Testosterone is associated with insulin resistance index independently of adiposity in women with polycystic ovary syndrome.

OBJECTIVE: To study the associations between androgens, glucose homeostasis, inflammation and statin treatment in women with polycystic ovary syndrome (PCOS). DESIGN AND METHODS: Oral glucose tolerance tests, androgens, hs-CRP and interleukin-1 receptor antagonist (IL-1Ra) were analyzed at baseline and after 6 months of atorvastatin (20 mg/d) or placebo treatment in 27 women with PCOS. RESULTS: Testosterone associated with insulin resistance measured with ISIMatsuda independently of BMI, age and SHBG concentrations and the full model, including IL-1Ra, hs-CRP and HDL-C, also showed independency of BMI and waist circumference (p ≤ .042). Free androgen index (FAI) associated with ISIMatsuda independently of adiposity (p ≤ .025) but in the full model with waist circumference the association was insignificant. ISIMatsuda decreased with testosterone >1.2 nmol/l compared with lower levels at baseline (p = .043) and at six months (p = .003). Accordingly, 30-minute insulin levels were increased with moderately elevated testosterone independently of adiposity (p ≤ .046). Increased fasting glucose and AUC insulin associated with statin treatment independently of adiposity and the associations attenuated after adjusting for testosterone. CONCLUSIONS: Moderately elevated testosterone concentrations together with obesity-related inflammatory factors modify glucose homeostasis by increasing insulin resistance and early insulin secretion.

The prevalence of Type 2 diabetes is not increased in normal-weight women with PCOS.

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.

Bone markers in polycystic ovary syndrome: A multicentre study.

OBJECTIVE: Hyperandrogenism, hyperinsulinaemia and obesity, known characteristics of polycystic ovary syndrome (PCOS), may influence bone mineral density and biochemical markers of bone turnover (BTMs) can provide a noninvasive assessment of bone turnover. To this end, the serum concentrations of BTMs and 25-hydroxyvitamin D (25OHD) were analysed in women with PCOS, and their possible associations with metabolic parameters of PCOS were determined. SUBJECTS AND METHODS: Bone formation markers procollagen type I amino-terminal propeptide (PINP) and osteocalcin (OC), and bone resorption marker carboxy-terminal cross-linking telopeptide of type I collagen (CTX), along with 25OHD, were measured in 298 women with PCOS and 194 healthy controls. RESULTS: Serum levels of PINP (47.0 ± 20.2 vs 58.1 ± 28.6 µg/L, P < .001) and OC (18.2 ± 7.5 vs 20.6 ± 9.8 µg/L, P < .001) were decreased in women with PCOS compared with controls, whereas no significant differences were found in CTX and 25OHD levels. Age-stratified analyses suggested that PINP (50.5 ± 21.7 vs 68.2 ± 26.6 µg/L, P < .001) and OC levels (20.4 ± 7.6 vs 25.5 ± 9.6 µg/L, P < .001) were decreased only in the younger age group (≤30 years) women with PCOS compared with controls. The formation markers and resorption marker decreased with age in both study groups. CONCLUSIONS: Bone formation markers were decreased in younger women with PCOS when compared with healthy women, which may affect bone mass in these women.

Racial and ethnic differences in the prevalence of metabolic syndrome and its components of metabolic syndrome in women with polycystic ovary syndrome: a regional cross-sectional study.

BACKGROUND: Polycystic ovary syndrome is a heterogeneous disorder and its presentation varies with race and ethnicity. Reproductive-age women with polycystic ovary syndrome are at increased risk of metabolic syndrome; however, it is not clear if prevalence of metabolic syndrome and clustering of its components differs based on race and ethnicity. Moreover, the majority of these women do not undergo routine screening for metabolic syndrome. OBJECTIVE: We sought to compare the prevalence of metabolic syndrome and clustering of its components in women with polycystic ovary syndrome in the United States with women in India, Brazil, Finland, and Norway. STUDY DESIGN: This is a cross-sectional study performed in 1089 women with polycystic ovary syndrome from 1999 through 2016 in 5 outpatient clinics in the United States, India, Brazil, Finland, and Norway. Polycystic ovary syndrome was defined by the Rotterdam criteria. Main outcome measures were: metabolic syndrome prevalence, blood pressure, body mass index, fasting high-density lipoprotein cholesterol, fasting triglycerides, and fasting glucose. Data from all sites were reevaluated for appropriate application of diagnostic criteria for polycystic ovary syndrome, identification of polycystic ovary syndrome phenotype, and complete metabolic workup. The US White women with polycystic ovary syndrome were used as the referent group. Logistic regression models were used to evaluate associations between race and metabolic syndrome prevalence and its components and to adjust for potential confounders, including age and body mass index. RESULTS: The median age of the entire cohort was 28 years. Women from India had the highest mean Ferriman-Gallwey score for clinical hyperandrogenism (15.6 ± 6.5, P < .001). The age-adjusted odds ratio for metabolic syndrome was highest in US Black women at 4.52 (95% confidence interval, 2.46-8.35) compared with US White women. When adjusted for age and body mass index, the prevalence was similar in the 2 groups. Significantly more Black women met body mass index and blood pressure criteria (P < .001), and fewer met fasting triglycerides criteria (P < .05). The age- and body mass index-adjusted prevalence of metabolic syndrome was highest in Indian women (odds ratio, 6.53; 95% confidence interval, 3.47-12.30) with abnormalities in glucose and fasting high-density lipoprotein cholesterol criterion and in Norwegian women (odds ratio, 2.16; 95% confidence interval, 1.17-3.98) with abnormalities in blood pressure, glucose, and fasting high-density lipoprotein cholesterol criterion. The Brazilian and Finnish cohorts had similar prevalence of metabolic syndrome and its components compared to US White women. CONCLUSION: Despite a unifying diagnosis of polycystic ovary syndrome, there are significant differences in the prevalence of metabolic syndrome and clustering of its components based on race and ethnicity, which may reflect contributions from both racial and environmental factors. Our findings indicate the prevalence of metabolic syndrome components varies in women with polycystic ovary syndrome, such that compared to White women from the United States, Black US women had the highest prevalence, whereas women from India and Norway had a higher prevalence of metabolic syndrome independent of obesity. The differences in clustering of components of metabolic syndrome based on ethnicity highlight the need to routinely perform complete metabolic screening to identify specific targets for cardiovascular risk reduction strategies in these reproductive-age women.

Normo- and hyperandrogenic women with polycystic ovary syndrome exhibit an adverse metabolic profile through life.

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: <30, 30-39, and >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.

Should we individualize lipid profiling in women with polycystic ovary syndrome?

STUDY QUESTION: Is it necessary to monitor lipid profiles in all young women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Lipid profiling is required when women with PCOS develop type 2 diabetes (T2D) or hypertension, but rarely changes clinical care before the age of 35 years. WHAT IS KNOWN ALREADY: PCOS consensus statements and guidelines recommend that women with PCOS should be screened for dyslipidaemia every second year or annually. STUDY DESIGN, SIZE, DURATION: Women from Denmark, Norway, Finland and Sweden, who had participated in research projects or clinical trials or in whom lipid profiles had been determined routinely as part of clinical care since 2000 were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: One thousand three hundred and twenty-seven women with PCOS (Rotterdam criteria) were included. Based on individual cardiovascular risk score and lipid levels, treatment level was guided by the European Society of Cardiology and the European Atherosclerosis Society Task Force for the management of dyslipidaemias. Change in clinical care was defined as need to (i) immediately start statin treatment or (ii) consider statin treatment if life-style intervention fails. MAIN RESULTS AND THE ROLE OF CHANCE: All in all, 74 (5.6%) women with PCOS should immediately start statin treatment, and statin treatment should be considered in 33 women (2.5%). Among women with T2D, 27/28 (96.4%) should initiate statin treatment and the corresponding number for women with hypertension was 42/57 (73.7%). In PCOS women who had not yet developed T2D or hypertension, lipid profiling only changed clinical care in 28 (2.3%). This number was further reduced to 12 (1.2%) in women below the age of 35 years, and to zero in normal-weight women below the age of 35 years. LIMITATIONS, REASONS FOR CAUTION: Findings can only be generalized to countries with low cardiovascular mortality rates. WIDER IMPLICATIONS OF THE FINDINGS: Lipid profiling is required when women with PCOS develop T2D or hypertension. However, lipid profiling rarely changes the clinical care of low risk PCOS patients before the age of 35, especially in the normal-weight women. STUDY FUNDING/COMPETING INTERESTS: The Academy of Finland, Sigrid Juselius Foundation and the Nordic Federation of Obstetrics and Gynecology. There are no conflicts of interest to be declared.

IL-1 receptor antagonist levels are associated with glucose tolerance in polycystic ovary syndrome.

OBJECTIVE: To investigate serum interleukin-1 receptor antagonist (IL-1Ra) levels in women with polycystic ovary syndrome (PCOS). SUBJECTS AND METHODS: Serum IL-1Ra levels were measured at baseline in 73 women with PCOS and 45 control subjects (18-47 years), and in 27 women with PCOS who underwent oral and intravenous glucose tolerance tests (OGTTs and IVGTTs). RESULTS: IL-1Ra concentrations predicted OGTT 2-h glucose levels independently of BMI and insulin resistance (P ≤ 0·001) in women with PCOS. Serum IL-1Ra concentration was elevated in women with PCOS compared with controls [mean (SD): 309·5 (208·8) vs 199·1 (81·4) ng/l, P < 0·001], but the difference disappeared after adjusting for BMI. An increment of five BMI units raised IL-1Ra levels by 108·5 ng/l [95% confidence interval (CI): 85·5-131·5, r(2) = 0·603] in women with PCOS and only by 77·0 ng/l (95% CI: 50·5-103·5, r(2) = 0·512) in controls when adjusted for BMI and age. Levels of IL-1Ra in obese women with PCOS reflected decreasing OGTT-derived insulinogenic index (P = 0·032) and disposition index (P = 0·046) independently of BMI. Increased levels of IL-1Ra correlated with indices showing increasing insulin resistance and AUC insulin (P ≤ 0·002). CONCLUSIONS: Increased IL-1Ra levels in women with PCOS were largely explained by increasing adiposity. However, serum IL-1Ra concentrations predicted 2-h glucose levels independently of BMI suggesting that increased IL-1Ra may be associated with disturbed glucose metabolism.

Androgen Profile Through Life in Women With Polycystic Ovary Syndrome: A Nordic Multicenter Collaboration Study.

CONTEXT: Women with polycystic ovary syndrome (PCOS) have increased androgen secretion throughout fertile life; however, the data on the effect of menopause on hyperandrogenemia in these women are scarce. Nevertheless, large comprehensive comparative studies on age-related androgen levels in women with PCOS are lacking. OBJECTIVE: The objective of the study was to investigate the effect of age on serum androgen levels in women with PCOS and to determine cutoff values for androgens and SHBG associated with a PCOS diagnosis. DESIGN: This was a case-control study. SETTING: The study was conducted in five university sites in the Nordic countries. PATIENTS: In all, 681 women with PCOS and 230 referent women were grouped according to age into seven age groups (18 to > 50 y). INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: T, SHBG, free androgen index (FAI), calculated free T (cFT), androstenedione (A4), and dehydroepiandrosterone sulfate were measured. RESULTS: Androgen levels in women with PCOS decreased with age toward menopause. The difference between women with PCOS and the referent women narrowed and individual variation increased as they approached menopause. T levels, FAI, and cFT were significantly higher in women with PCOS aged 18-44 years (P < .001, adjusted for body mass index). The best predictive factors for having PCOS were cFT (≥0.40 ng/dL, odds ratio [OR] 7.90), FAI (≥2.0, OR 6.71), and A4 (≥277.94 ng/dL, OR 6.16). CONCLUSIONS: Women with PCOS had elevated serum androgen levels also after menopause. The parameters that best predicted PCOS at all ages were cFT, A4, and FAI.

The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity.

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 4ß-hydroxycholesterol to cholesterol ratio (4ßHC : C). METHODS: In this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20 mg day(-1) (n = 15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4ßHC : C index. The respective 25-hydroxycholesterol and 5α,6α-epoxycholesterol ratios were used as negative controls. RESULTS: Treatment with atorvastatin decreased 4ßHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4ßHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference -0.0595, -0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4ßHC : C between study arms was statistically significant (atorvastatin -0.032, placebo 0.0055, P = 0.020, 95% CI of the difference -0.069, -0.0067). The ratios of 25-hydroxycholesterol and 5α,6α-epoxycholesterol to cholesterol did not change. CONCLUSIONS: The results establish atorvastatin as an inhibitor of CYP3A4 activity. Furthermore, 4ßHC : C is a useful index of CYP3A4 activity, including the conditions with altered cholesterol concentrations.

Statin therapy worsens insulin sensitivity in women with polycystic ovary syndrome (PCOS): a prospective, randomized, double-blind, placebo-controlled study.

CONTEXT: Statins have been shown to improve hyperandrogenism in women with polycystic ovary syndrome (PCOS). However, their use has also been associated with impairment of glucose metabolism and an increased risk of type 2 diabetes mellitus. Because women with PCOS are prone to disturbances in glucose metabolism, statin therapy could also have negative effects. OBJECTIVE: Our objective was to explore the effects of atorvastatin therapy on hormonal and metabolic parameters in women with PCOS. DESIGN AND SETTING: We conducted a randomized, double-blind, placebo-controlled 6-month follow-up study conducted at Oulu University Hospital, Finland. PATIENTS: Women with PCOS (Rotterdam criteria) were treated with atorvastatin (20 mg/d, n = 15) or placebo (n = 13) for 6 months. INTERVENTIONS: Fasting serum samples were collected at baseline and at 3 and 6 months. Oral and iv glucose tolerance tests were performed at 0 and 6 months. MAIN OUTCOME MEASURES: Androgen secretion and glucose metabolism were measured. RESULTS: Fasting levels and area under the curve of insulin increased significantly and insulin sensitivity (insulinogenic and Matsuda indexes) decreased during 6 months of atorvastatin therapy. Serum levels of dehydroepiandrosterone sulfate decreased in the atorvastatin group, whereas no change was observed in serum testosterone levels. Levels of C-reactive protein, total and low-density lipoprotein-cholesterol, and triglycerides decreased significantly during statin therapy. CONCLUSIONS: Atorvastatin therapy improves chronic inflammation and lipid profile, but it impairs insulin sensitivity in women with PCOS. Because women with PCOS have an increased risk of developing type 2 diabetes mellitus, the results suggest that statin therapy should be initiated on the basis of generally accepted criteria and individual risk assessment of cardiovascular disease, and not only because of PCOS.

Antimüllerian hormone levels decrease in women using combined contraception independently of administration route.

OBJECTIVE: To compare the effects of continuous use of oral (OC), transdermal, and vaginal combined contraceptives on the pituitary-ovarian axis and inhibition of follicular development. DESIGN: Spin-off study of a prospective, randomized trial. SETTING: University clinic. PATIENT(S): Forty-two of 54 healthy women completed the study. INTERVENTION(S): Treatment with combined OCs (ethinyl E2 [EE] and desogestrel), transdermal patches (EE and norelgestromin), or vaginal rings (EE and etonogestrel) for 9 weeks continuously. Blood sampling was performed before and at 5 and 9 weeks of treatment. MAIN OUTCOME MEASURE(S): Changes in serum hormone levels induced by combined contraceptives. RESULT(S): Serum antimüllerian hormone (AMH), FSH, inhibin B, LH, and E2 levels had decreased significantly in all study groups after 9 weeks of treatment. Significant declines were already detected after 5 weeks' use of combined contraceptives with regard to all hormone levels apart from those of serum AMH, where the decrease between baseline and 5 weeks was only moderate. Between groups, serum levels of AMH, inhibin B, LH, and E2 were comparable at baseline and after 5 and 9 weeks of treatment. CONCLUSION(S): The decrease of serum AMH levels during the use of all combined contraceptives indicates that folliculogenesis is arrested independently of administration route. CLINICAL TRIAL REGISTRATION NUMBER: NCT01087879.

Unfavorable hormonal, metabolic, and inflammatory alterations persist after menopause in women with PCOS.

CONTEXT: Women with polycystic ovary syndrome (PCOS) are known to suffer from hyperandrogenism and impaired glucose tolerance, as well as chronic inflammation, exposing them to an increased risk of cardiovascular diseases. However, the degree to which these hormonal and metabolic alterations persist after menopause (MP) is not well documented. OBJECTIVE: Our objective was to explore whether adverse metabolic and hormonal alterations persist after MP in women with PCOS. DESIGN: We conducted a cross-sectional university hospital-based study. PATIENTS AND INTERVENTIONS: Twenty-one pre-MP (n = 10) and post-MP (n = 11) women diagnosed with PCOS were compared with 29 healthy controls (pre-MP, n = 11; post-MP, n = 18). Two-hour oral glucose tolerance tests were performed, and ovarian steroid secretion capacity was assessed (human chorionic gonadotropin tests). Areas under the curves (AUC) were calculated. RESULTS: Both pre-MP and post-MP women with PCOS had increased insulin response in oral glucose tolerance tests (AUC(ins) pre-MP = 6733.7 vs. 3382.9; post-MP = 9732.1 vs. 3265.3) and were more insulin resistant than controls. Androgen secretion capacity was increased before and after MP in PCOS (AUC of androstenedione; pre-MP: 1218.4 vs. 853.2; post-MP: 1000.0 vs. 531.3). High-sensitivity C-reactive protein remained elevated after MP in PCOS (pre-MP: 1.3 vs. 0.7; post-MP: 1.4 vs. 0.9 mg/liter). Adjustment for body mass index did not alter the results except for glucose metabolism. CONCLUSIONS: The results indicate that impaired glucose metabolism, enhanced ovarian androgen secretion, and chronic inflammation observed in pre-MP women with PCOS persist after menopausal transition emphasizing life-long health risks related to this syndrome.

Adrenal androgen production capacity remains high up to menopause in women with polycystic ovary syndrome.

INTRODUCTION: Hyperandrogenism is one of the main features of polycystic ovary syndrome (PCOS). Of circulating androgens, 50% of androstenedione and testosterone are of ovarian and adrenal origin, whereas dehydroepiandrosterone (DHEA) and DHEA sulfate are almost uniquely of adrenal origin. Our previous studies have indicated that ovarian androgen production capacity is enhanced in women with PCOS, and it remains high until late reproductive age. To study whether this also applies to adrenal androgen production, ACTH tests were performed in healthy women and in women with PCOS. MATERIALS: Sixty-nine healthy women (aged 19-62 yr; body mass index 19.2-35.0 kg/m2) and 58 women with previously diagnosed PCOS (aged 18-59 yr; body mass index 19.0-42.9 kg/m2) participated in the study. METHODS: The subjects underwent ACTH stimulation tests, and serum cortisol, 17-hydroxyprogesterone, androstenedione, testosterone, DHEA, and DHEA sulfate levels were analyzed at 0, 30, and 60 min. RESULTS: Basal and ACTH-stimulated levels of most adrenal androgens decreased in healthy women with age, whereas in women with PCOS, only the concentrations of basal serum 17-hydroxyprogesterone decreased, and all areas under the curve (AUCs) remained unchanged and significantly higher (except for DHEA) than those in control women. Likewise, at the menopausal transition, pre- and postmenopausal women with PCOS exhibited mainly unchanged and higher basal androgen and AUC levels. CONCLUSIONS: Similarly to ovarian endocrine function, serum adrenal steroid levels and adrenal steroid production capacity remain enhanced at least up to menopause in women with PCOS.