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Differentiated thyroid carcinoma is the most common endocrinological malignancy with an increasing incidence over the last 30 years, with women being more frequently affected. In indicated cases, total thyroidectomy followed by adjuvant radioiodine administration is performed, despite current trends towards less aggressive treatment. We would like to investigate the possible adverse effects of radioiodine (RAI) on ovarian function using a simple serum biomarker. Anti-Müllerian hormone (AMH) appears to be the best endocrine marker for assessing physiological age-related oocyte loss for healthy women. The aim of our ongoing prospective study is to determine serum AMH to estimate ovarian reserve for premenopausal women treated with RAI. Over the course of one year, 33 serum samples from women with thyroid cancer and 3 serum samples from healthy women were examined. AMH levels were compared before radioiodine treatment and at regular intervals after treatment. Mean of the AMH level was 5.4 ng/ml (n=33) prior to RAI. The average level of AMH decreased to 1.8 ng/ml in 4-6 months after treatment. In 22.2 % of patients AMH dropped to 0 ng/ml from a non-zero value. Thereafter, we observed an increase in AMH, the average value was 2.7 ng/ml in 8-12 months. We demonstrated a significant decrease in AMH shortly after radioiodine treatment and a subsequent trend of increase at one year after treatment. Consequently, predicting the adverse effects of radioiodine by assessing a serum biomarker could help to select an appropriate treatment strategy for young women planning pregnancy.

Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are monospecialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo-pituitary disorders, whether organic or functional., (© 2024 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.)

Premature ovarian insufficiency (POI) is a cause of infertility and endocrine dysfunction in women, defined by loss of normal, predictable ovarian activity before the age of 40 years. POI is clinically characterized by amenorrhoea (primary or secondary) with raised circulating levels of follicle-stimulating hormone. This condition can occur due to medical interventions such as ovarian surgery or cytotoxic cancer therapy, metabolic and lysosomal storage diseases, infections, chromosomal anomalies and autoimmune diseases. At least 1 in 100 women is affected by POI, including 1 in 1,000 before the age of 30 years. Substantial evidence suggests a genetic basis to POI. However, the cause of idiopathic POI remains unknown in most patients, indicating that gene variants associated with this condition remain to be discovered. Over the past 10 years, tremendous progress has been made in our knowledge of genes involved in POI. Genetic approaches in diagnosis are important as they enable patients with familial POI to be identified, with the opportunity for oocyte preservation. Moreover, genetic approaches could provide a better understanding of disease mechanisms, which will ultimately aid the development of improved treatments., (© 2024. Springer Nature Limited.)

This article is a summary of normal menstrual bleeding and how to recognize abnormalities based on patient's symptoms as well as identify possible causes in order to direct treatment. This article discusses abnormal uterine bleeding including the definition, etiology, evaluation, and treatment. It also discusses primary ovarian insufficiency, transgender medicine, and menopause., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

Premature Ovarian Insufficiency (POI), also known as Premature Ovarian Failure (POF), is a heterogeneous disorder characterized by the cessation of ovarian function before age 40. Clinical symptoms include menstrual disorders: amenorrhea/oligomenorrhea or symptoms of estrogen deficiency. This review aims to provide the most important summary of the immunophenotypic profile of premature ovarian failure syndrome, along with a review of the latest reports on the usefulness of inflammatory markers. The inflammatory microenvironment in POI applies to many levels. Concomitants of autoimmune ovarian inflammation and impaired cellular immune response may be a picture of impaired regulation in autoimmune ovarian disease. The serum concentration of pro-inflammatory cytokines, like IL-6, IL-8, IL-17, tumor necrosis factor α (TNF-α), and interferon-gamma (IFN-γ), tend to increase, whereas levels of the anti-inflammatory cytokine, IL-10, tend to decrease. In our review, we focus on whether the measured immunological parameters could help in the diagnosis and prognosis of the syndrome. Among the inflammatory markers, neutrophil-to-lymphocyte ratio (NLR) is noteworthy, as it is decreased in patients with POI. It is important to stress that besides case series, we need properly powered studies with randomization to answer which treatment is effective, and how to deal with concurrent autoimmunity. In this review, we emphasize the importance of the premature ovarian failure syndrome immunoprofile for a proper understanding of the complexity of this syndrome, potential diagnostic points, and therapeutic targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this work paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Premature ovarian failure (POF), which is often comorbid with dry eye disease (DED) is a key issue affecting female health. Here, we explored the mechanism underlying comorbid POF and DED to further elucidate disease mechanisms and improve treatment. Datasets related to POF (GSE39501) and DED (GSE44101) were identified from the Gene Expression Omnibus (GEO) database and subjected to weighted gene coexpression network (WGCNA) and differentially expressed genes (DEGs) analyses, respectively, with the intersection used to obtain 158 genes comorbid in POF and DED. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses of comorbid genes revealed that identified genes were primarily related to DNA replication and Cell cycle, respectively. Protein-Protein interaction (PPI) network analysis of comorbid genes obtained the 15 hub genes: CDC20, BIRC5, PLK1, TOP2A, MCM5, MCM6, MCM7, MCM2, CENPA, FOXM1, GINS1, TIPIN, MAD2L1, and CDCA3. To validate the analysis results, additional POF- and DED-related datasets (GSE48873 and GSE171043, respectively) were selected. miRNAs-lncRNAs-genes network and machine learning methods were used to further analysis comorbid genes. The DGIdb database identified valdecoxib, amorfrutin A, and kaempferitrin as potential drugs. Herein, the comorbid genes of POF and DED were identified from a bioinformatics perspective, providing a new strategy to explore the comorbidity mechanism, opening up a new direction for the diagnosis and treatment of comorbid POF and DED., (© 2024. The Author(s).)

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.

The prediction of menopause and premature ovarian insufficiency (POI) involves understanding the factors that contribute to the timing of these events. Menopause is a natural biological process marked by the cessation of menstrual periods, typically occurring around the age of 51. On the other hand, POI refers to the loss of ovarian function before the age of 40. Several factors have been used to predict menopause and POI such as age, antimüllerian hormone, inhibins and follicle-stimulating hormone serum levels, antral follicle counts, menstrual cycle length, and, recently, some genetic markers. It seems that age has the best predictive power and all the other ones are only adding in a very limited way to the prediction of menopause. Low levels of antimüllerian hormone in young women might indicate a greater risk for POI and could facilitate early diagnosis. It is, however, important to note that predicting the exact timing of menopause and POI is challenging, and individual variations are significant. Although these factors can provide some insights, they are not foolproof predictors. Advances in medical research and technology may lead to more accurate methods for predicting menopause and POI in the future., Competing Interests: Declaration of Interests J.S.E.L. reports grants from Ansh Labs, Webster, TX, USA; Ferring, Hoofddorp, NL; Dutch Heart Association, Utrecht, the Netherlands; Zon MW, Amsterdam, the Netherlands; Roche Diagnostics, Rothkreuz, Switzerland; and personal fees from Ferring, Hoofddorp, the Netherlands; Titus Healthcare, Hoofddorp, the Netherlands; Gedeon Richter, Groot-Bijgaarden, Belgium; and is an unpaid board member and president of the AE-PCOS Society, outside the submitted work. Y.V.L. has nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Childhood cancer survivors are at risk for premature ovarian insufficiency, especially after treatment with alkylating agents. The objective of this report is to highlight a case in which this phenomenon caused a false-positive pregnancy test., Case Presentation: A workup was performed in a 14-year-old girl with a positive pregnancy test. She was diagnosed with stage IV neuroblastoma of the left adrenal gland at the age of 4 years. She received extensive treatment, including alkylating agents, and had been diagnosed with premature ovarian insufficiency. An LH/hCG suppression test was performed using high dose 17 bèta-estradiol: hCG levels normalized., Conclusions: The pregnancy test was false-positive due to production of low amounts of hCG by the pituitary gland as a result of high LH concentrations following premature ovarian insufficiency. It may be helpful to perform the LH/hCG suppression test to prove pituitary origin of the hCG overproduction., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)

Competing Interests: Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: none.

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., Competing Interests: Declaration of interests MH declares salary funding from the Australian National Health and Medical Research Council, support for meeting attendance from the UK National Institute for Health and Care Excellence, and the following roles: principal investigator for a clinical trial of salpingectomy vs salpingo-oophorectomy for prevention of ovarian cancer (TUBA-WISP II); board member for Breastscreen Victoria; editor for the Cochrane Collaboration; recipient of a fellowship from the Lundbeck Foundation (2022-23); site investigator for a clinical trial of a non-hormonal agent (Q-122) for vasomotor symptoms in patients with breast cancer (QUE Oncology, 2020-22); and site investigator for a clinical trial of a medical device for treating vaginal dryness (Madorra). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Purpose: To investigate the skeletal phenotype of adolescent girls with premature ovarian insufficiency (POI)., Methods: Data are presented from two adolescent girls who participated in a clinical research protocol to evaluate axial bone mineral density (BMD) (via dual-energy x-ray absorptiometry, DXA) and appendicular bone density, microarchitecture, and strength (via high-resolution peripheral quantitative computed tomography, HRpQCT). Anthropometric data were also obtained, and pubertal staging was performed by a clinician., Results: Both cases presented with an undetectable estradiol concentration and an elevated follicle stimulating hormone (FSH), meeting the criteria for POI. Each also received alkylating agents as part of their chemotherapy and radiotherapy, but in different locations as one presented with stage IV neuroblastoma and the other, metastatic medulloblastoma. Both had a low BMD of the axial and appendicular skeleton, as well as microarchitectural changes of the latter. The low BMD Z-score (<-2.0) seen when interpreting their DXA measurements for chronological age improved when adjusted for short stature, but it was not normalized. Lastly, most variables obtained by HRpQCT were abnormal for each participant, indicating that appendicular bone structure and strength were compromised., Conclusions: Chemotherapy and radiation affect growth, puberty, and bone accrual deleteriously. However, as these cases show, POI in an adolescent is not always classic primary ovarian insufficiency. Adolescents with brain cancer can present with signs of estrogen deficiency but may not be able to secrete FSH to the extent of elevation typically seen in long-term cancer survivors. Estrogen deficiency is almost universally present in either clinical setting and prompt recognition facilitates early provision of hormone replacement therapy that may then allow for a resumption of bone accrual as an adolescent approaches her peak bone mass., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Premature ovarian insufficiency (POI) is a condition in which there is a decline in ovarian function in women who are younger than 40 years resulting in a hypo-oestrogenic state with elevated gonadotrophins and oligomenorrhoea/amenorrhoea. This leads to short term complications of menopausal symptoms and long-term effects on bone and cardiovascular health, cognition as well as the impact of reduced fertility and sexual function associated with this condition. It is managed by sex steroid replacement either with HRT or combined hormonal contraception until the age of natural menopause (51) and this can provide a beneficial role with both symptom control and minimising the long-term adverse effects associated with this condition. Women who undergo a menopause between 40 and 45 years are deemed to have an "early menopause". The limited data available for this group suggest that they also have an increased morbidity if not adequately treated with hormone therapy. As such, women who have an early menopause should be managed in a similar way to those with POI, with the recommendation that they should take HRT at least until the natural age of menopause. This is the same for induced menopause that is caused by medical or surgical treatment that impacts the ovaries. It is important to ensure early diagnosis and access to specialist care to help support and manage these patients to reduce the symptoms and risks of long-term complications. This review looks at the diagnosis, causes, short and long-term complications and management of POI, early and induced menopause., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Premature ovarian insufficiency (POI) is extremely rare in the early stage of undifferentiated connective tissue disease. Patients with POI find it difficult to achieve successful pregnancy and delivery., Case Presentation: A 27-year-old female visited an outpatient department for premature ovarian insufficiency (POI) and infertility. She had regular menstrual periods since she was 14 years old and had no history of systemic disease. Laboratory tests showed low estrogen (15 ng/L, range 19.6-144.2 ng/L), elevated follicle-stimulating hormone (34 U/L), low anti-Mullerian hormone (0.1 μg/L), normal prolactin (11.48 ng/mL), and thyroid stimulating hormone (TSH) levels (0.97 mU/L). She demonstrated smaller bilateral ovarian volume and positivity to antinuclear and antiphospholipid antibodies. After the failure of conventional drug therapy and in vitro fertilization, the patient became pregnant naturally after treatment with glucocorticoids., Conclusion: Immunosuppression could help improve ovarian function and pregnancy outcomes in POI patients, but the therapeutic mechanisms are not clear and should be elucidated with more clinical studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Primary ovarian insufficiency (sometimes known as premature ovarian insufficiency) is a result of loss of ovarian follicular activity before the age of 40 years. It is an endocrine deficiency state in women, characterized by premature estrogen deprivation. In the absence of estrogen replacement, women experience bothersome menopause symptoms and a predisposition to accelerated aging and multimorbidity accumulation. Unless a true contraindication exists, estrogen therapy is recommended at least until the age of natural menopause. This Practice Pearl summarizes the clinical manifestations, diagnostic evaluation, and management of primary ovarian insufficiency., (Copyright © 2023 by The Menopause Society.)

Background: The metabolic characteristics of premature ovarian insufficiency (POI), a reproductive endocrine disease characterized by abnormal sex hormone metabolism and follicle depletion, remain unclear. Metabolomics is a powerful tool for exploring disease phenotypes and biomarkers. This study aims to identify metabolic markers and construct diagnostic models, and elucidate the underlying pathological mechanisms for POI., Methods: Non-targeted metabolomics was utilized to characterize the plasma metabolic profile of 40 patients. The metabolic markers were identified through bioinformatics and machine learning, and constructed an optimal diagnostic model by classified multi-model analysis. Enzyme-linked immunosorbent assay (ELISA) was used to verify antioxidant indexes, mitochondrial enzyme complexes, and ATP levels. Finally, integrated transcriptomics and metabolomics were used to reveal the dysregulated pathways and molecular regulatory mechanisms of POI., Results: The study identified eight metabolic markers significantly correlated with ovarian reserve function. The XGBoost diagnostic model was developed based on six machine learning models, demonstrating its robust diagnostic performance and clinical applicability through the evaluation of receiver operating characteristic (ROC) curve, decision curve analysis (DCA), calibration curve, and precise recall (PR) curve. Multi-omics analysis showed that mitochondrial respiratory chain electron carrier (CoQ10) and enzyme complex subunits were down-regulated in POI. ELISA validation revealed an elevation in oxidative stress markers and a reduction in the activities of antioxidant enzymes, CoQ10, and mitochondrial enzyme complexes in POI., Conclusion: Our findings highlight that mitochondrial dysfunction and energy metabolism disorders are closely related to the pathogenesis of POI. The identification of metabolic markers and predictive models holds significant implications for the diagnosis, treatment, and monitoring of POI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yu, Peng, Li, Fu, Wang, Ding, Li and Wu.)

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.

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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.

Competing Interests: Competing interests: Marie Christakis and Lindsay Shirreff sit on the medical advisory board of the Menopause Foundation of Canada. No other competing interests were declared.

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., (© 2023. The Author(s).)

Premature ovarian insufficiency (POI) is defined as loss of ovarian function in women less-than 40 years. This review summarises the causes and the possible treatment options. POI can be idiopathic, caused by genetic, autoimmune, or metabolic disease, or be induced by cancer therapy or surgery. POI causes infertility, increased morbidity and mortality, and decreased quality of life. Hormonal replacement therapy (HRT) can alleviate symptoms of POI and should be initiated at diagnosis. The benefit of HRT outweighs the minor side effects in most cases and should be continued until age of natural menopause.

Premature ovarian insufficiency (POI) affects 1 in 100 women and is a leading cause of female infertility. There are over 80 genes in which variants can cause POI, with these explaining only a minority of cases. Whole exome sequencing (WES) can be a useful tool for POI patient management, allowing clinical care to be personalized to underlying cause. We performed WES to investigate two French sisters, whose only clinical complaint was POI. Surprisingly, they shared one known and one novel likely pathogenic variant in the Perrault syndrome gene, LARS2. Using amino-acylation studies, we established that the novel missense variant significantly impairs LARS2 function. Perrault syndrome is characterized by sensorineural hearing loss in addition to POI. This molecular diagnosis alerted the sisters to the significance of their difficulty in following conversation. Subsequent audiology assessment revealed a mild bilateral hearing loss. We describe the first cases presenting with perceived isolated POI and causative variants in a Perrault syndrome gene. Our study expands the phenotypic spectrum associated with LARS2 variants and highlights the clinical benefit of having a genetic diagnosis, with prediction of potential co-morbidity and prompt and appropriate medical care, in this case by an audiologist for early detection of hearing loss., (© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.)

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., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Premature ovarian insufficiency (POI) is a common clinical disease of the reproductive system in which patients lose normal gonadal function prior to the age of 40. Common pathogenic factors include iatrogenic injury, genetics, inflammation, autoimmune, environmental and psychological factors. Patients with POI experience decreased estrogen secretion levels, ovulation disorder and infertility. POI appears frequently in clinical practice and the burden of the disease is heavy; however, the detailed pathological mechanism requires further experimental evaluation. Furthermore, there is a lack of effective treatment options. Certain causes of the pathogenesis of POI can be explained by epigenetic changes. Front fork transcription factor 3 (FOXO3) is a member of the forkhead box family of transcription factors. FOXO3 was initially considered to affect insulin/insulin growth factor signal transduction. However, the target gene range of FOXO3 includes numerous genes that affect metabolism and protein stability and are associated with aging. There is an association between decreased FOXO3 expression levels and POI. In the present review article, the role of FOXO3 in POI was evaluated, which emphasized the importance of this protein in the investigation of this disease. Moreover, the present review evaluated the evidence for the potential targets and biomarkers of FOXO3 that may be used in the treatment and diagnosis of POI.

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Premature ovarian insufficiency (POI) is the loss of ovarian function before the age of 40 years and can be spontaneous or iatrogenic. It is an important cause of infertility, and the diagnosis should be considered in any woman presenting with oligo/amenorrhoea, even in the absence of menopausal symptoms suchas hot flushes., Objective: The aim of this article is to provide an overview of the diagnosis of POI and its management with respect to infertility., Discussion: Diagnostic criteria for POI are follicle-stimulating hormone levels >25 IU/L on two occasions at least one month apart following 4-6 months of oligo/amenorrhoea, with exclusion of secondary causes of amenorrhoea. Approximately 5% of women will have a spontaneous pregnancy after a POI diagnosis; however, most women with POI will require a donor oocyte/embryo for pregnancy. Some women may elect to adopt or live childfree. Fertility preservation should be considered for those at risk of POI.

Objective: To determine the familiality of primary ovarian insufficiency (POI) at population level through examination of multigenerational genealogical information linked to electronic medical records., Design: Case-control study., Setting: Not applicable., Patient(s): Women with POI were identified using International Classification of Disease 9 and 10 codes in electronic medical records (1995-2021) from 2 major health care systems in Utah and reviewed for accuracy. Cases were linked to genealogy information in the Utah Population Database (UPDB). All included POI cases (n = 396) were required to have genealogy information available for at least 3 generations of ancestors. The risk of POI in relatives was compared with population rates for POI matched by age, sex, and birthplace., Intervention(s): Not applicable., Main Outcome Measure(s): Relative risk of POI in first-, second-, and third-degree relatives., Result(s): We identified 396 validated cases of POI with an associated 2,132 first-degree relatives, 5,245 second-degree relatives, and 10,853 third-degree relatives. We found an increased risk of POI among the extended relatives of cases. Specifically, first-degree relatives demonstrated an 18-fold increased risk of POI compared with controls relative risk ([RR],18.52 95% confidence interval [CI], 10.12-31.07), second-degree relatives demonstrated a 4-fold increase (RR, 4.21; CI, 1.15-10.79), and third-degree relatives demonstrated a 2.7-fold increase (RR, 2.65; CI, 1.14-5.21])., Conclusion(s): This is the first population-based study to assess the familial clustering of POI. The data demonstrate excess familiality, familial clustering of POI in excess compared with matched population rates of disease, among first-, second-, and third-degree relatives. These findings support a genetic contribution to POI., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Premature ovarian failure (POF) is defined as amenorrhea lasting for more than 4 months before 40 years of age, which is accompanied by a serum follicle-stimulating hormone (FSH) concentration above 40 mlU/mL. POF can cause a series of symptoms associated with low estrogen levels, such as hot flushes, excessive sweating, and infertility. This study aimed to report three cases of POF that were treated successfully with Korean medicine., Case Representation: Three patients with POF were selected for inclusion in this study. The treatment regimen consisted of herbal medicines, electroacupuncture, moxibustion, and Hominis placental pharmacopuncture. The basic treatment period was 3 months, and follow-up was performed after menstrual recovery. Following treatment, all three patients resumed menstruation without any adverse events. One patient also conceived successfully., Conclusions: These case reports suggest that Korean medicine could be effective for treating POF. Further preclinical and clinical studies are needed to investigate the mechanism of action of herbal medicines and acupuncture in improving menstruation and FSH levels., (Copyright © 2022. Published by Elsevier Inc.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To explore the diagnostic value of serum anti-Mullerian hormone (AMH) for patients with premature ovarian insufficiency (POI) and premature ovarian failure (POF)., Methods: Totally, 125 women with menstrual disorder treated in the Obstetrics and Gynecology Department of Ningbo Women & Children Hospital between January 2020 and December 2021 were enrolled. Among them, based on the follicle-stimulating hormone (FSH) level, 54 patients (25 IU/L < FSH ≤ 40 IU/L) were assigned to the POI group, and 71 patients (FSH > 40 IU/L) were assigned to the POF group. In addition, 72 individuals who went physical examination in the hospital and showed normal menstrual cycle were selected as the control (CON) group. Serum AMH in each group was quantified via enzyme-linked immunosorbent assay (ELISA) and Beckman Coulter Access active immunoassay analyzer, and the levels of serum neutral hormones [luteinizing hormone (LH), FSH, as well as estradiol (E2)] in each group were detected through the electrochemiluminescence method. The difference between AMH level acquired by the latest automatic method and that acquired by the traditional manual ELISA was compared, and the correlation of serum AMH with sex hormones was analyzed. In addition, receiver-operating characteristic (ROC) curves were drawn for determining the diagnostic value of serum AHM for POI ad POF., Results: Beckman Coulter Access quantified AMH more accurately and fastly (Beckman Coulter Access: 35 minutes; manual quantification: 3-4 hours) and was more sensitive than ELISA, with a requirement to less serum. The levels of serum AMH and E2 in the POF group were 0.04 ± 0.10 ng/mL and 35.16 ± 53.06 ng/mL, respectively, which were notably lower than those in the POI group ((0.69 ± 1.46) ng/mL and (3.96 ± 2.82) ng/mL) and CON group ((76.31 ± 97.84) ng/mL and (113.19 ± 114.84) ng/mL). The LH and FSH levels in the POF group were 37.86 ± 19.44 IU/L and 75.05 ± 35.31 IU/L, which were higher than those in POI group ((22.66 ± 26.15) IU/L and (11.30 ± 17.05) IU/L) and the CON group ((29.81 ± 4.45) IU/L and (6.78 ± 3.45) IU/L) ( P < 0.05). The POI group showed a notably lower serum AMH level and notably higher LH and FSH levels than the CON group ( P < 0.05), and the POI group was similar to the CON group in the E2 level ( P > 0.05). Serum AMH showed a positive correlation with E2 ( r = 0.291, P < 0.05) and a negative association with both FSH ( r = -0.476, P < 0.05) and LH ( r = -0.143, P < 0.1). The optimal cut-off value of serum AMH in predicting POI was 0.83 ng/mL, and the corresponding sensitivity and specificity were 95.8% and 85.2%. The optimal cut-off of serum AMH in predicting POF was 0.075 ng/mL, and the corresponding sensitivity and specificity were 81.7% and 94.4%. The area under ROC curve (AUC) of serum AMH + FSH in the diagnosis of POF was close to 1., Conclusion: Beckman Coulter Access AMH test is the latest automatic electrochemiluminescence sandwich immunoassay, with higher sensitivity and reproducibility than traditional manual ELISA and with ability to produce repeatable results. With the decline of ovarian function, the serum AMH of POI patients decreases gradually, and the serum AMH of POF patients decreases obviously, so serum AMH level has great value in predicting POI and POF and can be used as a sensitive index for early diagnosis of the two. Serum AMH combined with FSH can lift the diagnostic efficiency of POF., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Yan Cai et al.)

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.

Context: Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers., Objective: We sought to identify and characterize patients affected by POI caused by pathogenic variants in genes involved in DNA damage response during meiosis., Setting: Study subjects were recruited at academic centers., Patients or Other Participants: Individuals with a diagnosis of POI and their family members were enrolled for genetic analysis. Clinical findings, family history, and peripheral blood samples were collected., Research Design: Exome sequencing was performed on the study participants and their family members (when available). Protein conservation analysis and in silico modeling were used to obtain the structural model of the detected variants in the ZSWIM7 gene., Main Outcome Measure(s): Rare deleterious variants in known and candidate genes associated with POI., Results: Homozygous deleterious variants in the ZSWIM7 gene were identified in 2 unrelated patients with amenorrhea, an absence of puberty, and prepubertal ovaries and uterus. Observed variants were shown to alter the ZSWIM7 DNA-binding region, possibly affecting its function., Conclusions: Our study highlights the pivotal role of the ZSWIM7 gene involved in DNA damage response during meiosis on ovarian development and function. Characterization of patients with defects in DNA repair genes has important diagnostic and prognostic consequences for clinical management and reproductive decisions., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The natural lifespan of the ovary is occasionally interrupted by pathological processes; some are known, but many are unknown. Premature ovarian insufficiency (POI) can be a devastating diagnosis for an adolescent or for someone who has yet to start a family. Common causes of POI include genetic and chromosomal defects, autoimmune damage, and cancer treatments. Knowledge of the pathogenesis of this condition and an awareness of contemporary hormone replacement and fertility options are required to design a multidisciplinary therapeutic approach comprising reproductive medicine, endocrinology, clinical psychology, and assisted fertility expertise., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: To study the diagnostic yield, including variants in genes yet to be incriminated, of whole exome sequencing (WES) in familial cases of premature ovarian insufficiency (POI)., Design: Cross-sectional study., Setting: Endocrinology and reproductive medicine teaching hospital departments., Patients: Familial POI cases were recruited as part of a nationwide multicentric cohort. A total of 36 index cases in 36 different families were studied. Fifty-two relatives were available, including 25 with POI and 27 affected who were nonaffected. Karyotype analysis, FMR1 screening, single nucleotide polymorphism array analysis, and WES were performed in all subjects., Interventions: None., Main Outcome Measures: The primary outcome was a molecular etiology, as diagnosed by karyotype, FMR1 screening, single nucleotide polymorphism array, and WES., Results: A likely molecular etiology (pathogenic or likely pathogenic variant) was identified in 18 of 36 index cases (50% diagnostic yield). In 12 families, we found a pathogenic or likely pathogenic variant in a gene previously incriminated in POI, and in 6 families, we found a pathogenic or likely pathogenic variant in new candidate genes. Most of the variants identified were located in genes involved in cell division and meiosis (n = 11) or DNA repair (n = 4)., Conclusions: The genetic etiologic diagnosis in POI allows for genetic familial counseling, anticipated pregnancy planning, and ovarian tissue preservation or oocyte preservation. Identifying new genes may lead to future development of therapeutics in reproduction based on disrupted molecular pathways., Clinical Trial Registration Number: NCT 01177891., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to this work., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Menstrual cyclicity is a marker of health for reproductively mature women. Absent menses, or amenorrhea, is often the initial sign of pregnancy-an indication that the system is functioning appropriately and capable of generating the intended evolutionary outcome. Perturbations of menstrual regularity in the absence of pregnancy provide a marker for physiological or pathological disruption of this well-orchestrated process. New-onset amenorrhea with duration of 3 to 6 months should be promptly evaluated. Secondary amenorrhea can reflect structural or functional disturbances occurring from higher centers in the hypothalamus to the pituitary, the ovary, and finally, the uterus. Amenorrhea can also be a manifestation of systemic disorders resulting in compensatory inhibition of reproduction. Identifying the point of the breakdown is essential to restoring reproductive homeostasis to maintain future fertility and reestablish reproductive hormonal integrity. Among the most challenging disorders contributing to secondary amenorrhea is primary ovarian insufficiency (POI). This diagnosis stems from a number of possible etiologies, including autoimmune, genetic, metabolic, toxic, iatrogenic, and idiopathic, each with associated conditions and attendant medical concerns. The dual assaults of unanticipated compromised fertility concurrently with depletion of the normal reproductive hormonal milieu yield multiple management challenges. Fertility restoration is an area of active research, while optimal management of estrogen deficiency symptoms and the anticipated preventive benefits of hormone replacement for bone, cardiovascular, and neurocognitive health remain understudied. The state of the evidence for an optimal, individualized, clinical management approach to women with POI is discussed along with priorities for additional research in this population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.