galactosemia and premature ovarian insufficiency (POI) came to our attention. We performed a routine hormonal and ultrasound examination confirming low ovarian reserve. Due to low rates of pregnancies in individuals with POI (5%-10%), we were almost certain of the infeasibility of pregnancy. RESULTS: Surprisingly, several months after hospitalization, the patient conceived without any medical intervention and less than a year after the first birth she became pregnant again. While reviewing the literature, 90 pregnancies among galactosemic patients were identified. CONCLUSIONS: Ovarian failure is a long-term diet-independent complication of classic galactosemia, pertaining to about 90% of affected individuals. This case confirms its unpredicted course, as even the presence of unfavorable factors (absence of spontaneous puberty, early diagnosis of POI, undetectable AMH) may not preclude the chance for conception.

Whole-exome sequencing reveals new potential genes and variants in patients with premature ovarian insufficiency.

PURPOSE: Premature ovarian insufficiency (POI) is a heterogeneous disorder characterized by the cessation of menstrual cycles before the age of 40 years due to the depletion or dysfunction of the ovarian follicles. POI is a highly heterogeneous disease in terms of etiology. The aim of this study is to reveal the genetic etiology in POI patients. METHODS: A total of 35 patients (mean age: 27.2 years) from 28 different families diagnosed with POI were included in the study. Karyotype, FMR1 premutation analysis, single nucleotide polymorphism (SNP) array, and whole-exome sequencing (WES) were conducted to determine the genetic etiology of patients. RESULTS: A total of 35 patients with POI were first evaluated by karyotype analysis, and chromosomal anomaly was detected in three (8.5%) and FMR1 premutation was detected in six patients (17%) from two different families. A total of 29 patients without FMR1 premutation were included in the SNP array analysis, and one patient had a 337-kb deletion in the chromosome 6q26 region including PARK2 gene, which was thought to be associated with POI. Twenty-nine cases included in SNP array analysis were evaluated simultaneously with WES analysis, and genetic variant was detected in 55.1% (16/29). CONCLUSION: In the present study, rare novel variants were identified in genes known to be associated with POI, which contribute to the mutation spectrum. The effects of detected novel genes and variations on different pathways such as gonadal development, meiosis and DNA repair, or metabolism need to be investigated by experimental studies. Molecular etiology allows accurate genetic counseling to the patient and family as well as fertility planning.

Premature ovarian insufficiency. / Prematur ovarialinsuffisiens.

Premature ovarian insufficiency is a complex condition with a heterogenous aetiology, and is defined as loss of ovarian function before the age of 40. Early diagnosis and initiation of hormone replacement therapy is essential to alleviate symptoms and prevent later complications as a result of premature oestrogen deficiency. In this clinical review article we present an update on the diagnostics and treatment of the condition.

A novel PPRC1 point mutation in a Chinese family with premature ovarian failure: A case study.

BACKGROUND: Patients with premature ovarian failure (POF) have an at least 6-month history of amenorrhea and elevated follicle-stimulating hormone levels in plasma. Most of the POF causes are idiopathic and hereditary, and chromosomal abnormalities have been associated with POF development. A pedigree study was performed on a family with idiopathic POF to observe the possible link between gene mutation and POF development. METHODS: In total, eight women were diagnosed with POF and seven POF patients and five non-POF members from the same family were evaluated by whole exome sequencing and Sanger sequencing. An apoptotic assay, senescence staining, real-time polymerase chain reaction (qPCR) and overexpression of the peroxisome proliferator-activated receptor gamma coactivator-related 1 (PPRC1) gene were performed to examine the association of POF in vitro. RESULTS: Through whole exome sequencing and Sanger sequencing, a novel point mutation (NM_015062: c.2902C>T:p.Thr958Ile) was identified and verified in the PPRC1 gene on chromosome 10 (10q24.32). The point mutation only presented in all the seven POF cases and not in non-POF cases or public databases. Subsequent expression of PPRC1 in COV434 granulosa cells showed that PPRC1 might be involved in regulating granulosa cell apoptosis but not senescence-associated POF development. CONCLUSIONS: A novel point mutation in the PPRC1 gene was identified by the pedigree study and by sequence analysis of the case series with idiopathic POF in the present study. The subsequent PPRC1 expression analysis showed that PPRC1 was not involved in senescence-associated POF development. Further studies will be needed to confirm the link between PPRC1 gene mutation and POF.

A novel POF1B variant in a Chinese patient is associated with premature ovarian failure.

A novel mutation of POF1B was identified in a patient with premature ovarian failure.

New insights into the diagnosis and management of bone health in premature ovarian insufficiency.

Premature ovarian insufficiency (POI), defined as a loss of ovarian function before the age of 40 years, is a life-changing diagnosis that has numerous long-term consequences. Musculoskeletal complications, including osteoporosis and fractures, are a key concern for women with POI. The risk of bone loss is influenced by the underlying etiology of POI, and the degree and duration of estrogen deficiency. A decline in muscle mass as a result of estrogen and androgen deficiency may contribute to skeletal fragility, but has not been examined in women with POI. This article aims to review musculoskeletal health in POI; summarize the traditional and novel modalities available to screen for skeletal fragility and muscle dysfunction; and provide updated evidence for available management strategies.