Macarena Alpañés

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.

Prevalence of functional disorders of androgen excess in unselected premenopausal women: a study in blood donors

BACKGROUND The polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. On the contrary, the prevalences of other disorders of androgen excess such as idiopathic hyperandrogenism and idiopathic hirsutism remain unknown. We aimed to obtain an unbiased estimate of the prevalence in premenopausal women of (i) signs of androgen excess and (ii) PCOS, idiopathic hyperandrogenism and idiopathic hirsutism. METHODS A multicenter prevalence survey included 592 consecutive premenopausal women (393 from Madrid, Spain and 199 from Bologna, Italy) reporting spontaneously for blood donation. Immediately before donation, we conducted clinical and biochemical phenotyping for androgen excess disorders. We determined the prevalence of (i) hirsutism, acne and alopecia as clinical signs of androgen excess and (ii) functional disorders of androgen excess, including PCOS, defined by the National Institute of Child Health and Human Development/National Institute of Health criteria, idiopathic hyperandrogenism and idiopathic hirsutism. RESULTS Regarding clinical signs of hyperandrogenism, hirsutism and acne were equally frequent [12.2% prevalence; 95% confidence interval (CI): 9.5-14.8%], whereas alopecia was uncommon (1.7% prevalence, 95% CI: 0.7-2.7%). Regarding functional disorders of androgen excess, PCOS and idiopathic hirsutism were equally frequent (5.4% prevalence, 95% CI: 3.6-7.2) followed by idiopathic hyperandrogenism (3.9% prevalence, 95% CI: 2.3-5.4). CONCLUSIONS Clinical signs of hyperandrogenism and functional disorders of androgen excess show a high prevalence in premenopausal women. The prevalences of idiopathic hyperandrogenism and idiopathic hirsutism are similar to that of PCOS, highlighting the need for further research on the pathophysiology, consequences for health and clinical implications of these functional forms of androgen excess.

Role of Decreased Circulating Hepcidin Concentrations in the Iron Excess of Women with the Polycystic Ovary Syndrome

CONTEXT Hepcidin inhibits the intestinal absorption of iron and its deficiency causes juvenile hemochromatosis. OBJECTIVE The objective of the investigation was to study the involvement of hepcidin in the iron overload of patients with polycystic ovary syndrome (PCOS). DESIGN This was a case-control study followed by a randomized clinical trial. SETTING The study was conducted at an academic hospital. PATIENTS Thirty-four patients with PCOS and 30 women without hyperandrogenism, matched for age and body mass index, participated in the study. INTERVENTION Patients with PCOS were randomly allocated to treatment with either an antiandrogenic oral contraceptive or metformin for 24 wk. MAIN OUTCOME MEASURES Serum hepcidin levels and ferritin to hepcidin molar ratios were measured. RESULTS Patients with PCOS showed decreased circulating hepcidin levels and increased ferritin to hepcidin molar ratios compared with controls. Patients with PCOS presenting with chronic oligoamenorrhea (an iron sparing mechanism) showed a paradoxical decrease in serum hepcidin levels and an increase in ferritin to hepcidin molar ratios compared with the patients who had regular anovulatory menstrual cycles and with the controls. The major predictor of circulating hepcidin concentrations was the presence of PCOS, whereas the main determinants of the ferritin to hepcidin molar ratio were the insulin sensitivity index and menstrual dysfunction. Serum hepcidin levels did not change during treatment with either metformin or the antiandrogenic oral contraceptive pill, yet patients treated with the oral contraceptive pill normalized the ferritin to hepcidin molar ratio. CONCLUSIONS Patients with PCOS had reduced serum hepcidin concentrations that might contribute to their iron overload by favoring the intestinal absorption of iron. The imbalance between increased iron stores and reduced hepcidin levels was related to the insulin resistance and androgen excess characteristic of this syndrome.

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.

Management of Postmenopausal Virilization

CONTEXT Mild clinical signs of hyperandrogenism such as hirsutism may appear during the menopausal transition as part of the normal aging process, but the development of frank virilization suggests a specific source of androgen excess, including androgen-secreting tumors. PATIENT AND METHODS A 68-yr-old postmenopausal woman was referred because of a history of progressive development of hirsutism and frontal balding for the previous 8 yr, together with moderate hyperandrogenemia. Initial imaging procedures depicted a 2-cm solid nodule in the right adrenal gland and normal appearance of both ovaries. To confirm the source of androgen excess, we conducted simultaneous selective venous sampling of adrenals and ovaries. Sampling was consistent with an ovarian source. After bilateral laparoscopic salpingo-oophorectomy, the patient was diagnosed with bilateral ovarian hyperthecosis. Three weeks after surgery, her androgen levels had decreased to the normal female range. CONCLUSION Diagnosis of hyperandrogenism in postmenopausal women is challenging. Postmenopausal virilization may be associated with adrenal or ovarian androgen-secreting tumors or with benign conditions. A detailed clinical history is critical to differentiate the progressive development of virilization that characterizes benign causes from the rapid progression that characterizes malignant tumors. Imaging techniques do not always reveal the cause of hyperandrogenism and may even be misleading. Although technically difficult, combined adrenal and ovarian venous sampling may be required to confirm the source of androgen excess before the best surgical approach is determined.

The determinants of insulin sensitivity, β-cell function, and glucose tolerance are different in patients with polycystic ovary syndrome than in women who do not have hyperandrogenism.

OBJECTIVE To evaluate the pathogenetic mechanisms underlying abnormal glucose tolerance in polycystic ovary syndrome (PCOS). DESIGN Case-control study. SETTING Academic hospital. PATIENT(S) One hundred twelve patients with PCOS and 86 nonhyperandrogenic control women of similar age and body mass index (BMI). INTERVENTION(S) An oral glucose tolerance test (OGTT) served to explore glucose tolerance and to calculate insulin sensitivity, insulin secretion, and insulin disposition indexes. MAIN OUTCOME MEASURE(S) Frequency of abnormal glucose tolerance, indexes of insulin sensitivity, secretion and disposition, and markers of inflammation, androgen excess, and iron stores. RESULT(S) Obesity and age, but not PCOS, were associated with an increased frequency of abnormal glucose tolerance and diabetes. An imbalance between insulin resistance and secretion--translated into decreased insulin disposition index--predicted abnormal glucose tolerance in patients with PCOS and controls, yet these women differed in the factors associated with decreased insulin disposition. In patients with PCOS, hyperandrogenism, chronic inflammation, and family history of diabetes contributed to insulin resistance as the main pathogenetic mechanism. In nonhyperandrogenic women, familial aggregation of defective insulin secretion, adiposity, and increased body iron stores explained most of the decrease in insulin disposition. CONCLUSION(S) In addition to a major influence of obesity and age, the mechanisms underlying abnormal glucose tolerance are different in patients with PCOS compared with women who do not have hyperandrogenism.

Common variants in the sex hormone-binding globulin gene (SHBG) and polycystic ovary syndrome (PCOS) in Mediterranean women

STUDY QUESTION Is there an association between polycystic ovary syndrome (PCOS) and the sex hormone-binding globulin (SHBG) rs1799941, rs6257, rs6259 and rs727428 variants in a large series of Mediterranean women? SUMMARY ANSWER The rs727428 and rs6259 variants are associated with PCOS in Mediterranean women. WHAT IS KNOWN ALREADY The level of SHBG, the primary plasma transport protein for sex steroids, which regulates the bioavailability of these hormones to target tissues, is reduced in patients with PCOS. Single-nucleotide polymorphisms in the SHBG gene influence circulating SHBG levels in American patients with PCOS and may predict the development of type 2 diabetes. STUDY DESIGN, SIZE AND DURATION This was a genetic case-control association study including 1004 premenopausal Mediterranean women. PARTICIPANTS/MATERIALS, SETTING AND METHODS In an Academic setting, we genotyped a clinical cohort consisting of 281 patients with PCOS and 142 women without any evidence of androgen excess, and a population-based cohort comprised of 581 unselected female blood donors from Spain and Italy. The latter included 31 patients with PCOS and 550 controls, of whom 298 had no evidence of any androgen excess disorder and were considered hyper-normal controls. MAIN RESULTS AND THE ROLE OF CHANCE Mutant alleles of the rs727428 variant were more frequent in patients with PCOS compared with controls and with hyper-normal controls. This association was independent of obesity. Carrying mutant alleles of rs727428 was found to be associated with a 1.29 odds ratio (OR) for PCOS, whereas carrying mutant alleles of rs6259 associated with a 0.68 OR for PCOS. The rs1799941 and rs6257 variants were not associated with PCOS. None of the SHBG variants influenced serum SHBG concentrations. LIMITATIONS AND REASONS FOR CAUTION The associations found here were relatively weak and, arising from a case-control study, do not necessarily indicate a causative role of the SHBG variants in the development of PCOS. Also, we studied different patients and controls from different sources, making some of the interpretations difficult. Finally, the rs1799941 variant was not in Hardy-Weinberg equilibrium in the small group of patients with PCOS recruited from the general population, yet this variant was not associated with PCOS. WIDER IMPLICATIONS OF THE FINDINGS SHBG variants that influenced circulating SHBG levels in American patients with PCOS are also associated with this syndrome in Mediterranean women, pointing to SHBG as a candidate gene for PCOS. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by grants PI080944 and PI110357 from Instituto de Investigación Carlos III, Spanish Ministry of Economy and Competitiveness. CIBERDEM is also an initiative of Instituto de Investigación Carlos III. The Authors have no competing interests to declare.

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.