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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 .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.

The lack of ovulatory cycles may be considered as a major problem for women seeking pregnancy. This is reflected by the fact that about 20 percent of couples visiting a fertility clinic with an unfulfilled wish to conceive present with anovulation. Clinical manifestation of anovulation is oligomenorrhea (intermenstrual period > 35 days) or amenorrhea (intermenstrual period > 6 months). Although ovulation may occur in oligomenorrhea, the longer the time period between menstruations the smaller the chance of that cycle being ovulatory. Classification of anovulatory patients may be performed using the criteria of the World Health Organization (WHO) as determined by Rowe et al. Criteria needed to classify patients are 1) serum prolactin in the normal range, 2) oligo- or amenorroea, and 3) serum concentrations of follicle-stimulating hormone (FSH) and estradiol (E2).In case of a hyperprolactinemia, a macro-prolactinoma should be ruled out by a scan (CT or MRI) of the sella turcica, and hyperprolactinemia should be treated with a dopamine-agonist. In case of normoprolactinemia or when the oligo- or amenorrea persists after correction of the hyperprolactinemia, these patients may be classified according to WHO criteria as follows: WHO1) ± 10% hypogonadotropic, hypoestrogenic status; WHO2) ± 80% normogonadotropic, normoestrogenic status; or WHO3) ± 10% hypergonadotropic, hypoestrogenic status. The vast majority of these patients, the WHO2 group, appear to be a very heterogeneous population in which – besides anovulation – obesity, biochemical, or clinical hyperandrogenism (alopecia, acne, or hirsutism) and insulin resistance play an important role.

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 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.

Study question Does an individualised, weight- and AMH-based dosing approach with follitropin delta improve live birth rate, safety, and efficiency, compared to conventional dosing in IVF/ICSI? Summary answer Individualised ovarian stimulation performs similarly for live birth rate (increased in normal-high AMH), and reduces the incidence of OHSS and total FSH dosage. What is known already Previous studies investigated the effect of individualized gonadotropin dosing in IVF/ICSI using ovarian reserve tests such as anti-Müllerian hormone (AMH) and antral follicle count (AFC). A Cochrane Review concluded that individualised dosing in IVF is associated with a reduction of ovarian hyperstimulation syndrome (OHSS), but no effect on live birth rate. It is hypothesized that an individualised dosing approach is predominantly beneficial in the patients who are potentially normal or high responders. This study addresses the performance of a new human recombinant FSH (follitropin delta) with individualised dosing based on AMH and body weight. Study design, size, duration This is an individual participant data meta-analysis (IPD-MA) of three follitropin delta phase 3 trials, executed in Europe and North- and South America, South-East Asia, and Japan. All trials were randomized, controlled, assessor-blinded, multicenter studies in which individualised follitropin delta vs. conventional follitropin alpha or beta were compared. Women were followed from inclusion, at start of their first fresh IVF/ICSI cycle, until 4 weeks after live birth. Participants/materials, setting, methods Women aged 20-40 yrs, undergoing their first IVF/ICSI cycle, were randomly assigned to follitropin delta (AMH < 15 pmol/L: 12 µg/day; AMH ≥ 15 pmol/L: 0.10-0.19 µg/kg/day: maximum 12 µg/day) or conventional follitropin alpha or beta (150 IU/day for 5 days, possible subsequent dose adjustments). The IPD-MA was performed using logistic regression analysis. Planned subgroup analyses were performed for expected normal/high responders (serum AMH ≥15 pmol/L), and expected low responders (serum AMH Main results and the role of chance Nearly 2,700 women were randomised and exposed: n = 1,348 for conventional dosing regimen with follitropin alpha or beta, and n = 1,334 for individualised dosing with follitropin delta. Live birth rate was similar for both groups (29.5% in follitropin delta vs. 26.9% in follitropin alpha/beta; OR 1.14 (0.96-1.35)). However, in expected normal to high responders live birth rate was significantly increased for those receiving individualised follitropin delta (31.4% vs. 25.9%; OR 1.31 (1.06 - 1.62)). Mean number of transferred embryos/blastocysts was comparable (0.95 vs. 0.94, respectively; mean difference 0.0076; NS), and did not differ when subgroup analyses were performed for normal/high AMH and low AMH. The occurrence of early OHSS was significantly reduced in individualised follitropin delta (4.0% vs. 6.4%; OR 0.62 (95% CI 0.43-0.88)), in subgroup analyses a similar reduction was identified. Total dosage of FSH was significantly lower in individualized follitropin delta (84.5 vs. 112.1 µg; mean difference -27.5 µg (95% CI -30.0 - -25.1)), with a more pronounced effect in normal to high AMH (mean difference -36.5 µg (95% CI -39.2 - -33.7)). Gestational age and birth weight were similar. The IPD-MA identified similar findings among women from the three studies with their different ethnic backgrounds. Limitations, reasons for caution For individualised dosing with follitropin delta, it was observed that the number of cryopreserved embryos was significantly lower (2.4 vs. 3.0, mean difference -0.67 (p Wider implications of the findings Individualised dosing with gonadotropin delta is similarly successful in terms of live birth (increased for normal-high AMH women), reduces safety risks, and is more effective with regard to gonadotropin dosage, compared with conventional dosing in IVF/ICSI. Treatment costs are reduced by prescription of lower gonadotropin doses and OHSS reduction. Trial registration number NCT01956110, NCT03228680, NCT03296527

STUDY QUESTION What is the cumulative incidence of live birth and mean time to pregnancy (by conception after IVF/ICSI or natural conception) in women experiencing unexplained recurrent implantation failure (RIF) following IVF/ICSI treatment? SUMMARY ANSWER In 118 women who had experienced RIF, the reported cumulative incidence of live birth during a maximum of 5.5 years follow-up period was 49%, with a calculated median time to pregnancy leading to live birth of 9 months after diagnosis of RIF. WHAT IS KNOWN ALREADY Current definitions of RIF include failure to achieve a pregnancy following IVF/ICSI and undergoing three or more fresh embryo transfer procedures of one or two high quality embryos or more than 10 embryos transferred in fresh or frozen cycles. The causes and optimal management of this distressing condition remain uncertain and a range of empirical and often expensive adjuvant therapies is often advocated. Little information is available regarding the long-term prognosis for achieving a pregnancy. STUDY DESIGN, SIZE, DURATION Two hundred and twenty-three women under 39 years of age who had experienced RIF without a known cause after IVF/ICSI treatment in two tertiary referral university hospitals between January 2008 and December 2012 were invited to participate in this retrospective cohort follow up study. PARTICIPANTS/MATERIALS, SETTING, METHODS All eligible women were sent a letter requesting their consent to the anonymous use of their medical file data and were asked to complete a questionnaire enquiring about treatments and pregnancies subsequent to experiencing RIF. Medical files and questionnaires were examined and results were analysed to determine the subsequent cumulative incidence of live birth and time to pregnancy within a maximum 5.5 year follow-up period using Kaplan Meier analysis. Clinical predictors for achieving a live birth were investigated using a Cox hazard model. MAIN RESULTS AND THE ROLE OF CHANCE One hundred and twenty-seven women responded (57%) and data from 118 women (53%) were available for analysis. During the maximum 5.5 year follow up period the overall cumulative incidence of live birth was 49% (95% CI 39–59%). Among women who gave birth, the calculated median time to pregnancy was 9 months after experiencing RIF, where 18% arose from natural conceptions. LIMITATIONS, REASONS FOR CAUTION Since only 57% of the eligible study cohort completed the questionnaire, the risk of response bias limits the applicability of the study findings. WIDER IMPLICATIONS OF THE FINDINGS This study reports a favorable overall prognosis for achieving live birth in women who have previously experienced RIF, especially in those who continue with further IVF/ICSI treatments. However since 51% did not achieve a live birth during the follow-up period, there is a need to distinguish those most likely to benefit from further treatment. In this study, no clinical factors were found to be predictive of those achieving a subsequent live birth. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the University Medical Center Utrecht, in Utrecht and the Academic Medical Centre, in Amsterdam. NSM has received consultancy and speaking fees and research funding from Ferring, MSD, Merck Serono, Abbott, IBSA, Gedion Richter, and Clearblue. During the most recent 5-year period BCJMF has received fees or grant support from the following organizations (in alphabetic order); Actavis/Watson/Uteron, Controversies in Obstetrics & Gynecology (COGI), Dutch Heart Foundation, Dutch Medical Research Counsel (ZonMW), Euroscreen/Ogeda, Ferring, London Womens Clinic (LWC), Merck Serono, Myovant, Netherland Genomic Initiative (NGI), OvaScience, Pantharei Bioscience, PregLem/Gedeon Richter/Finox, Reproductive Biomedicine Online (RBMO), Roche, Teva, World Health Organisation (WHO). None of the authors have disclosures to make in relation to this manuscript.

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 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.

Background: Preeclampsia, coronary artery calcification (CAC), and atherosclerotic plaque are risk factors for the development of cardiovascular disease. We determined at what age CAC becomes apparent on coronary computed tomography after preeclampsia and to what extent modifiable cardiovascular risk factors were associated. Methods: We measured cardiovascular risk factors, CAC by coronary computed tomography, and coronary plaque by coronary computed tomography angiography in 258 previously preeclamptic women aged 40-63. Results were compared to 644 age- and ethnicity-equivalent women from the Framingham Heart Study with previous normotensive pregnancies. Results: Any CAC was more prevalent after preeclampsia than after a normotensive pregnancy (20% versus 13%). However, this difference was greatest and statistically significant only in women ages 45 to 50 (23% versus 10%). The degree of CAC advanced 4× faster between the ages of 40 to 45 and ages 45 to 50 in women with a history of preeclampsia (odds ratio, 4.3 [95% CI, 1.5–12.2] versus odds ratio, 1.2 [95% CI, 0.6–2.3]). Women with a preeclampsia history maintained greater advancement of CAC with age into their early 60s, although this difference declined after the perimenopausal years. Women with a previous normotensive pregnancy were 4.9 years (95% CI, 1.8–8.0) older when they had similar CAC scores as previously preeclamptic women. These observations were not explained by the greater prevalence of cardiovascular disease risk factors, and the higher Framingham Risk Scores also observed in women with a history of preeclampsia. Conclusions: Previously preeclamptic women have more modifiable cardiovascular risk factors and develop CAC ≈5 years earlier from the age of 45 years onwards compared to women with normotensive pregnancies. Therefore, women who experienced preeclampsia might benefit from regular cardiovascular screening and intervention before this age. Registration: URL: https://www.trialregister.nl/trial/5406 ; Unique identifier: NTR5531.

Introduction: Preeclampsia (PE) represents a hypertensive pregnancy disorder that is associated with increased cardiovascular disease (CVD) risk. This increased risk has been attributed to accelerated atherosclerosis, with inflammation being a major contributor. Neutrophils play an important role in the onset and progression of atherosclerosis and have been associated with vascular damage in the placenta as well as the chronic inflammatory state in women with PE. We therefore investigated whether circulating neutrophil numbers or reactivity were associated with the presence and severity of subclinical atherosclerosis in women with a history of PE. Methods: Women aged 45&ndash, 60 years with a 10 to 20 years earlier history of early onset preeclampsia (delivery &lt, 34 weeks of gestation) (n = 90), but without symptomatic CVD burden were screened for the presence of subclinical coronary artery disease (CAD) using both contrast-enhanced and non-contrast coronary CT angiography. Subclinical CAD was defined as a coronary artery calcium (CAC) score &ge, 100 Agatston Units and/or &ge, 50% coronary luminal stenosis. We assessed whether the numbers and activity of circulating neutrophils were associated with the presence of subclinical CAD and as secondary outcome measurements, with the presence of any calcium (CAC score &gt, 0 AU) or stenosis, categorized as absent (0%), minimal to mild (&gt, 0 and &lt, 50%), and moderate to severe (&ge, 50%) narrowing of the coronary artery. Blood was drawn just before CT and neutrophil numbers were assessed by flow cytometry. In addition, the presence of the chemokine receptors CXCR2 and CXCR4, which are known to be instrumental in neutrophil recruitment, and neutrophil activity upon stimulation with the bacterial peptide N-Formylmethionyl-leucyl-phenylalanine (fMLF) was assessed by flow cytometry. Results: Of the participating women, with an average age of 49 years, 13% (12 out of 90) presented with subclinical signs of CAD (CAC score &ge, 100 AU and/or &ge, 50% luminal stenosis), and 37% (33 out of 90) had a positive CAC score (&gt, 0). Total white blood cell count and neutrophil counts were not associated with the presence of subclinical CAD or with a positive CAC score. When assessing the presence of the chemokine receptors CXCR4 and CXCR2, we observed a slight decrease of neutrophil CXCR2 expression in women with CAC (median MFI 22.0 [interquartile range (IQR) 20.2&ndash, 23.8]) compared to women without CAC (23.8 [IQR 21.6&ndash, 25.6], p = 0.02). We observed no differences regarding neutrophil CXCR4 expression. In addition, expression of the early activity marker CD35 was slightly lower on neutrophils of women with subclinical CAD (median MFI 1.6 [IQR 1.5&ndash, 1.9] compared to 1.9 [IQR 1.7&ndash, 2.1] in women without CAD, p = 0.02). However, for all findings, statistical significance disappeared after adjustment for multiple testing. Conclusion: Our findings indicate that neutrophil counts and (re)activity are not directly associated with silent CAD disease burden and as such are not suitable as biomarkers to predict the presence of subclinical CAD in a high-risk population of women with a history of preeclampsia.

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 (β) 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 (β = 0.21(95%CI: 0.01–0.41), P = 0.05), insulin-resistance (β = 0.21(95%CI: 0.01–0.42), P = 0.04), triglycerides (β = 0.19(95%CI: 0.02–0.36), P = 0.03) and high-density lipoprotein (HDL)-cholesterol concentrations (β = 0.31(95%CI: 0.08–0.54), P 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.

BACKGROUND:Cardiovascular disease (CVD) is the leading cause of death in women worldwide. The cardiovascular risk profile deteriorates after women enter menopause. By definition, women diagnosed with premature ovarian insufficiency (POI) experience menopause before 40 years of age, which may render these women even more susceptible to develop CVD later in life. However, prospective long-term follow up data of well phenotyped women with POI are scarce. In the current study we compare the CVD profile and risk of middle aged women previously diagnosed with POI, to a population based reference group matched for age and BMI. METHODS AND FINDINGS:We compared 123 women (age 49.0 (± 4.3) years) and diagnosed with POI 8.1 (IQR: 6.8-9.6) years earlier, with 123 population controls (age 49.4 (± 3.9) years). All women underwent an extensive standardized cardiovascular screening. We assessed CVD risk factors including waist circumference, BMI, blood pressure, lipid profile, pulse wave velocity (PWV), and the prevalence of diabetes mellitus, metabolic syndrome (MetS) and carotid intima media thickness (cIMT), in both women with POI and controls. We calculated the 10-year CVD Framingham Risk Score (FRS) and the American Heart Association's suggested cardiovascular health score (CHS). Waist circumference (90.0 (IQR: 83.0-98.0) versus 80.7 (IQR: 75.1-86.8), p < 0.01), waist-to-hip ratio (0.90 (IQR: 0.85-0.93) versus 0.79 (IQR: 0.75-0.83), p < 0.01), systolic blood pressure (124 (IQR 112-135) versus 120 (IQR109-131), p < 0.04) and diastolic blood pressure (81 (IQR: 76-89) versus 78 (IQR: 71-86), p < 0.01), prevalence of hypertension (45 (37%) versus 21 (17%), p < 0.01) and MetS (19 (16%) versus 4 (3%), p < 0.01) were all significantly increased in women with POI compared to healthy controls. Other risk factors, however, such as lipids, glucose levels and prevalence of diabetes were similar comparing women with POI versus controls. The arterial stiffness assessed by PWV was also similar in both populations (8.1 (IQR: 7.1-9.4) versus 7.9 (IQR: 7.1-8.4), p = 0.21). In addition, cIMT was lower in women with POI compared to controls (550 μm (500-615) versus 684 μm (618-737), p < 0.01). The calculated 10-year CVD risk was 5.9% (IQR: 3.7-10.6) versus 6.0% (IQR: 3.9-9.0) (p = 0.31) and current CHS was 6.1 (1.9) versus 6.5 (1.6) (p = 0.07), respectively in POI versus controls. CONCLUSIONS:Middle age women with POI presented with more unfavorable cardiovascular risk factors (increased waist circumference and a higher prevalence of hypertension and MetS) compared to age and BMI matched population controls. In contrast, the current study reveals a lower cIMT and similar 10-year cardiovascular disease risk and cardiovascular health score. In summary, neither signs of premature atherosclerosis nor a worse cardiovascular disease risk or health score were observed among middle age women with POI compared to population controls. Longer-term follow-up studies of women of more advanced age are warranted to establish whether women with POI are truly at increased risk of developing CVD events later in life. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02616510.

STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference?SUMMARY ANSWER: International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS.WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist.STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength.PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels.MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management.LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided.WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program.STUDY FUNDING/COMPETING INTEREST(S): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.

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 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 (β [95% confidence interval (CI)], 0.009 [0.000 to 0.018]). Highest quartile dehydroepiandrosterone [β (95% CI), -0.008 (-0.015 to -0.001)] and androstenedione [β (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.

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 (E 2 ), 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, β = 0.15, 95% CI = 0.12, 0.18), and lower levels of TT (per 1 SD increase, β = −0.05, 95%CI = −0.08, −0.02), FAI (per 1 SD increase, β = −0.13, 95%CI = −0.15, −0.09), DHEAS (per 1 SD increase, β = −0.06, 95% CI = −0.09, −0.04) and DHEA (per 1 SD increase, β = −0.06, 95%CI = −0.09, −0.04) were associated with higher levels of NT-proBNP. However, no consistent association was found between E 2 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.

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.

Conventional ovarian stimulation protocols for IVF are designed to achieve maximum oocyte yields. Conventional protocols, however, are associated with patient discomfort, increased risk of ovarian hyperstimulation syndrome and higher costs. In recent years, mild stimulation protocols have risen in popularity. These protocols typically use lower doses (≤150 IU/day), shorter duration of exogenous gonadotrophins, or both, compared with conventional protocols, with the goal of limiting the number of retrieved oocytes to less than eight. The pregnancy rate per cycle (fresh embryo transfer only) is lower with mild stimulation compared with conventional stimulation; however, the cumulative pregnancy rate seems to be comparable between the approaches. Reports are conflicting on the effects of mild versus conventional stimulation on embryo quality. This article expands on a live debate held at the American Society for Reproductive Medicine 2015 Annual Meeting to compare the advantages and disadvantages of the 'more is better' (conventional protocol) versus 'less is best' (mild protocol) approaches to ovarian stimulation. Both protocols are associated with benefits and challenges, and physicians must consider the needs of the individual patient when determining the best treatment options. Further prospective studies comparing a variety of outcomes with conventional and mild stimulation are needed.

Publisher's version (útgefin grein), Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health., This work has been supported by MRC grant MC_U106179472 (FD, KO, JRBP), Samuel Oschin Comprehensive Cancer Institute Developmental Funds, Center for Bioinformatics and Functional Genomics and Department of Biomedical Sciences Developmental Funds (MRJ), NCI P30CA177558 (CH), NCI UM1CA186107 (PK), European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) and the European Union’s Horizon 2020 research and innovation program under grant agreements No 692065 (TL, RM, AS) and 692145 (RM), NICHD R01HD065029 (RS), Estonian Ministry of Education and Research (grant IUT34-16 to TL), NICHD R01HD057450 (MU), NICHD P50HD044405 (AD), NICHD R01HD057223 (AD), R01HD085227 (MGH, AD), deCode Genetics (GT, UT, KS, US), Raine Medical Research Foundation Priming Grant (BHM), SCGOPHCG RAC 2015-16/034 (SGW, BGAS), 2016-17/018 (BGAS), NIHR BRC, Wellcome Trust, MRC (TDS), Eris M. Field Chair in Diabetes Research (MOG), NIDDK P30 DK063491 (MOG), NIDDK U01DK094431, U01DK048381 (DE), NICHD U10HD38992 (RL), Estonian Ministry of Education and Research (grant IUT34-16), Enterprise Estonia (grant EU48695); the EU-FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, grant SARM, EU324509 to AS), Wellcome (090532, 098381, 203141); European Commission (ENGAGE: HEALTH-F4-2007-201413 to MIM), MRC G0802782, MR/M012638/1 (SF), Li Ka Shing Foundation, WT-SSI/John Fell Funds, NIHR Biomedical Research Centre, Oxford, Widenlife and NICHD 5P50HD028138-27 (CML), NICHD R01HD065029, ADA 1-10-CT-57, Harvard Clinical and Translational Science Center, from the National Center for Research Resources 1UL1 RR025758 (CKW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

A growing number of people desire ART with cryopreserved donor oocytes. The allocation of these oocytes to couples and mothers to be is a 2-fold process. The first step is to select a pool of recipients. The second step is to decide who should be treated first. Prioritizing recipients is critical in settings where demand outstrips supply. So far, the issue of how to fairly allocate cryopreserved donor oocytes has been poorly addressed. Our ethical analysis aims to support clinics involved in allocation decisions by formulating criteria for recipient selection irrespective of supply (Part I) and recipient prioritization in case supply is limited (Part II). Relevant criteria for recipient selection are: a need for treatment to experience parenthood; a reasonable chance for successful treatment; the ability to safely undergo an oocyte donation pregnancy; and the ability to establish a stable and loving relationship with the child. Recipients eligible for priority include those who: have limited time left for treatment; have not yet experienced parenthood; did not undergo previous treatment with cryopreserved donor oocytes; and contributed to the supply of donor oocytes by bringing a donor to the bank. While selection criteria function as a threshold principle, we argue that the different prioritization criteria should be carefully balanced. Since specifying and balancing the allocation criteria undoubtedly raises a moral dispute, a fair and legitimate allocation process is warranted (Part III). We argue that allocation decisions should be made by a multidisciplinary committee, staffed by relevant experts with a variety of perspectives. Furthermore, the committees’ reasoning behind decisions should be transparent and accessible to those affected: clinicians, donors, recipients and children born from treatment. Insight into the reasons that underpin allocation decisions allows these stakeholders to understand, review and challenge decisions, which is also known as accountability for reasonableness.

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.

Women with polycystic ovary syndrome (PCOS) have unfavorable metabolic profiles. Their offspring may be affected by such risks. The objective of the current study was to disclose associations between preconception health of these women and health of their offspring. 74 women diagnosed with PCOS according to the Rotterdam criteria were screened systematically before conception. Cardiovascular health of their offspring was assessed at 2.5-4 (n = 42) or at 6-8 years of age (n = 32). Multivariate linear regression analysis was performed with adjustments for potential confounders. In the primary analyses the association between preconception Body Mass index (BMI) and offspring BMI was evaluated. Secondly associations between preconception blood pressure, androgens, insulin-resistance (HOMA-IR), and LDL-cholesterol in women with PCOS and BMI and blood pressure of offspring were assessed. Results show that preconception BMI of women with PCOS was positively associated with sex- and age-adjusted BMI of their offspring at 6-8 years of age (β = 0.55 (95% CI: 0.12 to 0.97), p = .012). No other significant associations were found. In conclusion, our data suggest that preconception BMI in PCOS is significantly associated with offspring BMI at 6-8 year of age. If this suggestion could be confirmed this may provide an opportunity for improving the future health of these children.

OBJECTIVE: The stability of anti-Müllerian hormone (AMH) across and between menstrual cycles has been the subject of debate. The objective of this analysis was to study the inter- and intracycle variability in repeated measurements and assess the impact on an individualized gonadotropin dosing algorithm and predicted oocyte yield. DESIGN: Retrospective analysis of repeat AMH measures from a randomized controlled trial. PATIENTS: A total of 1326 women aged 18-40 years. MEASUREMENTS: Serum AMH levels at screening and at cycle day 2-3 in up to three ovarian stimulation cycles. AMH variability and its impact on gonadotropin dose and the predicted number of oocytes. RESULTS: Repeat serum AMH measurements were strongly correlated within individual women (correlation coefficient 0.92). AMH exhibited limited within-subject variation (coefficient of variation 23%), a small time-related decline (mean 6% decrease/y), but no systematic variation across the menstrual cycle. Irrespective of whether the AMH screening value or the AMH at the initiation of ovarian stimulation was used, for women with an AMH level

One of the barriers to access to fertility care is the relative complexity of fertility treatments. If these can be simplified, more patients may be able to take advantage of these treatments. In this overview, we review the potential benefits of simplifying ovarian stimulation by the means of four distinct methods: 1) using mild stimulation for IVF cycles; 2) using in vitro maturation to allow for the retrieval of oocytes that are not yet fully mature yet have the potential to result in live births; 3) conducting IVF in modified natural cycles which use no exogenous FSH stimulation; and 4) allowing embryo culture to take place in a novel intravaginal incubation system. These methods are considered to be somewhat unconventional, yet they have all been shown to lead to live births. In the era of individualized patient care, these techniques present viable alternatives to standard treatment. As experience and outcome data accumulate, they may prove to be not just alternatives to standard treatment, but potentially first-line treatment choices.

In this retrospective cohort study (n = 479), the proportion of women with premature ovarian insufficiency (POI) who conceived was assessed, the reproductive characteristics of women with POI who had previously been pregnant or had never been pregnant compared, and the interval between last conception and the menopause in women with POI who had become pregnant assessed. Time to pregnancy and maternal age at first childbirth were compared between women with POI and population-based controls (n = 2304). Women with POI who had previously been pregnant (n = 249 [52%]) experienced menopause at a later age compared with controls (35.0 years: interquartile range [IQR] 32.0-37.5 versus 30.0 years [IQR 23.0-35.0]; P

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 (β = 2.3 [95% confidence interval, CI: 0.5-4.0]) and higher aortic pulse pressure (β = −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 (β = −0.1 [95% CI: −0.2 to −0.1]), LDL-cholesterol (β = −0.4 [95% CI: −0.6 to −0.1]), and higher carotid intima-media thickness (β = −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.

The primary endpoint in reproductive medicine should be the healthy mother and offspring, and all other endpoints should be considered as surrogates. The infertile woman with polycystic ovary syndrome (PCOS) is a patient at high risk for adverse pregnancy and perinatal outcomes. In fact, multiple gestation, specific clinical and biochemical characteristics and comorbidities related to PCOS and the use of infertility treatments and biological manipulations can be all crucial factors. Infertility itself is considered a risk factor for obstetric complications, creating an inherent bias in studies of fertility treatment. Unfortunately, it is very difficult to precisely estimate the amount of that risk due to a lack of high-quality data and to heterogeneity of the studied populations, often mixing assisted reproduction technologies and spontaneous conceptions. The current chapter will summarise the current knowledge regarding pregnancy complications in women with PCOS and its potential pathophysiology.

The objective was to evaluate the effect of combined oral contraceptives (OCs) on sexual function, either alone or together with dehydroepiandrosterone (DHEA).An exploratory randomized, double-blind, placebo-controlled, comparative, crossover study was conducted in 81 OC users. Subjects discontinued their OC for one cycle before being randomized for 10cycles to a 30-mcg ethinyl estradiol (EE)/levonorgestrel (LNG) OC or a 30-mcg EE/drospirenone (DRSP) OC, along with daily use of 50mg dehydroepiandrosterone (DHEA) or placebo during five OC cycles before crossing over from DHEA to placebo or the reverse for another fivecycles. First, the effect on sexual function of five OC cycles + placebo was compared to baseline. Then, the effect of five OC cycles + DHEA was compared to the OC+placebo. Results regarding endocrine changes have been published separately. Primary efficacy outcomes of the current study were genital response (measured by vaginal pulse amplitude [VPA]) and sexual feelings (measured by the subjective self-assessment questionnaire [SSAQ]) to self-induced erotic fantasy and visual sexual stimuli in a laboratory setting and measures of desire and arousability using a sexual function diary (SFD). Secondary efficacy outcomes were the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale Revised.Eighty-one women were enrolled, and 74 women completed the study. Five cycles of OC+placebo resulted in a significant decline compared to baseline of four out of six SFD self-ratings of sexual desire and arousability with both OCs. The LNG OC also resulted in significant declines in the FSFI scores (baseline vs. LNG OC+placebo: total score, 28.7±3.7 vs. 25.6±7.4; arousal, 5.0±0.7 vs. 4.5±1.4; lubrication, 5.2±0.9 vs. 4.6±1.7; pain, 4.9±0.9 vs. 4.5±1.4), but no changes were observed using the DRSP OC. In the laboratory setting, five cycles of OC+DHEA showed no significant differences with placebo except for a significant increase in genital sensations (SSAQ) during erotic fantasy (OC+placebo vs. OC+DHEA: 3.3±1.4 vs. 3.6±1.5; p.05). No significant changes were observed for genital response (VPA) and the other two variables of the SSAQ assessed after visual erotic stimulus exposure. Using the SFD, 5 out of 10 variables showed a significant improvement with DHEA. Partner's initiative was rejected less often with OC+DHEA compared to placebo (OC+placebo vs. OC+DHEA: 1.1±1.5 vs. 0.8±1.0; p.05). Women with free testosterone levels in the upper quartile during DHEA co-administration showed significantly better effects on sexual arousal and desire compared to the three lower quartiles (lower vs. upper quartiles: sexual arousability: 25.0±19.8 vs. 41.2±29.0; sexual desire: 5.6±3.7 vs. 9.6±8.0; desire for sex with partner: 4.9±3.1 vs. 8.6±7.4; number of sex fantasies: 3.0±3.2 vs. 5.5±4.4; all p.05).In this exploratory study, OC use was associated with decreases in some measures of sexual functioning, whereas others remained unchanged. Maintaining or restoring physiological testosterone concentrations by the co-administration of DHEA to the OC may prevent these effects on sexuality, particularly in women with relatively high but physiologic levels of free testosterone during DHEA co-administration.The results of this exploratory study warrant further testing of the hypothesis that restoration and/or preservation of physiologic testosterone levels during OC use by co-administration of DHEA has favorable effects on those aspects of sexual function compromised by OCs.

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field.

Preeclampsia is associated with an increased risk of coronary artery disease (CAD), although evidence on premature CAD development after preeclampsia is limited.1 A cross-sectional study among 491 postmenopausal women with a mean age of 67 years showed an increased prevalence of coronary artery calcification (CAC) in participants with self-reported high blood pressure during any previous pregnancy in comparison with women without such a history.2 However, the association between hypertensive pregnancy, CAC, and coronary plaque formation has not been reconfirmed in prospective studies, and there are no data on the timeline by which atherosclerosis develops in women with previous preeclampsia. The aim of this study is to compare the prevalence of coronary artery atherosclerosis of asymptomatic women aged 45 to 55 years who have a history of preeclampsia with a population-based reference cohort. The rationale and design of the CREW-IMAGO study (Cardiovascular Risk Profile: Imaging and Gender-Specific Disorders) have been published previously (URL: http://www.trialregister.nl/trialreg/index.asp. Unique identifier: NTR5531).3 Asymptomatic women, aged 45 to 55 years, with a history of preeclampsia 10 to 20 years earlier were included in this multicenter, prospective cohort study. Medical records, including pregnancy characteristics and hospital admission, were available for all women. Outcomes were compared with women of similar age and ethnicity who participated …

Item does not contain fulltext Women who develop preeclampsia have an increased risk of cardiovascular disease (CVD) later in life. However, current guidelines on cardiovascular risk assessment and prevention are unclear on how and when to screen these women postpartum, and about the role of a positive history of preeclampsia in later-life CVD risk management. The aim of this review is to discuss the present knowledge on commonly used cardiovascular screening modalities available to women with a history of preeclampsia, and to discuss recent developments in early detection of CVD using cardiovascular imaging. Furthermore, we explore how female-specific risk factors may have additional value in cardiovascular screening, in particular in relatively young women, although their implementation in clinical practice is challenged by inconsistent results and lack of long-term outcome data. Non-invasive imaging techniques, e.g., coronary artery intima-media thickness (CIMT), can be helpful to detect subclinical atherosclerotic disease, and coronary artery calcium scoring (CACS) has shown to be effective in early detection of cardiovascular damage. However, while more short-term and long-term follow-up studies are becoming available, few studies have investigated women with a history of preeclampsia in the fourth and fifth decade of life, when early signs of premature CVD are most likely to become apparent. Further studies are needed to inform new and improved clinical practice guidelines, and provide long-term strategies to effectively prevent CVD, specifically targeted at women with a history of preeclampsia. Additionally, evaluation of feasibility, cost-effectiveness, and implementation of CVD screening and prevention initiatives targeted at former preeclampsia patients are needed.

Background The demand for donor oocytes has increased dramatically over the years. Today people in need of ART with the use of donor oocytes can appeal to commercial or public donor oocyte banks. The introduction of oocyte banks has shed a new light on the practice of ART using donor oocytes. The establishment and maintenance of oocyte banks should be sensitive to the ethical considerations. However, it is currently unclear which ethical aspects have to be taken into account. Objective and rationale The aim of this article is to identify the ethical aspects of establishing and maintaining oocyte banks for third-party ART. Search methods A systematic search was performed in July 2016 and February 2017 in both PubMed and Embase using a search string that combined synonyms for oocytes, donation or banking, reproductive care and ethics. We included a wide variety of English-language articles with a reasoned description of ethical aspects or moral considerations on oocyte donation or banking for third-party ART. Outcomes The practice of oocyte banking consists of three components, namely, the intake, storage and distribution of donor oocytes, and each is associated with multiple ethical challenges. The majority of the literature discusses ethical aspects with regard to the intake of donor oocytes, taking into account both the interests of the donor and those of the potential child. Ethical aspects related to the donor are the risks and psychosocial impact of donation, motivations and compensation in donor recruitment, and requirements for informed consent. Ethical aspects related to the potential child are 2-fold: first, the welfare standard and the selection of donors, and second, anonymity and disclosure. Ethical aspects of storing donor oocytes for ART are quality standards, confidentiality, issues of ownership and control, and international transport of donor oocytes. Ethical aspects of the distribution of donor oocytes concern the selection of recipients and the acceptability of treatment of 'non-traditional' families in particular, prioritization of recipients in case of scarcity, cross-border reproductive care, matching of recipients and donor oocytes, informed consent and counselling for recipients. Wider implications Our review demonstrates that multiple ethical aspects have to be taken into account when establishing and maintaining an oocyte bank. Yet, for many of these aspects there is no consensus regarding what approach should be employed. Remarkably, the existing literature focuses mainly on ethical aspects related to the intake of donor oocytes, while aspects related to storage and distribution of donor oocytes are less often addressed. An important gap in the existing literature should therefore be acknowledged. To conclude, our findings can serve as a starting point for clinicians in the field of ART, to conceptualize what challenges arise when establishing and maintaining oocyte banks for third-party ART. The review may also stimulate policy makers to set up a trustworthy and adaptive governance structure for the intake, storage and distribution of donor oocytes.

It has been proven that the use of high gonadotropin dose does not necessarily improve the final outcome of IVF. Mild ovarian stimulation is based on the principle of optimal utilization of competent oocytes/embryos and endometrial receptivity. There is growing evidence that the pregnancy or live birth rates with mild-stimulation protocols are comparable to those with conventional IVF; the cumulative pregnancy outcome has been shown to be no different, despite having fewer numbers of oocytes or embryos available with milder ovarian stimulation. Although equally effective, mild-stimulation IVF is associated with a greater safety profile, in terms of the incidence of ovarian hyperstimulation syndrome and venous thromboembolism. It is also found to be better tolerated by patients and less expensive. Emerging research evidence may lead to widespread acceptance of mild IVF, by both patients and IVF providers, and make IVF more accessible to women and couples worldwide.

Ovarian stimulation in infertility treatment can be applied in several ways. Strategy and choice of drugs used depends on the indication and goal of the infertility treatment. To understand and apply ovarian stimulation it is necessary to understand the basic concepts of the (patho)physiology of ovarian function (i.e., follicle development).

Objective:\ud \ud 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.\ud Methods:\ud \ud 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.\ud Results:\ud \ud 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.\ud Conclusion:\ud \ud 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.

Contains fulltext : 176974.pdf (Publisher’s version ) (Open Access) 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.

Objective:\ud \ud To compare the efficacy and safety of follitropin delta, a new human recombinant FSH with individualized dosing based on serum antimüllerian hormone (AMH) and body weight, with conventional follitropin alfa dosing for ovarian stimulation in women undergoing IVF.\ud \ud Design:\ud \ud Randomized, multicenter, assessor-blinded, noninferiority trial (ESTHER-1).\ud \ud Setting:\ud \ud Reproductive medicine clinics.\ud \ud Patient(s):\ud \ud A total of 1,329 women (aged 18–40 years).\ud \ud Intervention(s):\ud \ud Follitropin delta (AMH

To evaluate whether a short follicular phase of ovarian stimulation compromises the chance of pregnancy, subjects from a double-blind, randomized trial treated with a single dose of corifollitropin alfa (n=756) or daily recombinant FSH (n=750) were categorized as early responders if three follicles ⩾17mm were reached and human chorionic gonadotrophin (HCG) was administered prior to or on stimulation day 8, and as normal responders if three follicles ⩾17mm were reached and HCG was administered after stimulation day 8. In the corifollitropin alfa and recombinant FSH groups, 23.2% and 29.1%, respectively, were early responders (P=0.01). Regardless of the treatment group, the initial ovarian response was higher in early responders, but with two extra days of stimulation, the number and size of follicles on the day of HCG in the normal responders was similar to those of the early responders. The number of oocytes was similar in both response groups following corifollitropin alfa treatment (13.6 versus 14.5) and recombinant FSH treatment (12.8, both groups). The ongoing pregnancy rates were comparable for early and normal responders regardless of the treatment group, supporting successful outcome following a stimulation period of only 1week. During ovarian stimulation for assisted reproduction, some women respond earlier than others to treatment with follicle-stimulating agents and require fewer days of treatment. To evaluate whether such short stimulation jeopardizes the chance of pregnancy, clinical outcomes of early responders and normal responders were compared in women aged 18–36years treated with either a single dose of corifollitropin alfa (756 women) or daily recombinant FSH (750 women) for the first 7days of stimulation. On average, about 25% of the evaluated women were early responders. The initial ovarian response was higher in early responders than in normal responders but the number of eggs retrieved and the ongoing pregnancy rates in early and normal responders were similar regardless of the treatment group. This study shows that the chance of ongoing pregnancy was not compromised in women requiring only 1week of stimulation compared with women who required a longer duration of stimulation.

STUDY QUESTION: Do diabetic parents of patients with polycystic ovary syndrome (PCOS) encounter excess mortality compared with the mortality of men and women with type 2 diabetes, recruited without selection for PCOS?SUMMARY ANSWER: Type 2 diabetes among mothers of PCOS patients results in excess mortality compared with women with diabetes from the general population.WHAT IS KNOWN ALREADY: Insulin resistance is a prominent feature of PCOS. Because of the heritable nature of PCOS, parents of these patients are also prone to develop type 2 diabetes mellitus, which might influence their life expectancy.STUDY DESIGN, SIZE, DURATION: This reverse parent-offspring study included 946 mothers and 902 fathers of patients with PCOS.PARTICIPANTS/MATERIALS, SETTING, METHODS: The medical history of the parents was primarily obtained during the initial screening of each patient and updated via questionnaires. Mortality data of these parents were compared with the mortality rates of the general Dutch population and with mortality rates of a control population consisting of 1353 men and women diagnosed with type 2 diabetes mellitus. The standardized mortality ratio (SMR) was calculated as the ratio of the observed mortality of the parents to the expected mortality in the general Dutch population. The mortality of parents with type 2 diabetes mellitus relative to controls with diabetes but not related to anyone with PCOS was standardized for age, gender and calendar period using Poisson regression.MAIN RESULTS AND ROLE OF CHANCE: In total, 302 parents were deceased in 62 693 person-years. Mothers above age 60 had a significant excess mortality of 1.50 (95% CI 1.15-1.92) compared with the general Dutch population. Moreover, mothers with diabetes had two-times higher mortality risk compared with control women with diabetes (RR 2.0, 95% CI 1.19-3.41). No excess mortality among fathers of PCOS patients was observed.LIMITATIONS, REASON FOR CAUTION: Although recall bias for family history was previously demonstrated to be minimal for long-term chronic diseases, the prevalence of diabetes in the parents was based on their daughter's self-report and was not clinically confirmed. Also, no other additional clinical data regarding the parent population were available. Prospective long-term follow-up studies should be conducted to confirm this excess mortality.WIDER IMPLICATIONS OF THE FINDINGS: Our findings justify screening for type 2 diabetes mellitus among the mothers with a daughter suffering from PCOS to ensure that timely preventive and therapeutic measures according to the appropriate guidelines can be taken.STUDY FUNDING/COMPETING INTERESTS: No particular funding was received for this study. Y.V.L., M.E.R.-S., N.K., J.R.v.L., M.v.d.B., H.J.G.B. and E.J.G.S. do not have any conflict of interest. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Genovum, Merck-Serono, Organon, Schering Plough and Serono. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono, and Wyeth. These companies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

No abstract available.