Elena Fernández-Durán

Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS).

CONTEXT Sexual dimorphism suggests a role for androgens in body fat distribution. Women with polycystic ovary syndrome (PCOS), a mainly androgen excess disorder, often present with abdominal obesity and visceral adiposity. OBJECTIVE We hypothesized that women with PCOS have a masculinized body fat distribution favoring the deposition of fat in visceral and organ-specific adipose tissue depots. DESIGN This was a case-control study. SETTING The study was conducted at an academic hospital. PARTICIPANTS Women with PCOS (n = 55), women without androgen excess (n = 25), and men (n = 26) presenting with similar body mass index participated in the study. INTERVENTIONS There were no interventions. MAIN OUTCOME MEASURES Ultrasound measurements of adipose tissue depots including sc (minimum and maximum), preperitoneal, ip, mesenteric, epicardial, and perirenal fat thickness were obtained and total body fat mass was estimated using a body fat monitor. RESULTS Men and patients with PCOS had increased amounts of total body fat compared with control women. Men had increased thickness of intraabdominal adipose tissue depots compared with the control women, with the women with PCOS showing intermediate values that were also higher than those of control women in the case of ip and mesenteric fat thickness and was close to reaching statistical significance in the case of epicardial fat thickness. Women with PCOS also showed increased minimum sc fat thickness compared with the control women. Obesity increased the thickness of all of the adipose tissue depots in the 3 groups of subjects. CONCLUSIONS Women with PCOS have higher global adiposity and increased amounts of visceral adipose tissue compared with control women, especially in the ip and mesenteric depots.

Effects of Polycystic Ovary Syndrome (PCOS), Sex Hormones, and Obesity on Circulating miRNA-21, miRNA-27b, miRNA-103, and miRNA-155 Expression

CONTEXT MicroRNAs (miRNAs) are small, noncoding RNA sequences that negatively regulate gene expression at the post-transcriptional level. miRNA-21, miRNA-27b, miRNA-103, and miRNA-155 have been associated with metabolic disorders such as obesity and diabetes, which are also associated with polycystic ovary syndrome (PCOS). OBJECTIVE We aimed to evaluate the effects of sex, sex hormones, and PCOS and their interactions with obesity on the expression in the circulation of these miRNAs. DESIGN This was a case-control study. SETTINGS The setting was an academic hospital. PARTICIPANTS We included 12 control women, 12 patients with PCOS, and 12 men selected as to have similar body mass index (BMI) and age. Six subjects per group had normal weight (BMI < 25 kg/m(2)), and six subjects per group were obese (BMI ≥ 30 kg/m(2)). INTERVENTIONS Blood samples were collected early in the morning after a 12-hour fast. MAIN OUTCOME MEASURES We measured whole blood expression of miRNA-21, miRNA-27b, miRNA-103, and miRNA-155. RESULTS Obesity significantly reduced the expression of miRNA-21, miRNA-27b, and miRNA-103. However, there was a significant interaction between obesity and the group of subjects in the expression of miRNA-21, miRNA-27b, miRNA-103, and miRNA-155 consisting of obesity reducing the expression of these miRNAs in control woman and men, but tending to increase their expression in women with PCOS. These differences paralleled those observed in serum T concentrations. CONCLUSIONS The present results suggest that miRNAs that play an important role in metabolic and immune system processes are influenced by obesity and circulating androgen concentrations.

Evidence for masculinization of adipokine gene expression in visceral and subcutaneous adipose tissue of obese women with polycystic ovary syndrome (PCOS).

CONTEXT Sex hormones, particularly androgens, may influence not only adipose tissue distribution but also its functions. OBJECTIVE We explored the possibility of sexual dimorphism in adipose tissue and skeletal muscle function. DESIGN This was a case-control study. SETTING The setting was an academic hospital. PARTICIPANTS Participants were severely obese men (n = 7), control women (n = 7), and hyperandrogenic women presenting with polycystic ovary syndrome (PCOS) (n = 7) submitting to bariatric surgery and an independent series of 40 patients with PCOS and 40 control women matched for age and body mass index. INTERVENTIONS Samples of subcutaneous (SAT) and visceral adipose tissue (VAT) and skeletal muscle were obtained during bariatric surgery in severely obese subjects. MAIN OUTCOME MEASURES Gene expression of chemerin, lipocalin-2, and omentin-1 in tissue samples was measured. We analyzed the effects of PCOS and obesity on serum concentrations of these adipokines in the larger series of women with PCOS and in control women. RESULTS Expression of chemerin and lipocalin-2 was higher in VAT than in SAT in men and women with PCOS; the opposite was observed in control women. Omentin-1 expression was higher in VAT than in SAT in the three groups. No differences were observed in the skeletal muscle expression of these adipokines. Obesity increased serum chemerin and lipocalin-2 levels and tended to decrease omentin-1, irrespective of PCOS. CONCLUSIONS The present results suggest that there is sexual dimorphism in some adipose tissue functions and that this dimorphism may be related to differences in androgen concentrations because women with PCOS show a masculinized pattern of expression of some adipokines.

Surrogate Markers of Visceral Adiposity in Young Adults: Waist Circumference and Body Mass Index Are More Accurate than Waist Hip Ratio, Model of Adipose Distribution and Visceral Adiposity Index

Surrogate indexes of visceral adiposity, a major risk factor for metabolic and cardiovascular disorders, are routinely used in clinical practice because objective measurements of visceral adiposity are expensive, may involve exposure to radiation, and their availability is limited. We compared several surrogate indexes of visceral adiposity with ultrasound assessment of subcutaneous and visceral adipose tissue depots in 99 young Caucasian adults, including 20 women without androgen excess, 53 women with polycystic ovary syndrome, and 26 men. Obesity was present in 7, 21, and 7 subjects, respectively. We obtained body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), model of adipose distribution (MOAD), visceral adiposity index (VAI), and ultrasound measurements of subcutaneous and visceral adipose tissue depots and hepatic steatosis. WC and BMI showed the strongest correlations with ultrasound measurements of visceral adiposity. Only WHR correlated with sex hormones. Linear stepwise regression models including VAI were only slightly stronger than models including BMI or WC in explaining the variability in the insulin sensitivity index (yet BMI and WC had higher individual standardized coefficients of regression), and these models were superior to those including WHR and MOAD. WC showed 0.94 (95% confidence interval 0.88–0.99) and BMI showed 0.91 (0.85–0.98) probability of identifying the presence of hepatic steatosis according to receiver operating characteristic curve analysis. In conclusion, WC and BMI not only the simplest to obtain, but are also the most accurate surrogate markers of visceral adiposity in young adults, and are good indicators of insulin resistance and powerful predictors of the presence of hepatic steatosis.

Sexual dimorphism in adipose tissue function as evidenced by circulating adipokine concentrations in the fasting state and after an oral glucose challenge

STUDY QUESTION Do the circulating levels of a panel of adipokines involved in glucose metabolism exhibit sexual dimorphism in the fasting state and after an oral glucose load? SUMMARY ANSWER Our results indicate sexual dimorphism in the circulating concentrations of adipokines involved in intermediate metabolism in the fasting state and during an oral glucose load. This finding suggests an influence of sex steroids on adipose tissue function. WHAT IS KNOWN ALREADY Sexual dimorphism in adipose tissue distribution fully develops after puberty and modulates the risk for cardiometabolic disorders. However, the possibility that adipose tissue function exhibits sexual dimorphism as well as its distribution is unproved. STUDY DESIGN, SIZE, DURATION Cross-sectional case-control study including 32 subjects. PARTICIPANTS/MATERIALS, SETTING, METHODS Sixteen subjects with weight excess (8 men and 8 women, including 4 overweight and 4 obese subjects in each group) and 16 normal weight healthy volunteers (8 men and 8 women) presenting with similar age were submitted to a 75-g oral glucose tolerance test (oGTT). We measured circulating concentrations of insulin, glucose, chemerin, lipocalin-2, omentin-1, leptin and adiponectin and calculated their areas under the oGTT curve (AUC). MAIN RESULTS AND THE ROLE OF CHANCE Leptin and adiponectin concentrations were higher throughout the oGTT in women compared with men. Lipocalin-2 concentrations decreased during the oGTT in the whole group of study subjects. However, these levels remained higher in men with weight excess compared with normal weight men, whereas in women with weight excess lipocalin-2 levels at the end of the oGTT were lower compared with normal weight women. Sex was among the main determinants of the AUC of omentin-1 and leptin in linear regression models, and lower estradiol and testosterone concentrations were related to higher AUC of chemerin and omentin-1, respectively. Subjects with weight excess had higher AUC of chemerin and leptin and lower AUC of omentin-1 and adiponectin levels, independently of sex. LIMITATIONS, REASONS FOR CAUTION We included a relatively small sample size and, because this was a cross-sectional study, we cannot infer causality to the associations between the changes in circulating adipokine concentrations and the variables studied here. WIDER IMPLICATIONS OF THE FINDINGS Sexual dimorphism in adipose tissue function should be considered when studying adiposity and obesity, and also when designing strategies for their diagnosis and management.

Office Blood Pressure, Ambulatory Blood Pressure Monitoring, and Echocardiographic Abnormalities in Women With Polycystic Ovary Syndrome: Role of Obesity and Androgen Excess

Whether or not blood pressure (BP) and heart function of women with polycystic ovary syndrome (PCOS) are altered remains unclear, albeit subtle abnormalities in the regulation of BP observed in these women might suggest a mild masculinization of their cardiovascular system. To study the influence of obesity and androgen excess on BP and echocardiographic profiles of women with the syndrome, we conducted a cross-sectional case–control study comparing office and ambulatory BP monitoring, as well as echocardiographic assessments, in 63 premenopausal women with the classic phenotype, 33 nonhyperandrogenic women with regular menses, and 25 young men. Forty-nine subjects were lean and 72 had weight excess (body mass index ≥25 kg/m2). Participants had no previous history of hypertension and were nonsmokers. Men showed the highest BP readings, and the lowest readings were observed in control women, whereas women with PCOS had intermediate values. Undiagnosed hypertension was more common in subjects with weight excess irrespective of sex and hyperandrogenism. Women with PCOS and weight excess showed frequencies of previously undiagnosed hypertension that were similar to those of men with weight excess and higher than those observed in nonhyperandrogenic women. Lastly, male sex, weight excess and hypertension, the latter in men as well as in women with PCOS, increased left ventricular wall thickness. In summary, our results show that patients with classic PCOS and weight excess frequently have undiagnosed BP abnormalities, leading to target organ damage.

Referral bias in female functional hyperandrogenism and polycystic ovary syndrome

OBJECTIVE Women with polycystic ovary syndrome (PCOS) seeking health care in the United States may be more obese and hyperandrogenic than those present in the general population. We aimed to assess the impact of referral bias on European women with functional androgen excess disorders. DESIGN Cross-sectional study. METHODS We studied two groups of patients: i) 368 consecutive patients referred to our clinic for the study of functional hyperandrogenism (FH) (referral patients); ii) 57 consecutive premenopausal patients identified by screening during blood donation (unselected patients). We compared the anthropometric data from the groups of patients with those of two control populations: iii) a group of unselected premenopausal healthy female blood donors (unselected controls); and iv) data available from the local general premenopausal female population. RESULTS Referral patients with FH were more hirsute, had a higher percentage of hyperandrogenemia, and fulfilled PCOS criteria more frequently than unselected patients. The prevalence of obesity in unselected controls was similar to that observed in the general population, whereas referral patients and unselected patients were more frequently obese. The prevalence of obesity was also higher among referral patients compared to unselected patients. CONCLUSION Referral bias influences the phenotype of patients with FH. Patients studied at the clinical setting may show more severe hyperandrogenic and obese phenotypes than patients from the general population, even though PCOS appears to be associated with weight excess also in the general European population. This fact should be considered when establishing reference values and control populations for clinical and research purposes.

Combined oral contraceptives plus spironolactone compared with metformin in women with polycystic ovary syndrome: a one-year randomized clinical trial.

OBJECTIVE We aimed to compare a combined oral contraceptive (COC) plus the antiandrogen spironolactone with the insulin sensitizer metformin in women with polycystic ovary syndrome (PCOS). DESIGN We conducted a randomized, parallel, open-label, clinical trial comparing COC (30 μg of ethinylestradiol and 150 μg of desogestrel) plus spironolactone (100 mg/day) with metformin (850 mg b.i.d.) for one year in women with PCOS (EudraCT2008-004531-38). METHODS The composite primary outcome included efficacy (amelioration of hirsutism, androgen excess and menstrual dysfunction) and cardiometabolic safety (changes in the frequencies of disorders of glucose tolerance, dyslipidemia and hypertension). A complete anthropometric, biochemical, hormonal and metabolic evaluation was conducted every three months and data were submitted to intention-to-treat analyses. RESULTS Twenty-four patients were assigned to COC plus spironolactone and 22 patients to metformin. Compared with metformin, COC plus spironolactone caused larger decreases in hirsutism score (mean difference 4.6 points, 95% CI: 2.6-6.7), total testosterone (1.1 nmol/L, 0.4-1.7), free testosterone (25 pmol/L, 12-39), androstenedione (5.5 nmol/L, 1.8-9.2) and dehydroepiandrosterone sulfate (2.7 μmol/L, 1.4-4.0). Menstrual dysfunction was less frequent with COC plus spironolactone (OR: 0.06, 95% CI: 0.02-0.23). No differences were found in frequencies of abnormal glucose tolerance (OR: 1.7, 95% CI: 0.7-4.4), dyslipidemia (OR: 0.6, 95% CI: 0.2-1.8) or hypertension (OR: 0.3, 95% CI: 0.5-2.0). No major adverse events occurred and biochemical markers were similarly safe with both treatments. CONCLUSIONS COC plus spironolactone was more effective than metformin for symptoms of PCOS showing similar safety and overall neutral effects on cardiometabolic risk factors.

Androgens and polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a mainly hyperandrogenic disorder and is possibly the most frequent endocrinopathy in premenopausal women. Androgen excess is the primary defect in PCOS, because ovarian theca cells secrete increased amounts of androgens even after several passes in primary culture. Excessive androgen amounts might favor the visceral deposition of body fat in affected women, resulting in insulin resistance, compensatory hyperinsulinism and further androgen excess. This vicious circle starts early during life in women with PCOS, even during fetal development, manifests clinically during puberty and does not end after menopause. All the steps in the vicious circle contribute to the association of PCOS with metabolic dysfunction and cardiovascular risk factors. Fortunately, most, if not all, of the therapeutic strategies currently in use for the management of PCOS, including lifestyle modification and diet, oral contraceptives, antiandrogens and insulin sensitizers, may ameliorate androgen excess and its long-term consequences.

Non-targeted profiling of circulating microRNAs in women with polycystic ovary syndrome (PCOS): effects of obesity and sex hormones

PURPOSE Circulating micro-ribonucleic acids (miRNAs) are small noncoding RNA molecules that influence gene transcription. We conducted the present profiling study to characterize the expression of circulating miRNAs in lean and obese patients with polycystic ovary syndrome (PCOS), the most common endocrine and metabolic disorder in premenopausal women. BASIC PROCEDURES We selected 11 control women, 12 patients with PCOS and 12 men so that they were similar in terms of body mass index. Five control women, 6 men and 6 patients with PCOS had normal weight whereas 6 subjects per group were obese. We used miRCURY LNA™ Universal RT microRNA PCR for miRNA profiling. MAIN FINDINGS The expression of 38 miRNAs and was different between subjects with PCOS and male and female controls. The differences in 15 miRNAs followed a pattern suggestive of androgenization characterized by expression levels that were similar in patients with PCOS and men but were different compared with those of control women. The expression of 13 miRNAs in women with PCOS was similar to that of control women and different compared with the expression observed in men, suggesting sexual dimorphism and, lastly, we observed 5 miRNAs that were expressed differently in women with PCOS compared with both men and control women, suggesting a specific abnormality in expression associated with the syndrome. Obesity interacted with the differences in several of these miRNAs, and the expression levels of many of them correlated with the hirsutism score, sex hormones and/or indexes of obesity, adiposity and metabolic dysfunction. PRINCIPAL CONCLUSIONS The present results suggest that several serum miRNAs are influenced by PCOS, sex hormones and obesity. Our findings may guide the targeted search of miRNAs as clinically relevant markers for PCOS and its association with obesity and metabolic dysfunction in future studies.