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Objective: There are limited studies on urogenital symptoms in women who experience menopause before the age of 40 years due to primary ovarian insufficiency (POI) or bilateral oophorectomy (surgical POI). This study aimed to compare the urogenital symptoms, including sexuality, of women with POI to those without the condition., Methods: This cross-sectional study conducted was in seven Latin American countries, in which postmenopausal women (with POI and non-POI) were surveyed with a general questionnaire, the Menopause Rating Scale (MRS) and the six-item Female Sexual Function Index (FSFI-6). The association of premature menopause with more urogenital symptoms and lower sexual function was evaluated with logistic regression analysis., Results: Women with POI experience more urogenital symptoms (MRS urogenital score: 3.54 ± 3.16 vs. 3.15 ± 2.89, p  < 0.05) and have lower sexual function (total FSFI-6 score: 13.71 ± 7.55 vs. 14.77 ± 7.57 p  < 0.05) than women who experience menopause at a normal age range. There were no significant differences in symptoms when comparing women based on the type of POI (idiopathic or surgical). After adjusting for covariates, our logistic regression model determined that POI is associated with more urogenital symptoms (odds ratio [OR]: 1.38, 95% confidence interval [CI] 1.06-1.80) and lower sexual function (OR: 1.67, 95% CI 1.25-2.25)., Conclusion: POI, whether idiopathic or secondary to bilateral oophorectomy, is associated with symptoms that affect vaginal and sexual health.

Premature ovarian insufficiency (POI) is a rare condition characterized by loss of ovarian function before the age of 40. POI seems associated with mood disorders and sexual dysfunction. However, there is a lack of high-quality evidence relating to the impact of POI on sexual function. Therefore, we conducted a systematic review and meta-analysis to evaluate sexual function in women with POI compared to women without the condition. The following online databases were systematically searched up to January 2023: EMBASE, Medline (Ovid), Web of Science, Cochrane, PsychInfo, and Google Scholar. Random effects models were used for analyses, with data reported as Hedges' g and 95 % confidence interval, and the risk of heterogeneity was evaluated. The protocol of this study was registered with PROSPERO (CRD42023437203). A total of 10 studies were included in the systematic review and 5 studies involving 352 women with POI were included in the meta-analysis. Eight of the ten studies concluded that women with POI have reduced sexual function. An overall medium Hedges' g effect size of -0.72 was found (ranging between -0.20 and -1.29) in favor of control women, with moderate heterogeneity (I 2  = 64 %). Stratified studies of women on systemic hormone replacement therapy (HRT) showed an even higher Hedges' g effect size, of -0.82 (95 % CI -1.18, -0.47). In conclusion, sexual function in women with POI is reduced compared with control women. Sexual function should be discussed with women with POI and they should be offered psychosexual counseling., Competing Interests: Declaration of competing interest G. Jiskoot received an unrestricted research grant from the Waterloo Foundation and she received consultancy fees from Ferring. Y.V. Louwers received an internal research grant from the Erasmus MC (The Synergy grant) and she received fees from Ferring and Merck for presentations. J.L. reports grants from Ansh Labs, Webster, Tx, USA, from Ferring, Hoofddorp, NL, from Dutch Heart Association, Utrecht, NL, from Zon MW, Amsterdam, NL, from Roche Diagnostics, Rothkreuz, Switzerland and personal fees from Ferring, Hoofddorp, NL, from Titus Healthcare, Hoofddorp, NL, from Gedeon Richter, Groot-Bijgaarden, Belgium, and is an unpaid board member and president of the AE-PCOS Society, outside the submitted work. The author(s) 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 © 2024. Published by Elsevier B.V.)

Introduction: Premature menopause is a major complication of primary ovarian insufficiency (POI), and this loss is closely relates to bone mineral density (BMD). Previous research has indicated potential associations between BMD and POI. This study set out to provide the first systematic literature review and meta-analysison account of BMD content among women with POI., Methods: Studies including women with POI and controls were eligible from PubMed, Embase, Cochrane Library and Web of Science databases (from their inception to April 2022). Two reviewers independently evaluated study eligibility. The meta-analysis was performed using the DerSimonian and Laird random effects model., Results: Ten studies featuring 578 women with POI and 480 controls were selected. BMD content of femur neck (SMD:-0.76; 95 % CI: -1.20 to -0.31; P = 0.0008), the BMD content of nondominating forearm (SMD:-0.67; 95 % CI: -1.15 to -0.18; P = 0.007) were significantly decreased in women with POI. However, no differences were seen in other regions (lumbar spine, total hip, hipneck)., Discussion: The results of this study indicate that BMD content altered in patients with primary ovarian insufficiency. An implication of this is the possibility that hormone replacement therapy to minimize the prevalence of fracture morbidity and mortality associated with osteopenia in patients with POI., 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 © 2024. Published by Elsevier B.V.)

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.)

Purpose: Premature ovarian failure (POF) is the deterioration of normal ovarian function before the age of 40. In the presence of chemotherapy, radiation, genetic factors, autoimmune conditions, hypoandrogenemia, hypoestrogenemia and increased gonadotropin hormones, dry eye with early menopause findings may be encountered. The goal of our study is to compare the tear film alterations and meibomian gland status of patients diagnosed with POF at the time of diagnosis with healthy volunteers., Methods: In our study, 90 patients with POF and 60 control patients were evaluated. Complete ophthalmologic examinations of the patients, ocular surface disease index (OSDI) score, Oxford score for corneal and conjunctival involvement, Schirmer 1 and 2 tests, noninvasive tear break-up time (BUT), lower lid meibomian drop out grades with noncontact meibography, and meibomian gland distortion and shortening scores were compared between the two groups., Results: The mean age was 29.49±2.92 years in the patient group and 29.37±2.85 years in the control group (P=0.830). OSDI scores were statistically significant higher in the patient group (32.11±18.88) compared to the control group (12.93±14.92) (P<0.001). On Oxford scoring, there was a significant increase in the patient group (P<0.001). There was no significant difference between the groups in terms of Schirmer 1 and 2 tests (P=0.195, P=0.117). NIBUT was significantly lower in the patient group (11.93±4.59) compared to the control group (18.72±5.38) (P<0.001). While there was no difference between the groups in terms of lower lid meiboscores or meibomian gland length (P>0.005), there was a significant deterioration in the patient group in the distortion grading showing the morphological evaluation of the meibomian glands (p=0.037). In the ROC analysis, OSDI score (AUC=0.816, P<0.0001) and NIBUT (AUC=0.820, P<0.0001) parameters showed high specifity and sensitivity for the disease., Discussion: Ocular surface damage and dry eye symptoms are observed more frequently in patients with POF. We believe that hormonal insufficiency may cause deterioration in tear film composition, ocular surface damage with changes in tear homeostasis, and a change in the structure of the meibomian glands, starting with distortion at an early age., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background/aims: Among other risk factors, the decline in estrogen concentrations during menopause may compromise cognitive function. Whether early menopause (EM) is associated with an increased risk of dementia remains unclear. The purpose of this study was to systematically review and meta-analyze current evidence regarding the association between EM or premature ovarian insufficiency (POI) and the risk of dementia of any type., Materials and Methods: A comprehensive literature search was conducted through the PubMed, Scopus and CENTRAL databases up to August 2022. Study quality was assessed using the Newcastle-Ottawa scale. Associations were calculated as odds ratio (OR) with 95 % confidence interval (CI). The I 2 index was employed for heterogeneity., Results: Eleven studies (nine assessed as of good and two as of fair quality) were included in the meta-analysis (n = 4,716,862). Women with EM demonstrated a greater risk of dementia of any type than women of normal age at menopause (OR 1.37, 95 % CI 1.22-1.54; I 2 93%). However, after excluding a large retrospective cohort study, the results were altered (OR 1.07, 95 % CI 0.78-1.48; I 2 94%). Increased risk of dementia was also found in women with POI (OR 1.18, 95 % CI 1.15-1.21; I 2 0%). Subgroup analysis showed that this risk was mostly evident in cohort studies, and those which included women with natural menopause., Conclusions: Women with EM or POI may be at increased risk of dementia compared with women of normal age at menopause, but further research investigating that hypothesis is warranted., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Menopausal transition, resulting from a decline in estrogen concentrations, may compromise musculoskeletal health. However, it is unclear if early menopause (defined as age at menopause <45 years) and premature ovarian insufficiency (defined as age at menopause <40 years) are associated with increased risk of sarcopenia. The aim of this systematic review and meta-analysis was to synthesize studies evaluating the association between age at menopause and risk of sarcopenia., Methods: A comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to 31 December 2022. Data were expressed as standardized mean difference with 95 % confidence intervals. The I 2 index was employed to evaluate heterogeneity., Results: Six studies were included in the qualitative and quantitative analysis, with a total of 18,291 post-menopausal women. Compared with women of normal age at menopause (>45 years), women with early menopause demonstrated lower muscle mass, assessed by appendicular skeletal muscle mass/body mass index [standardized mean difference (SMD) -0.14, 95 % confidence interval (CI) -0.20 to -0.07, p < 0.001; I 2 0%]. However, no differences in muscle strength, assessed by handgrip strength (SMD -0.15, 95 % CI -0.31 to 0.01, p = 0.071; I 2 72%), and muscle performance, assessed by gait speed (SMD -0.11, 95 % CI -0.29 to 0.05, p = 0.18; I 2 79%), were found. Women with premature ovarian insufficiency had lower handgrip strength (SMD -0.3, 95 % CI -0.58 to -0.01, p = 0.04; I 2 74.6 %) and gait speed (SMD -0.13, 95 % CI -0.23 to -0.04, p = 0.004; I 2 0%) compared with women of normal age at menopause., Conclusion: Early menopause is associated with reduced muscle mass and premature ovarian insufficiency with reduced muscle strength and performance compared with normal age at menopause., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P = 1.59 × 10 -6 ) and SOHLH2 (3.48 years earlier menopause, P = 1.03 × 10 -4 ). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: The diagnosis of premature ovarian insufficiency (POI) is a traumatic event for many patients that involves poor fertility prognosis. After such diagnosis, spontaneous pregnancies are rare. The alternatives for building a family are oocyte donation, embryo donation, and adoption. However, we have few information on how many women with POI finally built a family after the diagnosis and which alternative they chose., Design: We performed a cross-sectional, descriptive study., Methods: We conducted a survey of all the women who consulted for POI in the department of endocrinology and reproductive medicine at la Pitié Salpêtrière between May 31, 1991, and January 12, 2021. We included patients who continued to be followed up regularly by our department or were contacted by mail or phone between June and September 2021. We excluded patients with Turner syndrome and POI secondary to oncological treatment and patients under 18 at the time of the survey., Results: 985 patients were referred to the department for POI, and 324 patients were finally analyzed. 41% of the women who wanted to build a family had children after the diagnosis: 53.9% by oocyte donation, 1 woman by embryo donation, 5.6% after ovarian stimulation, 13.5% by adoption, and 25.8% who had spontaneous pregnancy after a mean time of 2.5 years. Spontaneous pregnancy rate was 8.6% in the whole cohort., Conclusions: Having children after a diagnosis of POI is not uncommon but more often results from oocyte donation. This study will provide enlightened information for newly diagnosed women on the possibilities to build a family after POI diagnosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology.)

Objective: Menopausal transition has been known to be associated with the loss of muscle mass. However, muscle health in women with premature menopause, that is, premature ovarian insufficiency (POI), remains unclear. We aimed to investigate and compare muscle mass parameters and the prevalence of low muscle mass between patients with spontaneous POI and healthy controls., Methods: In this cross-sectional study, 59 women with spontaneous POI and 57 premenopausal controls with normal ovarian function were enrolled at the Women's Hospital, Zhejiang University School of Medicine (Hangzhou, China) from June 17, 2020, to August 20, 2021. Muscle mass parameters were measured by dual-energy x-ray absorptiometry, and low muscle mass was diagnosed using the Asian Working Group for Sarcopenia criteria. In addition, participants provided their sociodemographic data, menstrual and reproductive history, lifestyle factors, and medical history. Multivariate linear regression analysis was conducted., Results: Muscle mass parameters, including appendicular skeletal muscle mass (ASM), ASM/height2, ASM/weight, ASM/body mass index, total skeletal muscle mass (TSM), and TSM/weight, were significantly lower in women with POI as compared with healthy controls (ASM: 14.62 ± 2.08 vs 15.97 ± 1.78, P < 0.001; ASM/height2: 5.71 ± 0.64 vs 6.15 ± 0.62, P < 0.001; ASM/weight: 0.27 [0.25, 0.28] vs 0.28 [0.27, 0.29], P = 0.002; ASM/BMI: 0.68 ± 0.07 vs 0.73 ± 0.06, P = 0.001; TSM: 33.85 ± 4.08 vs 36.43 ± 3.56, P < 0.001; TSM/weight: 0.63 [0.59, 0.65] vs 0.64 [0.61, 0.67], P = 0.02). The prevalence of low muscle mass in POI patients was significantly higher than that in controls (32.20% vs 8.77%, χ2 = 9.70, P = 0.002). Furthermore, multivariate linear regression analyses demonstrated that POI status was an independent risk factor for ASM (β = -1.13; 95% CI, -1.62 to -0.65), ASM/height2 (-0.35, -0.47 to -0.22), ASM/weight (-0.01, -0.02 to -0.009), ASM/BMI (-0.05, -0.07 to -0.02), TSM (-2.16, -3.14 to -1.17), and TSM/weight (-0.03, -0.04 to -0.02)., Conclusions: Women with POI exhibit significant loss of muscle mass as compared with healthy controls. Early diagnosis and long-term health management in POI patients are important., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2022 by The North American Menopause Society.)

Turner syndrome (TS), a common chromosomal abnormality affecting females, is associated with partial or complete loss of the second sex chromosome. Although the classic karyotype is 45, X, the detection of mosaic TS is increasing. TS is a multi-system disorder with significant endocrine, cardiovascular and reproductive impacts. Accelerated ovarian follicular loss leads to primary amenorrhoea or premature ovarian insufficiency and infertility. Early diagnosis and counselling regarding hormone replacement therapy and future reproductive capacity, including fertility preservation, are essential to improve reproductive outcomes. Pubertal induction or estrogen replacement is usually required to optimise long-term health outcomes; however, initiation may be delayed due to delayed diagnosis. Spontaneous pregnancy occurs in a small number of women; however, many require donor oocytes and assisted reproductive technology to achieve a pregnancy. Pregnancy is a high risk especially when associated with congenital heart disease. Prepregnancy counselling by the multidisciplinary team (MDT) to identify contraindications and optimise pre-existing health issues is essential. Pregnancy management should be led by a maternal-fetal medicine unit with input from the MDT. This review examines reproductive health outcomes in women with TS and how best to manage them to reduce health risks and improve maternal and neonatal outcomes., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Premature ovarian insufficiency (POI) appears to be associated with depressive and anxiety symptoms. However, there is a lack of high-quality evidence relating to the risk of patients with POI developing depression or anxiety. Therefore, we conducted a systematic review and meta-analysis to quantify the risk of depressive and anxiety symptoms in women with POI. We searched English and Chinese databases to evaluate the risk of depression and anxiety disorders in patients with POI. The final search date was November 2021. The risk was quantified using meta-analysis, with an estimation of pooled odds ratio (OR) and 95% confidence interval (CI). Sources of heterogeneity were explored by subgroup analysis. A total of seven primary studies with 1316 individuals were included, five of which were related to depression and six to anxiety disorders. All included articles were case-control studies of high quality. Patients with POI were associated with a higher odds of depression and anxiety (depression: OR = 3.33, 95% CI = 2.31-4.81, P < 0.001; anxiety: OR = 4.89, 95% CI = 3.28-7.30, P < 0.001). Subgroup analysis also indicated that patients with POI are at a higher risk of anxiety and depression. POI appears to be associated with a high risk of depression and anxiety. Early psychosocial assessment and regular screening of patients with POI are also necessary. In addition, it is important to consider the mental health of patients with POI., (© 2023. The Author(s).)

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.

Premature ovarian failure (POF, POI - premature ovarian insufficiency) is a serious situation for a woman with reproductive plans that more or less precludes having her own bio-logical child. In addition to the lack of functional oocytes in the ovaries, it is also a premature lack of sex hormones, which has an overall negative effect on health. The article guides us through care both in the clinic of the gynecologist and through treatment in the center of reproductive medicine. The dia-gnosis and treatment of POF illustrates some endocrinological principles and connections.

Purpose: To assess sleep disturbances, levels of anxiety, depression and fatigue in women with premature ovarian insufficiency (POI)., Materials and Methods: The study included 62 women with POI and 62 age-matched controls. Women in both groups completed questionnaires. Pittsburgh Sleep Quality Index, Insomnia severity index, Epworth Sleepiness Scale, Hospital Anxiety and Depression Scale and Fatigue Severity Scale were used., Results: We found poor sleep quality, higher levels of insomnia in women with POI than in controls. Depression was much more prevalent and severe in POI women. Total anxiety score, the severity of anxiety and fatigue did not differ significantly between the groups. According to the multivariable logistic regression analysis, being married and having POI were associated with worse quality of sleep, and having more children was associated with an increase in depression levels in the whole cohort. Backward analysis showed that when POI status was taken as a reference, married women were at 6.5 fold increased risk of poor sleep quality., Conclusions: Women with premature ovarian failure are more likely to suffer from poor sleep quality, insomnia and depression than healthy women.

Primary ovarian insufficiency is characterized by accelerated loss of primordial follicles, which results in ovarian failure and concomitant menopause before age 40. About 1-3% of females in the general population are diagnosed with POI; however, greater than 80% of females with the inherited disease Classic Galactosemia will develop POI. Classic Galactosemia is caused by mutations in the GALT gene encoding the enzyme galactose-1 phosphate uridylyltransferase. While dietary restriction of galactose is lifesaving in the neonatal period, the development of complications including primary ovarian insufficiency is not mitigated. Additionally, the pattern(s) of follicle loss have not been completely characterized. The chronic accumulation of aberrant metabolites such as galactose-1-phosphate and galactitol are suspected culprits in the development of the sequelae, yet the mechanisms remain elusive.Our group uses a GalT gene-trapped mouse model to study the pathophysiology of primary ovarian insufficiency in Classic Galactosemia. We recently showed that differences in the Integrated Stress Response pathway occur in mutant ovaries that likely contribute to their primary ovarian insufficiency phenotype. Using immunofluorescent staining of histological sections of ovaries at progressive ages, we saw evidence of altered Integrated Stress Response activity in granulosa cells and primordial oocytes consistent with accelerated primordial follicle growth activation, aberrant DNA damage and/or repair, and increased cellular stress/death. Overall, our findings indicate that abnormal Integrated Stress Response in the Classic Galactosemia model ovary results in accelerated primordial follicle growth activation, sometimes referred to as "burnout." These aberrant early events help further clarify when/how the primary ovarian insufficiency phenotype arises under galactosemic conditions., (© 2022. The Author(s).)

Objective: To evaluate the association between premature ovarian insufficiency (POI) and mortality., Materials and Methods: This was a secondary analysis of a long-term cohort of Chilean women who received preventive health care between 1990 and 1993. The exposure variable was POI and the outcome was death, and follow-up time was 30 years. Patient data were extracted from medical records. Data related to deaths were obtained from the records of the official government registry as of January 2021. Cox regression proportional hazard models were used to estimate crude and adjusted hazard ratios (HR) and 95 % confidence intervals (CI)., Results: Data for a total of 1119 women were included in the analysis. Median age was 47 years (interquartile range: 44-52). The baseline prevalence of POI was 6.7 %. At the end of the follow-up, 34.7 % of women with POI had died, compared with 19.3 % of women without the condition (p < 0.001). A larger proportion of women with POI died from cardiovascular disease (12.0 % vs. 5.1 %; OR: 2.55, 95 % CI: 1.21-5.39) whereas there was no significant difference in cancer mortality (6.7 % vs. 7.7 %; OR: 0.86, 95 % CI: 0.34-2.19). In the adjusted Cox model, POI was among the main factors associated with mortality (hazard ratio [HR] 1.60, 95 % CI: 1.03-2.47), after diabetes (HR 2.51, 95 % CI: 1.40-4.51) and arterial hypertension (HR 1.75, 95 % CI: 1.29-2.37)., Conclusion: Although POI affects a small group of women, its association with mortality seems to be relevant; hence it is necessary to implement measures that reduce this risk., Competing Interests: The authors declare that they have no competing interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Purpose: Primary ovarian insufficiency (POI) has serious physical and psychological consequences due to estradiol deprivation, leading to increased morbidity and mortality. However, the causes of most POI cases remain unknown. Psychological stress, usually caused by stressful life events, is known to be negatively associated with ovarian function. It is important to explore high-frequency adverse life events among women with POI for future interventions., Methods: Forty-three women (mean age=33·8 years) were recruited who were newly- diagnosed with idiopathic POI (FSH levels >40 IU/L) to participate in semi-structured interviews through convenience sampling. The main questions covered by the topic guide were designed to explore adverse life events prior to POI diagnosis. Interviews were audio recorded, transcribed and analyzed thematically. Data were analyzed from June 2019 to August 2020., Results: Among the women with POI, mean age at diagnosis of POI was 33·8 years (range from 19 to 39 years), and the average time between the onset of irregular menstruation and POI diagnosis was 2.3 years. These women with POI had a relatively normal menstrual cycle before the diagnosis. A number of stressful life events prior to POI diagnosis were discussed by them as important factors influencing their health. Four core themes emerged: 1) persistent exposure to workplace stress, 2) persistent exposure to family-related adverse life events, 3) sleep problem/disturbance existed in women with POI before diagnosis, and 4) participants' general cognition and concerns about POI., Conclusions: Persistent exposures to adverse life events related to work stress, family stress and sleep problem existed in women with POI. Our findings are consistent with the hypothesis that adverse life events play a role in the development of POI. Future research should investigate how social environmental factors influence POI disease risks, and whether provision of tailored interventions (i.e. preventing or mitigating impact of adverse life events) aimed at high-risk populations may help prevent new POI cases and improve conditions of women with POI. We gained an in-depth understanding of the experiences of these women via 1:1 qualitative method, and find adverse life events are frequent in women with POI prior to the diagnosis., 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. The reviewer JZ declared a shared affiliation with the authors to the handling editor at the time of review., (Copyright © 2022 Sun, Fan, Guo, Pan, Zhang, Mao, Huang, Li, Gu, Wang, Zhang, Wang, Zhou, Li and Lai.)

Background: Fertility is thought to be not affected in women with systemic lupus erythematosus (SLE), however disease-related factors, psychosocial effects of chronic disease, as well as medications exposure might impair gonadal function., Objective: This systematic literature review (SLR) aimed to explore clinical, hormonal, serological and treatment factors associated with fertility outcomes in women of childbearing age with SLE., Methods: This SLR was conducted following the Preferred Reporting Items for systematic reviews and Meta-analysis (PRISMA) statement. All articles available in English (1972 - 30th April 2021) in Pubmed, EMBASE, Scopus and Cochrane Library were screened. Studies selection and data collection were performed by two independent reviewers. All data were extracted using a standardized template. The risk of bias of the included studies was assessed using the NIH risk-of-bias tool., Results: Of 789 abstracts evaluated, we included in this review 46 studies, of which 1 SLR, 16 cross-sectional studies, 18 cohort studies, 10 observational studies and 1 case-series, with data pertaining to 4704 patients (mean age 31.5 ± 3.7 years, disease duration 83.27 ± 38.3 months). Definitions of premature ovarian failure (POF) adopted in the studies varied in terms of the number of months of amenorrhea considered and the age of onset of amenorrhea. Clinical factors associated with the development of POF were older age at the time of initiation of therapy, and older age at the onset of SLE disease. Cyclophosphamide exposure (CYC) and its cumulative dose influenced gonadal function in SLE women, leading to amenorrhoea and POF, as reported in 19 studies. Mycophenolate, azathioprine, calcineurin inhibitors and steroids associated with a lower risk of POF compared to CYC. POF was less frequent in patients co-treated with CYC and gonadotropin-releasing hormone analogues (GnRH-a) compared with patients not receiving GnRH-a (risk ratio 0.28, 95%-CI [0.14; 0.55]). 11 studies evaluated the impact of damage accrual and disease activity on ovarian reserve with conflicting evidence. Finally, 18 studies investigated exposure to hormonal and serological factors and, among others, neither anti-Müllerian Hormone nor anti-corpus luteum antibodies were associated with POF., Conclusion: The strongest evidence regarding management factors associated with fertility in SLE women of childbearing age remains the treatment with CYC, as well as its cumulative dosage. Hormonal and serological factors appeared not to impact fertility outcomes, but they might be used as a surrogate of fertility, especially during the treatment with disease-specific drugs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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.)

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.

Objectives: 1) To assess the methodological quality of clinical practice guidelines (CPGs) associated with cardiovascular disease (CVD) in women with premature ovarian insufficiency (POI); 2) to formulate an algorithm to foster the implementation of guidelines by clinicians., Methods: A systematic search for CPGs in English and Chinese languages published between 2015 and 2020 was conducted. Assessment was conducted by two reviewers respectively via the Appraisal of Guidelines for Research and Evaluation II instrument. The interappraisal agreement was evaluated. Recommendations pertaining to the management of CVD in women with POI were extracted from high-score CPGs and developed into an algorithm, which was refined on the basis of expert feedback., Results: A total of 14 CPGs were included. Three CPGs were evaluated as "high quality," with five "average" and six considered "low quality." The consistency of agreement between reviewers was considered as substantial agreement to almost perfect agreement (0.72-0.90). The algorithm consisted of three categories: initial evaluation, management, and subsequent monitoring of CVD in POI. Only "management" had recommendations from all three high-quality CPGs., Conclusions: The overall methodological quality of most CPGs regarding CVD in women with POI is moderate to poor. A management algorithm with a clear implementation strategy was developed from high-scoring CPGs. Further research is needed to provide evidence-based health care in this field., Competing Interests: Financial disclosures/conflicts of interest: None reported., (Copyright © 2022 by The North American Menopause Society.)

Background: Primary ovarian insufficiency (POI) affects 1% of women and is associated with significant medical consequences. A genetic cause for POI can be found in up to 30% of women, elucidating key roles for these genes in human ovary development., Objective: We aimed to identify the genetic mechanism underlying early-onset POI in 2 sisters from a consanguineous pedigree., Methods: Genome sequencing and variant filtering using an autosomal recessive model was performed in the 2 affected sisters and their unaffected family members. Quantitative reverse transcriptase PCR (qRT-PCR) and RNA sequencing were used to study the expression of key genes at critical stages of human fetal gonad development (Carnegie Stage 22/23, 9 weeks post conception (wpc), 11 wpc, 15/16 wpc, 19/20 wpc) and in adult tissue., Results: Only 1 homozygous variant cosegregating with the POI phenotype was found: a single nucleotide substitution in zinc finger SWIM-type containing 7 (ZSWIM7), NM&#95;001042697.2: c.173C > G; resulting in predicted loss-of-function p.(Ser58*). qRT-PCR demonstrated higher expression of ZSWIM7 in the 15/16 wpc ovary compared with testis, corresponding to peak meiosis in the fetal ovary. RNA sequencing of fetal gonad samples showed that ZSWIM7 has a similar temporal expression profile in the developing ovary to other homologous recombination genes., Main Conclusions: Disruption of ZSWIM7 is associated with POI in humans. ZSWIM7 is likely to be important for human homologous recombination; these findings expand the range of genes associated with POI in women., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Dynein, axonemal, heavy chain 1 ( DNAH1 ) gene mutations have been found to be related to primary ciliary dyskinesia (PCD) and the DNAH1 gene is associated with abnormal flagellar morphology in spermatozoa. Infertility is a common condition in women presenting with primary ovarian insufficiency (POI) characterized by hypergonadotropic hypogonadism. The purpose of this study was to explore the clinical significance of genetic diagnostics in several Chinese primary infertile women with atypical POI. Methods: Four atypical POI patients and 100 healthy subjects were recruited, genetic pathogenicityc factors were investigated by whole exome sequencing (WES). Results: WES revealed a homozygous deletion mutation in the DNAH1 gene (NM&#95;015512.5; c.11726&#95;11727delCT, p.Pro3909Argfs*33) in one of the four POI patients. The 31-year-old affected woman presented with a normal menstrual cycle and elevated plasma levels of FSH, around the postmenopausal range, but had a normal antral follicle count and normal anti-Müllerian hormone levels. The patient, after two failed ovulation cycles, became pregnant in the third IVF cycle and delivered a healthy girl at term. Conclusions: The homozygous deletion mutation in the DNAH1 gene suggested that the patient might have a cilia movement disorder of the fallopian tubes, which is a known infertility factor. Moreover, the significantly elevated plasma level of FSH in this patient is likely one of the most important factors leading to her decreased fertility.

Postmenopausal women with ovary hormone deficiency (OHD) are subject to overactive bladder (OAB) symptoms. The present study attempted to elucidate whether low-intensity extracorporeal shock wave therapy (LiESWT) alters bladder angiogenesis, decreases inflammatory response, and ameliorates bladder hyperactivity to influence bladder function in OHD-induced OAB in human clinical trial and rat model. The ovariectomized (OVX) for 12 months Sprague-Dawley rat model mimicking the physiological condition of menopause was utilized to induce OAB and assess the potential therapeutic mechanism of LiESWT (0.12 mJ/mm 2 , 300 pulses, and 3 pulses/second). The randomized, single-blinded clinical trial was enrolled 58 participants to investigate the therapeutic efficacy of LiESWT (0.25 mJ/mm 2 , 3000 pulses, 3 pulses/second) on postmenopausal women with OAB. The results revealed that 8 weeks' LiESWT inhibited interstitial fibrosis, promoted cell proliferation, enhanced angiogenesis protein expression, and elevated the protein phosphorylation of ErK1/2, P38, and Akt, leading to decreased urinary frequency, nocturia, urgency, urgency incontinence, and post-voided residual urine volume, but increased voided urine volume and the maximal flow rate of postmenopausal participants. In conclusion, LiESWT attenuated inflammatory responses, increased angiogenesis, and promoted proliferation and differentiation, thereby improved OAB symptoms, thereafter promoting social activity and the quality of life of postmenopausal participants.

Infertility is a major health problem, and despite improved treatments over the years, there are still some conditions that cannot be treated successfully using a conventional approach. Therefore, new options are being considered and one of them is cell therapy using stem cells. Stem cell treatments for infertility can be divided into two major groups, the first one being direct transplantation of stem cells or their paracrine factors into reproductive organs and the second one being in vitro differentiation into germ cells or gametes. In animal models, all of these approaches were able to improve the reproductive potential of tested animals, although in humans there is still too little evidence to suggest successful use. The reasons for lack of evidence are unavailability of proper material, the complexity of explored biological processes, and ethical considerations. Despite all of the above-mentioned hurdles, researchers were able to show that in women, it seems to be possible to improve some conditions, but in men, no similar clinically important improvement was achieved. To conclude, the data presented in this review suggest that the treatment of infertility with stem cells seems plausible, because some types of treatments have already been tested in humans, achieving live births, while others show great potential only in animal studies, for now.

There is an increased risk of cardiovascular disease in women with premature ovarian insufficiency (POI). A relationship between cardiovascular disease and endocan levels has been shown. Endocan is a marker that is prominent in many diseases caused by endothelial dysfunction and can be measured in the blood. POI is also associated with endothelial dysfunction. The causes of POI include chromosomal and genetic defects, autoimmune processes, chemotherapy, radiation, infections and surgery, but many are unidentified (idiopathic). This study aimed to evaluate serum endocan levels in women with idiopathic POI. The blood for analysis was obtained at the early follicular phase of the menstrual cycle and endocan levels were measured using a commercially available enzyme-linked immunosorbent assay kit. There were 38 patients with idiopathic POI in the study group and 39 healthy subjects in the control group. The median ages of the women were not significantly different between the groups 34 [7] years vs. 34 [7] years, respectively ( p  = .862). The median endocan level was not different in the POI and control group 769 [727] vs. 1077 [403] pg/mL, respectively ( p  = .603). Endocan is not associated with the cardiovascular diseases risk linked with endothelial dysfunction in idiopathic POI. Clinical trial number: NCT03932877 (Clinicaltrials.gov)IMPACT STATEMENT What is already known on this subject? There is an increased risk of cardiovascular disease in premature ovarian insufficiency (POI) due to the decreased level of oestrogen, which is linked with endothelial dysfunction. What do the results of this study add? This study showed that endocan is not associated with the cardiovascular disease risk linked with endothelial dysfunction in idiopathic POI. What are the implications of these findings for clinical practice and/or further research? A marker to be used to predict the risk of cardiovascular disease in patients with POI could facilitate in improving the quality of life of these patients. Moreover, advantageous and easy-to-measure markers are needed in larger sample studies to better understand the cardiovascular diseases risk in POI.

Purpose: The current review aims to summarize the data available concerning the applicability of fertility preservation techniques to genetic conditions at risk of premature ovarian insufficiency (POI)., Methods: A literature review through the PubMed Database was carried out., Results: About 10% of cases of POI is related to genetic diseases. The most frequent conditions associated with POI are Turner syndrome and fragile X pre-mutation; mutation of BRCA 1-2 genes and several other mutations and genetic syndromes have recently been highlighted, although they rarely occur. If a diagnosis is issued before POI onset, counseling on currently available fertility preservation techniques is advisable. In case of spontaneous menarche (this can occur variably depending on the mutation) established techniques like embryo or oocyte cryopreservation can be proposed, even if, in some cases, their effectiveness may be reduced by ovarian alterations connected to the mutation. Ovarian tissue cryopreservation has recently been defined as an established medical procedure for fertility preservation in young cancer patients and may be an option for prepubertal patients. However, it is still experimental in special populations with genetic diseases causing POI. New innovative experimental techniques, like in vitro maturation of immature oocytes (IVM) and vitro activation (IVA) of immature follicles on ovarian tissue, have shown limited but encouraging data and they will be probably available in the near future. For a correct risk-benefit evaluation, the following aspects should be considered: actual knowledge about the pathology-specific efficacy of the various techniques, the average age of onset of POI, the possible risks associated with the procedure in relation to the underlying pathology, the probability of spontaneous conception, as well as the health implications of a possible future pregnancy.., Conclusions: Fertility preservation techniques represent a crucial opportunity for patients with genetic risk of POI. Early diagnosis increases the chances to apply these techniques. No specific recommendations concerning fertility preservation for each genetic pathology are available, and clinicians should first counsel the patient and her relatives about known risks and benefits of the available techniques, both those established and those considered as experimental.

Background: Mediated via the androgen receptor on granulosa cells, models of small growing follicle stages demonstrate dependence on testosterone. Androgen deficiency reduces ovarian response to follicle stimulation hormone (FSH), granulosa cell mass and estradiol (E2) production falls and FSH, therefore, rises. Though potentially of adrenal and/or ovarian origin, androgen deficiency in association with female infertility is almost universally primarily of adrenal origin, raising the possibility that women with presumptive diagnosis of primary ovarian insufficiency (POI), also called primary ovarian failure (POF) may actually suffer from secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism that leads to follicular arrest at small-growing follicle stages., Methods: This retrospective cohort study was performed in a private, academically affiliated infertility center in New York City. We searched the center's anonymized electronic research data bank for consecutive patients who presented with a diagnosis of POI, defined by age <41 year, FSH > 40.0 mIU/mL, amenorrhea for at least 6 month, and low testosterone (T), defined as total T (TT) in the lowest age-specific quartile of normal range. This study did not include patients with oophoritis. Since dehydroepiandrosterone sulfate (DHEAS) is the only androgen almost exclusively produce by adrenals, adrenal hypoandrogenism was defined by DHEAS < 100ug/dL. Thirteen of 78 presumed POI women (16.67%) qualified and represented the original study population. POI patients are usually treated with third-party egg donation; 6/13, however, rejected egg donation for personal or religious reasons and insisted on undergoing at least one last IVF cycle attempt (final study population). In preparation, they were supplemented with DHEA 25 mg TID and CoQ10 333 mg TID for at least 6 weeks prior to ovarian stimulation for IVF with FSH and human menopausal gonadotropins (hMG). Since POI patients are expected to be resistant to ovarian stimulation, primary outcome for the study was ovarian response, while secondary outcome was pregnancy/delivery., Results: Though POI/POF patients usually are completely unresponsive to ovarian stimulation, to our surprise, 5/6 (83.3%) patients demonstrated an objective follicle response. In addition, 2/6 (33.3%) conceived spontaneously between IVF cycles, while on DHEA and CoQ10 supplementation and delivered healthy offspring. One of those is currently in treatment for a second child., Conclusions: This preliminary report suggests that a surprising portion of young women below age 41, tagged with a diagnosis of POI/POF, due to adrenal hypoandrogenism actually suffer from a form of SOI, at least in some cases amenable to treatment by androgen supplementation. Since true POI/POF usually requires third-party egg donation, correct differentiation between POI and SOI in such women appears of great importance and may warrant a trial stimulation after androgen pre-supplementation for at least 6 weeks.

Alternative splicing (AS) contributes to gene diversification, but the AS program during germline development remains largely undefined. Here, we interrupted pre-mRNA splicing events controlled by epithelial splicing regulatory protein 1 (ESRP1) and found that it induced female infertility in mice. Esrp1 deletion perturbed spindle organization, chromosome alignment and metaphase-to-anaphase transformation in oocytes. The first polar body extrusion was blocked during oocyte meiosis owing to abnormal activation of spindle assembly checkpoint and insufficiency of anaphase-promoting complex/cyclosome in Esrp1 -knockout oocytes. Esrp1 -knockout hampered follicular development and ovulation; eventually, premature ovarian failure occurred in six-month-old Esrp1 -knockout mouse. Using single-cell RNA-seq analysis, 528 aberrant AS events of maternal mRNA transcripts were revealed and were preferentially associated with microtubule cytoskeletal organization. Notably, we found that loss of ESRP1 disturbed a comprehensive set of gene-splicing sites - including those within Trb53bp1 , Rac1 , Bora , Kif2c , Kif23 , Ndel1 , Kif3a , Cenpa and Lsm14b - that potentially caused abnormal spindle organization . Collectively, our findings provide the first report elucidating the ESRP1-mediated AS program of maternal mRNA transcripts, which may contribute to oocyte meiosis and female fertility in mice., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

The transcription factor p63 mediates distinct cellular responses, primarily regulating epithelial and oocyte biology. In addition to the two amino terminal isoforms, TAp63 and ΔNp63, the 3'-end of p63 mRNA undergoes tissue-specific alternative splicing that leads to several isoforms, including p63α, p63β and p63γ. To investigate in vivo how the different isoforms fulfil distinct functions at the cellular and developmental levels, we developed a mouse model replacing the p63α with p63β by deletion of exon 13 in the Trp63 gene. Here, we report that whereas in two organs physiologically expressing p63α, such as thymus and skin, no abnormalities are detected, total infertility is evident in heterozygous female mice. A sharp reduction in the number of primary oocytes during the first week after birth occurs as a consequence of the enhanced expression of the pro-apoptotic transcriptional targets Puma and Noxa by the tetrameric, constitutively active, TAp63β isoform. Hence, these mice show a condition of ovary dysfunction, resembling human primary ovary insufficiency. Our results show that the p63 C-terminus is essential in TAp63α-expressing primary oocytes to control cell death in vivo, expanding the current understanding of human primary ovarian insufficiency.

Introduction: Turner syndrome (TS) is associated with hypergonadotropic hypogonadism due to gonadal dysgenesis, which results in premature ovarian failure and subsequent infertility. Therefore, counseling and evaluation for fertility preservation are required as early as possible for women with TS., Case Presentation: A 23-year-old unmarried woman with mosaic TS (45, X [4/30] 46, XX [26/30]) presented to the pediatric department of our hospital for fertility counseling; she was accompanied by her mother. She was referred to the reproduction center of our hospital for ovarian reserve assessment and counseling regarding fertility preservation. We decided to retrieve oocytes using DuoStim as the controlled ovarian stimulation protocol. During the first and second oocyte retrievals, a total of 17 (9 and 8, respectively) mature metaphase II oocytes were cryopreserved., Conclusion: DuoStim may be a useful option for fertility preservation for women with TS and reduced ovarian reserve. This new strategy may obtain the required number of oocytes in the shortest time and preserve the future fertility of women with TS.

Aims: Premature ovarian failure (POF) is a phenomenon in which the ovaries fail before the age of 40 years. Prior research has used a wide range of mouse models designed to reflect different causes of POF, including genetic factors, iatrogenic factors, and immune factors. The current study employed a mouse model of POF induced by 4-vinylcyclohexene diepoxide (VCD). VCD can specifically kill primordial and primary ovarian follicles, which destroys the follicular reserve and causes POF. The current study sought to specify and extend the applications of this model by examining the effect of timing and VCD dose and by exploring the effect of the model on systems outside of the ovaries., Materials and Methods: A VCD-induced mouse model of POF was constructed using established methods (VCD injected continuously at a concentration of 160 mg/kg for 15 days). Evidence for a graded effect of VCD was observed using a range of concentrations, and the best windows for examining VCD's effects on follicles and associated tissues were identified., Key Findings: The mouse model used here successfully simulated two common complications of POF - emotional changes and decreased bone density. The model's application was then extended to examine the links between disease and intestinal microorganisms, and evidence was found linking POF to the reproductively relevant composition of the gut microbiota., Significance: These findings provide novel methodological guidance for future research, and they significantly extend the applications and scope of VCD-induced POF mouse models., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To investigate the associations between anti-Müllerian hormone (AMH) and bone mineral density (BMD) induced by ovarian insufficiency in premenopausal women., Methods: Subjects were consecutively enrolled from January 2015 to December 2018. Dual energy X-ray absorptiometry (DXA) examination was set as the gold standard, with T-scores less than -2.5/1 as thresholds for the definition of osteoporosis (OP)/osteopenia., Results: A total of 87 subjects were included in the low BMD group, and 39 subjects were included in the control group. Serum AMH levels were decreased significantly in the low BMD group ( p  < 0.05) with a negative correlation between AMH and age. Strong positive correlations between AMH and BMD/T-score existed in all subjects and subjects with low BMD, and remained even after age adjustment. An exploratory multivariate regression model indicated that age and AMH remained predictive and might be independent risk factors with adjusted odds ratios (ORs) of 0.9 ( p  = 0.009) and 36 ( p  < 0.001), respectively. The receiver operating characteristic (ROC) curve analysis estimated that the sensitivity and specificity were 78.2 and 76.9%, respectively, for identifying low BMD subjects from controls when the cut-off value for AMH was set to 0.800 ng/mL., Conclusions: Serum AMH levels are associated with low BMD in premenopausal women with suspected ovarian insufficiency.

An extra X chromosome occurs in ~ 1 in 1000 females, resulting in a karyotype 47,XXX also known as trisomy X syndrome (TXS). Women with TXS appear to be at increased risk for premature ovarian insufficiency; however, very little research on this relationship has been conducted. The objective of this case-control study is to compare ovarian function, as measured by anti-mullerian hormone (AMH) levels, between girls with TXS and controls. Serum AMH concentrations were compared between 15 females with TXS (median age 13.4 years) and 26 controls (median age 15.1 years). Females with TXS had significantly lower serum AMH compared to controls (0.7 ng/mL (IQR 0.2-1.7) vs 2.7 (IQR 1.3-4.8), p < 0.001). Additionally, girls with TXS were much more likely to have an AMH below the 2.5th percentile for age with 67% of them meeting these criteria (OR 11, 95% CI 2.3-42). Lower AMH concentrations in females with TXS may represent an increased risk for primary ovarian insufficiency in these patients and potentially a narrow window of opportunity to pursue fertility preservation options. Additional research is needed to understand the natural history of low AMH concentrations and future risk of premature ovarian insufficiency in girls with TXS.

Introduction: Subjects affected with Turner Syndrome (TS) suffer low bone mineral density and high risk of fracture from a young age. Estrogen deficiency is considered the main risk factor but other factors, such as intrinsic bone abnormalities, enhanced osteoclastogenesis, vitamin D deficiency and other comorbidities may contribute to the exalted bone fragility., Areas Covered: The authors performed a literature search in PubMed and EMBASE, using selected key words. They focused their search on pathogenetic mechanisms of osteoporosis in TS and updated the diagnosis, prevention and therapeutic interventions., Expert Opinion: Bone health is a concern in subjects with TS, and strategies to prevent osteoporosis and fractures should be considered from childhood. Advice on how to live a healthy lifestyle, including physical activity and correct nutrition, should be given during childhood in order to prevent bone impairment later in life. The screening for vitamin D deficiency should be performed between the ages of 9 and 11, and every 2-3 years thereafter. Early initiation of estrogen replacement therapy (ERT) between 11-12 years of age, prompt titration to the adult dose after 2 years, and long-term follow-up to guarantee compliance with ERT, are the key points of osteoporosis prevention in women with TS.

Objective: To test whether in vitro maturation (IVM) of oocytes is an option for preserving the fertility of women diagnosed with premature ovarian insufficiency (POI)., Design: Case report., Setting: University hospital., Patient(s): A 36-year-old amenorrheic patient was referred for fertility preservation (FP) counseling with a diagnosis of autoimmune POI. Serum follicle-stimulating hormone (21.0 and 36.3 mIU/mL) and luteinizing hormone (35.0 and 60.0 mIU/mL) levels taken 4 weeks apart were around the menopausal range. Although serum antimüllerian hormone level was low (0.76 and 0.65 ng/mL), total counts of antral follicles remained unexpectedly normal (24 and 22). Significant levels of serum antiperoxidase, anti-21-hydroxylase, and antiovary antibodies led to the diagnosis of autoimmune polyendocrinopathy. Due to the unknown time before follicular exhaustion, we undertook a FP program., Intervention(s): After unsuccessful follicular growth following a trial of ovarian stimulation using recombinant follicle-stimulating hormone (300 IU/day for 10 days), we decided to try IVM of immature oocytes aspirated from the remaining antral-stage follicles., Main Outcome Measure(s): Obtention of immature oocyte capable of maturing in vitro in a context of acute ovarian dysfunction., Result(s): Two cycles of IVM were performed, leading, after human chorionic gonadotropin priming, to six and 10 cumulus-oocyte complexes recovered and four and eight metaphase II oocytes. Finally, after intracytoplasmic sperm injection, a total of eight cleavage-stage embryos were frozen. When the patient presented in the clinic 1 year later for reutilization of the cryopreserved embryos, thyroid and adrenal functions were controlled with levothyroxine and hydrocortisone. Endometrium was primed with 17ß-estradiol (2 mg/day, vaginally) for 14 days. Progesterone (600 mg/day, vaginally) was subsequently combined with E 2 . Two embryos were thawed and further transferred into the uterus. The patient became pregnant and uneventfully delivered two baby boys at term., Conclusion(s): We report the first pregnancy and live birth achieved using IVM for FP in a woman diagnosed with autoimmune POI. The confirmation of our results would lead to modification in the management of young women diagnosed with autoimmune POI, who are usually not considered candidates for FP and often referred for egg donation when seeking pregnancy., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The second major cause of death is cancer. In fact, the effectiveness of anticancer treatments and positive long-term prognosis for young women has increased. However, the problem of post-cancer infertility plays a significant role, because chemotherapy can be gonadotoxic and lead to the functional death of ovaries. There is potential key solution to this problem: cryopreservation of ovarian tissue before cancer therapy with re-implantation after convalescence. Data regarding cryopreservation and re-transplantation of ovarian tissue from patients with ovarian insufficiency is limited. The aim of this treatment was the re-transplantation of cryopreserved ovarian tissue after anticancer therapy of patient with ovarian insufficiency (56 IU/l FSH, 8 ng/l β-estradiol, < 1.1 ng/ml anti-Mullerian hormone, 1 primary follicle per 10mm 3 )., Case Presentation: After the operation, four tissue fragments (10-16 × 8-13 × 1.0-1.2 mm) were cooled to 5 °C in the freezing medium (culture medium+ 6% ethylene glycol+ 6% dimethyl sulfoxide+ 0.15 M sucrose) for 24 h, frozen and thawed. Freezing was performed in four standard 5 ml cryo-vials with ice formation at - 9 °C, cooling from - 9 to - 34 °C at a rate of - 0.3 °C/min and plunging at - 34 °C into liquid nitrogen. After thawing in a 100 °C (boiling) water bath, the removal of cryoprotectants was performed in 0.5 M sucrose with 20 min. exposure in sucrose and 30 min. stepping rehydration. After thawing of one cryo-vial, part (5 mm 3 ) of experimental ovarian tissue after 7 day in vitro culture was histological evaluated and two ovarian fragments (8 × 7 × 1.0 mm and 7 × 6 × 1.0 mm) were re-transplanted. The quantity of follicles after cryopreservation and in vitro culture was not increased (P > 0.1): it was found 1 primordial follicle in 5 mm 3 of tissue. Thirty seven days after the re-transplantation of ovarian tissue, the restoration of the menstrual cycle of Patient W. was noted. Three months after the transplantation, the patient became spontaneously pregnant and delivered a healthy baby girl at term., Conclusions: Described protocol of conventional cryopreservation of ovarian tissue can be used for treatment of patients with ovarian insufficiency.

Context and Objectives: This study aimed to assess the effects of hormone replacement therapy (HRT) on bone mineral density (BMD) in young women who underwent allogeneic hematopoietic stem cell transplantation (HSCT)., Participants and Methods: This retrospective cohort included 234 female patients with premature ovarian insufficiency (POI) who underwent allogeneic HSCT between April 2009 and April 2016 at Seoul St. Mary's Hospital in Seoul, Korea. Inclusion criteria included adult patients who were age 40 years or younger at the time of transplantation and were followed for at least 3 years after HSCT., Results: At the first and second years after HRT, there was a significant increase in the BMD of the lumbar spine of the HRT group (n = 170) compared to that of the non-HRT group (n = 64) (P = .033 and P = .047, respectively). The BMD of the lumbar spine significantly increased from baseline by 4.16 ± 4.39% and 5.42 ± 5.86% after 1 and 2 years of HRT, respectively (P = .037 and P = .021). The BMD of the femoral neck and total hip also showed a significant percentage increase from baseline after 2 years of HRT. These changes were significant even in the presence of graft-versus-host disease or steroid exposure. For HRT that was initiated within 12 months after HSCT, the increase in BMD in the lumbar spine was greatest after 2 years of HRT., Conclusions: These results support that early and active hormonal therapy might be beneficial for BMD in female HSCT recipients with POI., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: We aimed to investigate the relationship between oxidative stress (OS) and subclinical atherosclerosis in patients with premature ovarian insufficiency (POI), by analyzing the dynamic thiol/disulfide homeostasis (TDH) parameters as an OS marker and carotid intima-media thickness (CIMT). Materials and methods : A total of 69 women, 34 with POI and 35 healthy controls were included in this prospective cross-sectional study. TDH parameters (plasma native thiol, total thiol, disulfide, disulfide/native thiol, native thiol/total thiol, and disulfide/total thiol ratios) and CIMT were measured and compared between the two groups. Results: In primary ovarian insufficiency group, native thiol ( p =.009) and total thiol ( p =.010) levels were significantly decreased, and CIMT values were significantly increased ( p = <.001). CIMT values were negatively correlated with native thiol ( r =-0.553, p =.001) and total thiol levels ( r =-0.565, p =.001); and positively correlated with age ( r  = 0.457, p =.007), BMI ( r  = 0.408, p =.017), and total cholesterol ( r  = 0.605, p <.001) in POI group. Conclusions: Decreased native thiol and total thiol levels demonstrate the defective anti-oxidant mechanism in POI. Negative correlation between native thiol, total thiol levels, and CIMT means the presence of abnormal anti-oxidant mechanisms may play a role in the development of subclinical atherosclerosis in patients with POI. This is a novel report on the mechanism of subclinical atherosclerosis in women with POI, which needs to be supported with further studies evaluating the pathophysiology of OS.

Premature ovarian insufficiency (POI) is a clinically and etiologically heterogeneous disorder characterized by menstrual irregularities and elevated levels of FSH before age of 40 years. Genetic anomalies are among the recognized causes of POI. Here, we aimed to identify the genetic cause of POI in an inbred pedigree with nine POI and two ichthyosis-affected members. Inheritance of POI and ichthyosis were, respectively, dominant and recessive. Reproduction-related information and measurements of relevant hormones were obtained. Genetic studies included homozygosity mapping, linkage analysis, exome sequencing, and screening of candidate variants. A mutation within ALOX12B, which is a known ichthyosis causing gene, was identified as cause of ichthyosis. ALOX12B encodes a protein involved in steroidogenesis and lipid metabolism. Considering the importance of steroidogenesis in reproduction functions, the possibility that the ALOX12B mutation is also cause of POI was considered. Screenings showed that the mutation segregated with POI status. Linkage analysis with respect to POI identified a single strongly linked locus (LOD > 3) that includes ALOX12B. Exome sequencing on POI-affected females identified the mutation in ALOX12B and also a sequence variation in SPNS2 within the linked locus. A possible contribution of the SPNS2 variation to POI was not strictly ruled out, but various data presented in the text including reported association of variations in related gene ALOX12 with menopause-age and role of ALOX12B in atretic bovine follicle formation argue in favor of ALOX12B. It is, therefore, concluded that the mutation in ALOX12B is the likely cause of POI in the pedigree.

We aimed to determine whether intraovarian injection of autologous platelet rich plasma (PRP) improves response to ovarian stimulation and in vitro fertilization (IVF) outcome in women with primary ovarian insufficiency (POI). Women (N=311; age 24-40) diagnosed with POI based on ESHRE criteria underwent intraovarian PRP injection. Markers of ovarian reserve, and IVF outcome parameters were followed. PRP treatment resulted in increased antral follicle count (AFC) and serum antimullerian hormone (AMH), while serum follicle stimulating hormone (FSH) did not change significantly. After PRP injection, 23 women (7.4%) conceived spontaneously, 201 (64.8%) developed antral follicle(s) and attempted IVF, and 87 (27.8%) had no antral follicles and therefore did not receive additional treatment. Among the 201 women who attempted IVF, 82 (26.4% of total) developed embryos; 25 of these women preferred to cryopreserve embryos for transfer at a later stage, while 57 underwent embryo transfer resulting in 13 pregnancies (22.8% per transfer, 4% of total). In total, of the 311 women treated with PRP, 25 (8.0%) achieved livebirth/sustained implantation (spontaneously or after IVF), while another 25 (8.0%) cryopreserved embryos. Our findings suggest that in women with POI, intraovarian injection of autologous PRP might be considered as an alternative experimental treatment option.

Context: Primary Ovarian insufficiency (POI) affects 1% of women aged <40 years and leads most often to definitive infertility with adverse health outcomes. Very recently, genes involved in deoxyribonucleic acid (DNA) repair have been shown to cause POI., Objective: To identify the cause of a familial POI in a consanguineous Turkish family., Design: Exome sequencing was performed in the proposita and her mother. Chromosomal breaks were studied in lymphoblastoid cell lines treated with mitomycin (MMC)., Setting and Patients: The proposita presented intrauterine and postnatal growth retardation, multiple pilomatricomas in childhood, and primary amenorrhea. She was treated with growth hormone (GH) from age 14 to 18 years., Results: We identified a novel nonsense variant in exon 9 of the minichromosome maintenance complex component 8 gene (MCM8) NM&#95;001281522.1: c0.925C > T/p.R309* yielding either a truncated protein or nonsense-mediated messenger ribonucleic acid decay.The variant was homozygous in the daughter and heterozygous in the mother. MMC induced DNA breaks and aberrant metaphases in the patient's lymphoblastoid cells. The mother's cells had intermediate but significantly higher chromosomal breaks compared with a control., Conclusion: We describe a novel phenotype of syndromic POI related to a novel truncating MCM8 variant. We show for the first time that spontaneous tumors (pilomatricomas) are associated with an MCM8 genetic defect, making the screening of this gene necessary before starting GH therapy in patients with POI with short stature, especially in a familial or consanguineous context. Appropriate familial monitoring in the long term is necessary, and fertility preservation should be considered in heterozygous siblings to avoid rapid follicular atresia., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Although there are many etiologies for delayed puberty in adolescent-aged girls, the pediatric provider should consider primary ovarian insufficiency if estradiol remains undetectable despite elevated levels of gonadotropins. Adolescent girls with this diagnosis will need holistic care from their primary care provider, focusing on both their medical and psychosocial needs. The following case study describes a 14-year-old girl who was referred to pediatric endocrinology for delayed puberty, in the setting of increased gonadotropins and undetectable estradiol. The differential diagnosis, evaluation, and management of primary ovarian insufficiency are reviewed as well as potential long-term health considerations., (Copyright © 2019 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

Objectives: We evaluated age at natural menopause and the prevalence of premature ovarian failure (POF) in a monocentric Caucasian cohort of patients with systemic lupus erythematosus (SLE)., Methods: In this cross-sectional study, we enrolled women affected by SLE compared with healthy controls (HC) to investigate data about natural menopause (amenorrhoea for at least 12 months at ≥40 years) and POF (amenorrhoea for at least 12 months at <40 years)., Results: We enrolled 196 SLE (median age 47.0 years, IQR 16.7; median disease duration 132 months, IQR 180) and 90 HC (median age 49.9 years, IQR 15.0). Ninety-four SLE (48.0%) and 26 HC (23.4%) were menopausal: median age at onset was significantly lower in SLE than HC (47 years, IQR 8.0 vs. 50.5 years, IQR 4; p=0.0001). POF was registered in 17% of the SLE, and in none of the HC (p<0.0001). POF was significantly associated with anti-Sm (p=0.0004), anti-RNP (p=0.02), anti-cardiolipin (p=0.0008), lupus anticoagulant (p=0.0002), treatment with cyclophosphamide (p=0.0001), azathioprine (p=0.0001), mycophenolate mofetil (p=0.0001), cyclosporine A (p=0.007)., Conclusions: SLE patients develop menopause at a younger age; moreover, a higher POF frequency was observed in SLE patients in comparison with HC. POF is associated with specific SLE-related autoantibodies and the use of immunosuppressant drugs, in particular cyclophosphamide.

The infertile patients with aging ovaries-also sometimes referred to as impending premature ovarian insufficiency (POI), impending premature ovarian failure (POF), or poor ovarian responders (POR), constitute a significant and increasing bulk of the patients appealing to IVF/ART. Different causes have been cited in the literature, among the identified etiologies, including chromosomal and genetic etiology, metabolic, enzymatic, iatrogenic, toxic, autoimmune, and infectious causes. Although the most successful and ultimate treatment of POI/POF/POR patients is egg donation (ED), many, if not most, of these infertile women are reluctant to consent to ED upon the initial diagnostic interview, requesting alternative solutions despite the low odds for success. Despite anecdotal case reports, no unequivocal treatment proved to be successful for these patients in prospective randomized controlled trials. Nevertheless, the addition of growth hormone (GH) to ovarian stimulation in POR with GH deficiency may improve the results of controlled ovarian hyperstimulation (COH) and the IVF success. In patients with autoimmune etiology for POR/POI, the combination of glucocorticosteroids, pituitary-ovarian suppression, and COH may be successful in achieving the desired conception., (Copyright © 2020 Blumenfeld.)

Objectives: This study aimed to investigate the prevalence of self-reported main pelvic floor disorders (PFD) (urinary incontinence [UI], pelvic organ prolapse [POP], and fecal incontinence [FI]) and its associated factors in women with premature ovarian insufficiency (POI) and a control group., Methods: This was a cross-sectional study wherein two groups were interviewed from August, 2017 to November, 2018-women with POI (n = 150) and a control group matched for age and body weight (n = 150). Sociodemographic variables and two questionnaires validated in Brazilian Portuguese language for PFD (Kings Health Questionnaire [KHQ] and Pelvic Floor Distress Inventory-20 [PFDI-20]) were used. Laycock's power, endurance, repetitions, fast contractions, every contraction timed (PERFECT) scale for pelvic floor muscle assessment was used in both groups., Results: The prevalence of self-reported UI was 27.33% and 37.33% for POI and control groups (P > 0.05), respectively. There was no perceived difference regarding the prevalence of POP (9.33% POI group vs 8% control group; P = 0.682) and FI (8% POI vs 4% control group; P = 0.145). The P (power) (P = 0.46), E (endurance) (P = 0.91), R (repetitions) (P = 0.88), and F (fast contractions) (P = 0.19) values were statistically similar in both the groups. Multivariate analysis (n = 141) showed that higher weight (odds ratio [OR] 1.047 [1.018-1.076]; P < 0.001) and gravidity rates (OR 1.627 [1.169-2.266]; P < 0.01) were risk factors for UI and higher weight (OR 1.046 [1.010-1.084]; P = 0.01), and presence of comorbidities (OR 8.75 [1.07-71.44]; P < 0.01) were risk factors for POP in the POI group; there was no variable that was associated with FI., Conclusions: Women with POI did not have significant differences when compared with the control group regarding the prevalence of PFD and pelvic floor muscle assessment. Having higher weight and gravidity rates were associated with self-reported UI, while the presence of comorbidities and higher weight were risk factors for POP in the POI group. : Video Summary:http://links.lww.com/MENO/A555.

Purpose: To determine whether geographic variation exists in osteoporosis knowledge, management, and barriers to care in the setting of premature ovarian insufficiency (POI), among general practitioners (GPs) and women with POI., Methods: Australian GPs completed an online questionnaire regarding osteoporosis knowledge, barriers to care and educational preferences for managing osteoporosis in POI. Women with POI/early menopause (EM) completed an online questionnaire regarding osteoporosis knowledge, risk factors and health beliefs. Clinicians and consumers in metropolitan areas were compared to those in rural areas., Results: Of 688 GP respondents, 62.2% practised in major capital cities, 13.1% in major regional cities, 7.8% in regional centres, 8.7% in rural areas and 8.1% in remote areas. Mean ± SD osteoporosis knowledge score was 9.1 ± 1.5/13, with no difference by location. Forty-one percent of GPs reported barriers to care which varied by location. Of 316 women with POI/EM, 61.1% lived in metropolitan, 22.5% in regional, 11.7% in rural and 4.4% in remote locations. The mean osteoporosis knowledge score was 8.2 ± 3.1/20, with lower scores in women living in rural and remote versus metropolitan locations (difference - 1.3; 95% CI - 2.3, - 0.25; p = 0.02). Women in rural areas were less likely to use vitamin D supplements and more likely to have a family history of osteoporosis (both p < 0.05)., Conclusions: GP knowledge gaps and specific, location-dependent care barriers for osteoporosis in POI were identified. Geographic differences in osteoporosis knowledge and risk factors exist in women with POI/EM. These factors require consideration when designing programs to improve bone health in POI.

Purpose: To determine the impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcome. The main purpose and research question of the study is to determine the impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcomes., Methods: Prospective study: 67 breast cancer patients between 18 and 40 years old, undergoing a fertility preservation by means of oocyte storage were considered. Inclusions criteria for the study were age between 18 and 40 years old, BMI between 18 and 28, breast cancer neoplasm stage I and II according to American Joint Committee on Cancer classification (2017) and no metastasis., Exclusion Criteria: age over 40 years old, BMI < 18 and > 28, breast cancer neoplasm stage III and IV and do not performed the BRCA test. A total of 21 patients had not performed the test and were excluded. Patients were divided into four groups: Group A was composed by 11 breast cancer patients with BRCA 1 mutations, Group B was composed by 11 breast cancer patients with BRCA 2 mutations, Group C was composed by 24 women with breast cancer without BRCA mutations, and Group D (control) was composed by 181 normal women., Results: Group A showed significant lower AMH levels compared to Group C and D (1.2 ± 1.1 vs 4.5 ± 4.1 p < 0.05 and 1.2 ± 1.1 vs 3.8 ± 2.5 p < 0.05). BRCA1 mutated patients showed a significant lower rate of mature oocytes (MII) compared to Group C (3.1 ± 2.3 vs 7.2 ± 4.4 p < 0,05) and Group D (3.1 ± 2.3 vs 7.3 ± 3.4; p < 0,05). Breast cancer patients needed a higher dose of gonadotropins compared to controls (Group A 2206 ± 1392 Group B2047.5 ± 829.9 Group C 2106 ± 1336 Group D 1597 ± 709 p < 0,05). No significant differences were found among the groups considering basal FSH levels, duration of stimulation, number of developed follicles, and number of total retrieved oocytes. Regarding BRCA2 mutation, no effect on fertility was shown in this study., Conclusions: The study showed that BRCA1 patients had a higher risk of premature ovarian insufficiency (POI) confirmed by a diminished ovarian reserve and a lower number of mature oocytes suitable for cryopreservation.