Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

BACKGROUND:The vaginal microbiota test predicts the success of in vitro fertilization (IVF), but with no therapy available to improve a low profile, couples must decide whether to proceed or postpone treatment. We aim to examine how couples interpret vaginal microbiome results and make postponement decisions within a shared decision making (SDM) framework. METHODS:Women undergoing IVF or IVF-intracytoplasmic sperm injection (IVF-ICSI) treatment at 2 Dutch hospitals received the ReceptIVFity test™, which classified the vaginal microbiome as high (52.6% chance of conception), medium (23.6%), or low (5.9%) profile based on predicted implantation success after a fresh embryo transfer. Physicians discussed the results with couples using SDM, after which the couples decided whether to proceed or postpone treatment. The primary outcome was the patients' perceived involvement in shared decision making, assessed with the SDM-Q-9 questionnaire. The secondary outcome was the proportion of couples postponing treatment after a low microbiome profile. RESULTS:Between October 2018 and November 2020, 728 women were enrolled. SDM-Q-9 responses showed high perceived involvement overall but lower scores for "exploring options," reflecting limited alternatives when the choice is to proceed or postpone treatment. A low profile was found in 35.4% (258/728). After the SDM consultation, 49.6% (128/258) chose to postpone treatment, with postponement rates increasing to over 80% among couples in later IVF cycles. Decisions were influenced by personal, emotional, and practical considerations, including the Dutch insurance reimbursement system (3 insured IVF or IVF-ICSI cycles regardless of postponement) and the absence of effective treatment to modify a low profile. CONCLUSIONS:These findings demonstrate that couples can understand and use prognostic information when supported by SDM and that the ReceptIVFity test™ facilitated discussion about chances of success, timing of treatment, decisions to proceed or postpone, and personal values.

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder with reproductive, metabolic, and psychological features, often underdiagnosed due to diagnostic inaccuracies and inconsistent knowledge among providers. These gaps highlight the need for improved diagnostic approaches to identify patients at risk earlier. This pilot study aimed to evaluate the validity of the PCOS risk algorithm (PriskA), a digital tool designed to assess PCOS risk in symptomatic women. A total of 144 women were referred for standardized endocrine screening at the Erasmus Medical centre and were included in the study, after excluding six women with inconclusive diagnoses. Of the 95 women with PCOS, 91 (96

BACKGROUND:While Anti-Müllerian hormone (AMH) helps personalise In Vitro Fertilization (IVF) stimulation protocols, a significant number of women still do not achieve an optimal ovarian response. To address this, we explore the utility of a polygenic score for age at natural menopause (ANM) as a predictor for ovarian response during IVF. METHODS:This cohort study included 435 women who underwent standardised IVF stimulation, and they were genotyped to calculate a polygenic score (PGS) for ANM. Linear regression and ANCOVA models were used to assess the associations between the PGS and ovarian response, oocyte and embryo quality and pregnancy rates, adjusting for genomic components and age. FINDINGS:A one standard deviation increase in the PGS for ANM was associated with 0.950 (p < 0.001) additional follicles two days before ovum pick-up. While the PGS did not significantly associate with the overall diminished ovarian response (DOR), a mean difference of -0.33 (p < 0.01) in PGS was observed when comparing individuals with fewer than 8 follicles retrieved to those with an optimal ovarian response. No association was found between the PGS and ongoing pregnancy. Causal mediation revealed that the effect of the PGS onto the number of follicles was partly mediated by AMH levels (proportion mediated = 31%, p = 0.002). INTERPRETATION:A lower PGS for ANM, indicative for earlier menopause, is independently associated with a reduced ovarian response during IVF stimulation, specifically fewer follicles retrieved and mostly independent of AMH levels. This highlights the potential of ANM-related genetic variants to inform personalised IVF protocols by predicting ovarian responsiveness. FUNDING:This study was supported by Ferring Pharmaceuticals.

Polyendocrine metabolic ovarian syndrome (PMOS), previously named polycystic ovary syndrome (PCOS), affects one in eight women. However, the term PCOS is inaccurate, implying pathological ovarian cysts, obscuring diverse endocrine and metabolic features, and contributing to delayed diagnosis, fragmented care, and stigma, while curtailing research and policy framing. Building on an international mandate for change, we outline an unprecedented, rigorous, multistep global consensus process for the name change. Funding and governance were established with engagement of 56 leading academic, clinical, and patient organisations. Using iterative global surveys (with responses from 14 360 people with PCOS and multidisciplinary health professionals from all world regions), modified Delphi methods, nominal group technique workshops, and marketing and implementation analyses, we identified principles prioritising scientific accuracy, clarity, stigma avoidance, cultural appropriateness, and implementation feasibility. An accurate new name was prioritised over retaining the PCOS acronym or a generic name. Implementation approaches prioritised evolution rather than transformation. Preferred terms were polyendocrine, metabolic, and ovarian, reflecting the condition's multisystem pathophysiology, and polyendocrine metabolic ovarian syndrome was the consensus new name. Accuracy was improved by omitting cysts and by capturing endocrine, metabolic, and ovarian dysfunction. A co-designed global implementation strategy, including a transition period, education, and alignment with health systems and disease classification, is under way.

Research Question:How does follitropin delta administered with an individualized dose based on body weight and AMH perform in daily practice, and is this comparable to results from a randomized phase III clinical trial in terms of ovarian response, pregnancy, and safety? Design:This is a descriptive analysis of real-world data obtained from the Erasmus University Medical Centre (EMC). Patients were treated with the dose of follitropin delta calculated according to the algorithm described in the ESTHER-1 trial. Outcome data were restricted to the first IVF cycle in patients with a regular ovulatory cycle treated with a GnRH antagonist protocol for whom the intended day of embryo transfer was day 5. Results:The ongoing pregnancy rate was 30.8% per started cycle, which is equivalent to the ESTHER-1 trial. The number of oocytes retrieved (10.3 ± 5.4) was also comparable. All other ovarian response parameters were within the range that was expected on the basis of the results of the ESTHER-1 trial. Conclusions:The use of follitropin delta in a real-world clinical setting results in ovarian response outcomes comparable in range to those in the follitropin delta arm of the ESTHER-1 registration trial. No differences were observed in treatment outcomes.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women. Current international PCOS assessment and management guidelines recommend anti-Müllerian hormone (AMH) as an alternative to transvaginal ultrasound for assessing polycystic ovarian morphology, which is one of three criteria for diagnosing PCOS. This study assessed the economic impact of using the Elecsys® AMH Plus immunoassay (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) for AMH testing in the United Kingdom health system to assess women with signs and symptoms of PCOS. A decision tree model estimated the costs and health outcomes of using the Elecsys AMH Plus immunoassay to determine polycystic ovarian morphology as part of PCOS assessment in a simulated cohort of women aged 25–45 years who were exposed to different diagnosis pathways. The comparator scenario was the standard of care, where transvaginal ultrasound was used for assessment. Base-case results indicated that the Elecsys AMH Plus immunoassay could lead to cost savings of £284,029 per year on the total cost of PCOS diagnosis (1.4% reduction vs. transvaginal ultrasound), in addition to savings on managing secondary comorbidities, such as type 2 diabetes and stroke care. Cost savings with the Elecsys AMH Plus immunoassay were observed in all scenarios versus using transvaginal ultrasound, including scenarios with various referral rates to specialists and dropout rates from the diagnosis pathway, and low adherence to lifestyle recommendations. With the known current delays in the United Kingdom for diagnosis of PCOS, implementing the Elecsys AMH Plus immunoassay for AMH testing may not only provide cost benefits, but also reduce waiting times for diagnosis and treatment, improving patient health outcomes.

Background:Polycystic ovary syndrome (PCOS) has diverse features. However, the name reflects only ovarian aspects, overlooking broader features. This study aimed to investigate international stakeholder perspectives on PCOS. Methods:We conducted international longitudinal anonymous online surveys and face-to-face workshops with individuals with PCOS and health professionals between 2015 and 2023, across six continents, seeking perspectives on clinical features of PCOS, the current name, the potential for renaming, the advantages and disadvantages of a name change, and possible alternative names. Findings:Results from 7708 survey respondents in 2015 and post publication of international guidelines in 2023, significantly improved recognition of the reproductive, cardiometabolic, hormonal, and psychological features of PCOS (p < 0·001). However, gaps remain, with ≥20% of patients and/or health professionals not recognising associations between PCOS and non-alcoholic fatty liver disease, pregnancy complications, cardiovascular risk factors, and endometrial cancer. Aligned to the breadth of PCOS, in the 2023 survey, a potential name change was explored with 85·6% of patients and 76·1% of health professionals agreeing that the name should be changed. Both groups agreed that a name change presents advantages with 59-90% agreeing with advantages and fewer than 27% agreeing with disadvantages. Terms such as 'endocrine' and 'metabolic' received the highest support in 2015 and 2023 for inclusion in a new name among both patients (78·5 and 86·2%) and health professionals (84·6 and 79·6%). Overall, 84% committed to a consensus-driven name change process on voting at a 2023 workshop. Interpretation:Widespread international engagement in 2015 showed major knowledge gaps on broad PCOS features, with follow-up in 2023 showing significant improvement after two international guidelines, widespread dissemination and advocacy group outreach. Stakeholders highlighted that the current name does not adequately reflect broad PCOS features and is confusing. They endorsed a name change, with perceived advantages outweighing potential disadvantages. This culminated in a commitment to a global consensus process to determine and implement a new name, alongside extensive education efforts, both of which are now underway. Funding:The Australian National Health and Medical Research Council (NHMRC) funded Centre for Research Excellence in Women's Health in Reproductive Life (CRE-WHiRL) [APP#1171592].

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, with a prevalence estimated between 10% and 13%. It is characterized by ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology. Antimüllerian hormone (AMH) plays a key role in regulating normal reproductive function in both males and females. Over the past few decades, significant progress has been made in understanding AMH, with numerous studies revealing its unexpected roles throughout the hypothalamic-pituitary-gonadal axis. Antimüllerian hormone and its receptor are also produced in the forebrain, where they contribute to the proper migration of gonadotropin-releasing hormone (GnRH) neurons during development. At the hypothalamic and pituitary levels, AMH has been shown to increase the frequency of GnRH pulses, which in turn leads to increased luteinizing hormone (LH) secretion. In PCOS, this regulatory mechanism appears to be disrupted. The LH/follicle-stimulating hormone ratio is often elevated because of altered GnRH pulse frequency. Elevated AMH levels contribute to this dysregulation by increasing GnRH pulsatility, which leads to enhanced LH secretion. This, in turn, stimulates theca cells to produce excessive androgens, resulting in hyperandrogenism, follicular arrest, and anovulation. Antimüllerian hormone levels are strongly correlated with these clinical features of PCOS and are predictive of outcomes in assisted reproductive treatments, including a higher risk of adverse pregnancy outcomes. Additionally, offspring born to mothers with PCOS tend to have elevated levels of AMH and androgens at birth, which may alter the hypothalamic-pituitary-gonadal axis and contribute to the development of PCOS later in life.

Polycystic ovary syndrome (PCOS) is a common and heterogeneous disorder currently diagnosed only in reproductive-age women. Familial clustering and twin studies have provided strong evidence for a genetic contribution to PCOS pathogenesis. First-degree relatives, including males and non-reproductive-age females, have reproductive and metabolic phenotypes consistent with a genetic susceptibility to these traits. PCOS is now recognized as a complex trait influenced by both genetic and environmental factors. Genome-wide association studies have identified ∼30 loci linked to PCOS, implicating pathways involved in gonadotropin secretion and action, folliculogenesis, steroidogenesis, age at menopause, and carbohydrate metabolism. Next-generation sequencing has found rare variants in AMH, AMHR2, and DENND1A, supporting these genes' central role in developing PCOS. Epigenetic mechanisms, such as DNA methylation and non-coding RNAs, influence gene regulation and may contribute to phenotypic heterogeneity. Unsupervised clustering has identified distinct reproductive and metabolic subtypes with unique genetic architectures, providing a biologically meaningful framework for classification. This shift from expert opinion-based diagnosis to data-driven classification has the potential to transform PCOS management and enable precision medicine approaches tailored to distinct subtypes of the disorder.

Polycystic ovary syndrome (PCOS) affects 10% to 13% of women globally. It is a condition with metabolic, reproductive, and psychological features, with health impacts across the lifespan. The etiology of PCOS is complex, with an interplay of several factors, including genetic and epigenetic susceptibility, androgen exposure in early life and adiposity-related dysfunction leading to hypothalamic-ovarian disturbance. Diagnosis is recommended based on the International PCOS Guideline criteria, with diagnosis confirmed in adults when 2 of out the following 3 criteria are met: (i) hyperandrogenism (clinical or biochemical); (ii) irregular cycles; and (iii) polycystic ovary morphology or elevated anti-M & uuml;llerian hormone (AMH) levels. With its clinical heterogeneity, distinct phenotypes, variation across the lifespan and ethnic variation, PCOS diagnosis can present significant diagnostic challenges to clinicians.

OBJECTIVE:To explore associations between clinical and patient-reported variables and depressive symptoms in women with premature ovarian insufficiency (POI). METHODS:An exploratory cross-sectional observational study was conducted using data from the center of expertise for women with POI, Erasmus MC, the Netherlands. To identify variables associated with depressive symptoms, as assessed by patient and clinician-reported outcome measures, we used logistic regression models. RESULTS:Between April 2020 and December 2023, 345 women with POI were included. In this cohort, the prevalence of depressive symptoms was 29.9%. No significant difference was found in depressive symptoms between women using estrogen plus progestogen therapy (EPT) (41.7%) and those not using EPT (42.6%, P =0.89). Younger age at diagnosis ( P =0.01), POI due to a genetic cause ( P =0.04), severe menopausal symptoms ( P <0.001), and lack of emotional support ( P <0.001) were independently associated with depressive symptoms. The use of EPT or levels of estradiol were not associated with depressive symptoms. CONCLUSIONS:The high prevalence of depressive symptoms among women with POI underscores a need for targeted mental health support. Our findings highlight that younger age at diagnosis, severe menopausal symptoms, and fertility-related grief are associated with depression in this population. Given that estradiol levels did not correlate with depressive symptoms, this suggests that psychosocial factors are crucial. Psychological interventions should focus on these factors to address the unique needs of this population.

Objective: To study genital response and sexual arousal in women with and without polycystic ovary syndrome (PCOS) and assess associations with sex steroid levels. Design: This observational prospective case-control study was conducted from March 2017 until March 2020. Subjects: Heterosexual women with (n-68) and without (n-67) PCOS, aged 18-40 years, in a steady relationship and without any comorbidities. Exposure: All participants underwent an extensive medical and endocrine screening as well as assessment of genital blood flow (vaginal pulse amplitude), assessed with photoplethysmography), and sexual arousal and affect (Likert scale questionnaire) in response to erotic and vibrotactile stimulation. Main Outcome Measures: Vaginal pulse amplitude, lubrication, subjective sexual arousal, and affect. Results: There were no significant differences in genital blood flow response and self-reported lubrication between women with and without PCOS. After adjusting for confounders, women with PCOS did report significantly lower positive affect in the fantasy and vibrotactile condition than those without PCOS. Regression analyses adjusted for confounders showed only few and weak associations of sexual responses with androgen levels explaining only a maximum of 6% of variance in all models in women with and those without PCOS. The PCOS group showed only weak associations between subjective sexual arousal and dehydroepiandrosterone (fantasy, beta=1.719, adjusted R-2=0.020) and sex hormone binding globulin (fantasy, beta=-1.728, adjusted R-2=0.044). Conclusion: Women with PCOS show similar genital sexual response and lubrication but lower positive affect than those without PCOS; however, only few and weak associations with the androgen levels were found. The androgen levels are not indicative of genital response and subjective arousal. Sexual function should be discussed in clinical care and psychosexual counseling should be offered. (c) 2024 by American Society for Reproductive Medicine.)

STUDY QUESTION:What is the predictive value of oligomenorrhea and other PCOS diagnostic characteristics in adolescence (age 15-18 years) for future fertility and cardiovascular and metabolic health at adult age? SUMMARY ANSWER:Adolescents with oligomenorrhea are more often treated to conceive but are as likely to have as much children as those with regular periods, while persisting oligomenorrhea may associate more often with cardiovascular or metabolic problems. WHAT IS KNOWN ALREADY:Adolescents with oligomenorrhea have a high risk for adult PCOS associated with subfertility due to ovulatory disorders and long-term health risks. Longitudinal studies to estimate the extent of these risks with input starting at adolescence and covering the complete reproductive lifespan are lacking. STUDY DESIGN, SIZE, DURATION:A 25-year prospective follow-up study based on a unique population-based adolescent study on menstrual irregularities performed between 1990 and 1997, the Pubertal Onset of Menstrual Cycle abnormalities, a Prospective study (POMP study). Of the 271 invited adults, 160 (59%) participated. PARTICIPANTS/MATERIALS, SETTING, METHODS:We contacted stratified samples of the POMP study cohort two decades after the initial study for a questionnaire assessing PCOS features, fertility history, pregnancy outcome, metabolic, and cardiovascular health. One hundred and sixty subjects completed the questionnaire. The mean adolescent age was 15.3 years, and the women were 39.6 years at the time of follow-up. One hundred and eight subjects had a regular menstrual cycle as adolescents and 52 were oligomenorrheic. MAIN RESULTS AND THE ROLE OF CHANCE:Of those with adolescent regular menstrual cycles 12 never tried to conceive, 4 tried but never conceived and 92 of 96 (96%) conceived, 89 of 96 (93%) delivering at least one living child. The median number of children was two. The mean time to pregnancy (TTP) was 8.4 months in the women with regular periods as adolescents and 13.2 months in case of oligomenorrhea (P = 0.08) and subfertility was present in respectively 18% and 26%. 47 of 52 adolescents with oligomenorrhea tried to conceive and 45 succeeded to have at least one live birth. Twenty-eight per cent of the subjects reported a change over time of their menstruation pattern. Fifty per cent of the girls with adolescent oligomenorrhea developed a regular cycle and 16% of those with regular periods changed to oligomenorrhea with significantly more reported subfertility (40%, P = 0.04). In case of persistent oligomenorrhea, a significant proportion (40%) underwent fertility treatment (P = 0.04). Adult BMI did not differ between groups. The risk for pregnancy-induced hypertension or pre-eclampsia was comparable between the groups. Gestational diabetes developed in three subjects each with persistent oligo amenorrhea. Adult diabetes, hypertension, and hypercholesterolemia were also mostly reported in case of persistent oligomenorrhea. In this group, the prevalence of combined cardiovascular and metabolic problems was 14% compared to 7% in the case of regular menstrual cycles as adolescent. LIMITATIONS, REASONS FOR CAUTION:The numbers in the study are small. However, the small difference between the percentage with a least one living child of those with adolescent oligomenorrhea versus those with adolescent regular menstrual cycles is reassuring. Time to pregnancy data may have been biased by early treatment of oligomenorrheic adults. WIDER IMPLICATIONS OF THE FINDINGS:Oligomenorrheic adolescents may be reassured that their chance to have a live birth is comparable with those with a regular menstrual cycle. STUDY FUNDING/COMPETING INTEREST(S):This research received no external funding, J.S.E.L. received unrestricted research grants from the following companies (in alphabetical order): Ansh Labs, Ferring, Merck, and Roche Diagnostics. He received consultancy fees or royalties from Ansh Labs, Art pred, Ferring, Gedeon Richter, and Roche Diagnostics. He received presentation fees from Ferring and Roche Diagnostics as well as support for attending meetings and/or travel from Ferring and Roche Diagnostics and he participated in the advisory board of the LOCI Trial UK. TRIAL REGISTRATION NUMBER:Dutch Trial Registry, NTR5871.

STUDY QUESTION What is the risk of endometrial cancer after long-term follow-up in women treated with ART between 1983 and 2001 compared with women in the general population and subfertile women who did not undergo ART?SUMMARY ANSWER The risk of endometrial cancer is not increased in women who underwent ART in the Netherlands between 1983 and 2001, neither compared with women from the general population nor compared with subfertile women not treated with ART.WHAT IS KNOWN ALREADY Concerns have been raised that subfertility treatment may be associated with increased risk of endometrial cancer. However, published studies show inconsistent results regarding the effects of ovarian stimulation and specific subfertility diagnoses on endometrial cancer risk.STUDY DESIGN, SIZE, DURATION A nationwide historic cohort study (the OMEGA-cohort) was conducted to examine the risk of cancer in women after ovarian stimulation for ART. The OMEGA-cohort comprises 30 625 women who received ovarian stimulation for ART (ART group) in 1983-2000 and 9988 subfertile women not treated with ART (non-ART group). After a median follow-up of 24 years, endometrial cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Endometrial cancer risk in the cohort was compared with that in the general population using person-years analyses, and between the ART group and non-ART group using multivariable Cox regression analyses.PARTICIPANTS/MATERIALS, SETTING, METHODS Detailed ART-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Personal Records Database. Information on hysterectomy and endometriosis was collected through linkage with the Dutch Nationwide Pathology Databank (Palga). Data about lifestyle factors, including BMI, were obtained through a self-administered questionnaire.MAIN RESULTS AND THE ROLE OF CHANCE After a median follow-up duration of 24 years, 137 endometrial cancers were diagnosed. Endometrial cancer risk after ART was not significantly increased compared with that in the general population (standardized incidence ratio = 1.19; 95% CI = 0.97-1.44) nor compared with that in the non-ART group (multivariably adjusted hazard ratio = 1.11; 95% CI = 0.74-1.67). Risk of endometrial cancer did not increase with longer follow-up or with more ART cycles, and the risk within the cohort, did not vary by cause of subfertility (male, tubal, unexplained, and other). Irrespective of ART treatment, endometrial cancer risk was increased in obese women and women with endometriosis, but decreased among parous women and women who used oral contraceptives.LIMITATIONS, REASONS FOR CAUTION Although the findings of the study are reassuring, the median age of the women at the end of follow-up (median age 56 years) was still rather young. Therefore, there is a need for at least 10-15 additional follow-up years to draw definitive conclusions. In addition, other large studies are needed to investigate the risk of endometrial cancer in women who underwent ART.WIDER IMPLICATIONS OF THE FINDINGS The results of this study contribute to knowledge about long-term health after ART treatment, which is valuable to subfertile couples, considering or undergoing fertility treatments, and their healthcare providers. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by a grant from the Dutch Cancer Society (NKI 2006-3631) and a departmental grant from the Department of Obstetrics and Gynecology of Erasmus Medical Center, Rotterdam, the Netherlands (2011-019). Ma.S. is Associate Editor of Human Reproduction Open; A.W.vd.B.-D received support for attending meetings and/or travel from the Dutch Cancer Society; C.B.L. is Editor-in-Chief of Human Reproduction; A.E.P.C. is Associate Editor of Human Reproduction Update, received royalties from Uptodate Hyperthecosis, and participated at the Data Safety Monitoring Board of the DSMB POEM Study; F.B. has received research support from Merck, honoraria or consultation fees from Merck Healthcare KGaA, Bensis Healthcare, CooperSurgical, and participated in an advisory board for Merck and Ferring; J.L. has received research support from Ferring, Merck, and Roche Diagnostics, consulting fees and honoraria from Ferring, participated on a Data Safety Monitoring Board or Advisory Board of the LOCI trial, is President of the AE-PCOS society, and Member of the ASRM Integrity Committee; J.M.J.S. has received honoraria from Ferring and Merck, support for attending meetings and/or travel from Ferring, Merck, and Good Life, and participated in the advisory board of Merck; L.L.v.L. received support for attending meetings and/or travel from Olympus Medical Expert training; M.M.v.R. received support for attending meetings and/or travel from Ferring; M.G. declares departmental research and educational grants from Ferring (location VUmc), unrelated to the presented work. The other authors declare no competing interests.TRIAL REGISTRATION NUMBER N/A.

Importance:Pregnant individuals with polycystic ovary syndrome (PCOS) present with a higher risk of pregnancy complications, including gestational diabetes, preeclampsia, and preterm birth. Myo-inositol supplementation may reduce these risks. Objective:To determine whether daily supplementation with myo-inositol during pregnancy among individuals with PCOS reduces the risk of a composite outcome of gestational diabetes, preeclampsia, and preterm birth. Design, Setting, and Participants:This double-blind, placebo-controlled, randomized trial was conducted at 13 hospitals in the Netherlands. Pregnant individuals with PCOS who were between 8 and 16 weeks' gestation were enrolled between June 2019 and March 2023. Final follow-up was complete on December 27, 2023. Analyses were conducted July 2024. Interventions:Participants were randomized on a 1:1 basis to receive sachets with either myo-inositol, 2 g, with 0.2 mg of folic acid twice daily (n = 230) or matching placebo with 0.2 mg of folic acid only (n = 234) until delivery. Main Outcomes and Measures:The primary outcome was a composite of gestational diabetes, preeclampsia, or preterm birth (before 37 weeks' gestation). Results:Among 464 participants, the mean (SD) age was 31.5 (3.8) years; 18 participants (3.9%) reported Asian race and 395 (86.1%) reported White race. The prevalence of biochemical hyperandrogenism was higher at baseline in the myo-inositol group than the placebo group (29.0% [53 of 180] vs 18.5% [37 of 193]). A primary outcome event occurred in 25.0% (n = 56) of participants in the myo-inositol group and 26.8% (n = 61) in the placebo group (relative risk, 0.93 [95% CI, 0.68-1.28]; P = .67). Conclusions and Relevance:Myo-inositol supplementation during pregnancy did not reduce the incidence of a composite of gestational diabetes, preeclampsia, or preterm birth in patients with PCOS. Trial Registration:onderzoekmetmensen.nl Identifier: NL67329.078.18.

Background: Optimal endocrine therapy for premenopausal breast cancer patients after chemotherapy requires accurate menopausal status assessment. Current methods for determining resumption of ovarian function after chemotherapy are suboptimal. This study aims to evaluate the predictive value of pretreatment anti-Müllerian hormone (AMH) serum levels for predicting resumption of ovarian function after chemotherapy (CT). Methods: This prospective study included premenopausal women with hormone receptor-positive breast cancer undergoing CT. AMH was measured using the picoAMH assay of Anshlabs. The primary outcome was resumption of ovarian function, defined as menstrual cycle resumption or estradiol levels above 110 pmol/L within 24 months after CT. Results: Among 109 patients, pretreatment AMH was a strong predictor of resumption of ovarian function (AUC 0.86) and an optimal cut-off of 0.62 μg/L was calculated. AMH >0.62 μg/L identified women at higher risk for ovarian function resumption (sensitivity 69.9 %, specificity 88.5 %), with a false negative rate of 11.5 % and false positive rate of 30.1 %. Combining AMH and age improved predictive accuracy only slightly. No additional predictors were identified. Survival analysis confirmed that women with low pretreatment AMH (<0.62 μg/L) or older age (>40.2 years) experienced significantly less frequent and delayed ovarian function resumption. Conclusion: Pretreatment AMH is a valuable tool for predicting ovarian function resumption after chemotherapy in breast cancer patients, so that a GnRH agonist can be recommended appropriately. However, the predictive value of pretreatment AMH for permanent ovarian insufficiency is too limited to determine the postmenopausal status sufficiently accurately to switch upfront to another endocrine treatment, the aromatase inhibitors.

To identify predictors of depressive symptoms in patients with Premature Ovarian Insufficiency (POI), assessed by patient and clinician reported outcome measures. HRT use showed no impact (41.7% vs. 42.6%, p = 0.89) on depression. Key predictors include severe menopausal symptoms, fertility-related grief, and lower FertiQoL. POI increases the risk of depression and anxiety, with potential causes including neuroendocrine dysregulation and psychosocial stressors. Elevated FSH and low estradiol levels are linked to these mental health risks. Psychosocial factors, such as infertility and the burdens of estrogen deficiency—like vasomotor symptoms, memory issues, reduced workability, lower bone density, and higher cardiovascular risk—may further contribute. While the exact mechanisms remain unclear, both hormonal and psychological factors likely play a role in the increased prevalence of anxiety and depression in individuals with POI. A cross-sectional observational study was performed based on data from the center of expertise for patients with POI, Erasmus MC the Netherlands. Between April 2020 and December 2023, 345 patients with POI were included in this analysis. Before the first visit, POI patients completed six PROM questionnaires, including BDI-II, GCS, WAS, FertiQoL, general health, medical history, lifestyle, and emotional support. All patients with POI who visited the multidisciplinary POI clinic between April 2020 and December 2023 were included. Patients who did not met the criteria for POI or patients who did not fill in the questionnaires were excluded. POI was diagnosed according the ESHRE 2016 guideline, patients should have a oligo/amenorrhea for at least 4 months, and an elevated FSH level (> 25 IU/l) on two occasions at least 4 weeks apart. Of the 345 patients, 103 (29.9%) patients reported depressive symptoms, while 242 (70.1%) did not. In this cohort, the majority (42.3%) were already using HRT at baseline. However, there was no difference in depressive symptoms between patients using HRT and those not using HRT (p = 0.89). The multivariable logistic regression model showed that a worse GCS score (OR 1.13, p < 0.001), PROMIS score for emotional support (OR 0.86, p < 0.001) and a lower age at diagnosis (OR 0.95, p = 0.01) resulted in a significantly higher chance of developing depressive symptoms. POI caused by known genetic variants (OR 0.10, p = 0.04) resulted in a lower chance of developing depressive symptoms. This multivariable logistic regression model explained almost half of the variance in depressive symptoms (R square = 0.45). In a subgroup of patients who filled in the FertiQoL (this questionnaire is only filled in when patients feel grieve regarding their wish to conceive), depressive symptoms were predicted by a worse GCS score (OR 1.09, p < 0.001), a worse FertiQoL score (OR 0.93, p < 0.001) and the use of dermal HT (OR 3.00, p = 0.05). The observational design of the study prevents conclusions about causal relationships between the identified factors and depression. Another limitation of the study is that the assessment of depressive symptoms, menopausal symptoms, and social support was conducted at a single time point at intake, preventing the analysis of changes over time. To fully address the mental health needs of patients with POI, a multidisciplinary approach is essential, incorporating psychological support, symptom management strategies, and tailored interventions to address the specific challenges faced by this population. No