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.

The case for mild stimulation for IVF: recommendations from The International Society for Mild Approaches in Assisted Reproduction.

The practice of ovarian stimulation for IVF is undergoing a fundamental re-evaluation as recent data begin to successfully challenge the traditional paradigm that ovarian stimulation should be aimed at the retrieval of as many oocytes as possible, in the belief that this will increase pregnancy rates. An opposing view is that live birth rate should not be the only end-point in evaluating the success of IVF treatment and that equal emphasis should be placed on safety and affordability. The International Society for Mild Approaches in Assisted Reproduction (ISMAAR) committee has carried out an up-to-date literature search, with the evidence being graded according to the University of Oxford's Centre for Evidence-Based Medicine. The recommendations were formulated taking into account the quality of evidence on the efficacy, risk and cost of each intervention. ISMAAR recommends adopting a mild approach to ovarian stimulation in all clinical settings as an increasing body of evidence suggests that mild stimulation is as effective as conventional stimulation, while being safer and less expensive. Mild ovarian stimulation could replace conventional stimulation, thus making IVF safer and more accessible worldwide.

Correction: Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

[This corrects the article DOI: 10.1371/journal.pgen.1007813.].

Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

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.

The cardiovascular risk profile of middle-aged women with polycystic ovary syndrome.

OBJECTIVES: Contradictory results have been reported regarding the association between polycystic ovary syndrome (PCOS) and cardiovascular disease (CVD). We assessed the cardiometabolic phenotype and prevalence of CVD in middle-aged women with PCOS, compared with age-matched controls from the general population, and estimated 10-year CVD risk and cardiovascular health score. DESIGN: A cross-sectional study. PARTICIPANTS: 200 women aged >45 with PCOS, and 200 age-matched controls. MEASUREMENTS: Anthropometrics, insulin, lipid levels, prevalence of metabolic syndrome and type II diabetes. Ten-year Framingham risk score and the cardiovascular health score were calculated, and carotid intima-media thickness (cIMT) was measured. RESULTS: Mean age was 50.5 years (SD = 5.5) in women with PCOS and 51.0 years (SD = 5.2) in controls. Increased waist circumference, body mass index and hypertension were more often observed in women with PCOS (P < .001). In women with PCOS, the prevalence of type II diabetes and metabolic syndrome was not significantly increased and lipid levels were not different from controls. cIMT was lower in women with PCOS (P < .001). Calculated cardiovascular health and 10-year CVD risk were similar in women with PCOS and controls. CONCLUSIONS: Middle-aged women with PCOS exhibit only a moderately unfavourable cardiometabolic profile compared to age-matched controls, even though they present with an increased BMI and waist circumference. Furthermore, we found no evidence for increased (10-year) CVD risk or more severe atherosclerosis compared with controls from the general population. Long-term follow-up of women with PCOS is necessary to provide a definitive answer concerning long-term risk for CVD.

Anti-Müllerian hormone variability and its implications for the number of oocytes retrieved following individualized dosing with follitropin delta.

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 <15 pmol/L, 93% would receive the same gonadotropin dose and attain an identical number of oocytes in 97% of cases. For women with an AMH level ≥15 pmol/L, 80% would receive an individualized dose within ±1.5 µg and 90% would attain ±1 oocyte. CONCLUSION: AMH variability had limited impact on individualized gonadotropin dosing, with 95% of women predicted to obtain an oocyte yield that does not vary beyond 1 oocyte count, irrespective of whether a random or early follicular AMH measurement was used to determine the individualized gonadotropin dose.

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.

Dydrogesterone: pharmacological profile and mechanism of action as luteal phase support in assisted reproduction.

The pharmacological and physiological profiles of progestogens used for luteal phase support during assisted reproductive technology are likely to be important in guiding clinical choice towards the most appropriate treatment option. Various micronized progesterone formulations with differing pharmacological profiles have been investigated for several purposes. Dydrogesterone, a stereoisomer of progesterone, is available in an oral form with high oral bioavailability; it has been used to treat a variety of conditions related to progesterone deficiency since the 1960s and has recently been approved for luteal phase support as part of an assisted reproductive technology treatment. The primary objective of this review is to critically analyse the clinical implications of the pharmacological and physiological properties of dydrogesterone for its uses in luteal phase support and in early pregnancy.

Ovarian stimulation protocols for IVF: is more better than less?

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.

Biosimilars to recombinant human FSH medicines: comparable efficacy and safety to the original biologic.

Two recombinant follicle-stimulating hormone (rFSH)-bearing similar biological medicines (biosimilars) have been authorized by the European Commission. Biosimilar is a regulatory concept alluding to the evidence-based high-standard comparability studies needed to demonstrate its equivalence to a reference original biologic. Because biosimilar development represents a shift from the long-lasting existing paradigms, a thorough understanding of the science behind it will contribute to helping prescribers make informed treatment choices. Contrary to chemically-synthesized medicines, biologics are subject to an inherent molecular variability. From the experience with original biologics, regulatory authorities have accumulated a wealth of knowledge as to what minor batch-to-batch physicochemical variations may be therapeutically acceptable in a given product. Furthermore, in spite of analytically detectable differences, the two original rFSH-bearing medicines currently on the market share fundamentally the same therapeutic profile. Unlike those original medicines, a biosimilar of an rFSH product and the corresponding reference biologic share essentially the same active pharmaceutical ingredient. They are also administered via the same route, at the same dose, and for the same indications. This article revises the background evidence over which the biosimilarity principle has been built, and highlights the therapeutic potential for follitropin biosimilars in order to reassure physicians on their benefit.

Autonomy and self-esteem of women who donate to an oocyte cryopreservation bank in the Netherlands.

Worldwide, oocyte donors donate voluntarily or receive varying amounts of money for donation. This raises ethical questions regarding the appropriateness of financial compensation, and the possibility of undue inducement and exploitation of oocyte donors. Are these donors capable of making an independent, well-considered decision? Regarding this matter, it is important to examine aspects such as autonomy-connectedness and self-esteem. In this cross-sectional study, demographic characteristics and donation motivations were assessed in 92 women who attended the University Medical Center (UMC) Utrecht as potential oocyte donors between June 2012 and July 2016. Demographic characteristics were assessed. Motivations were recorded in semi-structured interviews (response rate 59%). The Rosenberg Self-Esteem Scale was used to assess level of self-esteem. The Autonomy-Connectedness Scale was used to measure the level of autonomy-connectedness. The typical oocyte donor at the UMC Utrecht is a well-educated, employed, 31-year-old woman living with her partner in a completed family with two children, and donating on altruistic grounds. The donors showed higher autonomy-connectedness scores than the average female Dutch population and do not lack self-esteem (questionnaire response rate 66%). Concerns regarding exploitation and attraction of women with lower socioeconomic status, with shortcomings in autonomy-connectedness and self-esteem, could not be confirmed in this group.

Management of ovarian stimulation for IVF: narrative review of evidence provided for World Health Organization guidance.

In this paper, a review of evidence provided to the World Health Organization (WHO) guideline development, who prepare global guidance on the management of ovarian stimulation for women undergoing IVF, is presented. The purpose of ovarian stimulation is to facilitate retrieval of multiple oocytes during a single IVF cycle. Availability of multiple oocytes compensates for inefficiencies in subsequent stages of the cycle, which include oocyte maturation, IVF, embryo culture, embryo transfer, and implantation. Multiple embryos can be transferred in most women, and spare embryos can be frozen to allow for future chances of pregnancy without the need for repeated ovarian stimulation and oocyte retrieval. Our evidence synthesis team addressed 10 clinical questions on management of ovarian stimulation for IVF, prepared a narrative review of the evidence and drafted recommendations to be considered through WHO guideline development processes. Our main outcome measures were live birth, clinical pregnancy, and ovarian hyperstimulation syndrome.

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.

Reproductive characteristics of women diagnosed with premature ovarian insufficiency.

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 < 0.001). The median interval between last conception and menopause in the former group was 4.0 years (IQR 1.0-8.0). Time to pregnancy did not differ between women with POI and controls. Women with POI were younger at first childbirth compared with controls (27.3 years [IQR 23.4-30.5] versus 29.2 years [26.4-32.0]; P < 0.001). The reproductive capacity of young women with POI is comparable to women in the general population, up until a given age; thereafter a rapid loss of the potential to conceive occurs.

Insulin action in women with polycystic ovary syndrome and its relation to gestational diabetes.

STUDY QUESTION: How does insulin action change during pregnancy in women with polycystic ovary syndrome (PCOS) who develop gestational diabetes (GDM) compared with women with PCOS who do not? SUMMARY ANSWER: Women with PCOS who develop GDM already show disturbed insulin action early in pregnancy. WHAT IS KNOWN ALREADY: Pregnant women with PCOS are at increased risk of developing GDM compared with women without PCOS. STUDY DESIGN, SIZE, DURATION: This study represents a post hoc analysis of a subgroup of pregnant women with PCOS participating in a multicentre prospective cohort study. A total of 72 women were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS and a wish to conceive were included before conception and followed during pregnancy. Insulin, glucose, homeostasis model assessment of insulin resistance (HOMA-IR), sex hormone-binding globulin (SHBG) and testosterone were analysed at three different time points in women who developed GDM and women who did not. MAIN RESULTS AND THE ROLE OF CHANCE: Seventy-two pregnant women with PCOS were included of which 22 (31%) women developed GDM. Both insulin levels and HOMA-IR were significantly higher at each sampling point in women with PCOS who developed GDM. SHBG levels were significantly lower before conception and in the second trimester compared with women who did not develop GDM. Testosterone concentrations were significantly lower before conception in women who developed GDM. After adjusting for BMI, waist circumference and waist/hip ratio, the differences in insulin, HOMA-IR, SHBG and testosterone levels remained largely the same. LIMITATIONS, REASONS FOR CAUTION: Selection bias cannot be excluded since only women from one centre with a complete blood sampling set were included in this study. WIDER IMPLICATIONS OF THE FINDINGS: The knowledge that women with PCOS who develop GDM already have a disturbed insulin action early in pregnancy is likely to be useful in considering the pathophysiology processes underlying this disorder in this specific group of women. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Child Health research programme of the University Medical Centre Utrecht. M.A.d.W., A.J.G., S.M.V.-V., A.F. and M.P.H.K. have no conflicts of interest to disclose. M.J.C.E. has received grant support from the following companies (in alphabetic order): Illumina and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Ferring, Ova-Science, PregLem SA, Roche and Watson Laboratories. The authors declare complete independence from funders. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, number NCT00821379.