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Objective The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial. Design The study is a prospective longitudinal population-based cohort study. Methods The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n = 153), progestin-only contraceptive (POC, n = 842), and non-hormonal contraceptive users (n = 884). Results In the entire study population, current CHC use was significantly associated with prediabetes (OR: 2.0, 95% CI: 1.3–3.2) and type 2 diabetes (OR: 3.3, 95% CI: 1.1–9.7) compared to non-hormonal contraceptive use. After 5 years of use, the prediabetes risk increased 2.2-fold (95% CI: 1.3–3.7) and type 2 diabetes risk increased 4.5-fold (95% CI: 1.5–13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR: 1.9, 95% CI: 1.2–3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for BMI and socioeconomic status. Conclusions CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.

Introduction The aim of the study was to determine the association of body mass index (BMI), self-reported symptoms or diagnosis of polycystic ovary syndrome (PCOS), and hyperandrogenemia with the occurrence of gestational diabetes mellitus (GDM) through reproductive life. Material and methods A cohort of women born in 1966 were investigated at ages 14, 31 and 46. Women with self-reported PCOS symptoms (presence of both oligo-amenorrhea and hirsutism) at age 31 or with formally diagnosed polycystic ovaries (PCO)/PCOS by age 46 formed the group of self-reported PCOS (srPCOS, n = 222) and were compared with women without self-reported PCOS symptoms or diagnosis (n = 1357). We investigated also the association of hyperandrogenism (hirsutism or biochemical hyperandrogenism) at age 31 with the occurrence of GDM throughout reproductive life. Results Self-reported PCOS alone was not a risk factor for GDM, but combined with overweight at age 31 (odds ratio [OR] 2.43, 95% confidence interval [CI] 1.22-4.86) or 46 (OR 3.04, 95% CI 1.58-5.83) srPCOS was associated with GDM when compared with normal weight controls. The association disappeared when comparing overweight srPCOS women with overweight controls. However, hyperandrogenemia at age 31, but not hirsutism, was associated with GDM even after adjustment for BMI. Conclusions The increased risk of GDM in women with srPCOS was mostly attributed to overweight or obesity. Importantly, normal weight women with srPCOS did not seem to be at increased risk for developing GDM. However, hyperandrogenemia was associated with GDM even after adjustment for BMI. These findings strengthen the importance of weight management in reproductive-age women and suggest a noteworthy role of hyperandrogenemia in the pathophysiology of GDM.

Low grade inflammation is associated with many noncommunicable diseases. The association between skin diseases in general and systemic inflammation has not previously been studied at the population level. A whole-body investigation on 1,930 adults belonging to Northern Finland Birth Cohort 1966 was performed and high sensitive C-reactive protein (CRP) level was measured as a marker of low grade inflammation in order to determine the association between low grade inflammation and skin diseases in an unselected adult population. After adjustment for confounding factors the following skin disorders were associated with low grade inflammation in multinomial logistic regression analysis: atopic eczema (OR 2.2, 95% CI 1.2-3.9), onychomycosis (OR 2.0, 1.2-3.2) and rosacea (OR 1.7, 1.1-2.5). After additionally adjusting for body mass index and systemic diseases, the risks for atopic eczema (OR 2.4, 1.3-4.6) and onychomycosis (OR 1.9, 1.1-3.1) remained statistically significant. In conclusion, low grade inflammation is present in several skin diseases.

Context: Maternal gestational diabetes mellitus (GDM) and prepregnancy overweight/obesity [body mass index (BMI) ≥25 kg/m²] might adversely affect offspring cardiometabolic health. Objective: To assess the associations between maternal GDM and prepregnancy overweight/obesity with adult offspring cardiometabolic risk factors. Design: Longitudinal cohort study (ESTER Maternal Pregnancy Disorders Study and the Arvo Ylppö Longitudinal Study). Setting: Province of Uusimaa and Northern Finland. Participants: At a mean age of 24.1 ± 1.3 years, we classified offspring as offspring of mothers with GDM regardless of the prepregnancy BMI (OGDM; n = 193); normoglycemic mothers with prepregnancy overweight/obesity (ONO; n = 157); and normoglycemic mothers with prepregnancy BMI

Maternal hypothyroidism and/or hypothyroxinemia have been associated with child's poor neuropsychological development, but the results have been inconsistent.The Northern Finland Birth Cohort 1986 included all expected births within a year (9362 women, 9479 children) from the two northernmost provinces of Finland. Maternal serum samples (n = 5791) were obtained in early pregnancy (M ± SD = 10.7 ± 2.8 weeks' gestation), and serum samples from their children were obtained at 16 years of age (n = 5829). All samples were analyzed for thyrotropin, free thyroxine (fT4), and thyroid peroxidase antibodies. The children's school performance was evaluated by their main teachers at eight years of age, as well as by the adolescents themselves at 16 years of age. Data on possible severe intellectual deficiency and mild cognitive limitation were collected from healthcare records and registries for all children. Logistic regression estimated the odds of poor school performance or severe intellectual deficiency/mild cognitive limitation associated with exposure to maternal thyroid dysfunction. The odds of poor school performance associated with the adolescents' own thyroid function at age 16 were also estimated. Results are presented as odds ratios (OR) with confidence intervals (CI), adjusted for maternal/family covariates and child's sex.Girls of mothers with subclinical hypothyroidism had more self-evaluated difficulties in mathematics than did girls of euthyroid mothers (OR 1.62 [CI 1.06-2.49]). Boys of hypothyroxinemic mothers repeated a school class more often than did boys of euthyroid mothers (OR 5.46 [CI 1.19-25.06]). Adolescents of hyperthyroid mothers had increased odds of poor self-evaluated performance in mathematics (OR 1.61 [CI 1.01-2.49]). Maternal thyroid dysfunction did not increase the odds of a child having severe intellectual deficiency/mild cognitive limitation. At 16 years of age, girls with hyperthyroidism by laboratory measurements had more difficulties in Finnish language (OR 2.82 [CI 1.42-5.61]) than did euthyroid girls. Boys with hypothyroxinemia by laboratory measurement had higher odds of having difficulties in Finnish and/or mathematics (OR 2.13 [CI 1.26-3.62]) than did euthyroid boys.Maternal thyroid dysfunction during early pregnancy was associated with poorer scholastic performance of the adolescent. Additionally, adolescents' own thyroid dysfunction was associated with difficulties in school performance assessed by self-evaluation.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510

Aims Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C).

Adults who were born preterm with a very low birth weight have higher blood pressure and impaired glucose regulation later in life compared with those born at term. We investigated cardiometabolic risk factors in young adults who were born at any degree of prematurity in the Preterm Birth and Early Life Programming of Adult Health and Disease (ESTER) Study, a population-based cohort study of individuals born in 1985–1989 in Northern Finland. In 2009–2011, 3 groups underwent clinical examination: 134 participants born at less than 34 gestational weeks (early preterm), 242 born at 34–36 weeks (late preterm), and 344 born at 37 weeks or later (controls). Compared with controls, adults who were born preterm had higher body fat percentages (after adjustment for sex, age, and cohort (1985–1986 or 1987–1989), for those born early preterm, difference = 6.2%, 95% confidence interval (CI): 0.4, 13.2; for those born late preterm, difference = 8.0%, 95% CI: 2.4, 13.8), waist circumferences, blood pressure (for those born early preterm, difference = 3.0 mm Hg, 95% CI: 0.9, 5.1; for those born late preterm, difference = 1.7, 95% CI: −0.1, 3.4), plasma uric acid levels (for those born early preterm, difference = 20.1%, 95% CI: 7.9, 32.3; for those born late preterm, difference = 20.2%, 95% CI: 10.7, 30.5), alanine aminotransferase levels, and aspartate transaminase levels. They were also more likely to have metabolic syndrome (for those born early preterm, odds ratio = 3.7, 95% CI: 1.6, 8.2; for those born late preterm, odds ratio = 2.5, 95% CI: 1.2, 5.3). Elevated levels of conventional and emerging risk factors suggest a higher risk of cardiometabolic disease later in life. These risk factors are also present in the large group of adults born late preterm.

BACKGROUND The causal role of circulating sex hormone-binding globulin (SHBG) for type 2 diabetes is controversial. Information on the relations between SHBG and new biomarkers of cardiometabolic risk is scarce. METHODS We applied quantitative nuclear magnetic resonance metabolomics in three Finnish population-based cohorts to comprehensively profile circulating lipids and metabolites and study their associations with SHBG. Mendelian randomization was used to examine potential causality of SHBG on the metabolic measures and insulin resistance. Prospective associations and causal effect estimates of SHBG on type 2 diabetes were assessed via meta-analysis including summary statistics from the DIAGRAM consortium. RESULTS In cross-sectional analysis in 6475 young adults (mean age 31, 57% men), higher SHBG was linked with a more favourable cardiometabolic risk profile, including associations with lipoprotein subclasses, fatty acid composition, amino acids, ketone bodies and inflammation-linked glycoproteins. Prospective analysis of 1377 young adults with 6-year follow-up indicated that SHBG is also associated with future insulin resistance. Mendelian randomization suggested only minor, if any, causal effects of SHBG on lipid and metabolite measures and insulin resistance(n = 10,895).Causal effect estimates on type 2 diabetes for 41,439 cases and 103,870 controls indicated a causative protective role of SHBG (OR = 0.83 per 1-SD, 95% CI: 0.76, 0.91); however, effects were considerably weaker than observed in meta-analysis of prospective studies [hazard ratio (HR) = 0.47 per 1-SD, 95% CI: 0.41, 0.53]. CONCLUSION Circulating SHBG is strongly associated with systemic metabolism and predictive for insulin resistance and diabetes. The weaker causal estimates suggest that the observational associations are partly confounded rather than conferred directly via circulating SHBG.

Purpose: Although low cardiorespiratory fitness (CRF), physical inactivity, and obesity are associated with impaired autonomic function, they are also extensively interrelated. The present study aimed to assess the extent to which they contribute to autonomic function independently of each other. Methods: At the age of 46 yr, 1383 men and 1761 women without cardiorespiratory diseases and diabetes underwent assessments of vagally mediated heart rate (HR) variability (root mean square of successive differences in R-R interval (rMMSD)), peak HR during a submaximal step test (CRF), and 60-s HR recovery (HRR). Moderate-to-vigorous physical activity (MVPA; ≥3.5 METs, 2 wk) was measured by wrist-worn accelerometer and body fat percentage (Fat%) by bioimpedance Results: In men, CRF and Fat% were significantly associated with higher rMSSD (standardized β = 0.31 and -0.16) and HRR (β = 0.19 and -0.18), whereas higher MVPA was linked with higher HRR (β = 0.13) when including CRF, MVPA, and Fat% in the initial regression. After adjustments for other lifestyle and cardiometabolic factors, CRF remained significantly associated with rMMSD (β = 0.24) and HRR (β = 0.14), as did MVPA with HRR (β = 0.11). In women, CRF was associated with rMSSD (β = 0.23) and HRR (β = 0.15), and MVPA (β = 0.17) and Fat% (β = -0.07) with HRR, when CRF, MVPA, and Fat% were adjusted for each other. After further adjustments, CRF remained a significant determinant of rMSSD (β = 0.20) and HRR (β = 0.13), as did MVPA with HRR (β = 0.15). The final models explained 23% and 21% of variation in rMSSD and HRR in men, and 10% and 12% in women, respectively. Conclusions: CRF was a more important determinant of cardiac autonomic function than MVPA and body fat. Furthermore, MVPA but not body fat was independently associated with cardiac autonomic function in both men and women.

BACKGROUND: Adolescents and adults born as small preterm infants show more pronounced risk factors of cardiovascular disease. Whether similar risks apply across all degrees of preterm birth is poorly known. METHODS: We studied the association between preterm birth and cardiovascular risk factors in 6642 16-year-old adolescents of the population-based Northern Finland Birth Cohort 1986. Of these, 79 (1.2%) were born at RESULTS: Girls born early preterm had 6.7 mm Hg (95% confidence interval: 3.1–10.2) higher systolic blood pressure (BP) and 3.5 mm Hg (1.1–5.8) higher diastolic BP, but no difference in serum lipid levels compared with control girls. Boys showed no differences in BP, but boys born early preterm had 6.7% (0.2%–13.7%) higher total cholesterol, 11.7% (2.1%–22.3%) higher low-density lipoprotein cholesterol, and 12.3% (3.1%–22.4%) higher apolipoprotein B concentrations. The differences were similar (BP) or stronger (lipids) when adjusted for maternal smoking, birth weight SD score, parental education, pubertal stage, BMI, and lifestyle. There were similar associations with length of gestation as a continuous variable. Accordingly, mean differences between late preterm and controls were in the same direction but weaker, although most were not statistically significant. CONCLUSIONS: Preterm birth was associated with elevated BP in adolescent girls and an atherogenic lipid profile in boys. Because these associations were strongest among those born early preterm, our findings are consistent with a dose-response relationship between shorter length of gestation and cardiovascular risk factors.

Are there differences in estrogen and progesterone secretion in singleton pregnancies, up to Week 11, between spontaneous pregnancies, after controlled ovarian hyperstimulation and fresh embryo transfer (COH + ET) and after frozen embryo transfer in a spontaneous cycle (FET)?Serum progesterone and estradiol (E2) concentrations after COH + ET were higher in early pregnancy, lasting up to Week 7-8, than FET and spontaneous pregnancies, while hormone levels after FET did not differ from spontaneous pregnancies.The risk of adverse perinatal outcomes after COH + ET seems to be increased when compared with spontaneous pregnancies. One of the reasons suggested for this is related to ovarian hyperstimulation.This was a prospective cohort study consisting of three different groups of pregnant women which were followed-up weekly until Week 11 of their pregnancies. The spontaneous pregnancy group consisted of 41 women, the COH + ET group consisted of 39 and the FET group consisted of 30 women.Women in the control group with spontaneous conception were recruited from local prenatal clinics. Women in the COH + ET and FET groups were recruited from the Reproductive Unit of Oulu University Hospital. At each visit, a three-dimensional ultrasonography was performed to examine the ovarian volumes and vascularization. A blood sample was drawn to analyse progesterone and E2 levels. The pregnancy outcome was included in the analysis.At pregnancy Week 5, the serum progesterone levels were higher after the COH + ET (median 312, inter-quartile range 183-480 nmol/l), when compared with the spontaneous (63, 52-80 nmol/l; P0.001) and FET (74, 48-96 nmol/l; P0.001) pregnancies. At Week 11, the P (189, 124-260 nmol/l) was still higher in the COH + ET group (FET 101, 78-120 nmol/l, P0.001; spontaneous 115, 80-139 nmol/l, P0.01) than the other two groups. The E2 levels at Week 5 were also significantly higher after COH + ET (4.1, 2.2-6.6 nmol/l) than in the spontaneous pregnancies (1.1, 0.7-1.6 nmol/l, P0.001) or after FET (0.7, 0.6-0.9 nmol/l, P0.001). The volume of the ovaries and the intraovarian vasculature in the COH + ET group were significantly higher when compared with the other two groups (P0.001). The birthweight was negatively correlated with the serum P (R -0.340, P0.01) and E2 (R= -0.275, P0.05) in pregnancy Weeks 5-8. In the multivariate analysis evaluating the factors affecting birthweight of the newborn, the significant factors were the length of gestation, maternal height and progesterone or E2 secretion during Weeks 5-8.Because of the low number of patients in this study, larger cohort studies are required to confirm the findings.The findings here indicate that COH-induced increased luteal activity should be evaluated by measuring steroid levels or the ovarian size or vascularity, rather than number of oocytes retrieved. If unphysiologically high steroid activity during pregnancy after COH contributes to the risk of adverse perinatal outcomes after fresh embryo transfer, milder stimulation protocols or even freezing of all of the embryos should be considered.This study was supported by a research grant from the Academy of Finland. The authors declare no conflicts of interest.

Do teenage girls with a history of menstrual irregularity and/or elevated androgen levels in adolescence exhibit an increased risk of polycystic ovary syndrome (PCOS) and/or infertility later on in adulthood?Our results suggest that menstrual irregularity and/or elevated androgen levels at 16 years are still associated with symptoms of PCOS at 26 years as well as infertility problems at 26 years but not with decreased pregnancy or delivery rates at 26 years.Hyperandrogenaemia is associated with menstrual irregularity, hirsutism, acne and potentially higher risk for PCOS, but there are few follow-up studies investigating whether adolescent hyperandrogenaemia and/or menstrual irregularity are an early sign of PCOS.A prospective population-based cohort study was conducted using two postal questionnaires targeting girls in the Northern Finland Birth Cohort 1986 (NFBC1986, n = 4567). The NFBC1986 comprises all expected births from the year 1986 in the two northernmost provinces of Finland. Collection of the database was performed at the age of 16 and 26. The 16-year and 26-year questionnaires included one question about the regularity and length of the menstrual cycle. The 26-year questionnaire also included questions about symptoms of PCOS, reproduction and infertility problems.The response rates for the questionnaires were 80% (n = 3669) at 16 years and 50% (n = 2270) at 26 years. At 15-16 years, of 2448 girls, 709 (29%) girls reported menstrual irregularity (symptomatic girls) and 1739 (71%) had regular periods (non-symptomatic girls). After combining data from the two questionnaires a total of 2033 girls were included in the analyses. The χ(2) and Student's t-test was used to compare reproductive outcome and prevalence of clinical hyperandrogenaemia, PCOS and infertility at 26 years between the study groups. Univariate and multivariate logistic regression models were employed to estimate the association of menstrual irregularity at 16 years with clinical hyperandrogenaemia, PCOS and infertility at 26 years.At follow-up, the proportion of symptomatic girls who had conceived at least once (68.0 versus 67.9%) and had delivered at least one child (25.7 versus 28.1%) was similar to the non-symptomatic women and the groups had similar miscarriage rates (11.6 versus 12.1%). Logistic regression analyses indicated that menstrual irregularity at 16 years was associated with an increased risk of menstrual irregularity [adjusted odds ratio (OR) 1.37, 95% confidence interval (CI) 1.00-1.88, P = 0.050], PCOS (adjusted OR 2.91, 95% CI 1.74-4.84, P0.001) and infertility problems (adjusted OR 2.07, 95% CI 1.16-3.76, P = 0.013) at 26 years. At 26 years, women with PCOS (P = 0.013), hirsutism (P = 0.001) and acne (P0.001) exhibited significantly higher values of free androgen index (FAI) at 16 years than control women. There was a significant linear trend in the higher FAI quartiles at 16 years towards higher prevalence of PCOS (P = 0.005), hirsutism (P0.001) and acne (P0.001) at 26 years. Only 10.5% of the girls with menstrual irregularity at 16 years had PCOS at 26 years.The diagnosis of menstrual irregularity was based on a self-reported questionnaire, thus introducing a risk of information bias in reporting the symptoms. Moreover, ovarian ultrasonography was not available to aid the diagnosis of PCOS and there was no clinical evaluation of hyperandrogenism. The relatively low rate of participation to the questionnaire at 26 years may also have biased the results.Our findings confirm that menstrual irregularity and/or elevated androgen levels are already present in adolescence in women with PCOS and infertility in later life, which strengthens the importance of early identification of menstrual irregularity.This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland, the Sigrid Juselius Foundation, University Hospital Oulu and University of Oulu, the European Commission and the Medical Research Council, UK, Welcome Trust (089549/Z/09/Z). None of the authors have any conflict of interest.

ObjectiveReduced sex hormone-binding globulin (SHBG) concentration predicts insulin resistance and type 2 diabetes, but its association with cardiovascular disease (CVD) risk is unclear. We examined the association between SHBG and cardiovascular risk factors, independently of total testosterone (TT), in young men.DesignObservational, cross-sectional study.SettingGeneral community.ParticipantsThe study included 2716 men aged 31 years in the Northern Finland Birth Cohort in 1996 with clinical examination data and fasting blood samples.Outcome variablesBlood pressure (BP), lipids and C-reactive protein (CRP) as biological CVD risk markers.ResultsSHBG concentration was significantly and inversely related to systolic and diastolic BP, triglycerides and CRP, but positively to HDL cholesterol after adjusting for insulin, BMI, waist circumference, smoking, education and physical activity (allPPPConclusionsIn this cohort of young adult men, higher SHBG concentration was associated with a more favourable CVD risk profile, independently of TT. SHBG concentration modified the associations of TT with CVD risk factors.

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10 -8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD. © 2013 Nature America, Inc. All rights reserved.

Objective— Low high-density lipoprotein cholesterol (HDL-C) is associated with cardiometabolic pathologies. In this study, we investigate the biological pathways and individual genes behind low HDL-C by integrating results from 3 high-throughput data sources: adipose tissue transcriptomics, HDL lipidomics, and dense marker genotypes from Finnish individuals with low or high HDL-C (n=450). Approach and Results— In the pathway analysis of genetic data, we demonstrate that genetic variants within inflammatory pathways were enriched among low HDL-C associated single-nucleotide polymorphisms, and the expression of these pathways upregulated in the adipose tissue of low HDL-C subjects. The lipidomic analysis highlighted the change in HDL particle quality toward putatively more inflammatory and less vasoprotective state in subjects with low HDL-C, as evidenced by their decreased antioxidative plasmalogen contents. We show that the focal point of these inflammatory pathways seems to be the HLA region with its low HDL-associated alleles also associating with more abundant local transcript levels in adipose tissue, increased plasma vascular cell adhesion molecule 1 (VCAM1) levels, and decreased HDL particle plasmalogen contents, markers of adipose tissue inflammation, vascular inflammation, and HDL antioxidative potential, respectively. In a population-based look-up of the inflammatory pathway single-nucleotide polymorphisms in a large Finnish cohorts (n=11 211), no association of the HLA region was detected for HDL-C as quantitative trait, but with extreme HDL-C phenotypes, implying the presence of low or high HDL genes in addition to the population-genomewide association studies–identified HDL genes. Conclusions— Our study highlights the role of inflammation with a genetic component in subjects with low HDL-C and identifies novel cis -expression quantitative trait loci ( cis -eQTL) variants in HLA region to be associated with low HDL-C.

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.

The aim of the study was to investigate the impact of de novo hypertension in pregnancy, i.e. gestational (non-proteinuric) hypertension (GH) and preeclampsia (PE), on the long-term metabolic outcome of the offspring. Data was obtained from the Northern Finland Birth Cohort 1986 (NFBC 1986), including 9,362 pregnancies and subsequent births between 1985 and 1986. Pregnancies were categorised into three groups: (1) GH with blood pressure (BP) ≥ 140/90 mmHg, (2) PE with BP ≥ 140/90 mmHg and proteinuria, and (3) reference group with normal BP. The final study population included 331 offspring of mothers with GH, 197 with PE and 5,045 offspring of normotensive mothers. The main outcome measures were systolic and diastolic blood pressure (SBP, DBP), mean arterial pressure (MAP), body mass index (BMI), and serum lipid, glucose and insulin levels of the 16 year-old offspring. The children of mothers with GH had higher BP compared to the reference group (SBP percentage difference 2.7 (95 % CI 1.6, 3.8); DBP 3.4 (2.1, 4.6); MAP 3.1 (2.0, 4.1), P

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10 -8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research. © 2013 Nature America, Inc. All rights reserved.

Context: Polycystic ovary syndrome (PCOS) is associated with increased psychological distress, obesity and hyperandrogenism being suggested as key promoters. Objectives: To investigate the prevalence of anxiety/depression and their coexistence in women with PCOS/PCOS-related symptoms at ages 31 and 46. The roles of obesity, hyperandrogenism, and awareness of PCOS on psychological distress were also assessed. Design: Population-based follow-up. Setting: Northern Finland Birth Cohort 1966 with 15-year follow-up. Participants: At age 31, a questionnaire-based screening for oligoamenorrhea (OA) and hirsutism (H): 2188 asymptomatic (controls), 331 OA, 323 H, and 125 OA plus H (PCOS). Follow-up at age 46: 1576 controls, 239 OA, 231 H, and 85 PCOS. Interventions: Questionnaire-based screening for anxiety and depression symptoms (Hopkins Symptom Checklist-25) and previously diagnosed/treated depression at ages 31 and 46. Body mass index (BMI), serum testosterone/free androgen index, and awareness of polycystic ovaries/PCOS on psychological distress were also assessed. Main Outcomes: Population-based prevalence of anxiety and/or depression in women with PCOS/PCOS-related symptoms at ages 31 and 46. Results: Anxiety and/or depression symptoms, their coexistence, and rate of depression were increased at ages 31 and 46 in women with PCOS or isolated H compared with controls. High BMI or hyperandrogenism did not associate with increased anxiety or depression symptoms. The awareness of PCOS was associated with increased anxiety. Conclusions: Women with PCOS or isolated H present more often with anxiety and/or depression symptoms and their coexistence compared with controls. High BMI or hyperandrogenism did not provoke psychological distress in PCOS. The awareness of PCOS increased anxiety but did not associate with severe anxiety or depression., We studied psychological distress in women with PCOS symptoms and found high anxiety and depression rates in women with PCOS or isolated hirsutism lasting until perimenopausal age.

OBJECTIVE: To study the association between body size from birth to adulthood and self-reported symptoms of polycystic ovary syndrome (PCOS), particularly hirsutism and menstrual disturbances. DESIGN: Longitudinal, population-based study of a cohort of women born in 1966 in northern Finland. The study population included 2007 women who were not pregnant and did not use hormonal contraception. Of these 528 (26%) had self-reported symptoms of PCOS. RESULTS: Weight at birth, gestational age, being small for gestational age or growth retardation at birth were not associated with PCOS symptoms at 31 y. An increased risk of PCOS symptoms was observed among women with abdominal obesity (waist/hip ratio >85th percentile) at 31 y who had normal weight in adolescence and were overweight (body mass index (BMI) 25.0-29.9 kg/m(2)) or obese (BMI>30.0 kg/m(2)) at 31 y (relative risk (RR) (95% CI) 1.44(1.10-1.89)), and among women with abdominal obesity who were overweight or obese at both 14 and 31 y (1.71 (1.30-2.24)). A total of 30% and 41% of the women with PCOS symptoms in these groups could be attributed, respectively, to overweight, obesity and abdominal obesity at 31 y. CONCLUSIONS: These results suggest that obesity in adolescence and in adulthood, and also weight gain after adolescence, particularly in the presence of abdominal obesity, are associated with self-reported PCOS symptoms in adulthood. Thus, based on the results from intervention studies treating PCOS and the results of this study, the prevention of obesity and abdominal obesity is important among young women.

OBJECTIVE: We compared the metabolic and cardiovascular parameters of a reference group of women with those of women who used 2 contraceptive regimes that are used worldwide: the levonorgestrel-releasing intrauterine device and oral contraceptives. STUDY DESIGN: We investigated a cohort of 2814 women at age 31 years from the general population-based Northern Finland Birth Cohort who were born in 1966. Women were classified as oral contraceptive users (n = 687 women), levonorgestrel-releasing intrauterine device users (n = 168 women), or no use of hormonal contraception (reference group; n = 1959 women). The analyses were adjusted for body mass index, current alcohol use, household income, and area of residence. RESULTS: Compared with the reference group, oral contraceptive users had higher systolic and diastolic blood pressure, raised levels of inflammatory indices (C-reactive protein), and impaired insulin sensitivity. Levonorgestrel-releasing intrauterine device users displayed a lower high-density lipoprotein and total cholesterol, but a similar cholesterol/ high-density lipoprotein ratio, and higher leukocyte count compared with the reference group. Oral contraception users were insulin-resistant compared with levonorgestrel-releasing intrauterine device users with higher blood pressure, raised lipid levels (such as total cholesterol and triglycerides) and insulin levels, and lower homeostasis model assessment and insulin sensitivity, despite smaller waist and lower waist-hip ratio. CONCLUSION: Oral contraception usage was associated with adverse findings in several metabolic, cardiovascular, and inflammatory parameters, which is consistent with an increased future risk of cardiovascular and metabolic disease. These findings should invite more criticism of recent trends that encourage the prescription of oral contraceptives for years during reproductive life and especially in premenopausal women. In contrast, levonorgestrel-releasing intrauterine device or progestin-only pills may offer long-term health benefits over oral contraceptives and should be preferred to oral contraceptives for women in their forties and/or with metabolic risk factors for cardiovascular diseases and type 2 diabetes mellitus.

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10⁻⁸): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity. © 2009 Nature America, Inc. All rights reserved.

Udgivelsesdato: 2010-Feb-1 Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 x 10(-5)], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.

OBJECTIVE Fasting plasma glucose and risk of type 2 diabetes are higher among Indian Asians than among European and North American Caucasians. Few studies have investigated genetic factors influencing glucose metabolism among Indian Asians. RESEARCH DESIGN AND METHODS We carried out genome-wide association studies for fasting glucose in 5,089 nondiabetic Indian Asians genotyped with the Illumina Hap610 BeadChip and 2,385 Indian Asians (698 with type 2 diabetes) genotyped with the Illumina 300 BeadChip. Results were compared with findings in 4,462 European Caucasians. RESULTS We identified three single nucleotide polymorphisms (SNPs) associated with glucose among Indian Asians at P < 5 × 10−8, all near melatonin receptor MTNR1B. The most closely associated was rs2166706 (combined P = 2.1 × 10−9), which is in moderate linkage disequilibrium with rs1387153 (r2 = 0.60) and rs10830963 (r2 = 0.45), both previously associated with glucose in European Caucasians. Risk allele frequency and effect sizes for rs2166706 were similar among Indian Asians and European Caucasians: frequency 46.2 versus 45.0%, respectively (P = 0.44); effect 0.05 (95% CI 0.01–0.08) versus 0.05 (0.03–0.07 mmol/l), respectively, higher glucose per allele copy (P = 0.84). SNP rs2166706 was associated with type 2 diabetes in Indian Asians (odds ratio 1.21 [95% CI 1.06–1.38] per copy of risk allele; P = 0.006). SNPs at the GCK, GCKR, and G6PC2 loci were also associated with glucose among Indian Asians. Risk allele frequencies of rs1260326 (GCKR) and rs560887 (G6PC2) were higher among Indian Asians compared with European Caucasians. CONCLUSIONS Common genetic variation near MTNR1B influences blood glucose and risk of type 2 diabetes in Indian Asians. Genetic variation at the MTNR1B, GCK, GCKR, and G6PC2 loci may contribute to abnormal glucose metabolism and related metabolic disturbances among Indian Asians.

Genome-wide association studies (GWAS) of longitudinal birth cohorts enable joint investigation of environmental and genetic influences on complex traits. We report GWAS results for nine quantitative metabolic traits (triglycerides, high-density lipoprotein, low-density lipoprotein, glucose, insulin, C-reactive protein, body mass index, and systolic and diastolic blood pressure) in the Northern Finland Birth Cohort 1966 (NFBC1966), drawn from the most genetically isolated Finnish regions. We replicate most previously reported associations for these traits and identify nine new associations, several of which highlight genes with metabolic functions: high-density lipoprotein with NR1H3 (LXRA), low-density lipoprotein with AR and FADS1-FADS2, glucose with MTNR1B, and insulin with PANK1. Two of these new associations emerged after adjustment of results for body mass index. Gene-environment interaction analyses suggested additional associations, which will require validation in larger samples. The currently identified loci, together with quantified environmental exposures, explain little of the trait variation in NFBC1966. The association observed between low-density lipoprotein and an infrequent variant in AR suggests the potential of such a cohort for identifying associations with both common, low-impact and rarer, high-impact quantitative trait loci.

OBJECTIVE Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. RESEARCH DESIGN AND METHODS We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. RESULTS We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11–31], P = 2 × 10−5, and 14 g [4–23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39–120) lighter at birth than the 8% carrying none (Ptrend = 5 × 10−7). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. CONCLUSIONS Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.

OBJECTIVE: To investigate the occurrence of oligo-amenorrhoea and hirsutism, infertility and metabolic morbidity among first-degree relatives of women with and without self-reported oligo-amenorrhoea and hirsutism. DESIGN: Nested case-control study. SETTING, POPULATION AND METHODS: A postal questionnaire about symptoms of oligo-amenorrhoea and hirsutism was sent to all women of the Northern Finland Birth Cohort 1966 (n = 5889). From this population were randomly selected 98 women with both symptoms and 163 without symptoms. A further questionnaire on the occurrence of oligo-amenorrhoea, hirsutism, infertility, early balding and metabolic morbidity in their relatives was sent to this subpopulation. MAIN FINDINGS: We obtained data on 183 relatives of 43 women with symptoms and 412 relatives of 86 symptomless women. Compared with relatives of symptomless women, mothers of women with symptoms suffered significantly more often from hirsutism and menstrual disorders, and sisters more often from hirsutism and infertility, and had fewer children and were more often childless. There was an increased prevalence of diabetes in the sisters and of hypertension in the fathers of women with symptoms. CONCLUSIONS: These results strengthen earlier findings of significantly increased metabolic and reproductive morbidity in the relatives of women with symptoms of PCOS.

AIMS/HYPOTHESIS: Common variants of the gene encoding transcription factor 7-like 2 (TCF7L2) have a powerful effect on individual risk of type 2 diabetes (per allele odds ratio approximately 1.35). Polycystic ovary syndrome (PCOS) and type 2 diabetes are familial conditions sharing common features. Based on this, the aim of the present study was to establish whether variation in TCF7L2 also influences the development of PCOS. METHODS: We conducted a genetic association study of variants of TCF7L2 (rs7903146 and rs12255372) using both case-control and quantitative trait approaches. Case-control analyses were conducted in (1) 369 PCOS cases and 2574 controls of UK British/Irish origin, and (2) 540 women with PCOS symptoms and 1083 controls from the Northern Finland Birth Cohort of 1966. Quantitative trait analyses (androgen levels) were also performed (1249 individuals). RESULTS: There was no association between rs7903146 and PCOS in the UK case-control study (Cochran-Armitage test, p = 0.51); nor with symptomatic status in the Finnish cohort (p = 0.36). In addition, there were no relationships between the TCF7L2 single nucleotide polymorphism rs7903146 and androgen levels (UK cases, p = 0.99; Finnish controls, p = 0.57; Finnish symptomatic cases, p = 0.80). Results at rs12255372 were similar, reflecting strong linkage disequilibrium with rs7903146. CONCLUSIONS/INTERPRETATION: Our study was powered to detect an effect on PCOS susceptibility similar to that previously reported for these variants on type 2 diabetes. Failure to detect any evident association with PCOS provides the strongest evidence yet that the genetic architecture of these related conditions is qualitatively distinct.

STUDY QUESTION Are self-reported menstrual disorders associated with hyperandrogenaemia and metabolic disturbances as early as in adolescence? SUMMARY ANSWER Menstrual disorders at the age 16 are a good marker of hyperandrogenaemia, and an adverse lipid profile was associated with higher androgen levels. WHAT IS KNOWN AND WHAT THIS PAPER ADDS Hyperandrogenism per se has been suggested to be a significant metabolic risk factor in women and a cause of physical and psychological morbidity in adolescent girls. A weak positive correlation has been described between hyperandrogenaemia and obesity in adolescent girls, but the clinical consequences are still poorly understood. Hyperandrogenism and insulin resistance are also key features of polycystic ovary syndrome (PCOS), and women with PCOS are consequently at an increased risk of developing type 2 diabetes mellitus and/or metabolic syndrome, and may have increased cardiovascular morbidity. Our findings confirm that the association between menstrual disorders, hyperandrogenism, obesity and metabolic risks is already evident in adolescence. STUDY DESIGN This population-based, cross-sectional study used postal questionnaires to targeting 15-16-year-old girls in the Northern Finland Birth Cohort 1986 (n= 4567). PARTICIPANTS AND SETTING There were 3669 girls who answered the postal questionnaire and out of 3373 girls who also underwent clinical examinations and blood tests, 2448 were included in the analyses. The questionnaire included one question about the regularity and length of the menstrual cycle: 'Is your menstrual cycle (the interval from the beginning of one menstrual period to the beginning of the next period) often (more than twice a year) longer than 35 days?' The girls who answered 'yes' to this question were considered to be suffering from menstrual disorders and were classified as 'symptomatic'. The girls who answered 'no' were defined as 'non-symptomatic'. MAIN RESULTS AND THE ROLE OF CHANCE There were 709 (29%) girls who reported menstrual disorders (symptomatic girls) and 1739 who had regular periods (non-symptomatic girls). In the whole population and in both study groups, there were significant correlations between body mass index (BMI) (and waist-to-hip ratio), hyperandrogenaemia and metabolic parameters. Symptomatic girls exhibited significantly higher serum concentrations of testosterone (P= 0.010), lower levels of sex hormone-binding globulin (P =0.042) and higher free androgen indices [FAIs; geometric mean 3.38 (interquartile range (IQR): 2.27, 5.18) versus 3.08 (IQR: 2.15, 4.74), P= 0.002]. The two groups had comparable BMI and insulin sensitivity, and serum levels of glucose, insulin and lipids. There was a significant linear trend towards higher FAI values in the higher BMI quartiles in both symptomatic and non-symptomatic girls. In the whole population, there was a statistically significant linear decrease in high-density lipoprotein concentrations (P < 0.001) and higher triglyceride concentrations (P =0.004) in the upper FAI quartile. IMPLICATIONS Information regarding menstrual disorders in adolescence is a good marker of hyperandrogenaemia and may be an early risk factor for the development of PCOS in adulthood. The association between obesity, hyperandrogenism and metabolic risks is already evident in adolescence, which strengthens the importance of noting menstrual disorders at an early stage. BIAS, LIMITATIONS, GENERALIZABILITY: The cross-sectional nature of the study does not allow us to draw conclusions concerning the metabolic risks of this population in later life. The diagnosis of menstrual disorders was based on a questionnaire, suggesting a risk of information bias in reporting the symptoms. This study was not designed to diagnose PCOS, as ultrasonography was not available and there was no clinical evaluation of hyperandrogenism (i.e. hirsutism). However, we were able to take into account potential confounding factors in the analyses. STUDY FUNDING/COMPETING INTERESTS This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 104781, 120315, 129269, 1114194, SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643) and the Medical Research Council, UK (PrevMetSyn/SALVE). None of the authors have any conflict of interest to declare.

STUDY QUESTIONWhat is the effect of alternative administration routes of combined contraceptives (CCs) on androgen secretion chronic inflammation glucose tolerance and lipid profile?SUMMARY ANSWERThe use of oral transdermal and vaginal CCs impairs glucose tolerance and induces chronic inflammation.WHAT IS KNOWN AND WHAT THIS PAPER ADDSOral CCs worsen insulin sensitivity and are associated with increased levels of circulating inflammatory markers whereas the metabolic effects of transdermal and vaginal CCs have been reported to be minimal. This is the first study comparing three different administration routes of CCs on metabolic variables.STUDY DESIGN SIZE AND DURATIONThis randomized (computer-generated) open-label 9-week follow-up study was conducted at the Oulu University Hospital Finland. Fasting blood samples were collected at baseline and thereafter at 5 and 9 weeks of treatment and serum levels of 17-hydroxyprogesterone androstenedione testosterone C-reactive protein (CRP) sex hormone-binding globulin (SHBG) glucose insulin C-peptide total low-density lipoprotein and high-density lipoprotein cholesterol and triglycerides were measured. Oral glucose tolerance tests were performed and plasma levels of pentraxin 3 (PTX-3) were measured at 0 and 9 weeks. The randomization list with an allocation ratio of 1:1:1 and block size of six was computer generated and constructed by a pharmacist at the Oulu University Hospital. The research nurse controlled the randomization list and assigned participants to their groups at the first visit.PARTICIPANTS AND SETTINGForty-two of 54 healthy women who entered the study used oral contraceptive pills (n = 13) transdermal contraceptive patches (n = 15) or contraceptive vaginal rings (n = 14) continuously for 9 weeks. Inclusion criteria were regular menstrual cycles at least a 2-month washout as regards hormonal contraceptives and no medication.MAIN RESULTS AND THE ROLE OF CHANCESerum levels of SHBG increased and consequently the free androgen index (FAI) decreased in all study groups from baseline to 9 weeks of treatment [FAI oral: 1.3 (95% confidence interval CI: 0.94; 1.62) to 0.40 (0.25; 0.54); transdermal: 1.2 (0.96; 1.4) to 0.36 (0.30; 0.43); vaginal: 1.6 (1.1; 2.1) to 0.43 (0.29; 0.58) P < 0.001 in all groups]. Insulin sensitivity was reduced at 9 weeks in all three groups according to the Matsuda index [oral: 7.3 (5.5; 9.0) to 5.6 (3.9; 7.3); transdermal: 9.1 (6.7; 11.4) to 6.6 (4.5; 8.8); vaginal: 7.7 (5.9; 9.5) to 5.4 (3.9; 7.0) P= 0.004-0.024]. Levels of HDL cholesterol triglycerides and CRP rose in all three groups [CRP oral: 0.70 (0.38; 1.0) to 5.4 (1.0; 9.9) mg/l; transdermal: 0.77 (0.45; 1.1) to 2.9 (1.4;4.4) mg/l; vaginal: 0.98 (0.52; 1.4) to 3.7 (-0.25; 7.7 a negative value due to skewed distribution to right) mg/l P