Clustering Identifies Subtypes With Different Phenotypic Characteristics in Women With Polycystic Ovary Syndrome.

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.

Hormone replacement therapy in women with iatrogenic premature ovarian insufficiency after radiotherapy for cervical cancer: A retrospective cohort and survey study.

OBJECTIVES: This study assessed the uptake of hormone replacement therapy (HRT) in cervical cancer patients with iatrogenic menopause. Survival in relation to HRT use was assessed via a retrospective chart study, and the severity of menopausal symptoms, motivations and barriers to starting HRT were examined via questionnaires. STUDY DESIGN: In total, 293 women under the age of 51 and treated with radiotherapy for cervical cancer between 2010 and 2020 were identified. Medical records were searched for information on HRT use. If still living, women were sent digital questionnaires addressing menopausal symptoms, quality of life (QoL) and potential barriers and motivations concerning HRT use. Univariable data were analysed using Mann-Whitney U, chi-square, and Fisher's exact test, while logistical regression was used to analyse relationships between certain variables and use of HRT and survival. RESULTS: Overall HRT uptake was 78.1 %, which was related to age and Charlson Comorbidity Index, but independent of the duration of radiotherapy or FIGO stage. Overall survival was higher for HRT users (χ2(1) = 4.3, p = 0.038). Questionnaires were sent to 193 patients and 100 completed it (response rate 51.8 %). Main reasons for HRT use were relief of hot flushes and improvement in QoL. For women below age 51, QoL was indeed higher for current HRT users than for non-HRT users (EQ-index 0.8 vs. 0.7, p = 0.008). CONCLUSIONS: HRT prescription rate was inversely correlated with age. Survival was not negatively affected by HRT use. It is important to stress the benefits of HRT and address women's fears regarding its use.

Sexual function in women with premature ovarian insufficiency (POI): Systematic review and meta-analysis.

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 (I2 = 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.

Introducing a value-based healthcare approach for women with premature ovarian insufficiency (POI): Recommendations for patient-centered outcomes in clinical practice.

OBJECTIVE: To establish a set of clinician and patient-reported outcome measures (PROMs) and present the initial findings of a value-based healthcare (VBHC) program in patients with premature ovarian insufficiency (POI). METHODS: Employing a four-phase approach, we identified the most crucial domains for patients with POI and translated these into PROMs. Prior to each visit, patients completed questionnaires to evaluate: depression (BDI-II), menopausal symptoms (GCS), work ability (WAS) and infertility (FertiQoL). During the visits, cardiovascular health assessments and dual-energy X-ray absorptiometry (DEXA) scans to measure bone mineral density were performed. Data at intake is presented, and comparisons are drawn between women using and those not using hormone replacement therapy (HRT). Patient-reported experience measures (PREMs) were evaluated by a questionnaire. RESULTS: A total of 267 POI patients completed the PROM questionnaires, of whom 58.1 % were using HRT at intake. Over half of the patients (53.5 %), had a BDI-II score of 14 or higher, indicating mild to severe depression. The mean total GCS score was 20.9 (SD 11.3). The median work ability score was 7.5 (IQR 6.0-8.0) and the mean FertiQoL score 63.9 (SD 15.7). Additionally, 22.7 % of patients presented with hypertension, 6.2 % with hypercholesterolemia, and almost 50 % had low bone mass. Patients rated the VBHC program with a mean of 8.6 (SD 1.2). CONCLUSIONS: These findings underscore the necessity of a multidisciplinary VBHC program incorporating standardized screening and psychological treatment. We advocate for the implementation of patient-centered outcomes for clinical practice, which have been found to be highly relevant by patients with POI.

Age-related curves of AMH using the Gen II, the picoAMH and the Elecsys assays in women with polycystic ovary syndrome.

CONTEXT: Several challenges still exist to adopt the anti-Müllerian hormone (AMH) as a marker of polycystic ovary morphology (PCOM), as included in the recently updated international guideline. Although different evaluations of age- and assay-specific reference ranges have been published in the last 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 three different assays. DESIGN: Retrospective cross-sectional study. PATIENTS: 2,725 women aged 20 to 40 years with PCOS diagnosis were included. INTERVENTION (S): Serum AMH measurement by the Gen II (Beckman Coulter), the picoAMH (Ansh Labs), and the Elecsys (Roche) assays. MAIN OUTCOME MEAUSRE (S): Age-specific centile 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 LMS method for all the assays. AMH levels were significantly different between PCOS phenotypes. AMH levels were positive correlated to luteinizing hormone (LH), LH/follicular stimulating hormone (FSH) ratio, testosterone, androstenedione, free androgen index, mean follicular number, and mean ovarian volume. CONCLUSIONS: 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 PCOS women. These findings may help to interpret AMH levels in PCOS patients and facilitate the use of AMH as a diagnostic tool across age ranges.

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. RESULTS: The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10-12) and rs2228260 within XBP1 (P = 3.68 × 10-8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10-6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10-9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10-6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. CONCLUSIONS: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

Can we predict menopause and premature ovarian insufficiency?

The prediction of menopause and premature ovarian insufficiency (POI) involves understanding the factors that contribute to the timing of these events. Menopause is a natural biological process marked by the cessation of menstrual periods, typically occurring around the age of 51. On the other hand, POI refers to the loss of ovarian function before the age of 40. Several factors have been used to predict menopause and POI such as age, antimüllerian hormone, inhibins and follicle-stimulating hormone serum levels, antral follicle counts, menstrual cycle length, and, recently, some genetic markers. It seems that age has the best predictive power and all the other ones are only adding in a very limited way to the prediction of menopause. Low levels of antimüllerian hormone in young women might indicate a greater risk for POI and could facilitate early diagnosis. It is, however, important to note that predicting the exact timing of menopause and POI is challenging, and individual variations are significant. Although these factors can provide some insights, they are not foolproof predictors. Advances in medical research and technology may lead to more accurate methods for predicting menopause and POI in the future.

Clinical Relevance of Vaginal and Endometrial Microbiome Investigation in Women with Repeated Implantation Failure and Recurrent Pregnancy Loss.

Recent studies have investigated if and how the vaginal and endometrial microbiome might affect endometrial receptivity and reproductive health. Although there is no consensus on the existence of a core uterine microbiome yet, evidence shows that the dominance of Lactobacillus spp. in the female reproductive tract is generally associated with eubiosis and improved chances of successful implantation and an ongoing pregnancy. Conversely, vaginal and endometrial dysbiosis can cause local inflammation and an increase of pro-inflammatory cytokines, compromising the integrity and receptivity of the endometrial mucosa and potentially hampering successful embryonic implantation. This review provides a critical appraisal of the influence of the vaginal and endometrial microbiome as parts of the female reproductive tract on fertility outcomes, focusing on repeated implantation failure (RIF) and recurrent pregnancy loss (RPL). It seems that RIF as well as RPL are both associated with an increase in microbiome diversity and a loss of Lactobacillus dominance in the lower female reproductive system.

The prevalence of thyroid dysfunction and hyperprolactinemia in women with PCOS.

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.

Trabecular bone density in middle-aged women with reproductive disorders.

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.

Change in Androgenic Status and Cardiometabolic Profile of Middle-Aged Women with Polycystic Ovary Syndrome.

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.

Incidental findings on coronary computed tomography in women with selected reproductive disorders.

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.

Comparison of 3 Different AMH Assays With AMH Levels and Follicle Count in Women With Polycystic Ovary Syndrome.

CONTEXT: Anti-Müllerian hormone (AMH) levels strongly correlate with the number of antral follicles (total follicle count, TFC) in the ovary. In women with polycystic ovary syndrome (PCOS), this is reflected by significantly increased serum AMH levels. Different assays have been developed to measure AMH. However, little is known about the interassay correlation in women with increased AMH levels. OBJECTIVE: To investigate the correlation of AMH values between different AMH assays and with TFC in PCOS patients. METHODS: AMH levels were measured in 1660 PCOS patients, using 3 different AMH assays: Gen II (Beckman Coulter); picoAMH (Ansh Labs); and Elecsys (Roche). Passing Bablok regression was used to compare assay methods. Spearman's correlation was used to correlate AMH levels and TFC. RESULTS: Strong interassay correlations were present over the total range of AMH levels (0.81-0.94). Stratification in subgroups, revealed an AMH level-dependent interassay correlation with strong interassay correlations in the low (<2.80 ng/mL) and high (>7.04 ng/mL) subgroups (0.62-0.86). However, the correlation in the mid-AMH subgroup (2.80-7.04 ng/mL) was only moderate (0.28-0.56). A strong correlation was present between the total range of AMH levels and TFC (0.57-0.62). However, in all 3 AMH subgroups the correlation became moderate at best, independently of assay method (0.11-0.45). CONCLUSION: In conclusion, both the interassay correlation and the correlation between AMH level and follicle count depend on the range of serum AMH levels. This once more emphasizes the need of a standardization of AMH measurement for an accurate interpretation of AMH in clinical practice.

Cardiometabolic biomarkers in women with polycystic ovary syndrome.

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.

Association between an AMH promoter polymorphism and serum AMH levels in PCOS patients.

STUDY QUESTION: Do polymorphisms in the anti-Müllerian hormone (AMH) promoter have an effect on AMH levels in patients with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: We have identified a novel AMH promoter polymorphism rs10406324 that is associated with lower serum AMH levels and is suggested to play a role in the mechanism of regulation of AMH gene expression in women. WHAT IS KNOWN ALREADY: Follicle number is positively correlated with serum AMH levels, reflected by elevated AMH levels in women with PCOS. In addition, it is suggested that AMH production per follicle is higher in women with PCOS than in normo-ovulatory women, implying an altered regulation of AMH in PCOS. STUDY DESIGN, SIZE, DURATION: A discovery cohort of 655 PCOS women of Northern European ancestry and both an internal and external validation PCOS cohort (n = 458 and n = 321, respectively) were included in this study. Summary-level data of an AMH genome-wide association study meta-analysis including 7049 normo-ovulatory women was included as a control cohort. A genetic approach was taken through association analysis and in silico analysis of the associated variants in the AMH promoter. In vitro analysis was performed to investigate the functional mechanisms. PARTICIPANTS/MATERIALS, SETTING, METHODS: All common two-allelic single-nucleotide polymorphisms (SNPs) in the region Chr19:2 245 353-2 250 827 bp (Build 37) were selected for the analysis. Linear regression analyses were performed to determine the association between SNPs in the AMH promoter region and serum AMH levels. For the in silico analysis, the webtools 'HaploReg' v4.1 for ENCODE prediction weight matrices and 'atSNP' were used. In vitro analysis was performed using KK1 cells, a mouse granulosa cell line and COV434 cells, a human granulosa tumor cell line. Cells were transfected with the reference or the variant human AMH promoter reporter construct together with several transcription factors (TFs). Dual-Glo® Luciferase Assay was performed to measure the luciferase activity. MAIN RESULTS AND THE ROLE OF CHANCE: Polymorphism rs10406324 was significantly associated with serum AMH levels in all three PCOS cohorts. Carriers of the minor allele G had significantly lower log-transformed serum AMH levels compared to non-carriers (P = 8.58 × 10-8, P = 1.35 × 10-3 and P = 1.24 × 10-3, respectively). This result was validated in a subsequent meta-analysis (P = 3.24 × 10-12). Interestingly, rs10406324 was not associated with follicle count, nor with other clinical traits. Also, in normo-ovulatory women, the minor allele of this variant was associated with lower serum AMH levels (P = 1.04 × 10-5). These findings suggest that polymorphism rs10406324 plays a role in the regulation of AMH expression, irrespective of clinical background. In silico analysis suggested a decreased binding affinity of the TFs steroidogenenic factor 1, estrogen-related receptor alpha and glucocorticoid receptor to the minor allele G variant, however in vitro analysis did not show a difference in promoter activity between the A and G allele. LIMITATIONS, REASONS FOR CAUTION: Functional analyses were performed in a mouse and a human granulosa cell line using an AMH promoter reporter construct. This may have limited assessment of the impact of the polymorphism on higher order chromatin structures. Human granulosa cells generated from induced pluripotent stem cells, combined with gene editing, may provide a method to elucidate the exact mechanism behind the decrease in serum AMH levels in carriers of the -210 G allele. We acknowledge that the lack of follicle number in the external validation and the control cohort is a limitation of the paper. Although we observed that the association between rs10406324 and AMH levels was independent of follicle number in our discovery and internal validation PCOS cohorts, we cannot fully rule out that the observed effects on serum AMH levels are, in part, caused by differences in follicle number. WIDER IMPLICATIONS OF THE FINDINGS: These results suggest that variations in serum AMH levels are not only caused by differences in follicle number but also by genetic factors. Therefore, the genetic context should be taken into consideration when assessing serum AMH levels in women. This may have clinical consequences when serum AMH levels are used as a marker for the polycystic ovarian morphology phenotype. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used. J.S.E.L. has received consultancy fees from the following companies: Ferring, Roche Diagnostics and Ansh Labs and has received travel reimbursement from Ferring. J.A.V. has received royalties from AMH assays, paid to the institute/lab with no personal financial gain. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Changes in individual polycystic ovary syndrome phenotypical characteristics over time: a long-term follow-up study.

OBJECTIVE: To assess the effects of aging on the features of polycystic ovary syndrome (PCOS). DESIGN: Cohort study. SETTING: Tertiary care center. PATIENT(S): Women with PCOS, diagnosed according to the 2003 Rotterdam criteria, who visited our outpatient clinic repeatedly. INTERVENTION(S): Comparisons were made between the first visit and consecutive visits. MAIN OUTCOME MEASURE(S): Change in PCOS phenotype groups in terms of clinical and endocrine characteristics. RESULT(S): A total of 596 women visited the outpatient clinic repeatedly. An estimated change per 5-year age showed a decrease in the prevalence of phenotype A and an increase in the prevalence of not having PCOS. The serum levels of testosterone, androstenedione, and dehydroepiandrosterone sulfate as well as the free androgen index decreased significantly. Clinical characteristics showed an increase in terms of body mass index and waist circumference, whereas plasma glucose levels, insulin levels, and insulin resistance did not change significantly. CONCLUSION(S): The prevalence of PCOS phenotype groups changes over time. There is an important age effect that indicates a more regular menstrual cycle, decrease in the serum androgen levels, and improvement in polycystic ovarian morphology when aging occurs in women with PCOS.

Shared Genetics Between Age at Menopause, Early Menopause, POI and Other Traits.

Reproductive ageing leading to menopause is characterized by depletion of follicles and its regulating mechanisms are only partly understood. Early age at menopause and premature ovarian insufficiency (POI) are associated with several other traits such as cardiovascular disease, dyslipidemia, osteoporosis and diabetes. In large cohorts of Northern European women hundreds of Single Nucleotide Polymorphisms (SNPs) have been identified to be associated with age at menopause. These SNPs are located in genes enriched for immune and mitochondrial function as well as DNA repair and maintenance processes. Genetic predisposition to earlier menopause might also increase the risk of other associated traits. Increased risk for cardiovascular disease in women has been associated with age at menopause lowering SNPs. Pleiotropy between early age at menopause and increased mortality from coronary artery disease has been observed, implicating that genetic variants affecting age at menopause also affect the risk for coronary deaths. This review will discuss the shared genetics of age at menopause with other traits. Mendelian Randomization studies implicate causal genetic association between age at menopause and age at menarche, breast cancer, ovarian cancer, BMD and type 2 diabetes. Although the shared biological pathways remain to be determined, mechanisms that regulate duration of estrogen exposure remain an important focus.

Estrogens and Progestogens in Triple Negative Breast Cancer: Do They Harm?

Triple-negative breast cancers (TNBC) occur more frequently in younger women and do not express estrogen receptor (ER) nor progesterone receptor (PR), and are therefore often considered hormone-insensitive. Treatment of premenopausal TNBC patients almost always includes chemotherapy, which may lead to premature ovarian insufficiency (POI) and can severely impact quality of life. Hormone replacement therapy (HRT) is contraindicated for patients with a history of hormone-sensitive breast cancer, but the data on safety for TNBC patients is inconclusive, with a few randomized trials showing increased risk-ratios with wide confidence intervals for recurrence after HRT. Here, we review the literature on alternative pathways from the classical ER/PR. We find that for both estrogens and progestogens, potential alternatives exist for exerting their effects on TNBC, ranging from receptor conversion, to alternative receptors capable of binding estrogens, as well as paracrine pathways, such as RANK/RANKL, which can cause progestogens to indirectly stimulate growth and metastasis of TNBC. Finally, HRT may also influence other hormones, such as androgens, and their effects on TNBCs expressing androgen receptors (AR). Concluding, the assumption that TNBC is completely hormone-insensitive is incorrect. However, the direction of the effects of the alternative pathways is not always clear, and will need to be investigated further.

Characteristics of polycystic ovary syndrome throughout life.

Polycystic ovary syndrome is the most common endocrine disorder in women of reproductive age. It is a complex disease in which genetic, endocrine, environmental, and behavioral factors are intertwined, giving rise to a heterogeneous phenotype with reproductive, metabolic, and psychological characteristics. Polycystic ovary syndrome affects women's health and their quality of life across the life course. During different life stages, the polycystic ovary syndrome phenotype can change, which requires a personalized diagnostic approach and treatment. Polycystic ovary syndrome is a major cause of anovulatory infertility; this disorder is also associated with hirsutism and acne. Diagnosing polycystic ovary syndrome during adolescence is challenging because the polycystic ovary syndrome criteria include normal physiological events that occur during puberty. With increasing age, the syndrome evolves from a reproductive disease to a more metabolic disorder. Along with metabolic disturbances, including insulin resistance and abnormalities of energy expenditure, polycystic ovary syndrome is recognized as a major risk factor for the development of type 2 diabetes and cardiovascular disease in later life. Moreover, there is evidence for familial clustering of endocrine and metabolic features of polycystic ovary syndrome. Environmental factors such as diet and obesity appear to contribute to the phenotype. Treatment should be tailored to the specific concerns and needs of the individual patient and involves restoring fertility, treatment of the metabolic complaints, treatment of androgen excess, and providing endometrial protection. The complexity of the disorder, and the impact on quality of life, requires a timely diagnosis, screening for complications, and management strategies for the long-term health issues associated with polycystic ovary syndrome. The syndrome remains underdiagnosed, and women experience significant delays to diagnosis.

Premature and Early Menopause in Relation to Cardiovascular Disease.

Postmenopausal women have an increased risk for cardiovascular diseases. It has been postulated that the loss of ovarian function and subsequent deficiency of endogenous estrogens after menopause contributes to this elevated risk of cardiovascular disease in postmenopausal women. Compared with woman entering menopause at the mean age of 51 years, in women with early menopause or premature ovarian insufficiency the risk for cardiovascular disease is even greater. These women lack the cardioprotective effect of endogenous estrogens for many more years than do women entering natural menopause. The majority of data assessing the risk of cardiovascular disease in relation to age at menopause and specifically premature menopause are derived from large epidemiological cohort studies. In addition, observations in women undergoing bilateral oophorectomy at an early age provide convincing evidence regarding association between early menopause or POI and the development of cardiovascular events and mortality. Moreover, genetic variants associated with earlier age at menopause have also been found to increase the risk of cardiovascular events in women. It has been substantiated that hormone replacement therapy (HRT) decreases the risk for ischemic heart disease and eliminates the increased cardiovascular disease mortality. It is therefore crucial to start HRT as soon as possible, particularly in women with premature ovarian insufficiency.