Associations of preconception Body Mass Index in women with PCOS and BMI and blood pressure of their offspring.

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 (ß = 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.

Implications of the 2014 Androgen Excess and Polycystic Ovary Syndrome Society guidelines on polycystic ovarian morphology for polycystic ovary syndrome diagnosis.

The Androgen Excess and Polycystic Ovary Syndrome Society (AEPCOS) has recommended an updated threshold for polycystic ovarian morphology (PCOM) of 25 follicles or more, 10 ml or more of ovarian volume, or both. We describe the effect of these guidelines on reproductive and metabolic characteristics in 404 women. These women were separated into four groups: group A: hyperandrogenism and oligo-amenorrhoea (n = 157); group B: hyperandrogenism or oligo-amenorrhoea and PCOM meeting AEPCOS 2014 criteria (n = 125); group C: hyperandrogenism or oligo-amenorrhoea and PCOM meeting Rotterdam 2003 but not AEPCOS 2014 criteria (n = 72); and group D: non-PCOS not meeting either criteria (n = 50). Groups B, C and D did not differ across any metabolic markers. The AEPCOS 2014 guidelines may have limited utility in distinguishing metabolic risk factors and result in the exclusion of a large group of oligo-anovulatory women.

Are women with polycystic ovary syndrome at increased cardiovascular disease risk later in life?

To date, the world's leading cause of death amongst women is cardiovascular disease. Polycystic ovary syndrome (PCOS) is associated with an unfavorable cardiometabolic profile in early life. Apart from dyslipidemia, obesity and onset of type 2 diabetes mellitus, androgens are thought to influence cardiovascular health. The question rises whether women with PCOS are truly at risk for cardiovascular disease in later life. In this review paper, we aim to reflect on this assumed relation based on studies in different stages of life in women with PCOS. Cardiovascular risk factors (type 2 diabetes mellitus, obesity and metabolic syndrome), surrogate outcomes (flow-mediated dilation, carotid intima-media thickness and coronary artery calcium) and clinical long-term outcomes (cardiovascular disease and mortality) will be summarized. Data on cardiovascular disease and mortality in peri- and postmenopausal women with PCOS appear to be controversial. Whether androgens have a protective or unfavorable influence on the manifestation of cardiovascular disease remains uncertain. The need for large, prospective, well-phenotyped cohort studies of women with PCOS is high. Only then will we be able to answer this research question.

Endocrine and cardiometabolic cord blood characteristics of offspring born to mothers with and without polycystic ovary syndrome.

OBJECTIVE: To compare the endocrine and cardiometabolic cord blood characteristics of offspring of mothers with polycystic ovary syndrome (PCOS) with those of healthy controls. DESIGN: Cross-sectional case control study. SETTING: University medical centers. PATIENT(S): Offspring from mothers with PCOS (n = 61) and healthy controls (n = 82). INTERVENTION(S): Cord blood withdrawal from neonates. MAIN OUTCOME MEASURE(S): Cord blood estradiol, androstenedione, dehydroepiandrosterone sulfate (DHEAS), testosterone, sex hormone-binding globulin, free androgen index (FAI), insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, c-reactive protein, adiponectin, and leptin. RESULT(S): Androstenedione and leptin concentrations were increased in the offspring of women with PCOS compared with the controls: androstenedione median 2.9 (interquartile range [IQR] 2.3-3.9) nmol/L vs. 2.2 [IQR 1.6-2.7] nmol/L; and leptin median 13.6 [IQR 8.3-22.9] µg/L vs. 9.8 [IQR 6.0-16.5] µg/L. After adjusting for maternal and pregnancy-related confounders (such as maternal age, gestational age, birth weight), androstenedione appeared associated with PCOS in both male (relative change 1.36 [1.04; 1.78]) and female offspring (relative change 1.40 [1.08; 1.82]). Similarly, in male offspring the leptin concentrations appeared associated with PCOS after correction for confounders (relative change 1.55 [1.12; 2.14]). After correction for multiple testing, these associations attenuated. CONCLUSION(S): Observed results suggest that androstenedione concentrations are increased in the cord blood of male and female offspring of women with PCOS, although this requires confirmation. This finding would support the hypothesis that a maternal hyperandrogenic environment during pregnancy in women with PCOS may predispose their offspring to fetal hyperandrogenism. The potential associations between fetal hyperandrogenism and long-term health effects remain to be elucidated. CLINICAL TRIAL REGISTRATION NUMBER: NCT00821379.

Androgen levels in women with various forms of ovarian dysfunction: associations with cardiometabolic features.

STUDY QUESTION: Are differences in androgen levels among women with various forms of ovarian dysfunction associated with cardiometabolic abnormalities? SUMMARY ANSWER: Androgen levels differed substantially between women with and without ovarian dysfunction, and increased androgen levels were associated with impaired cardiometabolic features in all women irrespective of their clinical condition. WHAT IS KNOWN ALREADY: Sex steroid hormones play important roles in the development of cardiovascular diseases (CVD). Extremes of low as well as high androgen levels have been associated with increased CVD risk in both men and women. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 680 women with polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), natural post-menopausal women (NM), or regular menstrual cycles (RC) (170 women per group). PARTICIPANTS/MATERIALS, SETTING, METHODS: Measurements of serum testosterone, androstenedione and dehydroepiandrosterone sulfate were performed using liquid chromatography-tandem mass spectrometry. Assessments were taken of body mass index (BMI), blood pressure, lipid profiles, glucose, insulin and SHBG, and the bioactive fraction of circulating testosterone was calculated using the free androgen index (FAI). MAIN RESULTS AND THE ROLE OF CHANCE: PCOS women were hyperandrogenic [median FAI = 4.9 (IQR 3.6-7.4)], and POI women were hypoandrogenic [FAI = 1.2 (0.8-1.7)], compared with RC women [FAI = 1.7 (1.1-2.8)], after adjustment for age, ethnicity, smoking and BMI (P < 0.001). After adjustment for age, there were no significant differences in androgens between POI and NM (P = 0.15) women and between NM and RC (P = 0.27) women, the latter indicating that chronological aging rather than ovarian aging influences the differences between pre- and post-menopausal women. A high FAI was associated with elevated triglycerides (ß log FAI for PCOS: 0.45, P < 0.001, POI: 0.25, P < 0.001, NM: 0.20, P = 0.002), insulin (ß log FAI for PCOS: 0.77, POI: 0.44, NM: 0.40, all P < 0.001), HOMA-IR (ß log FAI for PCOS: 0.82, POI: 0.46, NM: 0.47, all P < 0.001) and mean arterial pressure (ß log FAI for PCOS: 0.05, P = 0.002, POI: 0.07, P < 0.001, NM: 0.04, P = 0.04) in all women; with increased glucose (ß log FAI for PCOS: 0.05, P = 0.003, NM: 0.07, P < 0.001) and decreased high-density lipoprotein (ß log FAI for PCOS: -0.23, P < 0.001, NM: -0.09, P = 0.03) in PCOS and NM women; and with increased low-density lipoprotein (ß log FAI for POI: 0.083, P = 0.041) in POI women. Adjustment for BMI attenuated the observed associations. Associations between FAI and cardiometabolic features were the strongest in PCOS women, even after adjustment for BMI. LIMITATIONS, REASONS FOR CAUTION: Associations between androgen levels and cardiometabolic features were assessed in PCOS, POI and NM women only, due to a lack of available data in RC women. Due to the cross-sectional design of the current study, the potential associations between androgen levels and actual future cardiovascular events could not be assessed. WIDER IMPLICATIONS OF THE FINDINGS: This study affirms the potent effect of androgens on cardiometabolic features, indicating that androgens should indeed be regarded as important denominators of women's health. Future research regarding the role of androgens in the development of CVD and potential modulatory effects of BMI is required. STUDY FUNDING/COMPETING INTERESTS: N.M.P.D. is supported by the Dutch Heart Foundation (grant number 2013T083). L.J. and O.H.F. work in ErasmusAGE, a center for aging research across the life course, funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA. M.K. is supported by the AXA Research Fund. Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; or the preparation, review or approval of the manuscript. J.S.E.L. has received fees and grant support from the following companies (in alphabetical order): Ferring, Merck-Serono, Merck Sharpe & Dome, Organon, Schering Plough and Serono. In the last 5 years, B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Actavis, COGI, Euroscreen, Ferring, Finox, Genovum, Gedeon-Richter, Merck-Serono, OvaScience, Pantharei Bioscience, PregLem, Roche, Uteron and Watson laboratories. With regard to potential conflicts of interest, there is nothing further to disclose.

Restoring testosterone levels by adding dehydroepiandrosterone to a drospirenone containing combined oral contraceptive: I. Endocrine effects.

OBJECTIVES: Combined oral contraceptives (COCs) decrease testosterone (T) levels. This study investigated restoration of T and other androgen concentrations during COC use by 'co-administration' of dehydroepiandrosterone (DHEA). STUDY DESIGN: In this randomized, double-blind, placebo-controlled study in 99 new COC starters (18-35 years old with body mass index range 18-34 kg/m²), a COC containing 30mcg ethinylestradiol (EE) and 3 mg drospirenone (DRSP) was used for 3cycles, followed by 6cycles of the same COC combined with either 50 mg/day DHEA or placebo. Total T, albumin, sex hormone-binding globulin (SHBG), DHEA-sulfate (DHEA-S), Δ4-androstenedione (AD), 3α-androstanediol glucuronide (ADG) and estradiol (E2) were measured, whereas free T and the free T index (FTI) were calculated. Assessments took place at baseline (no COC use), after the run-in period (COC use alone) and during the treatment period (DHEA or placebo). RESULTS: During COC use alone, androgen levels decreased, especially total T by 62% and free T by 86%, and SHBG increased by 243%. Total T increased with DHEA compared to placebo (change from end of run-in period to end of treatment period -- 1.3±1.2 nmol/L vs. 0.0±0.4 nmol/L; p<.0001) -- and was restored to baseline levels. Free T and the FTI increased significantly (p<.0001), but the free T level was still 53% below baseline levels. DHEA-S, AD and ADG increased significantly to levels above baseline (p<.0001 for each). DHEA had no effect on SHBG, albumin and E2. CONCLUSIONS: An EE/DRSP containing COC strongly suppressed endogenous androgen concentrations in all users. The addition of 50 mg DHEA to a COC regimen containing EE/DRSP restored total T to baseline levels, but free T levels were restored by only 47% as most of the T remains bound to SHBG. IMPLICATIONS: When using a COC that increases SHBG considerably, a daily dose of 50 mg DHEA is insufficient to normalize free T levels completely.

Ovarian response prediction in GnRH antagonist treatment for IVF using anti-Müllerian hormone.

STUDY QUESTION: What is the clinical value of anti-Müllerian hormone (AMH) for the prediction of high or low ovarian response in controlled ovarian stimulation for IVF using GnRH antagonist treatment? SUMMARY ANSWER: AMH as a single test has substantial accuracy for ovarian response prediction in GnRH antagonist treatment for IVF, with a higher accuracy for predicting a high response than for low response. WHAT IS KNOWN ALREADY: The role of AMH and other patient characteristics in ovarian response prediction has been studied extensively in long GnRH agonist protocols; however, little information is available regarding the clinical value in GnRH antagonists. STUDY DESIGN, SIZE, DURATION: This is an observational (retrospective) substudy as part of an ongoing cohort study. A total of 487 patients scheduled for IVF/ICSI between 2006 and 2011 were included in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients with a regular cycle who underwent their first IVF/ICSI cycle with GnRH antagonist treatment while receiving a starting dose of 150 or 225 IU recombinant FSH were included in the study. Patients were divided into three subgroups according to the following ovarian response categories: high (>15 oocytes or cycle cancellation), normal (4-15 oocytes) and low (<4 oocytes or cycle cancellation). Serum samples collected prior to IVF treatment were used to determine serum AMH levels. MAIN RESULTS AND THE ROLE OF CHANCE: According to the predefined ovarian response categories, 58 patients were classified as high, 326 as normal and 101 as low responders, and the ongoing pregnancy rates did not differ among groups (19.0, 22.1 and 16.8%, respectively, P = 0.9). For the prediction of high response, AMH had an area under the receiver-operating characteristic curve (AUC) of 0.87. Both female age and BMI had lower accuracy (AUC 0.66 and 0.58, respectively). For low response prediction, again AMH had a better accuracy (AUC 0.79) than female age and BMI (AUC 0.59 and 0.56, respectively). In a multivariate model, including the factors age, AMH, BMI, smoking, type and duration of subfertility, only BMI added some predictive value to AMH for both high and low response prediction. Clinical test characteristics demonstrated that using a specificity of ∼90%, the detection rate of AMH for high and low response, corresponding with a test cut-off of 4.5 and 0.8 µg/l, was ∼60 and ∼45%, respectively. LIMITATIONS, REASONS FOR CAUTION: The impact of the antral follicle count (AFC) on ovarian response prediction in GnRH antagonists was not assessed; however, previously studies demonstrated that for GnRH antagonists, AMH has a better accuracy than AFC. WIDER IMPLICATIONS OF THE FINDINGS: The current study demonstrates that AMH is an adequate predictor for both high and low response in GnRH antagonist cycles, showing a similar accuracy to GnRH agonists, as reported previously. The optimization and individualization of GnRH antagonist protocols may be improved by using an AMH-tailored approach. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Academic Institutional Resources of the Department of Reproductive Medicine of the UMC Utrecht. O.H., M.J.C.E, E.W.G.L and H.L.T. have nothing to declare. N.S.M. has received fees and/or grant support from the following companies (in alphabetic order): Anecova, Ferring, Informa, Merck Serono and MSD. B.C.J.M.F. has received fees and/or grant support from the following companies (in alphabetic order); Childhealth, CVON, Ferring, Ova-Science, PregLem, Roche and Watson laboratories. F.J.B. has received fees and/or grant support from the following companies (in alphabetic order); Merck Serono and MSD. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov, Protocol ID 13-109.

The impact of self-reported ethnicity versus genetic ancestry on phenotypic characteristics of polycystic ovary syndrome (PCOS).

CONTEXT: It is well established that ethnicity is associated with the phenotype of polycystic ovary syndrome (PCOS). Self-reported ethnicity was shown to be an inaccurate proxy for ethnic origin in other disease traits, and it remains unclear how in PCOS patients self-reported ethnicity compares with a biological proxy such as genetic ancestry. OBJECTIVE: We compared the impact of self-reported ethnicity versus genetic ancestry on PCOS and tested which of these 2 classifications better predicts the variability in phenotypic characteristics of PCOS. PATIENTS: A total of 1499 PCOS patients from The Netherlands, comprising 11 self-reported ethnic groups of European, African, American, and Asian descent were genotyped with the Illumina 610K Quad BeadChip and merged with the data genotyped with the Illumina HumanHap650K available for the reference panel collected by the Human Genome Diversity Project (HGDP), in a collaboration with the Centre Etude Polymorphism Humain (CEPH), including 53 populations for ancestry reference. MAIN OUTCOME MEASURES: Algorithms for inferring genetic relationships among individuals, including multidimensional scaling and ADMIXTURE, were applied to recover genetic ancestry for each individual. Regression analysis was used to determine the best predictor for the variability in PCOS characteristics. RESULTS: The association between self-reported ethnicity and genetic ancestry was moderate. For amenorrhea, total follicle count, body mass index, SHBG, dehydroepiandrosterone sulfate, and insulin, mainly genetic ancestry clusters ended up in the final models (P values < .004), indicating that they explain a larger proportion of variability of these PCOS characteristics compared with self-reported ethnicity. Especially variability of insulin levels seems predominantly explained by genetic ancestry. CONCLUSIONS: Self-reported ancestry is not a perfect proxy for genetic ancestry in patients with PCOS, emphasizing that by using genetic ancestry data instead of self-reported ethnicity, PCOS-relevant misclassification can be avoided. Moreover, because genetic ancestry explained a larger proportion of phenotypic variability associated with PCOS than self-reported ethnicity, future studies should focus on genetic ancestry verification of PCOS patients for research questions and treatment as well as preventive strategies in these women.

Excess mortality in mothers of patients with polycystic ovary syndrome.

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.

The significance of fragile X mental retardation gene 1 CGG repeat sizes in the normal and intermediate range in women with primary ovarian insufficiency.

STUDY QUESTION: Are fragile X mental retardation gene 1 (FMR1) CGG repeats in the normal and intermediate range (up to 55 repeats) associated with primary ovarian insufficiency (POI) in a large case-control study? SUMMARY ANSWER: No association was found between CGG repeats of intermediate size and POI compared with controls. WHAT IS KNOWN ALREADY: CGG repeats in the FMR1 gene in the premutation range (55-200 repeats) have consistenly associated with POI. Intermediate range CGG repeats have been considered for a potential association with POI. STUDY DESIGN, SIZE: A case-control study in 375 well-phenotyped Dutch women diagnosed with POI and 3368 controls with natural menopause ≥40 years of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: The FMR1 CGG repeat number was determined by PCR amplification in women diagnosed with POI and women with a known age at natural menopause ≥40 years. The prevalence of intermediate sized CGG repeats (45-54 repeats) was compared between POI cases and controls using Fisher's exact test. Differences in mean CGG repeat lengths on allele 1 and allele 2 between POI cases and controls were tested using analysis of variance. MAIN RESULTS AND THE ROLE OF CHANCE: The frequency of intermediate sized CGG repeats on the allele with the longest triple repeat number was not statistically significantly different between POI cases and controls (2.7 and 3.8%, respectively, odds ratio 0.72, 95% confidence interval: 0.38-1.39, P = 0.38). In women with POI, linear regression analysis for age at POI diagnosis and CGG repeat size also failed to show any association (ß = -0.018, P = 0.74). LIMITATIONS, REASONS FOR CAUTION: FMR1 CGG repeat lengths in POI cases and controls were genotyped in two different laboratories. The distributions of CGG repeats may vary among the different ethnic populations in our study. Also, in our study women with primary amenorrhea (N = 17) were included in the POI group. WIDER IMPLICATIONS OF THE FINDINGS: We found no association between intermediate sized CGG repeats and POI compared with controls. Therefore, a role for FMR1 CGG repeat sizes up to 55 repeats in the ovarian ageing process may be questioned. Moreover, there seems limited value in the evaluation of normal- and intermediate FMR1 repeat size in the diagnostic work-up of women affected by POI, or for prognostic purposes in women at risk of developing POI. STUDY FUNDING/COMPETING INTERESTS: The Prospect-EPIC study was funded by 'Europe Against Cancer' Program of the European Commission (SANCO); the Dutch Ministry of Health; the Dutch Cancer Society; ZonMW the Netherlands Organization for Health Research and Development; World Cancer Research Fund (WCRF) and the Dutch Heart Association.

Ovarian stimulation for IVF: mild approaches.

In contrast to current approaches, the aim of mild stimulation is to develop safer and more patient-friendly protocols in which the risks of the treatment as a whole are minimized. Mild stimulation is defined as the method when exogenous gonadotropins are administered at lower doses, and/or for a shorter duration in GnRH antagonist co-treated cycles, or when oral compounds (antiestrogens, aromatase inhibitors) are used for ovarian stimulation for IVF, with the aim of limiting the number of oocytes obtained to fewer than eight. In this chapter we discuss the relevant physiology of follicle development, the development of milder stimulation protocols, the implications of mild stimulation, the current state of affairs, and future developments.

Preconception predictors of gestational diabetes: a multicentre prospective cohort study on the predominant complication of pregnancy in polycystic ovary syndrome.

STUDY QUESTION: Can we develop an adequate preconception prediction model to identify those women with polycystic ovary syndrome (PCOS) who have an increased risk of developing gestational diabetes mellitus (GDM) during subsequent pregnancy? STUDY ANSWER: The risk of developing GDM in women with PCOS can be adequately predicted prior to conception by a prediction model. WHAT IS KNOWN ALREADY: Women with PCOS are at increased risk of pregnancy complications, especially GDM. GDM has serious short-term and long-term effects on mother and baby. STUDY DESIGN, SIZE, DURATION: This study is a part of a multicentre prospective cohort study, which was conducted between April 2008 and April 2012. A total of 326 women with PCOS were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS and a wish to conceive were included prior to conception and followed until 6 weeks after delivery. Maternal, neonatal and birth complications were reported. A multivariate model was developed to predict the most common pregnancy complication, GDM, by using univariate and multivariate logistic regression of preconception patient characteristics. The area under the curve (AUC) of the receiver-operating characteristic was used to test the performance of the model. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 189 women (58%) achieved an ongoing pregnancy (8% multiples) and delivered a live-born neonate. One or two maternal complications occurred in 62 (33%) pregnant women, mainly GDM (n = 41; 22%) and pregnancy-induced hypertension (n = 14; 7%). In children, one or two complications were observed in 49 (26%) of 206 children born, e.g. premature delivery (n = 23; 12%) and small for gestational age (n = 15; 8%). The preconception prediction model for GDM performed well (AUC 0.87, 95% CI 0.81-0.93). First-degree relatives with type 2 diabetes mellitus, serum levels of fasting glucose, fasting insulin, androstenedione and sex hormone-binding globulin before conception were identified as predictors. LIMITATIONS, REASONS FOR CAUTIONS: The prediction model has not yet been externally validated in another group of patients. Also, there were missing data for some of the determinants, which were accounted for by multiple imputation. WIDER IMPLICATIONS OF THE FINDINGS: Women with PCOS who achieve a pregnancy have an increased risk of GDM. The prediction model can be used to identify women particularly at risk for GDM who should be monitored closely to enable preventative measures that may reduce the risk of developing GDM and its adverse consequences. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for the study. M.A.W., S.M.V.V., A.J.G., A.F. and M.P.H.K. have nothing to disclose. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, European Society of Human Reproduction and Embryology and MSD. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, Merck-Serono, MSD, Organon, Schering Plough, Sharp & Dome and Serono. M.J.C. 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. TRIAL REGISTRATION NUMBER: NCT00821379 [Clinicaltrials.gov].

Individualized vaginal bleeding experience of women with uterine fibroids in the PEARL I randomized controlled trial comparing the effects of ulipristal acetate or placebo.

RESEARCH QUESTION: What is the individualized bleeding experience of women with fibroids and anaemia in a 3 month randomized placebo controlled trial (PEARL I) of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA)? SUMMARY ANSWER: In contrast to continuing excessive regular menstruation in the placebo group, a majority of women treated with UPA (63.1% of those on 5 mg/day and 71.3% of those on 10 mg/day) experienced the rapid onset of amenorrhoea or minimal blood loss [pictorial blood loss assessment chart (PBAC) < 12]. The remainder experienced various patterns of bleeding and intensity of blood loss that are described for the first time, including an association of irregular bleeding on UPA with sub-mucous fibroids. WHAT IS KNOWN ALREADY: The majority experience on UPA is amenorrhoea but the bleeding experience of the others has not been characterized. STUDY DESIGN, SIZE, DURATION: A 13 week randomized controlled trial in women, eligible for surgery for uterine fibroids and anaemia, comparing placebo (n = 48), UPA 5 mg (n = 95) or UPA 10 mg (n = 94). The treatment aim was fibroid shrinkage and the primary definitions and outcomes are published elsewhere; here the secondary outcome measure of vaginal bleeding pattern is described. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women, 18-50 years old, with fibroids and haemoglobin ≤10.2 g/dl, justifying surgery. At least one fibroid was 3-10 cm diameter and uterus ≤16 weeks pregnancy size. All used the daily PBAC methodology in a screening cycle (Ps) and throughout treatment, and for the 4 weeks preceding Week 26 and Week 38 in those who did not have surgery. An excessive menstruation is PBAC > 100. The bleeding patterns were characterized using the classification of Belsey, developed under auspices of WHO. MAIN RESULTS AND THE ROLE OF CHANCE: In the placebo group, all women had an excessive screening PBAC [median 376; interquartile range (IQR) 241-574]; 81.3% of them had regular menstrual bleeding and the intensity of bleeding remained similar, so that the median PBAC in the next three periods was 90, 92 and 93% of the screening value. Four of the 48 women had spontaneous improvement in bleeding and one developed amenorrhoea and elevation of gonadotrophins. In the placebo group, 22 women provided Week 26 and 21 women provided Week 38 PBAC data. The median Week 26 PBAC (312: IQR 102-524) and Week 38 PBAC (236; IQR 103-465) indicated ongoing excessive bleeding. In the UPA group, screening PBAC confirmed excessive bleeding (UPA 5 mg, median 358; IQR 232-621; UPA 10 mg, median 330; IQR 235-542). UPA was initiated from the start of a menstruation (P1) and no women had regular periods on treatment. Following P1 through the whole of the remaining 13 weeks of UPA treatment amenorrhoea or minimal loss (PBAC < 12 for whole phase) occurred in 63.1% (UPA 5 mg) or 71.3% (UPA 10 mg). The characterization of the individualized bleeding experience of the remaining women on 5 mg and 10 mg UPA, respectively, were infrequent bleeding in 17.9 and 12.8%; frequent or prolonged bleeding or both in 12.7 and 11.7% and irregular bleeding in 5.3 and 3.2%. In those with prolonged, frequent or irregular bleeding there was a high chance that sub-mucous fibroids were present (UPA 5 mg 100% and UPA 10 mg 78.6%) but no correlation with progesterone receptor modulator-associated endometrial changes. LIMITATIONS, REASONS FOR CAUTION: The follow-up PBAC data at Week 26 and Week 38 are only valid for women who did not have surgical intervention. These groups may not be representative of the groups at screening. WIDER IMPLICATIONS OF THE FINDINGS: This first detailed description of these SPRM bleeding patterns provides clinicians with an indication of potential responses in women using the SPRM UPA and provides an extended definition of bleeding in untreated women with excessive bleeding and fibroids. STUDY FUNDING/COMPETING INTEREST(S): Funded by PregLem/Gedeon Richter. D.H.B. is a member of the Scientific Advisory Board of PregLem, and in this role participated in the study design and supervision. Stock originally held in PregLem was given up when PregLem was incorporated into Gedeon Richter; D.H.B. does not currently hold stock. M.A.L. has received payment from Gideon Richter to attend a meeting to present these data (Barcelona, April 2013) but no financial support in preparing the manuscript. B.C.J.M.F. is a member of the Scientific Advisory Board of PregLem and has received fees and grant support from the following companies: Andromed, Ardana, Auxogyn, Ferring, Genovum, Gedeon Richter, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Roche, Schering, Schering Plough, Serono, Watson Laboratories and Wyeth. P.T. is a paid statistical consultant for PregLem SA. E.B. is a full time employee of PregLem and received payment from stocks sold in October 2010 from the company's full acquisition by Gedeon Richter Group. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT00755755 (PEARL I).

The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis.

UNLABELLED: BACKGROUND; Combined oral contraceptives (COCs) reduce levels of androgen, especially testosterone (T), by inhibiting ovarian and adrenal androgen synthesis and by increasing levels of sex hormone-binding globulin (SHBG). Although this suppressive effect has been investigated by numerous studies over many years, to our knowledge no systematic review concerning this issue had been performed. This systematic review and meta-analysis was performed to evaluate the effect of COCs on concentrations of total T, free T and SHBG in healthy women and to evaluate differences between the various types of COCs (e.g. estrogen dose, type of progestin) and the assays used to assess total T and free T. METHODS: A review of the literature was performed using database searches (MEDLINE, EMBASE and the Cochrane Central Register of Clinical Trials) and all publications (from inception date until July 2012) investigating the effect of COCs on androgen levels in healthy women were considered eligible for selection. Three reviewers were involved in study selection, data extraction and critical appraisal. For the meta-analysis, data on total T, free T and SHBG were extracted and combined using random effects analysis. Additional subgroup analyses were performed to evaluate differences between the various types of COCs (e.g. estrogen dose, type of progestin) and the assays used to assess total T or free T. RESULTS: A total of 151 records were identified by systematic review and 42 studies with a total of 1495 healthy young women (age range: 18-40 years) were included in the meta-analysis. All included studies were experimental studies and 21 were non-comparative. Pooling of the results derived from all the included papers showed that total T levels significantly decreased during COC use [mean difference (MD) (95% confidence interval, CI) -0.49 nmol/l (-0.55, -0.42); P < 0.001]. Significantly lower levels of free T were also found [relative change (95% CI) 0.39 (0.35, 0.43); P < 0.001], with a mean decrease of 61%. On the contrary, SHBG concentrations significantly increased during all types of COC use [MD (95% CI) 99.08 nmol/l (86.43, 111.73); P < 0.001]. Subgroup analyses revealed that COCs containing 20-25 µg EE had similar effects on total and free T compared with COCs with 30-35 µg EE. In addition, suppressive effects on T levels were not different when comparing different types of progestins. However, subgroup analyses for the estrogen dose and the progestin type in relation to changes in SHBG levels did show significant differences: COCs containing second generation progestins and/or the lower estrogen doses (20-25 µg EE) were found to have less impact on SHBG concentrations. CONCLUSIONS: The current literature review and meta-analysis demonstrates that COCs decrease circulating levels of total T and free T and increase SBHG concentrations. Due to the SHBG increase, free T levels decrease twice as much as total T. The estrogen dose and progestin type of the COC do not influence the decline of total and free T, but both affect SHBG. The clinical implications of suppressed androgen levels during COC use remain to be elucidated.

Environmental and developmental origins of ovarian reserve.

BACKGROUND Oocyte number is established early in life before a gradual loss of this ovarian reserve during reproductive life until oocyte availability becomes limiting at the menopause. Although there is a large genetic component to the ovarian reserve achieved before birth, other influences including the maternal endocrine and nutritional milieu, and environmental factors may represent important developmental determinants. Environmental and nutritional factors may also modify the downward trajectory of ovarian reserve in adult life. The combination of these early and later life influences has the potential to lead to diminished ovarian reserve, compromising fertility in later reproductive years and altering age at natural menopause. METHODS Literature searches of the ISI Web of Knowledge database were carried out using the main terms 'ovarian reserve' and 'menopause AND age' in conjunction with a range of other terms encompassing a variety of factors with potential effects on ovarian reserve. The various searches were inspected manually and the relevant papers selected for critical analysis and interpretation. RESULTS Evidence was identified supporting the view that elevated prenatal androgens have an adverse effect on the early establishment of ovarian reserve, although the implications for ovarian reserve in the polycystic ovary syndrome (which may also be programmed through prenatal androgen exposure) remain uncertain. Recent evidence is cited suggesting that effects of maternal nutrient restriction on ovarian reserve may also involve changes in prenatal androgen exposure. A general rationale is developed through examination of evidence which emphasizes the roles of the aryl hydrocarbon receptor (AHR) and the estrogen receptor (ER) systems in ovarian reserve modulation. Because of their similarity to the natural ligands, many environmental compounds have the ability to bind to these receptors (albeit at lower affinities) and thereby have the potential to influence either the initial setting of ovarian reserve during development or the trajectory of ovarian reserve during adult life. For example, exposure to compounds in cigarette smoke may accelerate loss of ovarian reserve in smokers leading to diminished ovarian reserve, earlier age at last child and earlier menopause. Socioenocomic factors are clearly associated with age at natural menopause, with correlations with economic status and education level. However, such effects in western societies are in general small, and the underlying mechanisms remain unclear. CONCLUSIONS Exposure to many environmental compounds, particularly to those that leach from plastics and other synthetic materials, is commonplace in modern societies to the extent that many are found at measurable concentrations in body fluids within most of the population. Relating fluid levels of individual compounds to parameters reflecting ovarian reserve in selected populations appears to be an effective way forward and, indeed, some early-stage findings do show some cause for concern. There is a pressing need for the development of practical advice enabling women to minimize their intake of AHR/ER ligands, perhaps through dietary/cosmetic choices or improved food packaging.

Comparison of early versus late initiation of GnRH antagonist co-treatment for controlled ovarian stimulation in IVF: a randomized controlled trial.

STUDY QUESTION: What is the impact of initiating GnRH antagonist co-treatment for in vitro fertilization (IVF) on cycle day (CD) 2 compared with CD 6 on live birth rate (LBR) per started cycle and on the cumulative live birth rate (CLBR)? SUMMARY ANSWER: Early initiation of GnRH antagonist does not appear to improve clinical outcomes of IVF compared with midfollicular initiation. WHAT IS KNOWN ALREADY: During ovarian stimulation for IVF, GnRH antagonist co-treatment is usually administered from the midfollicular phase onwards. Earlier initiation may improve the follicular phase hormonal milieu and therefore overall clinical outcomes. STUDY DESIGN, SIZE, DURATION: This open-label, multicentre randomized controlled trial was conducted between September 2009 and July 2011. A web-based program was used for randomization and 617 IVF-intracytoplasmic sperm injection (ICSI) patients were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Recombinant FSH (150-225 IU) was administered daily from CD 2 onwards in both groups. The study group (CD2; n = 308) started GnRH antagonist co-treatment on CD 2, whereas the control group (CD6; n = 309) started on CD 6. MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences in clinical outcomes between the two groups. A non-significant trend towards a higher LBR per started cycle and CLBR was observed in the CD6 group compared with the CD2 group (LBR: 24.0 versus 21.5%, P = 0.5; CLBR: 29.9 versus 26.7%, P = 0.6). LIMITATIONS, REASONS FOR CAUTION: The study was terminated prematurely because no significant difference was observed in clinical outcomes after 617 inclusions. A much larger study population would be needed to detect a small significant difference in favour of either study arm, which raises the question of whether this would be relevant for clinical practice. WIDER IMPLICATIONS OF THE FINDINGS: The present study shows that the additional treatment burden and costs of starting GnRH antagonist on CD 2 instead of on CD 6 are not justified, as early initiation of GnRH antagonist does not improve LBRs. STUDY FUNDING/COMPETING INTEREST(S): This study was partially supported by a grant from Merck Serono. O.H., M.J.C.E, A.V., P.A.D., R.E.B., G.J.E.O., C.A.G.H., G.C.D.M., H.J.V., P.F.M.H. and A.B. have nothing to declare. F.J.B. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gedeon Richter, Merck Serono, MSD and Roche. B.J.C. has received fees and grant support from the following companies (in alphabetic order): Ferring, Merck Serono and MSD. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, Ferring, Merck Serono and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, MSD, Merck Serono, Organon, Schering Plough and Serono. N.S.M. has received fees and grant support from the following companies (in alphabetic order): Anecova, Ferring, Merck Serono, MSD, Organon and Serono. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov, no. NCT00866034.

Comparison of the phenotype of Chinese versus Dutch Caucasian women presenting with polycystic ovary syndrome and oligo/amenorrhoea.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex disorder with variable prevalence and clinical presentation in different populations, which may be mediated by geographical and ethnic background. METHODS: We performed a comparison of phenotypic characteristics between 547 Chinese and 427 Dutch women with PCOS and oligo/amenorrhoea attending University Reproductive Centers in China and the Netherlands. RESULTS: Chinese women presenting with a clinical diagnosis of PCOS were observed to have a higher incidence of hyperandrogenism (HA) (P < 0.001) and amenorrhoea (P < 0.001) compared with Dutch women, but no difference was observed in the incidence of polycystic ovaries (PCOs). Using population-specific cut-off values, Chinese women with PCOS demonstrated a higher incidence of increased BMI (P < 0.001), waist circumference (WC) (P < 0.001) and waist-hip ratio (P < 0.001) than Dutch women. In both groups, HA was associated with increased age, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and serum LH while PCOs correlated with BMI, WC, HOMA-IR, fasting insulin and elevated total testosterone. Associations specific for ethnic background were found between LH and HA, and between both BMI and HOMA-IR, and PCOs. CONCLUSIONS: Reproductive and metabolic characteristics differed between the two ethnic groups. Chinese women were found to present more frequently with a phenotype associated with increased risk of metabolic complications later in life, compared with Dutch Caucasian women. Ethnicity seems to determine part of the specific phenotypical presentation of PCOS.

Contemporary genetic technologies and female reproduction.

BACKGROUND: The Fifth Evian Annual Reproduction (EVAR) Workshop Meeting discussed knowledge regarding contemporary genetics in female reproduction. METHODS: Specialist reproductive medicine clinicians and geneticists delivered presentations based on published literature and current research. The content of this report is based on the expert presentations and subsequent group discussions that took place during this Workshop. RESULTS: Numerous ovarian genes with a role in infertility have been identified. Future challenges for genetic screening of patients, such as those with polycystic ovary syndrome, primary ovarian insufficiency or endometriosis, include the identification of high-throughput strategies and how to apply these findings to infertile patients. The identification of high-quality embryos in IVF using objective technologies remains a high priority in order to facilitate single-embryo transfer. Gene expression profiling of cumulus cells surrounding the oocyte, and proteomic and metabolomic approaches in embryo culture media may significantly improve non-invasive embryo quality assessment. CONCLUSIONS: The way forward in advancing the knowledge of genes involved in reproduction was considered to be through genome-wide association studies involving large numbers of patients. Establishing international collaboration is required to enable the application of such technologies in sufficient numbers of patients.

Genetic polymorphisms of the glucocorticoid receptor may affect the phenotype of women with anovulatory polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by ovarian dysfunction. The association with obesity and insulin resistance is well established. Steroid hormones play a central role in the regulation of both ovarian function and body composition. This study aims to assess the influence of known functional polymorphisms in genes that are responsible for the production, metabolism and signal transduction of steroid hormones on the susceptibility to and phenotype of PCOS. METHODS: We included 518 Caucasian women with anovulatory PCOS (2003 Rotterdam criteria) and 2996 population-based controls. Functional polymorphic variants were selected in genes that affect the production of estradiol and cortisol [aromatase (CYP19), 11-beta-hydroxysteroid dehydrogenase type I (HSD11B1) and hexose-6-phosphate dehydogenase (H6PD)] and in genes for signal transduction proteins [estrogen receptor (ESR1 and ESR2) and glucocorticoid receptor (GCR)]. RESULTS: Genotype-frequencies were similar in PCOS cases and population-based controls. We observed possible associations between GCR genotype and LH levels that suggest an inhibitory influence of GCR, i.e., lower LH levels in association with GCR alleles that are known to increase receptor sensitivity (rs6195 and rs41423247) and higher LH levels in GCR variants that may inhibit receptor sensitivity (rs6190 and rs6198). CONCLUSIONS: The present study did not identify risk alleles for PCOS, although the study was limited by an absence of endocrine data for the population-based controls. However, GCR variants may influence gonadotrophin levels in women with anovulatory PCOS. We hypothesize that glucocorticoids can affect the function of the hypothalomo-pituitary-gonadal axis in humans.