Search

Background Cardiovascular risk could be increased in transgender persons, but the mechanism is undetermined. Aim The aim of this study was to assess the risk of cardiovascular outcomes in Danish transgender persons compared to controls. Methods The study design was a historical register-based cohort study in Danish transgenders and age-matched controls. The main outcome measure was cardiovascular diagnosis (any CVD) including medicine prescriptions for CVD during 2000–2018. The transgender cohort (n = 2671) included persons with International Classification of Diseases-10 diagnosis code of ‘gender identity disorder’ (n = 1583) and persons with legal sex change (n = 1088), 1270 were assigned female at birth (AFAB) and 1401 were assigned male at birth (AMAB). Controls (n = 26 710) were matched by age (n = 5 controls of same and n = 5 controls of other birth sex) of the respective transgender. Results The median (interquartile range) age at study inclusion was 22 (18; 29) years for AFAB and 26 (21; 39) years for AMAB. The mean (s.d.) follow-up time was 4.5 (4.2) years for AFAB and 5.7 (4.8) years for AMAB. The hazard ratio (HR) for any CVD was significantly higher in transgenders vs controls of same and other birth sex, with highest adjusted HR in transgenders AFAB vs control men: 2.20 (95% CI: 1.64;2.95), P Conclusions The risk of cardiovascular diagnosis was increased in transgenders. The mechanism should be further investigated.

Hypertension before and during early pregnancy has been associated with an increased risk of gestational diabetes mellitus (GDM) in retrospective analyses. We aimed to investigate the prospective blood pressure trackings in a population-based cohort of pregnant women, who were stratified according to their metabolic status in early third trimester.We recorded blood pressure longitudinally during pregnancy in 1230 women from the Odense Child Cohort, Denmark. Fasting glucose and insulin were measured at gestational weeks 28-30. Metabolic status was evaluated according to the WHO 2013 threshold for GDM (GDM-WHO: fasting plasma glucose ≥5.1 mmol/l), insulin and homeostatic model assessment of insulin resistance (HOMA-IR). Relationships between metabolic status in third trimester and blood pressure trajectories were evaluated with adjusted linear mixed models. Trajectory was defined as blood pressure records in pregnancy per 4 weeks interval.Prevalence of GDM-WHO was 40% (498/1230). GDM-WHO was associated with 1.46 (0.22-2.70) mmHg higher SBP and 1.04 (0.07-2.01) mmHg higher DBP trajectories in the overall cohort. The associations were driven by differences in the overweight group, with 3.14 (1.05-5.25) mmHg higher SBP and 1.94 (0.42-3.47) mmHg higher DBP per 4 weeks in women with GDM-WHO compared with women without GDM-WHO. GDM-WHO was not associated with blood pressure in women with normal weight. Blood pressure trajectories were elevated across quartiles of insulin resistance.GDM-WHO is associated with higher blood pressure in pregnancy, and there appears to be a stronger effect in overweight women.

Introduction: Previous data suggested a link between maternal polycystic ovary syndrome (PCOS) and offspring attention deficit hyperactivity disorder (ADHD), which could be mediated by higher prenatal androgen exposure. Material and methods: The study was part of the prospective Odense Child Cohort and included 1776 pregnant women, 165 (9%) with PCOS and 1607 (91%) controls. ADHD symptoms at 3 years of age were defined using the parent-reported questionnaire Child Behavior Checklist/1.5–5 (scores >90th centile of Danish national standard). Maternal blood samples were collected in the third trimester measuring total testosterone by mass spectrometry, sex hormone-binding globulin, and calculated free testosterone. Offspring anogenital distance was measured at 3 months of age. Regression models were performed with presence of ADHD symptoms as the dependent variable and adjusted for maternal age, body mass index, parity, smoking status, educational level, and parental psychiatric diagnoses. Results: ADHD symptoms were present in 105/937 (11%) boys and 72/839 (9%) girls. In boys, maternal PCOS was positively associated with ADHD symptoms (unadjusted odds ratio [OR] 1.91, 95% CI 1.07–3.43, p = 0.03, adjusted OR 2.20, 95% CI 1.20–4.02, p = 0.01), whereas maternal PCOS was not associated with ADHD symptoms in girls. Maternal total testosterone, free testosterone, and offspring anogenital distance were not associated with higher risk of ADHD symptoms in the offspring. Conclusions: Higher risk of ADHD in boys born of mothers with PCOS were not associated with maternal third-trimester testosterone levels or offspring anogenital distance.

Introduction The aim of this study was to compare blood pressure and prevalence of pregnancy-induced hypertension in women with polycystic ovary syndrome and the reference group throughout pregnancy. Material and methods This retrospective study was part of the prospective study Odense Child Cohort. Pregnant women were recruited from January 2010 to December 2012. Blood pressure was measured in 200 women with polycystic ovary syndrome and in 2197 in the reference group. Main outcome measures were blood pressure and pregnancy-induced hypertension. Pregnancy-induced hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg occurring after gestational week 20 at two separate visits. Mann-Whitney U test and Chi-square test were used to test differences between women with polycystic ovary syndrome and the reference group. Associations between polycystic ovary syndrome status (PCOS; the reference group) and blood pressure were tested using random mixed-effect linear regression analyses with subjects as random effect to comply with repeated blood pressure measurements. Results Median blood pressure was comparable in women with polycystic ovary syndrome and the reference group throughout pregnancy: systolic blood pressure 116 (111-123) vs 119 (112-124) (P = .06), diastolic blood pressure 72 (69-77) vs 73 (69-78) (P = .23) and mean arterial pressure 87 (83-93) vs 88 (84-92) (P = .13). In first trimester where systolic blood pressure was lower in polycystic ovary syndrome, median systolic blood pressure was 116 (111-123) vs 119 (112-124) mmHg (P = .04). The prevalence of pregnancy-induced hypertension was similar in polycystic ovary syndrome and the reference group: 17/200 (8.5%) vs 178/1997 (8.9%) (P = .84). Regression analyses showed no significant associations between polycystic ovary syndrome and blood pressure. Conclusions Blood pressure and prevalence of pregnancy-induced hypertension were comparable in pregnant women with polycystic ovary syndrome and the reference group.

Background Hypogonadism is prevalent during opioid treatment, but the effect of testosterone replacement treatment (TRT) on body composition, pain perception, and adrenal function is unclear. Purpose To measure changes in body composition, pain perception, quality of life, and adrenal function after TRT or placebo in opioid-treated men with chronic non-malignant pain. Methods Double-blind, placebo-controlled study in 41 men (>18 years) with total testosterone n = 20) or placebo (placebo-injections, n = 21). Outcomes Body composition (lean body mass and fat mass assessed by DXA), clinical pain intensity (numerical rating scale), and experimental pain perception (quantitative sensory assessment), quality of life (SF36), and adrenocorticotrophic hormone (ACTH) test. Data were presented as median (quartiles). Mann–Whitney tests were performed on delta values (24–0 weeks) between TRT and placebo. Results The median age was 55 years (46; 59) and total testosterone before intervention was 6.8 (5.0; 9.3) nmol/L. TRT was associated with change of testosterone levels: 12.3 (7.0; 19.9) nmol/L (P P Conclusions Six months of TRT improved body composition in men with opioid-induced hypogonadism without significant changes in outcomes of pain perception, quality of life, or adrenal function.

Introduction During pregnancy, maternal cortisol levels are increased 3-fold by the third trimester. The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD, isoforms 1 and 2) regulates the balance between cortisol and cortisone levels. Perfluoroalkyl substances (PFAS) have been reported to inhibit 11β-HSD1 and more potently 11β-HSD2, which could lead to reduced levels of cortisol and more extensively cortisone. Aim The aim of this work is to investigate a possible effect of early pregnancy PFAS exposure on late pregnancy activity of 11β-HSD1 and 11β-HSD2 assessed by cortisol and cortisone levels in diurnal urine (dU) and blood samples. Methods This study is part of the prospective cohort study, Odense Child Cohort (OCC). A total of 1628 pregnant women had serum (S) concentrations of 5 PFAS (perfluorooctanoic acid [PFOA], perfluorooctane sulfonic acid [PFOS], perfluorohexane sulfonic acid [PFHxS], perfluorononanoic acid [PFNA], and perfluorodecanoic acid (PFDA)) measured in the first trimester (median gestational week, GW 11). dU cortisol and cortisone (n = 344) and S-cortisol (n = 1048) were measured in the third trimester (median GW 27). Results In multiple regression analyses, a 2-fold increase in S-PFOS was significantly associated with lower dU-cortisone (β = –9.1%, P Conclusion Early pregnancy maternal S-PFAS were inversely associated with late pregnancy dU-cortisone, indicating reduced activity of 11β-HSD2.

Background: Gender affirming hormonal treatment (GAHT) is a cornerstone in transgender care. National data are sparse regarding use of hormonal treatment by transgender persons. Aim: To assess use of GAHT in transgender persons. Design: National register-based cohort study in Danish transgender persons followed from 2000 until 2018. The main outcome measure was prescription and purchase of GAHT. Persons with ICD-10 diagnosis code of “gender identity disorder” (CGI-cohort) and persons with legal sex change but without diagnosis (CPR-cohort) were included. In the CGI-cohort, transgender women were defined by prescription of estrogen and/or cyproterone acetate and/or testosterone-5-alpha reductase inhibitors, and transgender men were defined by prescription of testosterone after study inclusion. Discontinuation of GAHT was defined as no purchase of GAHT ≥13 months or shift from feminizing to masculinizing hormone treatment, or vice versa. Results: The cohort included 2789 transgender persons (n = 1717, CGI-cohort and n = 1072, CPR-cohort). The median age (interquartile range) at study inclusion was 26.1 (17.7) years for persons assigned male at birth (n = 1447) and 22.5 (10.5) years for persons assigned female at birth (n = 1342). In the CGI-cohort, the event rate for GAHT in transgender women increased from 4.0 (95% confidence interval [CI]: [3.1; 5.2]) events per 100 person in year 2000–2005 to 20.6 (17.8; 23.7) between 2014 and 2018. In transgender men, the event rate of GAHT increased from 4.2 (2.8; 6.2) to 18.8 (16.4; 21.6). The rate of discontinuation of GAHT was 0.06 (95% CI 0.049; 0.071) per person year. Conclusions: The event rate of GAHT increased during 2000–2018. Our data suggested high adherence to GAHT.

BACKGROUND: Chronic pain and opioid treatment are associated with increased risk of male hypogonadism and subsequently decreased muscle function. A diagnosis of hypogonadism is based on the presence of low total testosterone and associated symptoms. The effect of testosterone replacement therapy on muscle function in men with chronic pain and low total testosterone remains to be investigated.OBJECTIVES: To investigate the effects of testosterone replacement therapy on muscle function and gait performance in men treated with opioids for chronic non-cancer pain.MATERIALS AND METHODS: A double-blind, placebo-controlled study. Forty-one men (>18 years) with opioid-treated chronic pain and serum total testosterone < 12 nmol/L were randomized to 24 weeks testosterone replacement therapy (testosterone undecanoate injection three times/6 months, n = 20) or placebo injections (n = 21). Muscle function was measured as leg press maximal voluntary contraction, leg extension power using the Nottingham power rig and handgrip strength using a handheld dynameter. Gait performance was measured at usual and maximal gait speed on a 10-m track. Body composition (lean body mass and fat mass) was determined by dual-energy X-ray absorptiometry. Mann-Whitney tests were performed on ∆-values (24-0 weeks) between testosterone replacement therapy and placebo.RESULTS: At baseline, median (interquartile range) age was 55 ± 13 years and BMI was 30.7 ± 5.2 kg/m2 . ∆-muscle function and ∆-gait performance were similar between testosterone replacement therapy and placebo. Median ∆-leg press maximal voluntary contraction was 174.2 ± 406.7 Newton, following testosterone replacement therapy, and 7.6 ± 419.1 Newton, after placebo, p = 0.091. ∆-lean body mass was significantly higher following testosterone replacement therapy compared to placebo, 3.6 ± 2.7 versus 0.1 ± 3.5 kg, respectively (p < 0.001).DISCUSSION: Testosterone replacement therapy, compared to placebo, did not improve muscle function or gait performance despite increased lean body mass. Changes in body composition did not infer any changes in muscle function.CONCLUSION: 24 weeks testosterone replacement therapy in opioid-treated men with pain-related male hypogonadism did not improve muscle function.

Glucocorticoid-induced adrenal insufficiency is caused by exogenous glucocorticoid suppression of the hypothalamic-pituitary-adrenal axis and is the most prevalent form of adrenal insufficiency. The condition is important to diagnose given the risk of life-threatening adrenal crisis and impact on patients’ quality of life. The diagnosis is made with a stimulation test such as the ACTH test. Until now, testing for glucocorticoid-induced adrenal insufficiency has often been based on clinical suspicion rather than routinely but accumulating evidence indicates that a significant number of cases will remain unrecognized. During ongoing oral glucocorticoid treatment or initially after withdrawal, ~50% of patients have adrenal insufficiency, but, outside clinical studies, ≤ 1% of patients have adrenal testing recorded. More than 70% of cases are identified during acute hospital admission, where the diagnosis can easily be missed because symptoms of adrenal insufficiency are nonspecific and overlap those of the underlying and intercurrent conditions. Treatment of severe glucocorticoid-induced adrenal insufficiency should follow the principles for treatment of central adrenal insufficiency. The clinical implications and thus indication to treat mild-moderate adrenal deficiency after glucocorticoid withdrawal has not been established. Also, the indication of adding stress dosages of glucocorticoid during ongoing glucocorticoid treatment remains unclear. In patients with established glucocorticoid-induced adrenal insufficiency, high rates of poor confidence in self-management and delayed glucocorticoid administration in the acute setting with an imminent adrenal crisis call for improved awareness and education of clinicians and patients. This article reviews different facets of glucocorticoid-induced adrenal insufficiency and discusses approaches to the condition in common clinical situations.

Background Autoimmune hypophysitis is a rare condition that often results in enlargement of the pituitary gland and hypopituitarism due to inflammatory infiltration. Management of autoimmune hypophysitis can include long-term hormonal replacement and close control of the inflammatory pituitary mass. Mass-related symptoms in patients with autoimmune hypophysitis are treated with anti-inflammatory therapy, surgery, and/or radiotherapy. Case presentation We present a 25-year-old White man with visual field defects of the right eye, headache, and weight loss. Magnetic resonance imaging showed a sellar mass, and the patient underwent transcranial surgery. Histopathology revealed autoimmune hypophysitis with predominantly CD20 positive B-cell infiltration. Progression of visual field defects necessitated postoperatively anti-inflammatory treatment with prednisolone. Azathioprine was initiated under gradual tapering of prednisolone with stable conditions at first, but relapse followed after dose reduction. Therefore, rituximab treatment was initiated, which resulted in regression of the pituitary mass. Rituximab treatment was discontinued after 25 months. The patient has continuously been in remission for 4 years after rituximab treatment was stopped. Conclusion This case illustrates that rituximab might be an effective alternative treatment in B-cell predominant autoimmune hypophysitis.

STUDY QUESTIONAre higher testosterone levels during pregnancy in women with polycystic ovary syndrome (PCOS) associated with longer offspring anogenital distance (AGD)?SUMMARY ANSWERAGD was similar in 3-month-old children born of mothers with PCOS compared to controls.WHAT IS KNOWN ALREADYAGD is considered a marker of prenatal androgenization.STUDY DESIGN, SIZE, DURATIONMaternal testosterone levels were measured by mass spectrometry at Gestational Week 28 in 1127 women. Maternal diagnosis of PCOS before pregnancy was defined according to Rotterdam criteria. Offspring measures included AGD from anus to posterior fourchette (AGDaf) and clitoris (AGDac) in girls and to scrotum (AGDas) and penis (AGDap) and penile width in boys and body composition (weight and BMI SD scores) at age 3 months.PARTICIPANTS/MATERIALS, SETTING, METHODSThe study was part of the prospective study, Odense Child Cohort (OCC), and included mothers with PCOS (n = 139) and controls (n = 1422). The control population included women with regular menstrual cycles (MAIN RESULTS AND THE ROLE OF CHANCEAGD measures were comparable in offspring of women with PCOS compared to controls (all P > 0.2) despite significantly higher maternal levels of total testosterone (mean: 2.4 versus 2.0 nmol/l) and free testosterone (mean: 0.005 versus 0.004 nmol/l) in women with PCOS versus controls (both P LIMITATIONS, REASONS FOR CAUTIONThe diagnosis of PCOS was based on retrospective information and questionnaires during pregnancy. Women participating in OCC were more ethnically homogenous, leaner, more educated and less likely to smoke compared to the background population. Our study findings, therefore, need to be reproduced in prospective study cohorts with PCOS, in more obese study populations and in women of other ethnicities.WIDER IMPLICATIONS OF THE FINDINGSOur finding of the same AGD in girls born of mothers with PCOS compared to controls expands previous results of studies reporting longer AGD in adult women with PCOS. Our results suggest that longer AGD in adult women with PCOS could be the result of increased testosterone levels in puberty, perhaps in combination with weight gain.STUDY FUNDING/COMPETING INTEREST(S)Financial grants for the study were provided by the Danish Foundation for Scientific Innovation and Technology (09-067180), Ronald McDonald Children Foundation, Odense University Hospital, the Region of Southern Denmark, the Municipality of Odense, the Mental Health Service of the Region of Southern Denmark, The Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (2101-08-0058), Odense Patient data Explorative Network, Novo Nordisk Foundation (grant no. NNF15OC00017734), the Danish Council for Independent Research and the Foundation for research collaboration between Rigshospitalet and Odense University Hospital and the Health Foundation (Helsefonden). There is no conflict of interest of any author that could be perceived as prejudicing the impartiality of the research reported.

Background Osteoarthritis (OA) is the most common form of arthritis with multiple risk factors implicated including female sex and obesity. Metabolic dysregulation associated with obesity leading to metabolic syndrome is a proposed component of that association. Polycystic ovary syndrome (PCOS) commonly affects women of reproductive age and these women are at higher risk of developing metabolic syndrome and thus likely to represent a high-risk group for early OA development. There are no published studies exploring the epidemiology of knee, hip and hand OA in women diagnosed with PCOS. Study aim To assess the prevalence and incidence of knee, hip and hand osteoarthritis (OA) in women with polycystic ovary syndrome (PCOS) when compared with age-matched controls. Methods Prospective Danish national registry-based cohort study. The prevalence of OA in 2015 and incidence rates of OA over 11.1 years were calculated and compared in more than 75,000 Danish women with either a documented diagnosis of PCOS ± hirsutism (during the period of 1995 to 2012) or age-matched females without those diagnoses randomly drawn from the same population register. Results In 2015, the prevalence of hospital treated knee, hip and hand OA was 5.2% in women with PCOS diagnosis. It was 73% higher than that seen in age-matched controls. Significantly higher incidence rates were observed in the PCOS cohort compared with the age-matched controls during the follow-up period (up to 20 years), with the following hazard ratios (HR): 1.9 (95% CI 1.7 to 2.1) for knee, 1.8 (95% CI 1.3–2.4) for hand and 1.3 (95% CI 1.1 to 1.6) for hip OA. After excluding women with obesity, similar associations were observed for knee and hand OA. However, risk of developing hip OA was no longer significant. Conclusions In this large prospective study, women with PCOS diagnosis had higher prevalence and accelerated onset of OA of both weight and non-weight bearing joints, when compared with age-matched controls. Further studies are needed to understand the relative effect of metabolic and hormonal changes linked with PCOS and their role in promoting development of OA.

Introduction: Adult obesity is linked with polycystic ovary syndrome (PCOS), but the importance of body size at ages before PCOS is diagnosed is unknown. Objective: To investigate associations between a woman’s own birthweight, childhood body mass index (BMI), height and growth patterns in relation to her risk of PCOS. Methods: We included 65,665 girls from the Copenhagen School Health Records Register, born in the period 1960–1996, with information on birthweight and measured weight and height at the ages of 7–13 years. Overweight was defined using International Obesity Task Force (IOTF) criteria. From the Danish National Patient Register, 606 women aged 15–50 years were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox regression analysis. Results: Birthweight was not associated with PCOS. At the age of 7–13 years, girls with overweight had a higher risk of developing PCOS than girls without overweight; HR 2.83 (95% CI 2.34–3.42) at age 7 years and 2.99 (95% CI 2.38–3.76) at age 13 years. Furthermore, girls with overweight at both 7 and 13 years had a higher risk of developing PCOS than girls without overweight or overweight at only one age. Height was positively associated with PCOS risk at all ages. Girls who were persistently tall or changed from tall to average height had a higher risk of developing PCOS than girls with average height growth. Conclusion: Overweight and tall stature in childhood are positively associated with PCOS risk, but birthweight is not.

Background Maternal testosterone in pregnancy may have conditioning effects on offspring muscle strength. Purpose To investigate possible associations between maternal testosterone concentrations in third trimester and offspring handgrip strength (HGS) at 5 years. Methods In the prospective, population-based Odense Child Cohort, total testosterone (TT) at gestational week 27-28 and 5-year HGS were measured in 1017 mother-child pairs. TT was measured by liquid chromatography-tandem mass spectrometry and free testosterone (FT) was calculated from TT and sex hormone-binding globulin (SHBG). Multivariable regression analyses were performed with HGS Results Third-trimester FT concentration was 0.004 (0.002-0.007) nmol/L, geometric mean (mean − SD; mean + SD). The mean (SD) 5-year HGS was 8.7 (1.8) kg in boys and 8.1 (1.7) kg in girls (P 0.004 nmol/L was associated with higher risk of 5-year HGS Conclusion Third trimester FT was inversely associated with offspring muscle strength assessed by HGS at 5 years of age, which may suggest a negative effect of maternal FT on offspring muscle strength.

BACKGROUND: Lower thyroid function outside pregnancy is associated with an increased risk of type 2 diabetes mellitus. The relationship between thyroid function in early pregnancy and glucose status in 3rd trimester has not been investigated.AIMS: To study the association between 1st trimester thyroid function and 3rd trimester glucose status.DESIGN: In the prospective study Odense Child Cohort (OCC), 1,041 women had 1st trimester blood samples analysed for thyroid-stimulating hormone (TSH), free T4 (FT4), thyroid peroxidase antibody and HbA1c. Third trimester (week 28) fasting blood samples included plasma glucose, insulin and HbA1c. Oral glucose tolerance test (OGTT, 75 g glucose) was performed in 509 women. First trimester FT4 was dichotomized >vs. ≤ the 25th percentile (25p = 12.9 pmol/L). Homeostatic model assessment-insulin resistance (HOMA)-IR and HOMA-β were calculated.RESULTS: Women with FT4 ≤25p had significantly higher HbA1c in 1st and 3rd trimesters and higher 3rd trimester fasting glucose, insulin, HOMA-IR and HOMA-β compared to women with FT4 >25p. In multiple regression analyses, FT4 was an independent negative predictor of 3rd trimester HbA1c. FT4 levels in 3rd and 4th quartiles (high-normal FT4 levels) showed closest inverse associations with HbA1c (p-trend CONCLUSION: Women with lower levels of FT4 in early pregnancy had higher HbA1c in 3rd trimester and FT4 was an independent negative predictor of 3rd trimester HbA1c.

Transgender women are assigned male at birth but identified as women. The incidence of gender dysphoria is estimated to be around 1% of the population. Gender dysphoria may be associated with depression and low quality of life, which in most cases improves during gender-affirming hormonal treatment (GAHT). Feminizing hormonal treatment for transgender women or gender non-binary people typically includes natural estrogen (estradiol). Additional testosterone-blocking treatment is often needed to ensure the suppression of the pituitary-gonadal axis and may include cyproterone acetate, a gonadotropin-releasing hormone agonist (GnRH-a), or spironolactone. The health risks of cyproterone acetate as anti-androgen treatment are debated and randomized protocols with other anti-androgen treatments are requested. Orchiectomy is performed in some transgender women after various duration of GAHT. Currently, natural progesterone is not recommended as part of GAHT due to limited knowledge on the balance between risks and benefits. In the present article, we discuss evidence regarding established and upcoming feminizing treatment for adult transgender women or gender non-binary people seeking feminization. Data on study populations with transgender women are put into a wider context of literature regarding the effects of sex steroid hormones in cisgender study populations. Relevant follow-up and monitoring during feminizing treatment is debated. The review has a special focus on the pharmacotherapy of feminizing hormonal therapy.

Introduction: The number of persons with gender incongruence referred to health care is increasing, but national data on the incidence of gender incongruence are lacking. The aim of this study was to quantify the development in number of individuals with gender incongruence over time and to estimate the national incidence in Denmark. Material and methods: Historical descriptive cohort study. Individuals older than 18 years with legal sex-change in their person registration number were achieved from Statistics Denmark, and the National Health Register provided data on contact diagnoses related to gender-identity conditions. By combining these two data sources, we made estimates on incidence and incidence rates for individuals with gender incongruence in Denmark through a 41-year period 1980–2020. Results: Through 1980–2020, the annual number of legal sex-changes increased in individuals assigned female at birth from 5 to approximately 170 and among individuals assigned male at birth from 10 to approximately 150. The cumulative number of legal sex-changes at the end of 2019 was 1275 assigned female at birth and 1422 assigned male at birth and 66% of the legal sex-changes were in individuals below 30 years. Correspondingly, the annual number of contacts with the healthcare system due for gender-identity-related conditions increased from 30 during 1990–1999 to around 500 in 2017 (both genders combined), with a 10-fold increase from 2010 to 2017. Conclusions: The number of legal sex-changes and healthcare contacts due to gender-identity-related diagnoses increased substantially over the last 40 years with a more than 10-fold increase during the last decade. This calls for research on possible explanations for this increase, for research on the short-term and long-term health consequences of hormonal and surgical treatment regimens and for ensuring adequate healthcare facilities.

Aims To examine third trimester fasting venous plasma glucose (FVPG) according to the distribution of a Danish population of pregnant women and identify potential local FVPG thresholds for GDM diagnosis related to risks of adverse pregnancy outcomes. Methods In the observational Odense Child Cohort (OCC) study, 1516 women had FVPG measured at 27–28 weeks’ gestation and were considered normal by Danish criteria and remained untreated. Maternal FVPG from OCC were standardized according to the local FVPG mean and standard deviation calibrated to data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. Associations between maternal FVPG and clinical and anthropometric outcomes were analysed. Potential FVPG cut points were identified. Results Unadjusted areas under the ROC curve for FVPG to discriminate for large for gestational age (LGA) and hypertensive disorders of pregnancy were 0.61 (95% CI 0.56, 0.67) and 0.57 (95% CI 0.52, 0.63), respectively. The Youden FVPG cut point for LGA was 5.5 mmol/L and 5.0 mmol/L for hypertensive disorders of pregnancy. Conclusions This study identified a potential locally appropriate third trimester FVPG cut point between 5.5 and 5.7 mmol/L based on LGA risk in pregnancy. This cut point should be validated prospectively in other Danish cohorts.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is characterized by increased central fat mass (CFM), hyper-inflammation, and hemostatic alterations; the risk of cardiovascular disease may also be increased. Reduced fibrin lysability is a risk factor for cardiovascular disease. The present study assessed fibrin lysability in women with PCOS and controls of similar age and body mass index.MATERIAL AND METHODS: Ninety women with PCOS and 35 controls of comparable age and body mass index were included. Hemostatic markers (fibrin lysability, fibrinogen, coagulation factor XIII, plasminogen, plasminogen activator inhibitor 1 [PAI-1], plasmin inhibitor, thrombin activatable fibrinolysis inhibitor (TAFI), D-dimer), C-reactive protein (CRP), body mass index, waist-to-hip ratio, CFM determined by Dual-energy X-ray absorptiometry scan, and sex hormones (testosterone estradiol, and sex hormone binding globulin) were determined.RESULTS: TAFI and CRP were higher in women with PCOS, than controls. In women with PCOS, fibrin lysability correlated with CFM, waist-to-hip ratio, CRP, fibrinogen, and all hemostatic variables (P ≤ .004) except TAFI and D-dimer. CFM correlated with fibrinogen, CRP, coagulation factor XIII, waist-to-hip ratio, plasminogen, PAI-1, plasmin inhibitor, and TAFI (P < .02). In controls, fibrin lysability correlated with CFM, fibrinogen, coagulation factor XIII, and plasmin inhibitor (P ≤ .02). CFM correlated with PAI-1, plasmin inhibitor, coagulation factor XIII, fibrinogen, and CRP (P ≤ .05). Stepwise regression analysis revealed that fibrin lysability was associated with CFM, fibrinogen and CRP in women with PCOS (r2 = .46, P ≤ .001), but only with CFM in controls (r2 = .28, P < .001).CONCLUSIONS: Fibrin lysability was comparable in women with PCOS and controls. Fibrin lysability was associated with CFM and hyper-inflammation in women with PCOS, but only with CFM in controls. These findings suggest that obese women with PCOS and augmented inflammation could have an increased risk of cardiovascular disease.

Background: Perfluoroalkyl acids (PFAA) are repellants that cross the placental barrier, enabling interference with fetal programming. Maternal PFAA concentrations have been associated with offspring obesity and dyslipidemia in childhood and adulthood, but this association has not been studied in infancy. Objectives: We investigated associations between maternal PFAA concentrations and repeated markers of adiposity and lipid metabolism in infancy. Methods: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAA: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured in 649 women. Offspring were examined at birth (n=613) and at 3 months (n=602) and 18 months (n=503) of age. Total cholesterol, LDL, HDL, and triglyceride were evaluated at 3 months (n=262) and 18 months (n=198) of age. Mixed effects linear regression models estimated associations between PFAA and standardized (SDS) body mass index (BMI), ponderal index, and waist circumference. Associations between PFAA and body fat% (BF%) and plasma lipids SDS at 3 months and 18 months of age were investigated with linear regression models. Results: PFNA and PFDA were associated with higher BMI SDS [adjusted β=0.26; 95% confidence interval (CI): 0.03, 0.49 and β=0.58; 95% CI: –0.03, 1.19, respectively, for 1-ng/mL increases] and ponderal index SDS (β=0.36; 95% CI: 0.13, 0.59 and β=1.02; 95% CI: 0.40, 1.64, respectively) at 3 and 18 months of age (pooled) in girls. Corresponding estimates for boys were closer to the null but not significantly different from estimates for girls. In boys and girls (combined), PFNA and PFDA were associated with BF% at age 3 months (for 1-ng/mL PFDA, β=0.40; 95% CI: 0.04, 0.75), and PFDA was associated with total cholesterol SDS at 18 months (β=1.06; 95% CI: 0.08, 2.03) (n=83). Discussion: Prenatal PFAA were positively associated with longitudinal markers of adiposity and higher total cholesterol in infancy. These findings deserve attention in light of rising rates of childhood overweight conditions and dyslipidemia. https://doi.org/10.1289/EHP5184

Lifestyle intervention is first line treatment in obese women with polycystic ovary syndrome (PCOS). The effect of motivational interviewing (MI) as add on to standard advice (SA) on weight loss and quality of life (QoL) has not been evaluated in obese women with PCOS. We aimed to examine whether MI as add on to SA induced higher weight loss and improved QoL in obese women with PCOS. Thirty-seven obese women with PCOS (BMI ≥30 kg/m2) were randomized to MI + SA (n = 19) vs. SA (n = 18) for six months. Anthropometric measures (BMI, waist) and questionnaires (World Health Organization-5 (WHO-5), Major Depression Index (MDI), Short Form-36 (SF-36) and PCOS-Questionnaire (PCOS-Q)) were performed at baseline and at follow-up, www.clinicaltrials.gov, NCT02924025. Twenty-eight (14 + 14) women completed the study. At baseline, 24/28 women had WHO-5 scores

Polycystic ovary syndrome (PCOS) is common in premenopausal women. The majority of women with PCOS have insulin resistance and the risk of type 2 diabetes mellitus (T2D) is higher in women with PCOS compared to controls. In non-pregnant women with PCOS, glycemic status may be assessed by oral glucose tolerance test (OGTT), fasting plasma glucose (FPG) or HbA1c. OGTT has been reckoned gold standard test for diagnosing T2D, but OGTT is rarely used for diagnostic purpose in other non-pregnant individuals at risk of T2D, apart from PCOS. OGTT has questionable reproducibility, and high sensitivity of the 2-h glucose value is at the expense of relatively low specificity, especially regarding impaired glucose tolerance (IGT). Furthermore, lean women with PCOS are rarely diagnosed with T2D and only few percent of normal-weight women have prediabetes. Glycemic status is necessary at diagnosis and during follow-up of PCOS, especially in women with high risk of T2D (obesity, previous gestational diabetes (GDM)). We suggest that OGTT should be used in the same situations in PCOS as in other patient groups at risk of T2D. OGTT is indicated for diagnosing GDM; however, OGTT during pregnancy may not be indicated in lean women with PCOS without other risk factors for GDM.

Health-related quality of life (HRQoL) is impaired in polycystic ovary syndrome (PCOS), but the effect of treatment with metformin (M) and/or oral contraceptives (OCP) is undetermined. To assess changes in HRQoL during 12-month randomized treatment with M, OCP or M + OCP in PCOS. Ninety women with PCOS were randomized to treatment with M, OCP or M + OCP. HRQoL was evaluated by a PCOS-specific visual analog scale (PCOS-VAS) regarding 1: Facial hair, 2: Body hair, 3: Acne, 4: Irregular menses, 5: Weight and 6: PCOS in general, and Short Form 36 (SF-36). PCOS-VAS1(facial hair) improved during treatment with OCP (n = 23) compared to M (n = 19), and during M + OCP (n = 23) compared to M treatment, whereas changes in PCOS-VAS2-6 and SF-36 scores were comparable between the three medical intervention groups. Pooled data (n = 65) showed improved PCOS-VAS scores during treatment (all p

Low testosterone levels in aging men are associated with insulin resistance. Mitochondrial dysfunction, changes in glycogen metabolism, and lipid accumulation are linked to insulin resistance in skeletal muscle. In this randomized, double‐blinded, placebo‐controlled study, we investigated the effects of six‐month testosterone replacement therapy (TRT) and strength training (ST) on mitochondrial, glycogen, and lipid droplet (LD) content in skeletal muscle of aging men with subnormal bioavailable testosterone (BioT) levels. Mitochondrial, glycogen, and LD volume fractions in muscle biopsies were estimated by transmission electron microscopy. Insulin sensitivity (insulin‐stimulated Rd) and body composition were assessed by euglycemic‐hyperinsulinemic clamp and dual X‐ray absorptiometry, respectively. TRT significantly increased total testosterone levels, BioT, and lean body mass (LBM) (p < 0.05), whereas percent body fat decreased (p < 0.05), and insulin sensitivity was unchanged. Baseline mitochondrial volume fraction correlated inversely with percent body fat (ρ = −0.43; p = 0.003). Δ‐mitochondrial fraction correlated positively with Δ‐total testosterone (ρ = 0.70; p = 0.02), and Δ‐glycogen fraction correlated inversely with Δ‐LBM (ρ = −0.83; p = 0.002) during six‐month TRT, but no significant changes were observed in mitochondrial, glycogen, and LD volume fractions during TRT and ST. In conclusion, in this exploratory small‐scale study, the beneficial effects of six‐month TRT on total testosterone, LBM, and percent body fat were not followed by significant changes in fractions of mitochondria, glycogen, or lipid in skeletal muscle of aging men with lowered testosterone levels. Six‐month ST or combined three‐month ST+TRT did not change intramyocellular mitochondria, glycogen, and LD fractions compared to placebo. However, further studies with a larger sample size are needed.

Objective: Low circulating prolactin is a potential marker of metabolic risk during pregnancy. We aimed to investigate associations between prolactin and glucose status in pregnant women with and without gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS). Design: Prospective observational cohort study. From the Odense Child Cohort, 1497 pregnant women were included. Methods: Blood samples were assessed during first, second (prolactin, hemoglobin A1c (HbA1c)) and third trimester (fasting prolactin, testosterone, HbA1c, insulin, glucose). Oral glucose tolerance test (OGTT) was performed around gestation week 28 in 350 women with risk factors for GDM and in 272 randomly included women. GDM was defined by 2-h plasma glucose ≥9.0 mmol/L. Results: The median (IQR) prolactin increased from 633 (451–829) mIU/L in first–second trimester to 5223 (4151–6127) mIU/L at third trimester. Prolactin was inversely associated with HbA1c in first (r = −0.19, P r = −0.07, P = 0.014). In third trimester, women with GDM (n = 37; 6.0%) had lower prolactin compared to women without GDM (4269 vs 5072 mIU/L, P = 0.004). Third trimester prolactin multiple of the median (MoM) was inversely associated with risk of GDM in multivariate regression analysis (OR 0.30, P = 0.034). PCOS was diagnosed in 10.0% (n = 146). Early pregnancy prolactin MoM was positively associated to PCOS diagnosis (OR 1.38, P = 0.051). Conclusions: Low prolactin levels during pregnancy were associated with higher HbA1c and risk of GDM. A diagnosis of PCOS was associated with higher early pregnancy prolactin levels.

Background: Phthalates are plastic softeners with anti-androgenic properties. Prenatal exposure has led to lower testosterone (T) levels and smaller testicles in adult rats. To our knowledge, no studies have examined associations between prenatal phthalate exposure and sex hormone concentrations in infants. Objective: To study associations between phthalate exposure in Danish pregnant women and T, luteinizing hormone (LH), follicle stimulating hormone (FSH), Δ4-androstenedione (adion), 17α-hydroxyprogesterone (17-OHP) dehydroepiandrosterone sulfate (DHEAS) concentrations in their infants (N = 479) during mini-puberty. Methods: Concentrations of 12 phthalate metabolites from six phthalate diesters were measured in urine samples collected from 2010 to 2012 from 479 pregnant women participating in the Odense Child Cohort at gestational week 28 (range 20.4–30.4). Serum T, LH, FSH, adion, 17-OHP, DHEAS, weight and height were measured approximately three months after expected date of birth. Associations between prenatal phthalate exposure and gonadotropin and androgen metabolite concentrations were estimated in boys and girls separately in adjusted linear regression models. Results: T concentration was lower in boys prenatally exposed to phthalates. Maternal urinary concentrations of summed mono-iso-butyl and mono-n-butyl phthalate (∑MBPi+n) and summed metabolites of di-iso-nonyl phthalate (∑DiNPm) were associated with lower T/LH ratio in male offspring and a dose-response association was found. FSH was 14% (95% CI: 1; 25) lower among male offspring from mothers exposed to ∑DiNPm in the highest compared to the lowest tertile. No association was found for girls. Conclusion: Even in these low exposed children, we found a significant decrease in T/LH ratio during mini-puberty in boys prenatally exposed to phthalates, which may suggest impairment of Leydig cells. The children will be followed as they approach adrenarche and pubarche in order to assess if long-term adverse effects persist.

Endoscopic pituitary surgery has shown promising results. This study reports the experiences of experienced microscopic pituitary surgeons changing to the endoscopic technique, and the beneficial effects on the postoperative outcomes. 45 transsphenoidal endoscopic-assisted surgeries performed in 2016–2017 were compared with 195 microscope-assisted surgeries performed in 2007–2017 for pituitary adenoma. Tumour size, hormonal status and vision were assessed preoperatively and 3–5 months postoperatively. Cases were identified through electronic patient records. GTR was achieved in 39% of the endoscopic operations vs. 22% of microscopic operations, p = 0.018. Mean duration of surgery was 86 min (77–95) with the endoscopic technique vs. 106 min (101–111) with the microscopic technique, p 0.05). Normalization of visual impairment occurred in 37% of the cases with preoperative visual impairment in the endoscopic group vs. 35% of those in the microscopic group (p > 0.05). The endoscopic technique performed better as a surgical procedure for pituitary adenomas. We found no statistically significant differences in complication rate or visual improvement between the two techniques.

BACKGROUND: Transgender men are assigned female sex at birth, but identify as men. The anabolic and androgenic sex hormone testosterone has been positively associated with aggression. Therefore, transgender men are warned of increasing aggression when initiating testosterone therapy.AIM: To explore the literature regarding the effects of testosterone therapy on aggression-related constructs in transgender men.METHODS: Following PRISMA-guidelines, PsycINFO, MEDLINE®, EMBASE, and PubMed® were searched in November 2019. Risk of bias was analyzed using the Newcastle-Ottawa-Scale, and result-synthesis was grouped by aggression-outcome.RESULTS: Seven prospective cohort studies investigating aggression-dimensions pre- and post-testosterone therapy, reporting on data from 664 transgender men, were eligible. The studies had moderate to high risk of bias due to non-randomization, lack of appropriate control groups, and reliance on self-report. The behavioral tendency to react aggressively increased in three studies out of four (at three months follow-up), whereas only one study out of five found angry emotions to increase (at seven months follow-up). In contrast, one out of three studies reported a decrease in hostility after initiation of testosterone therapy. The remaining studies found no change in aggressive behavior, anger or hostility during hormone therapy.DISCUSSION AND CONCLUSION: Four out of seven studies reported an increase in aggression-related constructs, while one study reported a decrease. In all studies reporting changes, the follow-up period was less than 12 months, indicating that gender-affirming testosterone therapy could have a short-term impact on aggression-related constructs. However, the available studies carried a risk of bias, which indicates a need for further research.

IntroductionThe number of individuals with gender dysphoria seeking gender-affirming treatment is increasing. The short-term and long-term effects of masculinising treatment with testosterone are debated as serum testosterone increases up to 20-fold compared with cisgender women. We will investigate short-term and long-term effects of masculinising testosterone treatment on preclinical and clinical coronary disease, muscle strength and power, oxygen consumption (VO2) max, cardiac and respiratory function and quality of life including aggression in transgender men.Methods and analysesProspective, single-centre, observational cohort study at the Body Identity Clinic (BIC), Odense University Hospital, Denmark. Investigations are performed at inclusion and following 1, 3, 5 and 10 years of testosterone therapy. Non-calcified coronary plaque volume and calcium score are estimated by coronary CT angiography. CT is only performed at inclusion and following 1 and 10 years. Upper body muscle strength and power are measured by a ‘low row’ weight stack resisted exercise machine. Evaluation of aggression and quality of life is assessed by questionnaires, VO2 max is estimated by maximal testing on bike ergometer, and cardiac and respiratory functions are measured by echocardiography and spirometry, respectively. Markers of cardiovascular risk and inflammation and also cortisol and cortisone are assessed in blood, diurnal urine and/or hair samples. Our cohort (BIC), including dropouts, will be an embedded subcohort in a future national registry study in all individuals with gender dysphoria and controls. Data are available on International Statistical Classification of Diseases and Related Health Problems 10th version diagnostic codes, prescriptions, socioeconomics and causes of death.Ethics and disseminationThe Regional Committee on Health Research Ethics for Southern Denmark (S-20190108) and the Danish Data Protection Agency (19/27572) approved the study. Signed informed consent will be obtained from all participants. All findings will be published in peer-reviewed journals or at scientific conferences.Trial registration numberNCT04254354.

Publisher's version (útgefin grein), Objective: To date, little is known about differences in the knowledge, diagnosis making and treatment strategies of health care providers regarding polycystic ovary syndrome (PCOS) across different disciplines in countries with similar health care systems. To inform guideline translation, we aimed to study physician reported awareness, diagnosis and management of PCOS and to explore differences between medical disciplines in the Nordic countries and Estonia. Methods: This cross-sectional survey was conducted among 382 endocrinologists and obstetrician-gynaecologists in the Nordic countries and Estonia in 2015–2016. Of the participating physicians, 43% resided in Finland, 18% in Denmark, 16% in Norway, 13% in Estonia, and 10% in Sweden or Iceland, and 75% were obstetrician-gynaecologists. Multivariable logistic regression models were run to identify health care provider characteristics for awareness, diagnosis and treatment of PCOS. Results: Clinical features, lifestyle management and comorbidity were commonly recognized in women with PCOS, while impairment in psychosocial wellbeing was not well acknowledged. Over two-thirds of the physicians used the Rotterdam diagnostic criteria for PCOS. Medical endocrinologists more often recommended lifestyle management (OR = 3.6, CI 1.6–8.1) or metformin (OR = 5.0, CI 2.5–10.2), but less frequently OCP (OR = 0.5, CI 0.2–0.9) for non-fertility concerns than general obstetrician-gynaecologists. The physicians aged 56 (adjusted odds ratio (OR) = 0.4, 95% CI 0.2–0.8). Conclusion: Despite well-organized healthcare, awareness, diagnosis and management of PCOS is suboptimal, especially in relation to psychosocial comorbidities, among physicians in the Nordic countries and Estonia. Physicians need more education on PCOS and evidence-based information on Rotterdam diagnostic criteria, psychosocial features and treatment of PCOS, with the recently published international PCOS guideline well needed and welcomed., This study was supported by the Sigrid Juselius foundation, the Academy of Finland (grant no: 321763) and the Finnish Medical Association.

Background: Fetal programming of the endocrine system may be affected by exposure to perfluoroalkyl substances (PFAAs), as they easily cross the placental barrier. In vitro studies suggest that PFAAs may disrupt steroidogenesis. "Mini puberty" refers to a transient surge in circulating androgens, androgen precursors, and gonadotropins in infant girls and boys within the first postnatal months. We hypothesize that prenatal PFAA exposure may decrease the concentrations of androgens in mini puberty.Objectives: To investigate associations between maternal serum PFAA concentrations in early pregnancy and serum concentrations of androgens, their precursors, and gonadotropins during mini puberty in infancy.Methods: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAAs: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured at median gestational week 12 (IQR: 10, 15) in 1628 women. Among these, offspring serum concentrations of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAS), androstenedione, 17-hydroxyprogesterone (17-OHP), testosterone, luteinizing (LH) and follicle stimulating hormones (FSH) were measured in 373 children (44% girls; 56% boys) at a mean age of 3.9 (+/- 0.9 SD) months. Multivariate linear regression models were performed to estimate associations.Results: A two-fold increase in maternal PFDA concentration was associated with a reduction in DHEA concentration by -19.6% (95% CI: -32.9%, -3.8%) in girls. In girls, also, the androstenedione and DHEAS concentrations were decreased, albeit non-significantly (p Conclusion: Prenatal PFDA exposure was associated with significantly lower serum DHEA concentrations and possibly also with lower androstenedione and DHEAS concentrations in female infants at mini puberty. The clinical significance of these findings remains to be elucidated.

In this review, we discuss pituitary adenomas (PA), which account for 10-25% of the intracranial tumours. Despite their benign nature, PA often show invasive growth. Pressure on neighbouring structures may cause hypopituitarism or vision field impairment. For PA, except prolactinomas, surgical treatment is first choice. The primary surgical technique is transsphenoidal surgery. Pituitary function, vision and post-operative magnetic resonance imaging scan is evaluated in a multidisciplinary team of neurosurgeons and endocrinologist 6-8 weeks post-operatively. Follow-up and treatment of pituitary adenomas is highly specialised and requires a team of dedicated endocrinologists and neurosurgeons.

OBJECTIVE: To determine the comparative efficacy and safety of antipsychotics for youth with early-onset schizophrenia using network meta-analytic methods combining direct and indirect trial data.METHOD: The authors systematically searched MEDLINE, the Cochrane Library, and clinicaltrials.gov and selected randomized controlled trials allocating youth with schizophrenia spectrum disorders to a (non-clozapine) antipsychotic versus placebo or another antipsychotic. Major efficacy outcomes were Positive and Negative Syndrome Scale (PANSS) total and positive symptoms. Major safety outcomes were weight, plasma triglyceride levels, extrapyramidal symptoms, akathisia, and all-cause discontinuation. Sixteen additional outcomes were analyzed. A random-effects arm-based network meta-analysis was applied, and consistency was assessed by pairwise meta-analysis. Confidence in PANSS total estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.RESULTS: Twelve 6- to 12-week trials (N = 2,158; 8-19 years old; 61% boys) involving 8 antipsychotics (aripiprazole, asenapine, paliperidone, risperidone, quetiapine, olanzapine, molindone, and ziprasidone) were analyzed. PANSS total symptom change was comparable among antipsychotics (low- to moderate-quality evidence), except ziprasidone (very low- to low-quality evidence), and all antipsychotics were superior to placebo (low- to high-quality evidence), except ziprasidone and asenapine (low- to moderate-quality evidence). PANSS positive changes and additional efficacy outcomes were comparable among antipsychotics. Weight gain was primarily associated with olanzapine; extrapyramidal symptoms and akathisia were associated with molindone; and prolactin increased with risperidone, paliperidone, and olanzapine. Serious adverse events, discontinuation of treatment, sedation, insomnia, or change in triglycerides did not differ among antipsychotics.CONCLUSION: This network meta-analysis showed comparable efficacy among antipsychotics for early-onset schizophrenia, except that efficacy appeared inferior for ziprasidone and unclear for asenapine. Adverse reaction profiles varied substantially among the investigated antipsychotics and were largely consistent with prior findings in adults. Protocol registration information-Antipsychotic Treatment for Children With Schizophrenia Spectrum Disorders: Network Meta-Analysis of Randomised Trials; https://www.crd.york.ac.uk/PROSPERO/; CRD42013006676.

Background & aims: The susceptibility to overweight in adults born during winter season may suggest foetal programming of prenatal vitamin D levels on adiposity. We investigated whether cord or pregnancy serum 25-hydroxyvitamin D (s-25OHD) was associated with infant and child body fat measures in a Danish population-based prospective cohort. Methods: In the Odense Child Cohort, 1905 singletons had cord s-25OHD and data on waist circumference (WC), weight, body mass index (BMI), and sum of skin folds (SSF) at median 3.7 months, 18.9 months and three years’ age. Early and late pregnancy samples of s-25OHD (mean gestational age 12 and 29 weeks) were chosen as secondary exposures. Multiple linear and logistic regression as well as linear mixed models was applied testing the relation between cord and pregnancy s-25OHD and body fat outcomes and their Z-scores by use of updated national reference populations. Models were adjusted for maternal educational level, maternal ethnicity, pre-gestational BMI and season of birth, a priori stratified by sex. Results: The median [IQR] cord s-25OHD was 45.5 [31.1; 60.9] nmol/L. Cord s-25OHD 90th vs. ≤90 percentile) associate with cord or pregnancy s-25OHD. Conclusion: Cord or pregnancy s-25OHD was not associated with measures of body fat or adiposity in children up to three years of age. Our data suggested no programming effect of maternal s-25OHD on offspring obesity in a relatively lean and healthy population of mothers.

Objective To determine predictors of maternal serum (S) and urinary (U) cortisol and cortisone levels during the third trimester and to examine associations between maternal cortisol status, offspring sex, and maternal polycystic ovary syndrome (PCOS) status. Design Prospective observational study. Setting The study is part of the prospective Odense Child Cohort. Patient(s) The study cohort included 1,489 women (with PCOS, n = 145; without PCOS, n = 1,344). Intervention(s) Fasting blood samples, 24-hour urinary samples. Main Outcome Measure(s) Fasting morning S-cortisol and 24-hour U-cortisol/U-cortisone (24-hour U-C/C) were collected at gestational week 28 and measured by liquid chromatography–tandem mass spectrometry. Result(s) Maternal S-cortisol levels were significantly higher in women pregnant with girls (n = 702) vs. boys (n = 787): mean (mean − SD; mean + SD) 833 (643; 1,079) vs. 799 (588; 1,083) nmol/L. In multiple regression analyses, maternal S-cortisol was positively associated with female offspring and inversely associated with maternal age and parity. When women were divided according to PCOS status, 24-hour U-cortisone was higher: 467 (334; 652) vs. 415 (286; 604) nmol/24 hours; and 24-hour U-C/C was lower in women with PCOS compared with women without PCOS. Conclusion(s) Maternal third trimester S-cortisol levels were positively associated with female offspring. Cortisol metabolism was higher in women with PCOS vs. women without PCOS.

BACKGROUND: Insulin resistance is common in polycystic ovary syndrome (PCOS). PCOS may be associated with increased risk of gestational diabetes mellitus (GDM).OBJECTIVES: To (1) review literature regarding PCOS and hyperglycaemia in pregnancy and (2) present original data from Odense Child Cohort (OCC) regarding GDM in PCOS.METHODS: Literature search including original studies from 2000-18. OCC included 2548 pregnant women, 9.5% (n = 241) had PCOS. Fasting plasma glucose was measured in 1519 and 659 oral glucose tolerance tests were performed (with risk factor for GDM, n = 384, without risk factors, n = 275), applying two different GDM criteria.RESULTS: 30 studies were eligible using 12 different sets of diagnostic criteria for GDM. Ten studies included n > 50, control group, assessment of GDM and BMI. Results were not uniform, but supported that higher BMI, higher age, Asian ethnicity, and fertility treatment increased the risk of GDM in PCOS. In OCC, women with PCOS and controls had similar prevalences of GDM independent of different sets of criteria for GDM.CONCLUSION: PCOS may not be an individual risk factor for GDM. Pregnancies in PCOS are characterized by factors known to increase risk of GDM, especially high BMI and fertility treatment.

Background: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism. In pregnancy, testosterone levels may be higher in women with PCOS compared with controls. Aims: To compare total testosterone (TT), free testosterone (FT), and sex hormone-binding globulin (SHBG) levels in third-Trimester pregnant women with PCOS and controls and to establish reference ranges for TT, FT, and SHBG in PCOS and controls. Methods: The study was part of the prospective study, Odense Child Cohort. PCOS was diagnosed by questionnaires and/or patient records. Fasting blood samples were collected at gestational week 28 and plasma TT was measured by liquid chromatography-Tandem mass spectrometry in women with PCOS (n = 145) and in women without PCOS (controls, n = 1341). Results: Levels of TT (mean, 2.4 vs 2.0 nmol/L) and FT (mean, 0.005 vs 0.004 nmol/L) were higher, whereas SHBG levels (mean, 447 vs 477 nmol/L)were lower inwomenwith PCOS vs controls (all P,0.001). Reference intervals for TT, FT, and SHBG in women with PCOS and controls were overlapping, and partitioning of reference intervals was an ambiguous decision. In multiple regression analyses, TT and FT levels were positively associated with PCOS status and BMI and inversely associated with age and parity. Offspring sex did not predict maternal TT and FT. Conclusions: TT and FT levels were higher in third-Trimester pregnant women with PCOS compared with controls. Separate reference interval for FT in women with PCOS should be considered.

The metabolic syndrome (MetS) is a conglomerate of clinical findings that convey into increased morbidity and mortality from type 2 diabetes mellitus (T2D) and cardiovascular disease. Hyperprolactinemia (hyperPRL) is associated with components of MetS, especially during pregnancy. Endogenous levels of sex steroids are high during pregnancy in contrast to untreated or replaced hypogonadism in most patients with a prolactinoma and hypogonadism may confer increased risk of MetS in hyperPRL. Dopamine-D2-agonist therapy can improve MetS in patients with a prolactinoma and lower glucose levels in patients with T2D. HyperPRL is a biomarker for decreased dopaminergic tonus in the hypothalamic-pituitary circuit. Patients with a prolactinoma, patients with schizophrenia and/or T2D often have disturbances in this balance and the finding of lower prolactin (PRL) levels in polycystic ovary syndrome (PCOS) may indicate increased dopaminergic tonus. Recent studies supported that PRL levels within or above reference range may be differently related to MetS. In healthy study populations and in PCOS, PRL levels were inversely associated with metabolic risk markers. Ongoing research on PRL fragments, vasoinhibins, may help explain some of the contradicting findings between prolactin levels and metabolism. Improved knowledge about MetS in hyperPRL can characterize subgroups of patients with hyperPRL, who would not otherwise be considered as candidates for dopamine-D2-agonist therapy such as patients with postpartum cardiomyopathy and postmenopausal women with T2D.

STUDY QUESTION: What is the prevalence of reactive hypoglycemia (RH) in polycystic ovary syndrome (PCOS) versus age- and body mass index (BMI)-matched healthy controls.SUMMARY ANSWER: The prevalence of RH was increased in PCOS versus controls.WHAT IS KNOWN ALREADY: Previous studies suggested an increased prevalence of RH in PCOS.STUDY DESIGN, SIZE, DURATION: Cross-sectional study of 88 women with PCOS and 34 healthy age- and BMI-matched controls.PARTICIPANTS/MATERIALS, SETTING, METHODS: Eighty-eight women with PCOS and 34 age- and BMI-matched controls were included. The study was conducted at Odense University Hospital, Denmark. Participants underwent 5 h oral glucose tolerance test (5 h OGTT). Indices of insulin resistance, β-cell function, and area under the curve (AUC) for glucose, insulin and C-peptide were calculated. Insulin clearance was estimated as 5 h AUC C-peptide/insulin. RH was defined as blood glucose ≤3.3 mmol/l during 5 h OGTT.MAIN RESULTS AND THE ROLE OF CHANCE: RH occurred in 15/88 (17%) women with PCOS versus 0/34 controls ( ITALIC! P = 0.01). Nine out of 15 women with RH were obese and 6 were lean ( ITALIC! P = 0.42). Obese patients with RH had significantly higher 5 h AUCs insulin and C-peptide compared with lean patients with RH ( ITALIC! P = 0.02 and 0.04, respectively). Obese patients with RH had significantly lower 5 h AUC C-peptide/insulin versus obese patients without RH ( ITALIC! P = 0.02). In lean patients with RH, 5 h AUCs insulin and C-peptide were similar to lean controls.LIMITATIONS, REASONS FOR CAUTION: The 5 h OGTT was used to diagnose RH and may be a limitation of the study. Although the 5 h OGTT is the most widely accepted method, no gold standard exists in terms of diagnosing RH. The 5 h OGTT was suggested to over-estimate the incidence of RH compared with meal test.WIDER IMPLICATIONS OF THE FINDINGS: The study supports previous suggestions of increased prevalence of RH in women with PCOS compared with controls.STUDY FUNDING/COMPETING INTERESTS: This study was funded by Jacob Madsen's and Olga Madsen's Foundation, Institute of Clinical Research, Odense University Hospital, Kolding Hospital, AP Møller's Foundation, Bernhard and Marie Kleins Foundation, The Novo Nordisk Foundation, and The Danish Medical Association. The authors declare no conflict of interest.TRIAL REGISTRATION NUMBER: The trial was registered at www.clinicaltrials.gov (registration numbers NCT00451568 (patients) and NCT01995773 (controls)).

Background Polycystic ovary syndrome (PCOS) is associated with obesity and low grade inflammation and the risk for cardiovascular disease (CVD) could be increased in PCOS. Methods National register-based study including women with PCOS and no previous diagnosis of CVD, hypertension, or dyslipidemia. PCOS Denmark (N = 18,112) included women with PCOS in the Danish National Patient Register. PCOS Odense University Hospital (OUH, N = 1165) was an embedded cohort including premenopausal women with PCOS and clinical and biochemical examination. Three age-matched controls were included per patient in PCOS Denmark (N = 52,769). The main study outcome was CVD events including hypertension and dyslipidemia defined according to nationwide in- and outpatient hospital contact diagnosis codes and/or inferred from filled medicine prescriptions. Results The age at inclusion was median (quartiles) 29 (23–35) years and follow up was 11.1 (6.9–16.0) years. The Hazard ratio (95% CI) for development of CVD in PCOS Denmark was 1.7 (1.7; 1.8) (P

Background: Perfluoroalkyl substances (PFASs) are persistent chemicals with suspected endocrine disrupting abilities applied in consumer products. PFASs have potentially modulating effects on glucose homeostasis. Insulin resistance prevails during third trimester of pregnancy, and this challenge of glucose homeostasis may reveal putative effects of PFAS concentrations on glycemic status. Objective: To investigate associations between five serum PFASs and glucose-related outcomes in pregnant Danish women based on their risk of gestational diabetes mellitus (GDM). Methods: In the prospective Odense Child Cohort serum concentrations of five PFASs - perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) - were measured at median gestational week (GW) 11 in pregnant women. An oral glucose tolerance test (OGTT) was performed at GW 28. The statistical analysis was conducted among 158 women with high GDM risk and 160 women with low GDM risk matched by gestational age. Multiple linear regression models were performed to estimate associations between PFAS concentrations and glucose, insulin, C-peptide, homeostatic model of assessment of insulin resistance (HOMA-IR) and beta cell function (HOMA-%β), and insulin sensitivity (Matsuda index) during the 2-h OGTT. Results: In women with high risk for GDM, a two-fold increase in PFHxS concentration was significantly associated with increased fasting glucose, fasting insulin and HOMA-IR after adjusting for age, parity, educational level and pre-pregnancy BMI. Adjusting for the same confounders, a doubling in PFNA concentration was associated with higher fasting insulin and HOMA-%β.In women with low GDM risk, no associations were found between PFAS concentrations and glucose-related outcomes. Conclusion: PFHxS and PFNA concentrations were associated with impaired glycemic status in metabolically vulnerable pregnant women and might further enhance the risk of developing GDM. Keywords: Odense Child Cohort, Perfluoroalkyl substances, Glycemic status, Pregnancy, Oral glucose tolerance test

The metabolic syndrome (MetS) is a conglomerate of clinical findings that convey into increased morbidity and mortality from type 2 diabetes mellitus (T2D) and cardiovascular disease. Hyperprolactinemia (hyperPRL) is associated with components of MetS, especially during pregnancy. Endogenous levels of sex steroids are high during pregnancy in contrast to untreated or replaced hypogonadism in most patients with a prolactinoma and hypogonadism may confer increased risk of MetS in hyperPRL. Dopamine-D2-agonist therapy can improve MetS in patients with a prolactinoma and lower glucose levels in patients with T2D. HyperPRL is a biomarker for decreased dopaminergic tonus in the hypothalamic-pituitary circuit. Patients with a prolactinoma, patients with schizophrenia and/or T2D often have disturbances in this balance and the finding of lower prolactin (PRL) levels in polycystic ovary syndrome (PCOS) may indicate increased dopaminergic tonus. Recent studies supported that PRL levels within or above reference range may be differently related to MetS. In healthy study populations and in PCOS, PRL levels were inversely associated with metabolic risk markers. Ongoing research on PRL fragments, vasoinhibins, may help explain some of the contradicting findings between prolactin levels and metabolism. Improved knowledge about MetS in hyperPRL can characterize subgroups of patients with hyperPRL, who would not otherwise be considered as candidates for dopamine-D2-agonist therapy such as patients with postpartum cardiomyopathy and postmenopausal women with T2D.

OBJECTIVE To define the prevalence and pregnancy outcomes related to elevated fasting venous plasma glucose (FVPG) in a Danish pregnancy cohort. RESEARCH DESIGN AND METHODS This was an observational cohort study including 1,516 women without gestational diabetes mellitus (GDM) by Danish criteria. FVPG measured at 28 weeks’ gestation was related to pregnancy outcomes. RESULTS With use of the World Health Organization (WHO) 2013 threshold of FVPG ≥5.1 mmol/L, 40.1% of the cohort qualified as having GDM. There was no evidence of excess fetal growth, hypertension in pregnancy, or cesarean delivery in women with FVPG CONCLUSIONS The WHO 2013 FVPG threshold for GDM is unsuitable for Denmark. It inappropriately labels as having GDM an unmanageably large number of women who are at low absolute risk of pregnancy complications.

Introduction: Polycystic ovary syndrome is associated with obesity and insulin resistance in the non-pregnant state, but little is known about insulin sensitivity in the pregnant state. Our objective was to compare insulin resistance in pregnant women with and without polycystic ovary syndrome and explore the impact of polycystic ovary syndrome on body composition in offspring at birth and at three years of age. Material and methods: A prospective cohort study including 2548 live-born singleton mother–child pairs residing in Odense municipality, Denmark, during 2010–2013. Of the 2548 women, 241 (9.4%) had polycystic ovary syndrome. Results: Homeostatic model assessment for insulin resistance assessments were comparable in women with and without polycystic ovary syndrome. However, the subgroup of overweight women with polycystic ovary syndrome had significantly higher levels of homeostatic model assessment for insulin resistance than overweight women without polycystic ovary syndrome (mean ± 2 SD): 4.4 (3.1) vs. 3.6 (3.4), p = 0.004. Maternal polycystic ovary syndrome did not affect offspring birthweight after accounting for age. However, polycystic ovary syndrome, adjusted for maternal body mass index, was associated with increased body mass index at three years of age (mean ± 2 SD): 16.0 (2.2) vs. 15.7 (2.1) kg/m 2, p = 0.04. Conclusion: In our cohort, maternal polycystic ovary syndrome was not associated with insulin resistance after correcting for body mass index and was not an independent predictor of offspring birthweight. However, both polycystic ovary syndrome and high maternal body mass index may increase risk of childhood obesity at three years of age.

Objective: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and obesity. Prospective population-based data regarding development and possible predictors of type 2 diabetes (T2D) in PCOS are limited. Design: National Patient Register–based study. Methods: Patients with PCOS [PCOS Denmark and embedded cohort, PCOS Odense University Hospital (OUH)] and a control population with no previous diagnosis of T2D. PCOS OUH (N = 1,162) included premenopausal women with PCOS and standardized clinical and biochemical examination. PCOS Denmark (N = 18,477) included women with PCOS in the Danish National Patient Register. Three age-matched controls were included per patient (N = 54,680). Main outcome: T2D events according to diagnosis codes and filled medicine prescriptions. Results: The median (quartiles) follow-up was 11.1 (6.9 to 16.0) years. The hazard ratio (HR) with 95% confidence interval (CI) for development of T2D in PCOS Denmark was HR = 4.0 (95% CI, 3.7 to 4.3; P, 0.001), and the total event rate of T2D was 8.0 per 1000 person years in PCOS Denmark vs 2.0 per 1000 person years in controls (P, 0.001). The median age at diagnosis of T2D was 31 (26 to 37) years in PCOS Denmark vs 35 (27 to 44) years in controls (P, 0.001). In multiple regression analyses, body mass index, glycated hemoglobin, fasting blood glucose, 2-hour blood glucose, homeostasis model assessment of insulin resistance, and triglycerides were positively associated with development of T2D, whereas higher number of births was negatively associated with development of T2D. Conclusion: The event rate of T2D was higher in PCOS compared with controls, and T2D was diagnosed at a younger age.

STUDY QUESTION: Is oral glucose tolerance test (OGTT) needed in all women with polycystic ovary syndrome (PCOS)?SUMMARY QNSWER: OGTT is not routinely needed in women with PCOS and BMI < 25 kg/m2.WHAT IS KNOWN ALREADY: PCOS is associated with insulin resistance and increased prevalence of prediabetes and Type 2 diabetes (T2D) which is closely linked to obesity and possibly age, ethnicity and PCOS phenotype. Several guidelines recommend OGTT upon diagnosis of PCOS and during follow-up.STUDY DESIGN, SIZE, DURATION: A Nordic cross-sectional study including 876 women.PARTICIPANTS/MATERIALS, SETTING, METHODS: The 876 Nordic women with PCOS, aged 14-57 years, were examined for T2D and prediabetes (impaired glucose tolerance [IGT] or impaired fasting glucose (IFG) by OGTT.MAIN RESULT AND THE ROLE OF CHANCE: Of all study subjects 3% (23/876) had T2D, 23% (204/876) prediabetes and 74% (649/876) had normal glucose tolerance (NGT). Increased BMI and waist circumference were significantly (P < 0.001) associated with prevalence of prediabetes and T2D. No normal-weight woman (BMI < 25 kg/m2) was diagnosed with T2D. The prevalence of BMI ≥ 25 kg/m2 was 66% (578/ 876). 91% of women (21/23) with T2D had BMI ≥ 30 kg/m2. Testosterone levels and PCOS phenotype did not predict 2-h glucose levels during OGTT after adjustment for BMI and age.LIMITATIONS, REASONS FOR CAUTION: The present study included cross-sectional data and prospective studies are needed to confirm our results. These results may not apply to populations of other ethnic origin.WIDER IMPLICATIONS OF THE FINDINGS: Routine OGTT may not be indicated in normal-weight women with PCOS.STUDY FUNDING/COMPETING INTEREST(S): None.TRIAL REGISTRATION NUMBER: N/A.

Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls. Glucose transport in myotubes was comparable in patients with PCOS vs. controls and was unchanged by testosterone treatment (p=0.21 PCOS vs. controls). These results suggest that testosterone treatment of myotubes increases the aromatase and androgen receptor gene expression without affecting insulin sensitivity and if testosterone is implicated in muscular insulin resistance in PCOS, this is by and indirect mechanism. Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7 days testosterone treatment (100 nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls. Glucose transport in myotubes was comparable in patients with PCOS vs. controls and was unchanged by testosterone treatment (p = 0.21 PCOS vs. controls). These results suggest that testosterone treatment of myotubes increases the aromatase and androgen receptor gene expression without affecting insulin sensitivity and if testosterone is implicated in muscular insulin resistance in PCOS, this is by and indirect mechanism.

Objective: To compare the metabolic profiles of normo- and hyperandrogenic women with polycystic ovary syndrome (PCOS) with those of control women at different ages during reproductive life. Design: Case-control study. Setting: Not applicable. Patient(s): In all, 1,550 women with normoandrogenic (n = 686) or hyperandrogenic (n = 842) PCOS and 447 control women were divided into three age groups: 39 years). Interventions(s): None. Main Outcome Measure(s): Body mass index (BMI), waist circumference, blood pressure, glucose, insulin, cholesterol, lipoproteins, triglycerides and high-sensitivity C-reactive protein. Result(s): Both normo- and hyperandrogenic women with PCOS were more obese, especially abdominally. They had increased serum levels of insulin (fasting and in oral glucose tolerance tests), triglycerides, low-density lipoprotein, and total cholesterol, higher blood pressure, and lower high-density lipoprotein levels independently from BMI compared with the control population as early as from young adulthood until menopause. The prevalence of metabolic syndrome was two-to fivefold higher in women with PCOS compared with control women, depending on age and phenotype, and the highest prevalence was observed in hyperandrogenic women with PCOS at late reproductive age. Conclusion(s): When evaluating metabolic risks in women with PCOS, androgenic status, especially abdominal obesity and age, should be taken into account, which would allow tailored management of the syndrome from early adulthood on. (C) 2016 by American Society for Reproductive Medicine.

As a universally common endocrinopathy in women of reproductive age, the polycystic ovarian syndrome is characterized by composite clinical phenotypes reflecting the contributions of reproductive impact of ovarian dysfunction and metabolic abnormalities with widely varying symptoms resulting from interference of the genome with the environment through integrative biological mechanisms including epigenetics. We have performed a genome-wide DNA methylation analysis on polycystic ovarian syndrome and identified a substantial number of genomic sites differentially methylated in the whole blood of PCOS patients and healthy controls (52 sites, false discovery rate < 0.05 and corresponding p value < 5.68e-06), highly consistently replicating biological pathways extensively implicated in immunity and immunity-related inflammatory disorders (false discovery rate < 0.05) that were reportedly regulated in the DNA methylome from ovarian tissue under PCOS condition. Most importantly, our genome-wide profiling focusing on PCOS patients revealed a large number of DNA methylation sites and their enriched functional pathways significantly associated with diverse clinical features (levels of prolactin, estradiol, progesterone and menstrual cycle) that could serve as novel molecular basis of the clinical heterogeneity observed in PCOS women. As a universally common endocrinopathy in women of reproductive age, the polycystic ovarian syndrome is characterized by composite clinical phenotypes reflecting the contributions of reproductive impact of ovarian dysfunction and metabolic abnormalities with widely varying symptoms resulting from interference of the genome with the environment through integrative biological mechanisms including epigenetics. We have performed a genome-wide DNA methylation analysis on polycystic ovarian syndrome and identified a substantial number of genomic sites differentially methylated in the whole blood of PCOS patients and healthy controls (52 sites, false discovery rate < 0.05 and corresponding p value < 5.68e-06), highly consistently replicating biological pathways extensively implicated in immunity and immunity-related inflammatory disorders (false discovery rate < 0.05) that were reportedly regulated in the DNA methylome from ovarian tissue under PCOS condition. Most importantly, our genome-wide profiling focusing on PCOS patients revealed a large number of DNA methylation sites and their enriched functional pathways significantly associated with diverse clinical features (levels of prolactin, estradiol, progesterone and menstrual cycle) that could serve as novel molecular basis of the clinical heterogeneity observed in PCOS women.