Decreased role of neuropeptides in the microvascular function in migraine patients with polycystic ovary syndrome.

BACKGROUND AND AIMS: To understand pathophysiological mechanisms underlying migraine as a cardiovascular risk factor, we studied neuropeptide action and endothelial function as measures of peripheral microvascular function in middle-aged women with or without migraine. METHODS: We included women with the endocrine disorder polycystic ovary syndrome (PCOS), a population with supposed elevated cardiovascular risk, with and without comorbid migraine. In 26 women without and 23 women with migraine in the interictal phase (mean age 50.8 ± 2.9 years) local thermal hyperemia (LTH) of the skin of the volar forearm was measured cross-sectionally under control conditions, after inhibition of neuropeptide release by 5% lidocaine/prilocaine (EMLA) cream application, and after inhibition of nitric oxide formation by iontophoresis of NG-monomethyl-l-arginine (L-NMMA). Hereafter, changes in the natural logarithm of the reactive hyperemia index (lnRHI) and augmentation index (AI) during reperfusion after occlusion-derived ischemia were measured. RESULTS: While mean values under control conditions and L-NMMA conditions were similar, migraine patients had a significantly higher mean area of the curve (AUC) of the total LTH response after EMLA application than those without (86.7 ± 26.5% versus 67.9 ± 24.2%; p = 0.014). This was also reflected by a higher median AUC of the plateau phase under similar conditions in women with migraine compared to those without (83.2% (IQR[73.2-109.5]) versus 73.2% (IQR[54.3-92.0]); p = 0.039). Mean changes in lnRHI and AI scores were similar in both groups. CONCLUSIONS: In PCOS patients with migraine, neuropeptide action was lower compared with those without migraine. While larger studies are warranted, these findings provide a potential mechanism supporting previous findings that migraine may be independent from traditional risk factors, including atherosclerosis.

Predicting pregnancy chances leading to term live birth in oligo/anovulatory women diagnosed with PCOS.

RESEARCH QUESTION: Which patient features predict the time to pregnancy (TTP) leading to term live birth in infertile women diagnosed with polycystic ovary syndrome (PCOS)? DESIGN: Prospective cohort follow-up study was completed, in which initial standardized phenotyping was conducted at two Dutch university medical centres from January 2004 to January 2014. Data were linked to the Netherlands Perinatal Registry to obtain pregnancy outcomes for each participant. All women underwent treatment according to a standardized protocol, starting with ovulation induction as first-line treatment. Predictors of pregnancies (leading to term live births) during the first year after PCOS diagnosis were evaluated. RESULTS: A total of 1779 consecutive women diagnosed with PCOS between January 2004 and January 2014 were included. In the first year following screening, 659 (37%) women with PCOS attained a pregnancy leading to term birth (≥37 weeks of gestational age). A higher chance of pregnancy was associated with race, smoking, body mass index (BMI), insulin, total testosterone and sex hormone-binding globulin (SHBG) concentrations (c-statistic = 0.59). CONCLUSIONS: Predictors of an increased chance of a live birth include White race, no current smoking, lower BMI, insulin and total testosterone concentrations, and higher SHBG concentrations. This study presents a nomogram to predict the chances of achieving a pregnancy (leading to a term live birth) within 1 year of treatment.

Randomized Controlled Trial of Neurokinin 3 Receptor Antagonist Fezolinetant for Treatment of Polycystic Ovary Syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS), a highly prevalent endocrine disorder characterized by hyperandrogenism, is the leading cause of anovulatory infertility. OBJECTIVE: This proof-of-concept study evaluated clinical efficacy and safety of the neurokinin 3 (NK3) receptor antagonist fezolinetant in PCOS. METHODS: This was a phase 2a, randomized, double-blind, placebo-controlled, multicenter study (EudraCT 2014-004409-34). The study was conducted at 5 European clinical centers. Women with PCOS participated in the study. Interventions included fezolinetant 60 or 180 mg/day or placebo for 12 weeks. The primary efficacy end point was change in total testosterone. Gonadotropins, ovarian hormones, safety and tolerability were also assessed. RESULTS: Seventy-three women were randomly assigned, and 64 participants completed the study. Adjusted mean (SE) changes in total testosterone from baseline to week 12 for fezolinetant 180 and 60 mg/day were -0.80 (0.13) and -0.39 (0.12) nmol/L vs -0.05 (0.10) nmol/L with placebo (P < .001 and P < .05, respectively). Adjusted mean (SE) changes from baseline in luteinizing hormone (LH) for fezolinetant 180 and 60 mg/d were -10.17 (1.28) and -8.21 (1.18) vs -3.16 (1.04) IU/L with placebo (P < .001 and P = .002); corresponding changes in follicle-stimulating hormone (FSH) were -1.46 (0.32) and -0.92 (0.30) vs -0.57 (0.26) IU/L (P = .03 and P = .38), underpinning a dose-dependent decrease in the LH-to-FSH ratio vs placebo (P < .001). Circulating levels of progesterone and estradiol did not change significantly vs placebo (P > .10). Fezolinetant was well tolerated. CONCLUSION: Fezolinetant had a sustained effect to suppress hyperandrogenism and reduce the LH-to-FSH ratio in women with PCOS.

Does an association exist between menstrual cycle length within the normal range and ovarian reserve biomarkers during the reproductive years? A systematic review and meta-analysis.

BACKGROUND: Regular menstrual cycling during the reproductive years is an indicator of spontaneous ovulation but sometimes falsely perceived as an indicator of preserved fertility. In contrast, menstrual cycle shortening, a physiologic occurrence preceding the menopausal transition, is not usually perceived as an indicator of decreased ovarian reserve in the general population. OBJECTIVE AND RATIONALE: The individual decrease in menstrual cycle length (MCL) might represent a sensitive biomarker of diminishing ovarian reserve. The aim of this systematic review and meta-analysis is to examine the possible association between MCL in regularly cycling women (21-35 days) and ovarian reserve tests (ORT), fecundability in natural cycles and IVF outcomes. SEARCH METHODS: An electronic database search employing PubMed, Web of Science, Trip, EBSCO, ClinicalTrials.gov and the Cochrane library was performed to identify research articles, only on human, published between January 1978 and August 2019. Search terms were pregnancy OR fertility OR fecundity OR fecundability, anti-Müllerian hormone OR AMH OR antral follicle count OR AFC OR ovarian reserve OR ovarian reserve test, in vitro fertilization OR ART OR assisted reproductive therapy OR assisted reproductive treatment OR assisted reproductive technology OR IVF OR ICSI, menstrual cycle length OR menstrual cycle characteristics. We combined these terms to complete the search. All prospective and retrospective studies exploring an association between MCL and proxies of ovarian reserve were included. The exclusions included studies of PCOS, ovarian failure, oral contraception treatment, prior chemotherapy and/or radiotherapy or ovarian surgery. The Newcastle-Ottawa scale was used to assess the quality of studies that were eligible for meta-analysis. OUTCOMES: Eleven studies were eligible for meta-analysis, including 12 031 women. The included studies had a low risk of bias. Short MCL (21-27 days) was associated with lower ORT values as compared to normal (28-31 days), long (32-35 days) and all other (28-35 days) MCL sets. The estimated weighted mean difference (WMD) of AMH level was -1.3 ng/mL (95% CI: -1.75 to -0.86, P < 0.001) between the short and normal MCL sets. The estimated WMD of AFC values was -5.17 (95% CI: -5.96 to -4.37, P < 0.001) between the short and normal MCL sets. The weighted overall odds ratio (OR) of fecundability in natural cycles between women with short versus normal MCL sets was statistically significant (overall OR 0.81; 95% CI 0.72-0.91, P < 0.001). In the IVF setting, fewer oocytes were retrieved in short MCL in comparison to normal, long and all other MCL sets, with an estimated WMD of -1.8 oocytes (95% CI: -2.5 to -1.1, P < 0.001) in the short versus normal MCL sets. The weighted overall OR of clinical pregnancy rate between women with short versus all other MCL sets was statistically significant (overall OR 0.76; 95% CI: 0.60 to 0.96, P = 0.02). Low levels of heterogeneity were found in most meta-analyses of MCL and qualitative ovarian reserve biomarkers, while heterogeneity was high in meta-analyses performed for quantitative measures. WIDER IMPLICATIONS: MCL in regularly cycling women is closely related to ovarian reserve biomarkers during the reproductive years. A short MCL, as compared to normal, is significantly associated with lower ORT values, reduced fecundability and inferior IVF outcomes, independent of age. The results imply that short MCL may be a sign of ovarian aging, combining the quantitative and qualitative facets of ovarian reserve. Educational efforts ought to be designed to guide women with short MCL at a young age, who desire children in the future, to seek professional counselling.

Cardiometabolic health in offspring of women with PCOS compared to healthy controls: a systematic review and individual participant data meta-analysis.

BACKGROUND: Women diagnosed with polycystic ovary syndrome (PCOS) suffer from an unfavorable cardiometabolic risk profile, which is already established by child-bearing age. OBJECTIVE AND RATIONALE: The aim of this systematic review along with an individual participant data meta-analysis is to evaluate whether cardiometabolic features in the offspring (females and males aged 1-18 years) of women with PCOS (OPCOS) are less favorable compared to the offspring of healthy controls. SEARCH METHODS: PubMed, Embase and gray literature databases were searched by three authors independently (M.N.G., M.A.W and J.C.) (last updated on 1 February 2018). Relevant key terms such as 'offspring' and 'PCOS' were combined. Outcomes were age-specific standardized scores of various cardiometabolic parameters: BMI, blood pressure, glucose, insulin, lipid profile and the sum scores of various cardiometabolic features (metabolic sum score). Linear mixed models were used for analyses with standardized beta (ß) as outcome. OUTCOMES: Nine relevant observational studies could be identified, which jointly included 1367 children: OPCOS and controls, originating from the Netherlands, Chile and the USA. After excluding neonates, duplicate records and follow-up screenings, a total of 885 subjects remained. In adjusted analyses, we observed that OPCOS (n = 298) exhibited increased plasma levels of fasting insulin (ß = 0.21(95%CI: 0.01-0.41), P = 0.05), insulin-resistance (ß = 0.21(95%CI: 0.01-0.42), P = 0.04), triglycerides (ß = 0.19(95%CI: 0.02-0.36), P = 0.03) and high-density lipoprotein (HDL)-cholesterol concentrations (ß = 0.31(95%CI: 0.08-0.54), P < 0.01), but a reduced birthweight (ß = -116(95%CI: -195 to 38), P < 0.01) compared to controls (n = 587). After correction for multiple testing, however, differences in insulin and triglycerides lost their statistical significance. Interaction tests for sex revealed differences between males and females when comparing OPCOS versus controls. A higher 2-hour fasting insulin was observed among female OPCOS versus female controls (estimated difference for females (ßf) = 0.45(95%CI: 0.07 to 0.83)) compared to the estimated difference between males ((ßm) = -0.20(95%CI: -0.58 to 0.19)), with interaction-test: P = 0.03. Low-density lipoprotein-cholesterol differences in OPCOS versus controls were lower among females (ßf = -0.39(95%CI: -0.62 to 0.16)), but comparable between male OPCOS and male controls (ßm = 0.27(95%CI: -0.03 to 0.57)), with interaction-test: P < 0.01. Total cholesterol differences in OPCOS versus controls were also lower in females compared to the difference in male OPCOS and male controls (ßf = -0.31(95%CI: -0.57 to 0.06), ßm = 0.28(95%CI: -0.01 to 0.56), interaction-test: P = 0.01). The difference in HDL-cholesterol among female OPCOS versus controls (ßf = 0.53(95%CI: 0.18-0.88)) was larger compared to the estimated mean difference among OPCOS males and the male controls (ßm = 0.13(95%CI: -0.05-0.31), interaction-test: P < 0.01). Interaction test in metabolic sum score revealed a significant difference between females (OPCOS versus controls) and males (OPCOS versus controls); however, sub analyses performed in both sexes separately did not reveal a difference among females (OPCOS versus controls: ßf = -0.14(95%CI: -1.05 to 0.77)) or males (OPCOS versus controls: ßm = 0.85(95%CI: -0.10 to 1.79)), with P-value < 0.01. WIDER IMPLICATIONS: We observed subtle signs of altered cardiometabolic health in OPCOS. Therefore, the unfavorable cardiovascular profile of women with PCOS at childbearing age may-next to a genetic predisposition-influence the health of their offspring. Sensitivity analyses revealed that these differences were predominantly observed among female offspring aged between 1 and 18 years. Moreover, studies with minimal risk of bias should elucidate the influence of a PCOS diagnosis in mothers on both sexes during fetal development and subsequently during childhood.

Endogenous sex hormones and risk of venous thromboembolism in young women.

BACKGROUND: The risk of venous thromboembolism (VTE) in young women can predominantly be attributed to exogenous hormone use. The influence of (abnormalities in) endogenous sex hormones, as in polycystic ovary syndrome (PCOS) or primary ovarian insufficiency (POI), on VTE risk is uncertain. OBJECTIVES: Th assess the association between endogenous sex hormone levels and VTE risk. METHODS: Women aged ≤45 years from the MEGA case-control study who provided a blood sample in the absence of exogenous hormone exposure or pregnancy were included. Sex hormone-binding globulin (SHBG), estradiol, follicle-stimulating hormone (FSH) and testosterone were measured. The free androgen index (FAI) and estradiol to testosterone ratio (E:T) were calculated. VTE risk was assessed according to quartiles (Qs) of levels and clinical cut-offs as proxies for PCOS (FAI > 4.5) and POI (FSH > 40 U/L). Logistic regression models were used to estimate adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Six hundred and sixty-five women (369 cases; 296 controls) were eligible for the analyses. Testosterone and FSH levels, E:T and POI (FSH > 40 U/L vs FSH ≤ 40 U/L) were not associated with VTE risk. For estradiol, VTE risk was increased with levels in Q4 vs Q1 (OR 1.6; 95% CI 1.0-2.5). There was a dose-response relationship between SHBG levels and VTE risk, with the highest OR at Q4 vs Q1: 2.0 (95% CI 1.2-3.3). FAI > 4.5 (PCOS proxy) vs FAI ≤ 4.5 was associated with increased VTE risk (OR 3.3; 95% CI 0.9-11.8). CONCLUSIONS: Estradiol, SHBG and FAI were associated with VTE risk, suggesting a role for endogenous sex hormones in the pathophysiology of VTE in young women.

Coronary artery calcification in middle-aged women with premature ovarian insufficiency.

OBJECTIVE: Women with premature ovarian insufficiency (POI) enter menopause before age 40. Early menopause was associated with increased risk for coronary artery disease (CAD), death from cardiovascular disease and all-cause mortality. We compared the prevalence of CAD between middle-aged women on average 10 years following the initial POI diagnosis, with a population-based cohort. DESIGN: Cross-sectional case-control study. PARTICIPANTS: Women from two Dutch University Medical Centers above 45 years of age previously diagnosed with POI (n = 98) were selected and compared with age- and race-matched controls from the Multi-Ethnic Study of Atherosclerosis (MESA). MEASUREMENTS: The primary outcome was detectable coronary artery calcium (CAC) determined by coronary computed tomography (CCT). RESULTS: Women with POI had significantly higher blood pressure, cholesterol and glucose, despite lower BMI compared to controls. Similar proportions of detectable CAC (CAC score >0 Agatston Units) were observed in women with POI and controls (POI n = 16 (16%), controls n = 52 (18%), P = 0.40 and Padj  = 0.93). In women with POI separately, we were not able to identify associations between CVD risk factors and CAC. The following CVD risk factors in controls were positively associated with CAC: age, diabetes mellitus, hypertension and LDL cholesterol. HRT use was negatively associated with CAC in controls. CONCLUSIONS: The presence of CAC did not differ significantly in women with POI around 50 years of age, compared to an age- and race-matched control group. We observe no increased calcified coronary disease in POI patients, despite the presence of unfavourable cardiovascular risk factors in these women.

Pre-Conception Characteristics Predict Obstetrical and Neonatal Outcomes in Women With Polycystic Ovary Syndrome.

Context: Women with polycystic ovary syndrome (PCOS) are at increased risk for obstetric and perinatal complications. At present, it is unknown how characteristics of PCOS relate to the likelihood of these complications. Objective: To evaluate which preconception features are associated with obstetric and perinatal disease among infertile women with PCOS. Design: Data from two prospective cohort studies completed from January 2004 until January 2014 were linked to Dutch Perinatal national registry outcomes. Setting: Two Dutch university medical centers. Participants: 2768 women diagnosed with PCOS were included. Participants underwent an extensive standardized preconception screening. Exclusion criteria included: age <18 years or >45 years, language barrier, or failure to meet PCOS criteria. Interventions: None. Main Outcome Measures: Outcome measures were obtained from the Dutch Perinatal national registry and included: preeclampsia, preterm delivery, small for gestational age (SGA), low Apgar score, and any adverse outcome. Results: 1715 (62% of participants) women with PCOS were identified as undergoing a pregnancy with live birth after screening. In fully adjusted models, prepregnancy free androgen index was associated with subsequent preeclampsia [OR (95% CI), 1.1 (1.0 to 1.1)]. Fasting glucose [1.4 (1.2 to 1.7)] and testosterone [1.5 (1.2 to 1.7)] predicted preterm delivery. Fasting insulin [1.003 (1.001 to 1.005)], and testosterone [1.2 (1.1 to 1.4)] predicted any adverse outcome. SGA was only predicted by features nonspecific to PCOS. Conclusions: Primary disease characteristics of PCOS, chiefly hyperandrogenism and impaired glucose tolerance, predict suboptimal obstetric and neonatal outcomes. Increased surveillance during pregnancy should focus on women with PCOS and these features to help mitigate disease risk.

Estrogen deprivation and cardiovascular disease risk in primary ovarian insufficiency.

OBJECTIVE: To evaluate the association between estrogen (E) exposure and deficiency and cardiovascular disease (CVD) risk among women with primary ovarian insufficiency (POI). DESIGN: Cross-sectional study conducted between 1996 and 2016. SETTING: Tertiary referral centers. PATIENT(S): A total of 385 women with POI, defined by amenorrhea and FSH levels ≥40 IU/L before 40 years of age, were recruited. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Women underwent a standardized intake questionnaire including data on menstrual cyclicity. Lifetime E exposure and E-free period were assessed. Serum was analyzed for endocrine and CVD profiles. The Framingham 30-year risk of CVD was calculated. RESULT(S): Lifetime E exposure (mean ± SD) was 19.3 ± 7.0 years, E-free period was 3.1 ± 4.1 years, and age at screening was 34.8 ± 7.4 years. In multivariate models E-free interval associated positively with estimated risk of hard and general CVD events (ß 0.18 [95% confidence interval 0.08, 0.29]; 0.20 [0.05, 0.35], respectively), and lifetime E exposure associated negatively with estimated risk of hard and general CVD events (-0.15 [-0.24, -0.05]; -0.16 [-0.29, -0.03], respectively), as well as low density lipoprotein cholesterol (-0.03 [-0.06, 0.00]) and non-high density lipoprotein cholesterol (-0.04 [-0.07, 0.00]). CONCLUSION(S): Prolonged E deprivation is associated with an increased estimated risk of CVD, whereas prolonged E exposure is associated with a reduced estimated risk. These results support the policy of early and continued use of E replacement therapy in women with POI. CLINICAL TRIAL REGISTRATION NUMBER: NCT0230904.

Sex steroids, sex hormone-binding globulin and levels of N-terminal pro-brain natriuretic peptide in postmenopausal women.

BACKGROUND: Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) has a well-documented prognostic value for cardiovascular disease and sex-hormones are suggested to modulate NT-proBNP levels. OBJECTIVE: To examine whether endogenous sex-hormones and sex hormone-binding globulin (SHBG) are associated with NT-proBNP levels in postmenopausal women free of clinical cardiovascular diseases. METHODS: Total estradiol (E2), total testosterone (TT), androstenedione (AD), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG) and NT-proBNP were assessed in 4112 postmenopausal women free of cardiovascular diseases from the prospective population-based Rotterdam Study. Free androgen index (FAI) was calculated as ratio of TT to SHBG concentration. TT, AD, DHEA(S), SHBG, FAI and NT-proBNP were natural log transformed. Regression coefficients and 95% Confidence Intervals (CI) were calculated using multivariable linear regression models adjusting for confounders. RESULTS: In models adjusted for multiple confounders (age, reproductive, life style and cardiovascular risk factors) higher SHBG (per 1 SD increase, ß = 0.15, 95% CI = 0.12, 0.18), and lower levels of TT (per 1 SD increase, ß = -0.05, 95%CI = -0.08, -0.02), FAI (per 1 SD increase, ß = -0.13, 95%CI = -0.15, -0.09), DHEAS (per 1 SD increase, ß = -0.06, 95% CI = -0.09, -0.04) and DHEA (per 1 SD increase, ß = -0.06, 95%CI = -0.09, -0.04) were associated with higher levels of NT-proBNP. However, no consistent association was found between E2 and AD and NT-proBNP levels. Additionally, stratification by BMI did not affect any of observed associations. CONCLUSION: Our findings support the hypothesis that higher androgens might be associated with lower natriuretic peptide levels in postmenopausal women.

High Androgens in Postmenopausal Women and the Risk for Atherosclerosis and Cardiovascular Disease: The Rotterdam Study.

Context: Polycystic ovary syndrome (PCOS) is closely linked to hyperandrogenism (HA). In PCOS, HA has been associated with metabolic disturbances that increase the risk for cardiovascular disease (CVD). Objective: To assess the association of high serum androgen levels, as a postmenopausal remnant of PCOS, with the prevalence of atherosclerosis and incidence of CVD in postmenopausal women. Design: The Rotterdam Study, a prospective population-based cohort study. Median follow-up was 11.36 years. Setting: General community. Participants: A total of 2578 women aged >55 years. Exclusion criteria were missing informed consent or follow-up data, perimenopausal status, and menopause by surgical intervention or at an unnatural age (age <40 or >62). Intervention: None. Main Outcomes and Measures: Linear, logistic, and Cox regression models assessed the association of top quartiles (P75) of serum testosterone, free androgen index (FAI), dehydroepiandrosterone, and androstenedione and sex hormone-binding globulin with coronary artery calcium, carotid intima-media thickness (IMT), pulse wave velocity, peripheral artery disease, and incidence of coronary heart disease (CHD), stroke, and CVD. Results: Mean age (standard deviation) was 70.19 (8.71) years, and average time since menopause was 19.85 (9.94) years. Highest quartile FAI was associated with higher pulse wave velocity (ß [95% confidence interval (CI)], 0.009 [0.000 to 0.018]). Highest quartile dehydroepiandrosterone [ß (95% CI), -0.008 (-0.015 to -0.001)] and androstenedione [ß (95% CI), -0.010 (-0.017 to -0.003)] levels were associated with a lower IMT. We found no association between high androgen levels and incident stroke, CHD, or CVD. Conclusion: Postmenopausal high androgen levels were not associated with an elevated risk for CVD. Cardiovascular health in women with PCOS might be better than was anticipated.

Cardiovascular and Metabolic Health of 74 Children From Women Previously Diagnosed With Polycystic Ovary Syndrome in Comparison With a Population-Based Reference Cohort.

Women with polycystic ovary syndrome (PCOS) have compromised cardiovascular health profiles and an increased risk of pregnancy complications. In order to evaluate potential consequences, we aim to compare the cardiovascular and metabolic health of the children from women with PCOS with a population-based reference cohort. We included children from women with PCOS between the age of 2.5 to 4 years (n = 42) and 6 to 8 years (n = 32). The reference groups consisted of 168 (3-4 years old) and 130 children (7-8 years old). In an extensive cardiovascular screening program, we measured anthropometrics and blood pressure (all children), heart function and vascular rigidity (young children), metabolic laboratory assessment and carotid intima thickness (old age-group). Results showed that young PCOS offspring have a significantly lower diastolic blood pressure (ß = 2.3 [95% confidence interval, CI: 0.5-4.0]) and higher aortic pulse pressure (ß = -1.4 [95% CI: -2.5 to -0.2]), compared to the reference population. Furthermore, a higher left ventricle internal diameter but a lower tissue Doppler imaging of the right wall in systole compared to the reference group was found. Older offspring of women with PCOS presented with a significantly lower breast and abdominal circumference, but higher triglycerides (ß = -0.1 [95% CI: -0.2 to -0.1]), LDL-cholesterol (ß = -0.4 [95% CI: -0.6 to -0.1]), and higher carotid intima-media thickness (ß = -31.7 [95% CI: -46.6 to -16.9]) compared to the reference group. In conclusion, we observe subtle but distinct cardiovascular and metabolic abnormalities already at an early age in PCOS offspring compared to a population-based reference group, despite a lower diastolic blood pressure, breast, and abdominal circumference. These preliminary findings require confirmation in independent data sets.

Increased rates of complications in singleton pregnancies of women previously diagnosed with polycystic ovary syndrome predominantly in the hyperandrogenic phenotype.

OBJECTIVE: To study the presence of several maternal and neonatal complications in a cohort of women with hyperandrogenic as well as normoandrogenic polycystic ovary syndrome (PCOS) and women with PCOS who received different fertility treatments. DESIGN: Prospective multicenter cohort study. SETTING: Hospitals and midwifery practices. PATIENT(S): One hundred and eighty-eight women with PCOS and singleton pregnancies (study group) and 2,889 women with a naturally conceived singleton pregnancy (reference group). INTERVENTION(S): Observational study. MAIN OUTCOME MEASURE(S): Maternal and neonatal pregnancy complications. RESULT(S): Women with PCOS had a statistically significantly increased risk of developing gestational diabetes (adjusted odds ratio [AOR] 4.15; 95% confidence interval [CI], 2.07-8.33) compared with the reference group, and their infants were more often born small for gestational age (AOR 3.76; 95% CI, 1.69-8.35). In a subgroup analysis, maternal complications were statistically significantly more often present in women with hyperandrogenic (defined as a free androgen index >4.5) PCOS (n = 76; 40% of all PCOS women) compared with those with normoandrogenic PCOS (n = 97; 52% of all PCOS women) (45% vs. 24%; P=.003); no statistically significant differences were observed between these groups regarding neonatal complications. CONCLUSION(S): Women with PCOS have an increased risk of maternal and neonatal pregnancy complications, especially women with the hyperandrogenic phenotype. CLINICAL TRIAL REGISTRATION NUMBER: NCT00821379.

Cardiovascular RiskprofilE - IMaging and gender-specific disOrders (CREw-IMAGO): rationale and design of a multicenter cohort study.

BACKGROUND: Reproductive disorders, such as polycystic ovary syndrome (PCOS), primary ovarian insufficiency (POI) and hypertensive pregnancy disorders (HPD) like pre-eclampsia (PE), are associated with an increased risk of cardiovascular disease (CVD). Detection of early signs of cardiovascular disease (CVD), as well as identification of risk factors among women of reproductive age which improve cardiovascular risk prediction, is a challenge and current models might underestimate long-term health risks. The aim of this study is to assess cardiovascular disease in patients with a history of a reproductive disorder by low-dose computed tomography (CT). METHODS: Women of 45 - 55 years, who experienced a reproductive disorder (PCOS, POI, HPD), are invited to participate in this multicenter, prospective, cohort study. Women will be recruited after regular cardiovascular screening, including assessment of classical cardiovascular risk factors. CT of the coronary arteries (both coronary artery calcium scoring (CACS), and contrast-enhanced coronary CT angiography (CCTA)) and carotid siphon calcium scoring (CSC) is planned in 300 women with HPD and 300 women with PCOS or POI. In addition, arterial stiffness (non-invasive pulse wave velocity (PWV)) measurement and cell-based biomarkers (inflammatory circulating cells) will be obtained. DISCUSSION: Initial inclusion is focused on women of 45 - 55 years. However, the age range (40 - 45 years and/or ≥ 55 years) and group composition may be adjusted based on the findings of the interim analysis. Participants can potentially benefit from information obtained in this study concerning their current cardiovascular health and expected future risk of cardiovascular events. The results of this study will provide insights in the development of CVD in women with a history of reproductive disorders. Ultimately, this study may lead to improved cardiovascular prediction models and will provide an opportunity for timely adjustment of preventive strategies. Limitations of this study include the possibility of overdiagnosis and the average radiation dose of 3.5 mSv during coronary and carotid siphon CT, although the increased lifetime malignancy risk is negligible. TRIAL REGISTRATION: Netherlands Trial Register, NTR5531 . Date registered: October 21st, 2015.

Safety after extended repeated use of ulipristal acetate for uterine fibroids.

OBJECTIVE: To assess long term safety of extended repeated 3-month courses of ulipristal acetate (UPA) 10 mg/day, for up to 8 courses, with focus on endometrial and laboratory safety parameters. METHODS: This long-term, multi-center, open-label cohort, follow up study consisted of up to 8 consecutive 3-month courses of daily UPA 10 mg, each separated by a drug free period of 2 spontaneous menstrual bleeds. Sixty-four pre-menopausal women, with moderate to severe symptomatic uterine myoma(s) and heavy bleeding were enrolled and were studied for approximately 4 years. The main outcome measures were endometrial histology, laboratory parameters and general safety. RESULTS: All data was reported in a descriptive manner with no formal statistical comparisons. In the 64 women, non-physiological changes (mostly cyst formation, epithelial and vascular changes) in endometrial histology at screening and after treatment courses 4 and 8 were observed in 18.0%, 21.4% and 16.3% of biopsies, respectively. After treatment cessation, such changes were observed in 9.1% of biopsies. All endometrial biopsies were benign after course 8. The median endometrial thickness was 7.0 mm, 10-18 days after the start of menses following treatment courses 5-8, compared to 9.0 mm at screening (before UPA treatment). No changes in the number and type of laboratory results outside the normal ranges were observed with the increasing treatment courses. In total, adverse events were reported in 10 (16%), 12 (19%), 8 (14%) and 5 (9%) subjects, during treatment courses 5, 6, 7 and 8, respectively of which the most frequent adverse events were headache and hot flush. CONCLUSION: The results of this study further support the safety profile of extended repeated 3 months treatment of symptomatic fibroids with ulipristal acetate 10 mg/day. Repeated UPA treatment courses did not result in any changes of concern in endometrial histology, endometrial thickness, or laboratory safety measures.

Maintaining physiological testosterone levels by adding dehydroepiandrosterone to combined oral contraceptives: I. Endocrine effects.

OBJECTIVE: To determine whether adding dehydroepiandrosterone to combined oral contraceptives (COCs) maintains physiological levels of free testosterone. STUDY DESIGN: A randomized, double-blind, placebo-controlled, two-way crossover study conducted in 81 healthy women (age range: 20-35 years; Body mass index (BMI) range: 18-35 kg/m2) using oral contraceptives. Androgens, sex hormone-binding globulin (SHBG), estradiol (E2) and estrone (E1) were measured, and free testosterone and the free testosterone index were calculated. Subjects discontinued oral contraceptive use for at least one menstrual cycle before being randomized to receive five cycles of ethinyl estradiol (EE) combined with either levonorgestrel (EE/LNG group) or drospirenone (EE/DRSP group) together with either dehydroepiandrosterone (DHEA) (50 mg/day orally) or placebo. Subsequently, all subjects crossed over to the other treatment arm for an additional five cycles. RESULTS: Both COCs decreased the levels of all androgens measured. Significant decreases (p<.05) were found with EE/LNG and EE/DRSP for total testosterone (54.5% and 11.3%, respectively) and for free testosterone (66.8% and 75.6%, respectively). Adding DHEA to the COCs significantly increased all androgens compared to placebo. Moreover, including DHEA restored free testosterone levels to baseline values in both COC groups and total testosterone levels to baseline in the EE/LNG group and above baseline in the EE/DRSP group. SHBG concentrations were significantly higher with EE/DRSP compared to EE/LNG (p<.0001). The addition of DHEA did not affect the levels of SHBG. CONCLUSIONS: Taking COCs reduces total and free testosterone levels and increases SHBG concentrations. By coadministration with DHEA, physiological levels of total and free testosterone are restored while using EE/LNG. With EE/DRSP, only the free testosterone level is normalized by DHEA coadministration. IMPLICATIONS: A daily oral dose of 50-mg DHEA maintains physiological free and total testosterone levels in women who are using an EE/LNG-containing COC.

Biomarker Profiles in Women with PCOS and PCOS Offspring; A Pilot Study.

OBJECTIVE: To study metabolic/inflammatory biomarker risk profiles in women with PCOS and PCOS offspring. DESIGN: Cross-sectional comparison of serum biomarkers. SETTING: University Medical Center Utrecht. PATIENTS: Hyperandrogenic PCOS women (HA-PCOS, n = 34), normoandrogenic PCOS women (NA-PCOS, n = 34), non-PCOS reference population (n = 32), PCOS offspring (n = 14, age 6-8 years), and a paedriatic reference population (n = 30). MAIN OUTCOME MEASURE(S): Clustering profile of adipocytokines (IL-1b, IL-6, IL-13, IL-17, IL-18, TNF-α, adiponectin, adipsin, leptin, chemerin, resistin, RBP4, DPP-IV/sCD26, CCL2/MCP-1), growth factors (PIGF, VEGF, sVEGF-R1), soluble cell adhesion molecules (sICAM-1/sCD54, sVCAM-1/sCD106), and other inflammatory related proteases (MMP-9, S100A8, Cathepsin S). Differences in median biomarker concentrations between groups, and associations with the free androgen index (FAI; Testosterone/SHBG x100). RESULTS: The cluster analysis identified leptin, RBP-4, DPP-IV and adiponectin as potential discriminative markers for HA-PCOS with a specifically strong correlation in cases with increased BMI. Leptin (R2 = 0.219) and adiponectin (R2 = 0.182) showed the strongest correlation with the FAI. When comparing median protein concentrations adult PCOS women with or without hyperandrogenemia, the most profound differences were observed for leptin (P < 0.001), DPP-IV (P = 0.005), and adiponectin (P < 0.001). Adjusting for age, BMI and multiple testing attenuated all differences. In PCOS offspring, MMP-9 (P = 0.001) and S100A8 (P < 0.001) concentrations were significantly higher compared to a healthy matched reference population, even after correcting for age and BMI and adjustment for multiple testing. CONCLUSION: In this preliminary investigation we observed significant differences in adipocytokines between women with or without hyperandrogenic PCOS and non-PCOS controls, mostly influenced by BMI. Leptin and adiponectin showed the strongest correlation with the FAI in adult women with PCOS. In PCOS offspring other inflammatory biomarkers (MMP-9, S100A8) were increased, suggesting that these children may exhibit increased chronic low-grade inflammation. Additional research is required to confirm results of the current exploratory investigation.

The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance.

BACKGROUND: Here we describe the consensus guideline methodology, summarise the evidence-based recommendations we provided to the World Health Organisation (WHO) for their consideration in the development of global guidance and present a narrative review on the management of anovulatory infertility in women with polycystic ovary syndrome (PCOS). OBJECTIVE AND RATIONALE: The aim of this paper was to present an evidence base for the management of anovulatory PCOS. SEARCH METHODS: The evidence to support providing recommendations involved a collaborative process for: (i) identification of priority questions and critical outcomes, (ii) retrieval of up-to-date evidence and exiting guidelines, (iii) assessment and synthesis of the evidence and (iv) the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation, the methodologist evaluated the quality of the supporting evidence that was then graded as very low, low, moderate or high for consideration during consensus. OUTCOMES: Evidence was synthesized and we made recommendations across the definition of PCOS including hyperandrogenism, menstrual cycle regulation and ovarian assessment. Metabolic features and the impact of ethnicity were covered. Management includes lifestyle changes, bariatric surgery, pharmacotherapy (including clomiphene citrate (CC), aromatase inhibitors, metformin and gonadotropins), as well as laparoscopic surgery. In-vitro fertilization (IVF) was considered as were the risks of ovulation induction and of pregnancy in PCOS. Approximately 80% of women who suffer from anovulatory infertility have PCOS. Lifestyle intervention is recommended first in women who are obese largely on the basis of general health benefits. Bariatric surgery can be considered where the body mass index (BMI) is ≥35 kg/m2 and lifestyle therapy has failed. Carefully conducted and monitored pharmacological ovulation induction can achieve good cumulative pregnancy rates and multiple pregnancy rates can be minimized with adherence to recommended protocols. CC should be first-line pharmacotherapy for ovulation induction and letrozole can also be used as first-line therapy. Metformin alone has limited benefits in improving live birth rates. Gonadotropins and laparoscopic surgery can be used as second-line treatment. There is no clear evidence for efficacy of acupuncture or herbal mixtures in women with PCOS. For women with PCOS who fail lifestyle and ovulation induction therapy or have additional infertility factors, IVF can be used with the safer gonadotropin releasing hormone (GnRH) antagonist protocol. If a GnRH-agonist protocol is used, metformin as an adjunct may reduce the risk of ovarian hyperstimulation syndrome. Patients should be informed of the potential side effects of ovulation induction agents and of IVF on the foetus, and of the risks of multiple pregnancy. Increased risks for the mother during pregnancy and for the child, including the exacerbating impact of obesity on adverse outcomes, should also be discussed. WIDER IMPLICATIONS: This guidance generation and evidence-synthesis analysis has been conducted in a manner to be considered for global applicability for the safe administration of ovulation induction for anovulatory women with PCOS.