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Context: Hierarchical clustering (HC) identifies subtypes of polycystic ovary syndrome (PCOS)., Objective: This work aimed to identify clinically significant subtypes in a PCOS cohort diagnosed with the Rotterdam criteria and to further characterize the distinct subtypes., Methods: Clustering was performed using the variables body mass index (BMI), luteinizing hormone (LH), follicle-stimulating hormone, dehydroepiandrosterone sulfate, sex hormone-binding globulin (SHBG), testosterone, insulin, and glucose. Subtype characterization was performed by analyzing the variables estradiol, androstenedione, dehydroepiandrosterone, cortisol, anti-Müllerian hormone (AMH), total follicle count (TFC), lipid profile, and blood pressure. Study participants were girls and women who attended our university hospital for reproductive endocrinology screening between February 1993 and February 2021. In total, 2502 female participants of European ancestry, aged 13 to 45 years with PCOS (according to the Rotterdam criteria), were included. A subset of these (n = 1067) fulfilled the National Institutes of Health criteria (ovulatory dysfunction and hyperandrogenism). Main outcome measures included the identification of distinct PCOS subtypes using cluster analysis. Additional clinical variables associated with these subtypes were assessed., Results: Metabolic, reproductive, and background PCOS subtypes were identified. In addition to high LH and SHBG levels, the reproductive subtype had the highest TFC and levels of AMH (all P < .001). In addition to high BMI and insulin levels, the metabolic subtype had higher low-density lipoprotein levels and higher systolic and diastolic blood pressure (all P < .001). The background subtype had lower androstenedione levels and features of the other 2 subtypes., Conclusion: Reproductive and metabolic traits not used for subtyping differed significantly in the subtypes. These findings suggest that the subtypes capture distinct PCOS causal pathways., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Importance: As part of the 2023 international evidence-based polycystic ovary syndrome (PCOS) guideline, this meta-analysis investigated the inclusion of Anti-Müllerian hormone (AMH) levels in the diagnostic criteria for PCOS., Objective: To answer the following three questions: 1) Are AMH levels effective in diagnosing PCOS in adult women? 2) Are AMH levels effective in diagnosing PCOS in adolescents? Are AMH levels effective in diagnosing polycystic ovarian morphology (PCOM)?, Data Sources: Searches were conducted in six databases until July 31, 2023., Study Selection and Synthesis: Eligible studies were those conducted in humans, published in English, and reporting sensitivity, specificity, and/or area under the curve values. Extracted data included study population, age, body mass index, AMH assay, cut-off value of AMH levels, sensitivity, specificity, and area under the curve values. The risk of bias was assessed using the quality assessment of diagnostic accuracy studies tool. A random effects model was used to test diagnostic accuracy., Main Outcomes: Pooled sensitivity and specificity to use AMH levels for PCOS diagnosis in adults as well as adolescents and for detecting PCOM in adults., Results: Eighty-two studies were included. The adult AMH-PCOS meta-analyses (n = 68) showed a pooled sensitivity and specificity of 0.79 (95% confidence interval [CI], 0.76-0.82; I 2 = 86%) and 0.87 (95% CI, 0.84-0.89; I 2 = 91%). The adolescent AMH-PCOS meta-analysis (n = 11) showed a pooled sensitivity and specificity of 0.66 (95% CI, 0.58-0.73; I 2 = 74%) and 0.78 (95% CI, 0.71-0.83; I 2 = 45%). The adult AMH-PCOM meta-analysis (n = 7) showed a pooled sensitivity and specificity of 0.79 (95% CI, 0.72-0.85; I 2 = 94%) and 0.87 (95% CI, 0.78-0.93; I 2 = 94%). CONCLUSION AND RELEVANCE: This study investigated the most profound change in the 2023 international evidence-based PCOS guideline, which now recommends AMH levels for defining PCOM in adults in accordance with the diagnostic algorithm. Antimüllerian hormone levels alone are insufficient for PCOS diagnosis and are nonspecific for PCOM in adolescents. Multiple factors influence AMH levels and cause heterogeneity as well as limitations in this study. Consequently, no international cut-off value could be recommended, emphasizing the need for research on more individualized cut-off values., Competing Interests: Declaration of Interests K.V.D.H. has nothing to disclose. J.S.E.L. reports grants from Ansh Labs, Webster, Tx, USA, from Ferring, Hoofddorp, NL, from Roche Diagnostics, Rotkreuz, Switzerland, from Merck, Schiphol-Rijk, NL, and personal fees from Ferring, Hoofddorp, NL, from Titus Healthcare, Hoofddorp, NL, from Gedeon Richter, Groot-Bijgaarden, Belgium, from Ansh Labs, Webster, TX, USA, from Roche Diagnostics, Rotkreuz, Switzerland, and is an unpaid board member and president of the AE-PCOS Society, and a member of the ASRM Research Integrity Committee, outside the submitted work. C.T.T. receives funding from the Australian National Health and Medical Research Council supported Centre for Research in Women's Health in Reproductive Life. A.M. receives fellowship (salary) funding from the Australian National Health and Medical Research Council. H.T. receives funds from fellowship (salary) and grants from the Australian National Health and Medical Research Council and Australian Federal Government. Y.V.L. has nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Several challenges still exist to adopt the anti-müllerian hormone (AMH) as a marker of polycystic ovary morphology, as included in the recently updated international guideline. Although different evaluations of age- and assay-specific reference ranges have been published in the past few years, these studies have mainly been conducted in normo-ovulatory or infertile women., Objective: To develop an age-specific percentile distribution of AMH in patients with polycystic ovary syndrome (PCOS) measured by 3 different assays., Design: Retrospective cross-sectional study., Patients: A total of 2725 women aged 20 to 40 years with PCOS diagnosis were included., Interventions: Serum AMH measurement by the Gen II (Beckman Coulter), the picoAMH (Ansh Labs), and the Elecsys (Roche) assays., Main Outcome Measures: Age-specific percentile curves for all the assays and correlations between AMH, clinical, hormonal, and ultrasound characteristics., Results: Age-related nomograms for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of AMH were calculated using the Lambda-Mu-Sigma method for all the assays. AMH levels were significantly different between PCOS phenotypes. AMH levels were positively correlated to LH, LH/FSH ratio, testosterone, androstenedione, free androgen index, mean follicular number, and mean ovarian volume., Conclusion: To our knowledge, this is the first study reporting age-specific percentile nomograms of serum AMH levels measured by the Gen II, the picoAMH, and the Elecsys assays in a large population of women with PCOS. These findings may help to interpret AMH levels in patients with PCOS and facilitate the use of AMH as a diagnostic tool across age ranges., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: To study the value of current definitions for follicle number per ovary and ovarian volume in the diagnosis of polycystic ovary syndrome (PCOS)., Design: Cross-sectional study., Setting: University tertiary care center., Patient(s): Women diagnosed with PCOS after standardized screening were eligible for inclusion in the PCOS group. Women without PCOS who underwent the same screening, had regular menstrual cycles, normal hormonal values, and no other endocrine pathology were eligible for inclusion., Intervention(s): Not applicable., Main Outcome Measure(s): Follicle number per ovary and ovarian volume in women with PCOS, stratified by age. Linear regression models to investigate the influence of body mass index (BMI) on follicle number per ovary and ovarian volume. Differences in follicle number per ovary and ovarian volume between the PCOS phenotypes and the additional value of ovarian volume compared with follicle number per ovary., Result(s): A total of 2,492 women (16-50 years) with PCOS and 152 women without PCOS were included. Most women with PCOS up to age of 35 exhibit a follicle number per ovary ≥20 (87.8%-100%) (using an ultrasound transducer ≥8 MHz) or ≥12 (95.1%-98.6%) (using a transducer <8 MHz), followed by a decline in follicle number per ovary >35 years. Median ovarian volume was below the 10 mL cutoff in every age group, for both ultrasound transducers. Follicle number per ovary and ovarian volume were higher in women with PCOS compared with women without PCOS in every age category. In our cohort, 13/2,297 women with PCOS (0.6%) would not have received the diagnosis if ovarian volume was not considered a marker for polycystic ovarian morphology. For both ultrasound transducers, women with phenotype A (ovulatory dysfunction + hyperandrogenism + polycystic ovarian morphology) exhibited the highest follicle number per ovary and ovarian volume, followed by phenotype D (ovulatory dysfunction + polycystic ovarian morphology), then phenotype C (hyperandrogenism + polycystic ovarian morphology), and then phenotype B (ovulatory dysfunction + hyperandrogenism). No clinically significant correlation between BMI and follicle number per ovary or ovarian volume was observed., Conclusion(s): Criteria to define follicle number per ovary should be established per age category, as follicle number per ovary decreases with age. Ovarian volume shows a less clear decline with age and has a lower discriminative power, and therefore could be excluded from the diagnostic criteria. Follicle number per ovary does not need to be stratified by BMI., Competing Interests: Declaration of Interests K.v.d.H. has nothing to disclose. F.B. has nothing to disclose. E.v.S. has nothing to disclose. M.E.L. has nothing to disclose. J.S.E.L. reports grants from Ansh Labs, Ferring, Roche Diagnostics, Merck, outside the submitted work; personal fees from Ferring, Titus Healthcare, Gedeon Richter, Ansh Labs, Roche Diagnostics; honoraria and travel expenses from Ferring and Roche Diagnostics; data safety monitoring board for LOCI Trail UK; an unpaid Board Member and President of the Androgen Excess and PCOS Society; and a member of the American Society for Reproductive Medicine Research Integrity Committee, outside the submitted work. Y.V.L. reports honoraria fees from Ferring and Merck; travel support from Ferring; and funding from Synergy Erasmus Medical Center grant, outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Ovulatory dysfunction is usually caused by an endocrine disorder, of which polycystic ovary syndrome (PCOS) is the most common cause. PCOS is usually associated with estrogen levels within the normal range and can be characterized by oligo-/anovulation resulting in decreased progesterone levels. It is suggested that decreased progesterone levels may lead to more autoimmune diseases in women with PCOS. In addition, it is often claimed that there is an association between hyperprolactinemia and PCOS. In this large well-phenotyped cohort of women with PCOS, we have studied the prevalence of thyroid dysfunction and hyperprolactinemia compared to controls, and compared this between the four PCOS phenotypes., Methods: This retrospective cross-sectional study contains data of 1429 women with PCOS and 299 women without PCOS. Main outcome measures included thyroid stimulating hormone (TSH), Free Thyroxine (FT4), and anti-thyroid peroxidase antibodies (TPOab) levels in serum, the prevalence of thyroid diseases and hyperprolactinemia., Results: The prevalence of thyroid disease in PCOS women was similar to that of controls (1.9% versus 2.7%; P = 0.39 for hypothyroidism and 0.5% versus 0%; P = 0.99 for hyperthyroidism). TSH levels were also similar (1.55 mIU/L versus 1.48 mIU/L; P = 0.54). FT4 levels were slightly elevated in the PCOS group, although within the normal range (18.1 pmol/L versus 17.7 pmol/L; P < 0.05). The prevalence of positive TPOab was similar in both groups (5.7% versus 8.7%; P = 0.12). The prevalence of hyperprolactinemia was similarly not increased in women with PCOS (1.3%% versus 3%; P = 0.05). In a subanalysis of 235 women with PCOS and 235 age- and BMI-matched controls, we found no differences in thyroid dysfunction or hyperprolactinemia. In according to differences between PCOS phenotypes, only the prevalence of subclinical hypothyroidism was significantly higher in phenotype B (6.3%, n = 6) compared to the other phenotypes., Conclusion: Women with PCOS do not suffer from thyroid dysfunction more often than controls. Also, the prevalence of positive TPOab, being a marker for future risk of thyroid pathology, was similar in both groups. Furthermore, the prevalence of hyperprolactinemia was similar in women with PCOS compared to controls., Competing Interests: JL 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 remaining 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 © 2023 van der Ham, Stekelenburg, Louwers, van Dorp, Schreurs, van der Wal, Steegers-Theunissen and Laven.)

Besides age, estrogen exposure plays a crucial role in changes in bone density (BD) in women. Premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS) are conditions in reproductive-aged women in which the exposure to estrogen is substantially different. Women with a history of preeclampsia (PE) are expected to have normal estrogen exposure. Within the CREw-IMAGO study, we investigated if trabecular BD is different in these women because of differences in the duration of estrogen exposure. Trabecular BD was measured in thoracic vertebrae on coronary CT scans. Women with an reduced estrogen exposure (POI) have a lower BD compared to women with an intermediate exposure (PE) (mean difference (MD) -26.8, 95% confidence interval (CI) -37.2 - -16.3). Women with a prolonged estrogen exposure (PCOS) have the highest BD (MD 15.0, 95% CI 4.3 - 25.7). These results support the hypothesis that the duration of estrogen exposure in these women is associated with trabecular BD.

Understanding the cardiovascular disease (CVD) risk for women with polycystic ovary syndrome (PCOS) at reproductive age is crucial. To investigate this, we compared the cardiometabolic profiles of different PCOS groups over a median interval of 15.8 years. The study focused on three groups: (1) women with PCOS who were hyperandrogenic at both initial and follow-up screening (HA-HA), (2) those who transitioned from hyperandrogenic to normoandrogenic (HA-NA), and (3) those who remained normoandrogenic (NA-NA). At initial and follow-up screenings, both HA-HA and HA-NA groups showed higher body mass indexes compared to the NA-NA group. Additionally, at follow-up, the HA-HA and HA-NA groups exhibited higher blood pressure, a higher prevalence of hypertension, elevated serum triglycerides and insulin levels, and lower levels of HDL cholesterol compared to the NA-NA group. Even after adjusting for BMI, significant differences persisted in HDL cholesterol levels and hypertension prevalence among the groups (HA-HA: 53.8%, HA-NA: 53.1%, NA-NA: 14.3%, p < 0.01). However, calcium scores and the prevalence of coronary plaques on CT scans were similar across all groups. In conclusion, women with PCOS and hyperandrogenism during their reproductive years exhibited an unfavorable cardiometabolic profile during their post-reproductive years, even if they changed to a normoandrogenic status.

Objective: To determine the prevalence of incidental findings (IFs) on coronary computed tomography (CCT) in women aged 45-55 years and previously diagnosed with reproductive disorders such as polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) or preeclampsia (PE)., Methods: A total of 486 middle-aged women with PCOS (n = 101), POI (n = 97) or a history of PE (n = 288) underwent a CCT as part of a prior prospective study. IFs were categorized by their significance (minor, moderate and major). Follow-up information was collected from patients' records. To investigate the impact of different field of views (FOVs), a subset of scans was analyzed in full FOV and small FOV., Results: In 96/486 (19.8%) women, one or more IFs were detected, of which 54/486 (11.1%) were classified as moderate/major and 48/486 (9.9%) required follow-up. A moderate/major IF was detected in 16/101 (15.9%) women with PCOS, 13/97 (13.4%) women with POI and 25/288 (8.7%) women with a history of PE. In 78 women with an IF detected in the full FOV, the IF was still visible in 60 (76.9%) women in the small FOV. In the full FOV, 46 women required follow-up, but using the small FOV this was reduced to 30 women., Conclusion: Using CCT as a cardiovascular disease screening tool in women with selected reproductive disorders increases the probability of detecting IFs that can cause anxiety and may generate extra costs, but can also reveal clinically relevant findings. Using a small FOV centered around the heart resulted in a lower prevalence of IFs and required less follow-up., (© 2022. The Author(s).)

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Apart from the reproductive problems, PCOS is also associated with metabolic disturbances, and therefore, it also affects adolescents and postmenopausal women with PCOS as well as their offspring and other first-degree relatives. Adolescents with PCOS show unfavorable cardiometabolic biomarkers more often than controls, such as overweight/obesity and hyperandrogenism, and studies also suggest an unfavorable lipid profile. During reproductive age, women with PCOS develop additional cardiometabolic biomarkers, such as hypertension, insulin resistance, and metabolic syndrome. Growing evidence also supports the important role of inflammatory cytokines in cardiovascular health in these women. During menopausal transition, some PCOS characteristics ameliorate, whereas other biomarkers increase, such as body mass index, insulin resistance, type 2 diabetes, and hypertension. Offspring of women with PCOS have a lower birth weight and a higher body mass index later in life than controls. In addition, fathers, mothers, and siblings of women with PCOS show unfavorable cardiometabolic biomarkers. Therefore, cardiovascular screening and follow-up of women with PCOS and their offspring and siblings are of utmost importance., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Given all its systemic adaptive requirements, pregnancy shares several features with physical exercise. In this pilot study, we aimed to assess the physiological response to submaximal cardiopulmonary exercise testing (CPET) in early pregnancy. In 20 healthy, pregnant women (<13 weeks gestation) and 20 healthy, non-pregnant women, we performed a CPET with stationary cycling during a RAMP protocol until 70% of the estimated maximum heart rate (HR) of each participant. Hemodynamic and respiratory parameters were non-invasively monitored by impedance cardiography (PhysioFlow ® ) and a breath-by-breath analyzer (Oxycon TM ). To compare both groups, we used linear regression analysis, adjusted for age. We observed a similar response of stroke volume, cardiac output (CO) and HR to stationary cycling in pregnant and non-pregnant women, but a slightly lower 1-min recovery rate of CO (-3.9 [-5.5;-2.3] vs. -6.6 [-8.2;-5.1] L min -1  min -1 ; p = .058) and HR (-38 [-47; -28] vs. -53 [-62; -44] bpm/min; p = .065) in pregnant women. We also observed a larger increase in ventilation before the ventilatory threshold (+6.2 [5.4; 7.0] vs. +3.2 [2.4; 3.9] L min -1  min -1 ; p < .001), lower P ET CO 2 values at the ventilatory threshold (33 [31; 34] vs. 36 [34; 38] mmHg; p = .042) and a larger increase of breathing frequency after the ventilatory threshold (+4.6 [2.8; 6.4] vs. +0.6 [-1.1; 2.3] breaths min -1  min -1 ; p = .015) in pregnant women. In conclusion, we observed a slower hemodynamic recovery and an increased ventilatory response to exercise in early pregnancy., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)