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.

Effect of Iron Depletion by Bloodletting vs. Observation on Oxidative Stress Biomarkers of Women with Functional Hyperandrogenism Taking a Combined Oral Contraceptive: A Randomized Clinical Trial.

Women with functional hyperandrogenism show both increased markers of oxidative stress and a mild iron overload. Combined oral contraceptives (COC) may worsen redox status in the general population. Since iron depletion ameliorates oxidative stress in other iron overload states, we aimed to address the changes in the redox status of these women as a consequence of COC therapy and of bloodletting, conducting a randomized, controlled, parallel, open-label clinical trial in 33 adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. After three months of treatment with a COC, participants were randomized (1:1) to three scheduled bloodlettings or observation for another nine months. After taking a COC, participants showed a mild decrease in their plasma electrochemical antioxidant capacity, considering fast-acting antioxidants [MD: −1.51 (−2.43 to −0.60) µC, p = 0.002], and slow-acting antioxidants [MD: −1.90 (−2.66 to −1.14) µC, p < 0.001]. Women submitted to bloodletting showed a decrease in their non-enzymatic antioxidant capacity levels (NEAC) throughout the trial, whereas those individuals in the control arm showed a mild increase in these levels at the end of the study (Wilks' λ: 0.802, F: 3.572, p = 0.041). Decreasing ferritin and plasma hemoglobin during the trial were associated with worse NEAC levels. COC may impair redox status in women with functional hyperandrogenism. Decreasing iron stores by scheduled bloodletting does not override this impairment.

Diet composition and physical activity in overweight and obese premenopausal women with or without polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS) is a complex polygenic disorder in which environmental factors play an important modifying role. We aimed to find differences in diet and life-style that might contribute to the development of PCOS among overweight or obese premenopausal women. We compared diet composition and self-reported physical activity among 22 patients with PCOS and 59 women without androgen excess recruited from a total of 113 consecutive premenopausal women reporting for management of weight excess. After correcting for a difference in age between women with PCOS and controls, there were no overall statistical significant differences between them in the total caloric intake, in the intake of macro- and micro-nutrients, caffeine, fiber and alcohol, in the proportion of women exercising regularly, or in the number of hours of exercise per week. The proportion of fat in the diets of the overweight and obese women irrespective of PCOS was well-above current recommendations, yet this excessive fat intake occurred at the expense of monounsaturated fatty acids mostly. In conclusion, diet composition and physical activity were apparently not decisive for the development of PCOS among overweight and obese premenopausal women.

Postprandial responses of circulating energy homeostasis mediators to single macronutrient challenges: influence of obesity and sex hormones.

We analysed the influence of obesity, sex and sex steroids on the postprandial responses of circulating energy homeostasis mediators and their receptors to different macronutrient challenges. Seventeen women with polycystic ovary syndrome (PCOS, 8 with obesity), 17 non-hyperandrogenic control women (8 with obesity) and 19 control men (9 with obesity) were submitted, on alternate days, to isocaloric (300 kcal) oral glucose, lipid and protein loads. We evaluated serum ghrelin, leptin, soluble leptin receptor and adiponectin levels and the leukocyte gene expression of ghrelin (GHRL) and its receptor (GHSR), leptin receptor (LEPR) and adiponectin receptor 1 (ADIPOR1) during the macronutrient challenges. The postprandial responses of circulating energy homeostasis mediators were entirely different than those of their related genes. After macronutrient loads the postprandial response of serum energy homeostasis mediators showed a generalized physiological decrease that was blunted in subjects with obesity but was not influenced by sex, sex hormones or PCOS. However, gene expression of GHRL, LEPR and ADIPOR1 showed a marked increase following the ingestion of glucose compared with lipids and proteins, regardless of obesity and sex steroids. The physiological decrease after macronutrient loads, that was deregulated in obesity, did not reflect the acute leukocyte gene expression mainly after glucose, and may suggest a possible role for ghrelin, leptin and adiponectin in the postprandial inflammatory process.

Iron Overload in Functional Hyperandrogenism: In a Randomized Trial, Bloodletting Does Not Improve Metabolic Outcomes.

CONTEXT: Functional hyperandrogenism may be associated with a mild increase in body iron stores. Iron depletion exerts a beneficial effect on metabolic endpoints in other iron overload states. OBJECTIVES: (i) To determine the effect of iron depletion on the insulin sensitivity and frequency of abnormal glucose tolerance in patients with functional hyperandrogenism submitted to standard therapy with combined oral contraceptives (COC). ii) To assess the overall safety of this intervention. DESIGN: Randomized, parallel, open-label, clinical trial. SETTING: Academic hospital. PATIENTS: Adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. INTERVENTION: After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to 3 scheduled bloodlettings or observation for another 9 months. MAIN OUTCOME MEASURES: Changes in insulin sensitivity index and frequency of prediabetes/diabetes, and percentage of women in whom bloodletting resulted in plasma hemoglobin <120 g/L and/or hematocrit <0.36. RESULTS: From 2015 to 2019, 33 women were included by intention-to-treat. During the follow-up, insulin sensitivity did not change in the whole group of women or between study arms [mean of the differences (MD): 0.0 (95%CI: -1.6 to 1.6)]. Women in the experimental arm showed a similar odds of having prediabetes/diabetes than women submitted to observation [odds ratio: 0.981 (95%CI: 0.712 to 1.351)]. After bloodletting, 4 (21.1%) and 2 women (10.5%) in the experimental arm had hemoglobin (Hb) levels <120 g/L and hematocrit (Hct) values <0.36, respectively, but none showed Hb <110 g/L or Hct <0.34. CONCLUSIONS: Scheduled bloodletting does not improve insulin sensitivity in women with functional hyperandrogenism on COC.

Bloodletting has no effect on the blood pressure abnormalities of hyperandrogenic women taking oral contraceptives in a randomized clinical trial.

Normoferritinemic women with functional hyperandrogenism show a mild iron overload. Iron excess, hyperandrogenism, and cardioautonomic dysfunction contribute to blood pressure (BP) abnormalities in these patients. Furthermore, combined oral contraceptives (COC) prescribed for hyperandrogenic symptoms may worse BP recordings. Iron depletion by phlebotomy appears to lower BP in other acquired iron overload conditions. We aimed to determine the effect of iron depletion on the office BP, ambulatory BP monitoring, and frequency of hypertension in patients with functional hyperandrogenism submitted to standard therapy with COC. We conducted a phase 2 randomized, controlled, parallel, open-label clinical trial (NCT02460445) in adult women with functional hyperandrogenism including hyperandrogenic polycystic ovary syndrome and idiopathic hyperandrogenism. After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to three scheduled bloodlettings or observation for another 9 months. Main outcome measures were the changes in office BP, 24-h-ambulatory BP, and frequency of hypertension in both study arms. From June 2015 to June 2019, 33 women were included in the intention-to-treat analyses. We observed an increase in mean office systolic BP [mean of the differences (MD): 2.5 (0.3-4.8) mmHg] and night-time ambulatory systolic BP [MD 4.1 (1.4-6.8) mmHg] after 3 months on COC. The percentage of nocturnal BP non-dippers also increased, from 28.1 to 92.3% (P < 0.001). Office and ambulatory BP did not change throughout the experimental period of the trial, both when considering all women as a whole or as a function of the study arm. The frequency of the non-dipping pattern in BP decreased during the experimental period [OR 0.694 (0.577-0.835), P < 0.001], regardless of the study arm. Decreasing iron stores by scheduled bloodletting does not override the BP abnormalities caused by COC in women with functional hyperandrogenism.

Acute-phase glycoprotein profile responses to different oral macronutrient challenges: Influence of sex, functional hyperandrogenism and obesity.

Acute-phase glycoprotein 1H-NMR spectroscopy profiles serve as surrogate markers of chronic inflammation in metabolic disorders such as obesity, diabetes and polycystic ovary syndrome (PCOS). The latter is associated with increased height-to-width (H/W) ratios of GlycA and GlycB after fasting, but not to glycoprotein areas, regardless of obesity. We studied the responses to separate glucose, lipid and protein oral challenges of five glycoprotein variables (GlycA, GlycB, and GlycF areas and the GlycA and GlycB H/W ratios) in 17 women with PCOS, 17 control women, and 19 healthy men. Glucose and protein ingestion resulted into decreases in all glycoprotein variables, whereas lipid ingestion increased GlycA, GlycF and induced minimal changes in GlycB and GlycB H/W. We found no effects of obesity or group of subjects on postprandial glycoprotein variables regardless of the macronutrient being ingested. However, a statistically significant interaction indicated that obesity blunted the decrease in some of these variables in control women and men, whereas obese women with PCOS showed larger changes when compared with their non-obese counterparts. In conclusion, acute-phase glycoprotein profiles indicate an anti-inflammatory response during postprandial phase that is less pronounced after lipid ingestion, and is counteracted by the chronic inflammatory background associated with obesity and PCOS.

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. DESIGN: Case-control study. PATIENTS: Consecutive overweight and obese premenopausal women seeking advice for weight loss, of whom 32 were diagnosed with PCOS and 72 had no evidence of androgen excess and were considered controls. MEASUREMENTS: Spanish versions of the Short Form 36 Health Survey (SF-36) questionnaire and the Nottingham Health Profile (NHP) were self-administered by the women. RESULTS: Patients with PCOS and controls had similar body mass index, yet controls were older. General HR-QoL mean scores were similar in both groups, yet patients with PCOS scored worse in the role-emotional item of SF-36, and controls scored worse in the pain item of NHP. Increasing grades of obesity, on the contrary, were associated with worse scores in the NHP, and SF-36 items related to general and physical aspects of HR-QoL. When compared with the standards established for the Spanish general population, both patients with PCOS and controls frequently presented with abnormal scores, yet only increasing grades of obesity were associated with more frequent abnormal scoring. CONCLUSIONS: Obesity impaired general HR-QoL to a greater extent than PCOS in overweight and obese premenopausal women.

2D Diffusion-Ordered 1 H-NMR Spectroscopy Lipidomic Profiling after Oral Single Macronutrient Loads: Influence of Obesity, Sex, and Female Androgen Excess.

SCOPE: Postprandial dysmetabolism plays a major role in the pathogenesis of metabolic disorders such as obesity and the polycystic ovary syndrome (PCOS). The aim is to characterize the circulating lipoprotein particle profiles in response to oral glucose, lipid, and protein challenges. METHODS AND RESULTS: 17 women with PCOS, 17 control women, and 19 healthy men selected to have similar age and body mass index are studied. Blood samples are collected following the ingestion of 300 kcal in the form of glucose, lipids, or proteins, and they are submitted to two-dimensional (2D) diffusion-ordered 1 H-NMR spectroscopy. Regardless of macronutrient administered, the number of very low-density (VLDL) particles increases whereas low density-lipoprotein (LDL) decreases. High density-lipoprotein (HDL) particles increase only after lipid ingestion. Obese subjects show an increase in the number of large VLDL particles and a decrease in large LDL particles, with a significant reduction in the average particle size of LDL. Patients with PCOS show a particularly unfavorably smaller LDL particle size response to oral lipid intake, regardless of obesity. CONCLUSIONS: Oral macronutrient challenges induce immediate class-specific postprandial changes in particle number and size of lipoproteins, with lipids inducing a more pro-atherogenic lipoprotein profile compared to glucose and proteins, particularly in obese subjects and women with PCOS.

TLR2 and TLR4 Surface and Gene Expression in White Blood Cells after Fasting and Oral Glucose, Lipid and Protein Challenges: Influence of Obesity and Sex Hormones.

We studied if macronutrients of the diet have different effects on leukocyte activation, and if these effects are influenced by sex hormones or obesity. We analyzed leukocyte cell surface and gene expression of toll-like receptors 2 and 4 (TLR2 and TLR4) during fasting and after macronutrient loads in women with polycystic ovary syndrome and female and male controls. Fasting TLR2 surface expression in neutrophils was higher in men than in women. Obese subjects presented higher TLR2 gene expression than nonobese individuals, particularly in men. In contrast, surface TLR4 expression was lower in men and in obese individuals. Postprandial cell-surface expression decreased similarly after all macronutrient loads. Neutrophil TLR2 decreased only in obese subjects whereas TLR4 showed a greater decrease in nonobese individuals. However, TLR2 gene expression increased after glucose ingestion and decreased during the lipid load, while TLR4 was induced in response to lipids and mostly to glucose. Postprandial TLR gene expression was not influenced by group of subjects or obesity. Both cell-surface and gene postprandial expression inversely correlated with their fasting levels. These responses suggest a transient compensatory response aiming to prevent postprandial inflammation. However, obesity and sex hormones showed opposite influences on surface expression of TLR2 and TLR4, but not on their gene expression, pointing to regulatory posttranscriptional mechanisms.

Postprandial inflammatory responses after oral glucose, lipid and protein challenges: Influence of obesity, sex and polycystic ovary syndrome.

BACKGROUND & AIMS: Most evidence linking the polycystic ovary syndrome (PCOS) with chronic low-grade inflammation has been obtained in the fasting state. We have studied the postprandial inflammatory response to oral glucose, lipid and protein challenges and the possible influences of obesity, sex and PCOS on these responses. METHODS: On alternate days, we submitted 17 women with PCOS (9 non-obese, 8 obese), 17 control women (9 non-obese, 8 obese) and 19 control men (10 non-obese, 9 obese) to isocaloric (300 Kcal) oral macronutrient loads. We assayed serum for TNF-α, IL-6, IL-18, IL-10, pentraxin-3 and galectin-3 concentrations and leukocytes for expression of TNF, IL6, IL10 and their receptors TNFRSF1B, IL6R and IL10RA. RESULTS: Circulating IL-6 levels decreased after glucose and protein ingestion but slightly increased after oral lipid intake. Leukocyte IL6 expression did not change after the ingestion of any macronutrient yet IL6R expression increased during all macronutrient challenges, the largest increase being observed after glucose ingestion. Serum TNF-α similarly decreased during either macronutrient load, whereas TNF expression increased after macronutrient ingestion, the highest increase observed after oral glucose. TNFRSF1B expression also increased after glucose intake but not after lipid or protein ingestion. No global effect of obesity or group on postprandial circulating IL-6, TNF-α, or IL6, IL6R, TNF and TNFRSF1B expression was found. Circulating IL-18 concentrations decreased during all oral challenges, whereas in case of galectin-3 and pentraxin-3 only the protein load caused a reduction in its concentrations. Of the genes studied here, IL10 showed the largest increase in expression throughout all the postprandial curves, particularly after glucose. Obesity blunted the increase in IL10 expression. IL10RA expression decreased after glucose ingestion but remained unchanged during lipid and protein loads. CONCLUSIONS: Glucose ingestion, as opposed to lipid and protein intake, results into the largest increase in leukocyte gene expression of inflammatory mediators. The expression of the anti-inflammatory cytokine IL10 was the largest observed here, suggesting a compensatory mechanisms against postprandial inflammation that may be blunted in obesity. However, these responses did not translate into the circulating concentrations of these inflammatory mediators during the immediate postprandial phase.

Metabolic Cytokines at Fasting and During Macronutrient Challenges: Influence of Obesity, Female Androgen Excess and Sex.

SCOPE: Cytokines have pleiotropic functions within the organism and their levels may be influenced by obesity, visceral adiposity and sex hormones. Diet composition may also affect their systemic concentrations during fasting and in the postprandial period. Hence, we studied the influence of sex steroids and obesity on the circulating levels of a panel of metabolic cytokines in the fasting state and after single macronutrient challenges. METHODS: On alternate days we submitted 17 women with polycystic ovary syndrome (PCOS) (9 non-obese, 8 obese), 17 non-hyperandrogenic control women (9 non-obese, 8 obese) and 19 control men (10 non-obese, 9 obese) to isocaloric oral glucose, lipid and protein loads. Serum levels of omentin-1, vaspin, lipocalin-2, adipsin, PAI-1, chemerin, FGF-21 and FGF-23 were determined by Luminex multiplex technology. RESULTS: During fasting, obese patients presented higher levels of PAI-1, chemerin and adipsin but decreased FGF-23 and omentin-1 compared with non-obese subjects. Vaspin showed sexual dimorphism with lower levels in men than women with PCOS and female controls. Following macronutrient ingestion, most metabolic cytokines presented a similar physiological response consisting of a decrease in circulating concentrations, which was inversely associated with the fasting levels of these molecules. Protein intake caused the major postprandial decrease whereas glucose did not significantly reduce PAI-1, FGF-23 and vaspin, and even increased FGF-21. Regardless of the macronutrient administered, vaspin levels showed a larger reduction in non-obese individuals while the decrease in PAI-1 was particularly noticeable in the obese subgroup. The postprandial reductions of omentin-1 and FGF-23 after glucose and protein loads were influenced by obesity. No major differences were found between patients with PCOS and male and female controls. CONCLUSIONS: Obesity, but not PCOS or sex, markedly influences metabolic cytokine levels at fasting and after macronutrient ingestion. The observed postprandial decrease in their circulating concentrations might represent a physiological compensatory mechanism against food-induced inflammation and oxidative stress. This mechanism is altered by obesity and is differently modulated by macronutrients, suggesting a larger contribution of glucose to stressful postprandial responses.

Diagnosis of disorders of glucose tolerance in women with polycystic ovary syndrome (PCOS) at a tertiary care center: fasting plasma glucose or oral glucose tolerance test?

BACKGROUND: The risk of developing prediabetes and type 2 diabetes (dysglycemia) may be increased in women with PCOS. Whether an oral glucose tolerance test (OGTT) should be performed routinely in all PCOS women at presentation or should be recommended only to a selected subset of patients is still controversial. BASIC PROCEDURES: At a tertiary care center, we conducted a retrospective, observational study including 400 women with PCOS submitted to an OGTT. Our primary objective was to assess the diagnostic agreement between two algorithms commonly used for the screening of dysglycemia in these women: i) relying only on fasting plasma glucose (FPG) or ii) considering both fasting and/or 120-min plasma glucose concentrations during an OGTT. We conducted the analysis considering all patients as a whole, and also after stratifying them by body weight, androgen concentrations and age. MAIN FINDINGS: The OGTT detected dysglycemia in 24.5% of patients, whereas only 14.3% women would have been diagnosed using FPG levels alone. The latter missed as many as 40% of women with dysglycemia in our series, including all cases of diabetes. Diagnostic agreement between both algorithms was only 0.55 (κ = 0.103; 95% CI: 0.05-0.16). Areas under the receiver operating characteristic curve for dysglycemia were 0.86 (95%CI: 0.81-0.91) for FPG and 0.91 (95%CI = 0.87-0.95) for 120-min plasma glucose during the OGTT. FPG was not accurate in predicting dysglycemia in women with PCOS regardless of the presence of insulin resistance, weight excess, hyperandrogenemia and age. PRINCIPAL CONCLUSIONS: Relying on FPG alone is not adequate for the screening of disorders of glucose tolerance in women with PCOS; such diagnosis should rely on the results of an OGTT regardless of age, weight and/or androgen concentrations.

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 increase in serum visfatin after bariatric surgery in morbidly obese women is modulated by weight loss, waist circumference, and presence or absence of diabetes before surgery.

BACKGROUND: Previous studies addressing the changes in serum visfatin levels after bariatric surgery yielded conflicting results. METHODS: We measured serum visfatin levels in 41 morbidly obese women before bariatric surgery and after losing at least 15% of the initial weight, and analyzed the results taking into account the type of surgery, reproductive and diabetic status, among others. Body mass index, waist circumference, lipid profile, and insulin resistance determined by homeostasis model assessment (HOMA-IR) were also measured. RESULTS: Patients lost 30.3 +/- 6.1% of the initial body weight, and serum visfatin levels increased from 22.2 +/- 20.9 to 32.2 +/- 27.6 ng/ml (P = 0.031). A multiple regression model (R (2) = 0.314, F = 3.555, P = 0.017) including the percentage of weight loss, changes in waist circumference, HOMA-IR, high-density lipoprotein-cholesterol, and triglycerides (also expressed as percentage from baseline), the surgical procedure, time elapsed since surgery, and previous diabetic status as independent variables showed that weight loss (beta = -0.670, P = 0.010), previous diabetic status (beta = -0.330, P = 0.036), and change in waist circumference (beta = 0.556, P = 0.031) were the main determinants of the percentual increase in serum visfatin levels observed after bariatric surgery. CONCLUSION: Serum visfatin increased after bariatric surgery in relation to the amount of weight lost and to the changes in waist circumference, and this increase was higher in diabetic patients.

Obesity is the major determinant of the abnormalities in blood pressure found in young women with the polycystic ovary syndrome.

CONTEXT: Obesity and insulin resistance predispose patients with the polycystic ovary syndrome (PCOS) to abnormalities in blood pressure regulation. OBJECTIVE: Our objective was to evaluate the impact of obesity on the blood pressure profiles of PCOS patients. PATIENTS, SETTING, AND DESIGN: Thirty-six PCOS patients and 20 healthy women participated in a case-control study at an academic hospital. MAIN OUTCOME MEASURES: We conducted ambulatory blood pressure monitoring and office blood pressure determinations. RESULTS: Hypertension (defined as increased office blood pressure confirmed by ambulatory blood pressure monitoring or by masked hypertension) was present in 12 PCOS patients and eight controls (P = 0.618). No differences between patients and controls were found in office and ambulatory blood pressure monitoring values and heart rate, yet the nocturnal decrease in mean blood pressure was smaller in patients (P = 0.038). Obese women (13 patients and eight controls) had increased frequencies of office hypertension (29% compared with 3% in lean plus overweight women, P = 0.005), increased diastolic (P = 0.009) and mean (P = 0.015) office blood pressure values, and increased heart rate values during the daytime (P = 0.038), nighttime (P = 0.002), and 24-h (P = 0.009) periods, independently of having PCOS or not. The frequency of a nocturnal nondipper pattern was 62% in obese PCOS patients, compared with 26% in lean plus overweight PCOS patients (P = 0.036) and 25% in obese and in lean plus overweight controls. CONCLUSIONS: Abnormalities in the regulation of blood pressure are common in young women with PCOS, yet, with the exception of the nondipper pattern, these abnormalities result from the frequent association of this syndrome with obesity.

Comparison of ethinyl-estradiol plus cyproterone acetate versus metformin effects on classic metabolic cardiovascular risk factors in women with the polycystic ovary syndrome.

CONTEXT: Oral contraceptives may worsen the metabolic profile of patients with polycystic ovary syndrome (PCOS), favoring the use of insulin sensitizers in these patients. OBJECTIVE: The aim of the study was to compare the effects of a contraceptive pill on metabolic classic cardiovascular risk factors with those of the insulin sensitizer metformin. DESIGN: We conducted a randomized, parallel, open-label clinical trial. SETTING: The study was conducted at an academic hospital. PATIENTS: Thirty-four consecutive PCOS patients were studied. INTERVENTIONS: Patients were randomized to oral treatment with metformin (850 mg twice daily) or with the Diane(35) Diario pill (35 microg of ethinyl-estradiol plus 2 mg of cyproterone acetate) for 24 wk. MAIN OUTCOME MEASURES: Hyperandrogenism, lipid profiles, and indexes of glucose tolerance and insulin sensitivity were measured at baseline and after 12 and 24 wk of treatment. RESULTS: Diane(35) Diario resulted in higher reductions in hirsutism score and serum androgen levels compared with metformin. Menstrual regularity was restored in all the patients treated with Diane(35) Diario compared with only 50% of those receiving metformin. Plasma apolipoprotein A-I and HDL-phospholipid levels increased with Diane(35) Diario, whereas metformin did not induce any change in the lipid profile. On the contrary, the insulin sensitivity index increased with metformin but did not change with Diane(35) Diario. No differences in the frequencies of abnormalities of glucose tolerance and dyslipidemia were found between both treatments. CONCLUSIONS: Diane(35) Diario appears to be superior to metformin for the control of hyperandrogenism and for the restoration of menstrual regularity in PCOS patients, and it is not associated with any clinically relevant worsening in the classic metabolic cardiovascular risk profile of these women.

Thyroid hormone deficiency and postmenopausal status independently increase serum osteoprotegerin concentrations in women.

OBJECTIVE: To study the impact of thyroxine (T4) withdrawal on serum osteoprotegerin concentrations in women, using a healthy euthyroid control group matched for age and postmenopausal status as reference. SUBJECTS AND DESIGN: Nineteen women with differentiated thyroid carcinoma were studied the last day on T4 suppressive treatment, 4-7 days after withdrawal and the day before whole body scanning. Eighteen women matched for age and postmenopausal status served as controls. Serum thyroid hormones, urinary bone markers and serum osteoprotegerin concentrations were measured. Statistical methods included repeated measures analysis of variance and one-way analysis of variance. RESULTS: Patients progressed from subclinical or mild hyperthyroidism at baseline to normal free T4 and triiodothyronine levels 4-7 days later, ending in overt hypothyroidism before scanning. Serum osteoprotegerin increased, and urinary deoxypyridolines/creatinine and pyridolines/creatinine ratios decreased, with acute hypothyroidism (P = 0.026, P = 0.003, and P < 0.001 respectively). Urinary deoxypyridolines/creatinine ratio, pyridolines/creatinine ratio, and serum osteocalcin during hypothyroidism were lower compared with those of healthy controls (P = 0.023, P = 0.019, and P = 0.011 respectively). Serum osteoprotegerin concentrations were higher in postmenopausal patients when compared with premenopausal ones, irrespective of the changes in thyroid function (P = 0.001). CONCLUSION: Serum osteoprotegerin concentrations increase following acute hypothyroidism after T4 withdrawal in women with differentiated thyroid carcinoma, and also with postmenopausal status.

The decrease in serum IL-18 levels after bariatric surgery in morbidly obese women is a time-dependent event.

BACKGROUND: We have evaluated the impact of the reproductive status of morbidly obese women, and of the time elapsed since surgery, on the response of the proinflammatory serum cardiovascular risk marker interleukin-18 (IL-18) to the sustained and marked weight loss achieved after bariatric surgery. METHODS: Serum IL-18 levels were measured in 33 morbidly obese women before bariatric surgery and after losing at least 15% of the initial weight, irrespective of the time needed to achieve this goal (5 to 33 months). RESULTS: Patients lost 30.7 +/- 7.8% of the initial weight, with a concomitant reduction of serum IL-18 concentrations (P<0.001). A stepwise multiple regression analysis showed that the percentual decrease in serum IL-18 levels was determined by the interaction between the time elapsed since surgery and the percentual reduction of waist circumference (R2 = 0.333, F = 15.500, beta = 0.577, P<0.001), but not by the individual effects of the time elapsed since surgery, percentual body weight loss, percentual reduction of waist circumference, menopausal status or type of surgical procedure, or by the interaction between the time elapsed since surgery with the percentual body weight loss or with menopausal status. CONCLUSION: Serum IL-18 levels decrease after bariatric surgery in a time-dependent manner, in relation to the reduction in waist circumference. The fact that the amelioration of the obesity-associated inflammatory process requires time and not only weight loss, might contribute to explain early non-surgical cardiovascular complications of bariatric surgery.

Vitamin D deficiency is associated with the metabolic syndrome in morbid obesity.

BACKGROUND & AIMS: Vitamin D deficiency has been recently associated with the metabolic syndrome. However, it is not known whether this possible association of vitamin D deficiency with the metabolic syndrome is still present at very high degrees of obesity, as in morbidly obese patients. METHODS: Transversal, observational study that included 73 consecutive morbidly obese patients (body mass index 40 kg/m(2)). In every patient, anthropometric variables were recorded, fasting blood was assayed for 25-hydroxyvitamin D concentrations, lipid profiles, glucose and insulin levels, and insulin resistance was estimated by homeostasis model assessment. RESULTS: Vitamin D deficiency was present in 37 of the 73 patients (50.7%). As defined by revised Adult Treatment Panel III criteria, 46 of the 73 obese patients (63%) had the metabolic syndrome. Vitamin D deficiency was more prevalent in morbidly obese patients presenting with the metabolic syndrome, compared with those who did not achieve the criteria for this syndrome (60.9% vs. 33.3% respectively, P = 0.023). When serum concentrations of 25-hydroxyvitamin D were categorized in tertiles, there was an association of the prevalence of the metabolic syndrome with the former (P = 0.038). Serum high-density lipoprotein cholesterol concentrations were lower (37.0+/-7.8 mg/dl vs. 44.9+/-8.7 mg/dl, P = 0.003), and triglycerides levels were higher (163.3+/-81.5 mg/dl vs. 95.1+/-24.2 mg/dl, P = 0.001) in the vitamin D-deficient group. CONCLUSION: Vitamin D deficiency is associated with the metabolic syndrome in morbidly obese patients.