Francisco Álvarez-Blasco

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.

Antiandrogenic contraceptives increase serum adiponectin in obese polycystic ovary syndrome patients.

Increasing evidence suggests that adipocyte function is altered in the polycystic ovary syndrome (PCOS) as a result of androgen excess, providing an explanation for its frequent association with abdominal adiposity and insulin resistance. We here compared the response of serum adiponectin and leptin levels to the amelioration of androgen excess by means of treatment with an antiandrogenic oral contraceptive pill, as compared with the response to insulin sensitization with metformin. Thirty‐four women presenting with PCOS were randomized to treatment with an oral contraceptive containing 35 µg ethinyl‐estradiol plus 2 mg cyproterone acetate (Diane35 Diario) or with metformin (850 mg twice daily). Serum adiponectin and leptin levels were evaluated at baseline and after 12 and 24 weeks of treatment. In obese PCOS women, treatment with Diane35 Diario resulted in an increase in serum adiponectin levels and in the adiponectin/leptin ratio, in parallel with a marked decrease in serum androgen concentrations, whereas no statistically significant changes were observed during treatment with metformin. On the contrary, leptin concentrations did not show any statistically significant change during the study with any of the drugs studied here. In summary, our present results might suggest a direct inhibitory effect of androgen excess on adiponectin secretion by adipocytes in obese PCOS women, supporting the hypothesis that androgen excess contributes to adipocyte dysfunction in these women.

Effects of metformin versus ethinyl-estradiol plus cyproterone acetate on ambulatory blood pressure monitoring and carotid intima media thickness in women with the polycystic ovary syndrome

OBJECTIVE To compare the effects of metformin versus an antiandrogenic contraceptive pill on ambulatory blood pressure monitoring (ABPM) and carotid intima media thickness (CIMT) in women with polycystic ovary syndrome (PCOS). DESIGN Clinical randomized trial. SETTING Academic hospital. PATIENT(S) Thirty-four consecutive PCOS patients. INTERVENTION(S) PCOS patients randomized to oral treatment with metformin (n = 19) or with Diane(35) Diario pill (n = 15) for 24 weeks. MAIN OUTCOME MEASURE(S) ABPM recordings and ultrasound measurements of CIMT as marker of subclinical atherosclerosis obtained at baseline and after treatment. RESULT(S) Metformin resulted in reductions in daytime and 24-hour average systolic and diastolic blood pressure whereas Diane(35) Diario induced a slight increase in these parameters. Compared with a nonhyperandrogenic control group, the increased CIMT values of PCOS patients decreased to the normal range after treatment with either metformin or Diane(35) Diario. CONCLUSION(S) Metformin treatment decreased daytime ABPM recordings whereas Diane(35) Diario exerted the opposite effect. The safer blood pressure profile of metformin should be considered in PCOS patients who present with a history of hypertension or who are at risk for this disorder. Treatment with either Diane(35) Diario or metformin improved CIMT mean values.

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.

Serum uric acid concentration as non-classic cardiovascular risk factor in women with polycystic ovary syndrome: effect of treatment with ethinyl-estradiol plus cyproterone acetate versus metformin

BACKGROUND Serum uric acid levels have emerged as a cardiovascular risk factor, and interventions aimed to decrease its level have been related with an improvement in clinical and non-clinical cardiovascular outcomes. METHODS Serum uric acid levels were measured in 40 polycystic ovary syndrome (PCOS) patients and 40 non-hyperandrogenic women matched for BMI and grade of obesity, and were followed-up in 34 PCOS patients who were randomized to an oral contraceptive containing 35 mg ethinyl-estradiol plus 2 mg cyproterone acetate (Diane(35) Diario) or metformin (850 mg twice daily) for 24 weeks. RESULTS There were no statistically significant differences in uric acid levels between PCOS and non-hyperandrogenic control women. Considering all PCOS and non-hyperandrogenic control women as a whole, obese women showed higher uric acid concentrations than lean and overweight women, and the main determinant of serum uric acid level was the BMI. In PCOS women, Diane(35) Diario treatment was related with a decrease in uric acid levels (P = 0.018), whereas no changes were observed with metformin. CONCLUSIONS Obesity is the main determinant of serum uric acid concentrations in PCOS patients, yet amelioration of androgen excess with an antiandrogenic contraceptive pill results in a significant decrease in these levels, an effect that is not observed with metformin. ClinicalTrials.gov NLM Identifier: NCT00428311.

The striking similarities in the metabolic associations of female androgen excess and male androgen deficiency

Androgen excess in women and androgen deficiency in men facilitate abdominal adiposity and related metabolic disorders. Moreover, obesity-associated gonadal dysfunction consists of hyperandrogenism in women but hypogonadism in men. We have reviewed the existing evidence on the interplay between sex steroids, adipose tissue and lean mass distribution, and developed a novel hypothesis to explain these apparent paradoxes. We hypothesize that the most beneficial adipose tissue distribution and function is that of normal women, who have low androgen and high estrogen concentrations. Any imbalance favoring an increase in androgen levels in women, and the very high androgen levels characteristic of healthy men, influence adipose tissue distribution and function. Sex steroids determine a favorable (female) or unfavorable (male) body fat distribution and function. However, sex hormones also provide defensive mechanisms against visceral fat accumulation: androgens increase lean and muscle mass in men, decreasing the amount of visceral fat relative to total body mass and its negative consequences, whereas estrogens determine the metabolically safer deposition of body fat into the subcutaneous gluteal-femoral depot in women. This delicate equilibrium may be altered by the presence of gonadal dysfunction, a sedentary life-style or the normal ageing process leading to sarcopenia, and by the development of obesity leading to abdominal adiposity and metabolic disorders in both sexes. In conclusion, sex hormones and gonadal dysfunction play important roles in the pathogenesis of diabesity and its metabolic associations.

Role of haptoglobin in polycystic ovary syndrome (PCOS), obesity and disorders of glucose tolerance in premenopausal women.

Background Hp2 alleles of the haptoglobin α–chain polymorphism reduce the anti-oxidant properties and increase the pro-inflammatory actions of this acute-phase protein in a gene-dosage fashion. We hypothesized that the haptoglobin polymorphism might contribute to the increased oxidative stress and low-grade chronic inflammation frequently associated with polycystic ovary syndrome, obesity, and abnormalities of glucose tolerance. Methodology/Principal Findings Serum haptoglobin and the haptoglobin α–chain polymorphism were determined in 141 patients with polycystic ovary syndrome and 102 non-hyperandrogenic women. Of the whole group of 243 premenopausal women, 117 were obese and 51 showed abnormal glucose tolerance. Although serum haptoglobin concentrations were similar in PCOS patients and controls, the former presented with an increased frequency of Hp2 alleles (62% vs. 52%, P = 0.023). Circulating haptoglobin levels increased with obesity (P<0.001), yet no association was found between obesity and haptoglobin genotypes. No differences were observed in haptoglobin levels or genotype frequencies depending on glucose tolerance. Fifty percent of the variation in serum haptoglobin concentrations was explained by the variability in serum C-reactive protein concentrations, BMI, insulin sensitivity and haptoglobin genotypes. Conclusions/Significance Serum haptoglobin concentrations in premenopausal women are largely dependent on the haptoglobin polymorphism and on the presence of obesity, with insulin resistance and chronic inflammation possibly modulating this relationship. The association of polycystic ovary syndrome with Hp2 alleles suggests that the anti-oxidant and anti-inflammatory properties of haptoglobin may be reduced in these patients.

Obesity impairs general health-related quality of life (HR-QoL) in premenopausal women to a greater extent than polycystic ovary syndrome (PCOS).

Objective  Obesity is frequently associated with the polycystic ovary syndrome (PCOS) and both conditions may impact on the health‐related quality of life (HR‐QoL) of affected patients. We aimed to estimate the relative impact of obesity and PCOS on the general HR‐QoL of premenopausal women.

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.