The effect of changes in adiposity on testosterone levels in older men: longitudinal results from the Massachusetts Male Aging Study

OBJECTIVE: Changes in adiposity affecting total testosterone (TT) and free testosterone (FT) levels have not been examined in a population-based survey. We aimed to determine whether changes in adiposity predict follow-up levels and rates of change in TT, FT and sex hormone-binding globulin (SHBG) in men. DESIGN: The Massachusetts Male Aging Study is a randomly sampled, population-based cohort interviewed at baseline (T(1), 1987-1989; n = 1,709; aged 40-70 years) and followed-up approximately 9 years later (T(2), 1995-1997; n = 1,156). Men were categorized as overweight (body mass index (BMI) >or= 25 kg/m(2)) or having obesity (BMI >or= 30 kg/m(2)), waist obesity (waist circumference >or= 102 cm), or waist-to-hip ratio (WHR) obesity (WHR>0.95). For each adiposity group, we constructed four categories to represent changes between T(1) and T(2): overweight (or obese, etc.) at neither wave, T(1) only, T(2) only, or both waves. RESULTS: After adjustment for confounding variables, men who were overweight at T(2) only, or at both waves, had significantly lower mean T(2) TT and SHBG levels than men in the neither group (P<0.05). Mean FT did not differ between any overweight group and the neither group. Men who were obese at both times, had the highest mean BMI, the highest fraction of severely obese men, and significantly greater rate of decline in FT than the neither group. CONCLUSIONS: In men who become overweight, the greater rate of decline in TT, but not FT, is related mostly to a lesser age-related increase in SHBG. Since weight gain is highly prevalent in older men, over-reliance on TT levels in the diagnosis of androgen deficiency could result in substantial misclassification.     

Sex hormone-binding globulin levels and cardiovascular risk factors in morbidly obese subjects before and after weight reduction induced by diet or malabsorptive surgery

One of the main goals of weight reduction in morbidly obese subjects is its benefit on coronary heart disease (CHD) risk. A cross-sectional study was designed to randomly assign 79 morbidly obese subjects (27 men and 52 women; age: 30-45 years) either to a diet protocol (20 kcal per kg fat-free mass (FFM); 55% carbohydrates, 30% fat, and 15% proteins) or to malabsorptive surgery (biliopancreatic diversion). Fatness parameters, measured by dual-energy X-ray absorptiometry, lipid profile, insulin, leptin, sex steroid hormones and sex hormone-binding globulin (SHBG) levels were compared at baseline and 1 year after the beginning of the study. The data showed that plasma SHBG levels, but not testosterone levels, correlated negatively to fasting insulin levels and positively to HDL-cholesterol in both men and women. Total leptin levels were significantly lower (P<0.0001) in post-BPD subjects of both sexes compared to dietary treated obese subjects. The logarithm of plasma leptin correlated significantly and positively with insulin but negatively with SHBG.A step-down regression analysis showed that FFM and SHBG, but not insulin levels, were the most powerful independent variables for predicting HDL-cholesterol levels in morbidly obese patients. The negative relationship between SHBG levels and CHD risk appears to be mediated by a concomitant variation in body fatness. Finally, in obese patients, SHBG levels seem to be an indicator of total adiposity rather than an index of an altered insulin/glucose homeostasis.     

雄激素及其受体与老年男性冠状动脉粥样硬化性心脏病的相关性研究

目的 观察老年男性冠状动脉粥样硬化性心脏病(冠心病)患者性激素及雄激素受体水平的变化及相关性. 方法 横断面调查老年男性539例,其中健康人(对照组)400例,年龄62～92岁,平均(71.4±5.2)岁;冠心病患者139例,年龄60～88岁,平均(73.6±6.4)岁.测定总睾酮、游离睾酮、脱氢表雄酮硫酸酯(DHEAS)、性激素结合球蛋白(SHBG)、雌二醇、黄体生成素(LH)、卵泡刺激素(FSH)水平,同时采用流式细胞术检测外周血雄激素受体(AR)水平. 结果 老年男性冠心病患者DHAES、总睾酮、SHBG、游离睾酮、AR荧光强度均低于对照组(均为P<0.01),而FSH、E2高于对照组(均为P<0.01).年龄与总睾酮、游离睾酮呈负相关(r分别为-0.28、-0.17,P<0.01和P<0.05);与E2、SHBG呈正相关(r分别为0.33、0.14,P<0.01和P<0.05).AR荧光强度与收缩压呈负相关(r=-0.12,P<0.01).Logistic回归分析显示,总睾酮(OR=1.065,95%CI:1.012～1.121,P<0.05)、SHBG(OR=0.994,95%CI:0.990～0.998,P<0.01)和AR(OR=0.971,95%CI:0.956～0.986,P<0.01)与老年男性冠心病相关. 结论 老年男性冠心病患者存在低水平的DHEAS、总睾酮、SHBG、游离睾酮、AR,同时存在高水平的FSH、E2;低水平总睾酮、SHBG和AR可能是老年男性冠心病独立的危险因素.     

Sex steroid hormones,upper body obesity,and insulin resistance

Low plasma levels of SHBG and free testosterone have been associated with increased insulin resistance and risk for type 2 diabetes in males. As truncal obesity, a condition accompanied by increased insulin resistance, is also associated with low SHBG and testosterone levels, the independent association of low free testosterone and SHBG with excessive insulin resistance remains to be determined. In this study we evaluated whether in normogonadic men, plasma levels of SHBG and free testosterone are primarily related to insulin resistance or to generalized and regional adiposity. Hyperinsulinemic-euglycemic clamps and iv glucose tolerance tests were performed in 24 healthy volunteer and 33 patients with mild type 2 diabetes. The 2 groups were chosen to have similar body mass index and were found to have similar body composition and fat distribution, assessed by underwater weighing, skinfold thickness, and magnetic resonance imaging of the abdomen. In the 2 groups combined, plasma levels of SHBG correlated inversely with fat accumulation in both sc and intraabdominal areas. Plasma levels of free testosterone correlated inversely with both truncal and peripheral skinfold thickness only in the nondiabetic men. No associations between plasma levels of sex steroid hormones and insulin resistance, hepatic glucose output, or insulin secretion were found to be independent of adiposity. Furthermore, although patients with diabetes were more insulin resistant than those without diabetes, the 2 groups had similar plasma concentrations of free testosterone (55 +/- 14 and 67 +/- 27 pmol/liter, respectively), SHBG (19 +/- 13 and 19 +/- 13 nmol/liter), estradiol (83 +/- 5 and 81 +/- 21 pmol/liter), and dehydroepiandrosterone sulfate (3.6 +/- 2.2 and 2.8 +/- 1.7 nmol/liter). We conclude that in normogonadal nondiabetic males, the variability in plasma bioavailable testosterone concentrations is predictive of the variability in fat deposition in the sc adipose tissue compartments of both truncal and peripheral areas. Low plasma levels of bioavailable testosterone do not independently predict excessive insulin resistance, beta-cell dysfunction, or hepatic glucose output in normogonadal men.     

Age, body mass index, race and other determinants of steroid hormone variability: the HERITAGE Family Study.

OBJECTIVE AND METHODS: To investigate from the HERITAGE Family Study database, 13 steroid hormones (androstane-3alpha, 17beta-diol glucuronide, androsterone glucuronide, cortisol, dehydroepiandrosterone (DHEA), DHEA ester (DHEAE), DHEA sulfate (DHEAS), dihydrotestosterone (DHT), estradiol, 17-hydroxyprogesterone, progesterone, pregnenolone ester, sex hormone binding globulin (SHBG) and testosterone in each sex for their relationships with age, body mass index (BMI), race and key lifestyle variables. Sample sizes varied from 676 to 750 per hormone. Incremental regression methods were used to examine the contributions of the variables to steroid hormone variability. RESULTS: Age was a major predictor for most steroid hormones. The greatest contribution of age was a negative relationship with DHEAS (R(2)=0.39). BMI was also associated with the variability of several steroid hormones, being the most important predictor of SHBG (R(2)=0.20) and of testosterone (R(2)=0.12) concentrations. When age and BMI were included, race still contributed significantly to the variations in cortisol (R(2)=0.02 for men and 0.04 for women), DHT (R(2)=0.02 for men and 0.03 for women), and progesterone (R(2)=0.03 for women). Nevertheless, race appeared to be less important than age and BMI. In addition, lifestyle indicators (food and nutrient intakes, smoking and physical activity) influenced steroid hormone variability. Their contributions, however, were minor in most cases once age, BMI and race had been taken into account. CONCLUSIONS: We conclude that age was the most important factor, followed by BMI, race and lifestyle factors in explaining steroid hormone variability.     

Sex hormones, inflammation and the metabolic syndrome: a population-based study

OBJECTIVE: Mild hypoandrogenism in men is associated with features of the metabolic syndrome, but the association with the metabolic syndrome itself using an accepted definition has not been described. DESIGN: Men with the metabolic syndrome were identified and testosterone and sex hormone-binding globulin (SHBG) levels were determined in a population-based cohort of 1896 non-diabetic middle-aged Finnish men. RESULTS: Calculated free testosterone and SHBG were 11% and 18% lower (P<0.001) in men with the metabolic syndrome (n=345, World Health Organisation definition). After categorisation by tertiles and adjusting for age and body mass index, total and free testosterone and SHBG were inversely associated with concentrations of insulin, glucose, triglycerides, C-reactive protein (CRP) and CRP-adjusted ferritin and positively associated with high-density lipoprotein cholesterol. Men with free testosterone levels in the lowest third were 2.7 (95% confidence interval (CI) 2.0-3.7) times more likely to have the metabolic syndrome in age-adjusted analyses, and 1.7 (95% CI 1.2-2.4) times more likely even after further adjusting for body mass index. Exclusion of men with cardiovascular disease did not alter the association. The inverse association of SHBG with the metabolic syndrome was somewhat stronger. CONCLUSIONS: Low testosterone and SHBG levels were strongly associated not only with components of the metabolic syndrome, but also with the metabolic syndrome itself, independently of body mass index. Furthermore, sex hormones were associated with inflammation and body iron stores. Even in the absence of late-stage consequences such as diabetes and cardiovascular disease, subtle derangements in sex hormones are present in the metabolic syndrome, and may contribute to its pathogenesis.     

Testosterone and estradiol among older men

CONTEXT: Testosterone and estradiol levels decline with age in men. This change may affect multiple clinical outcomes, but there have been few reports of the distribution and correlates of testosterone and estradiol concentrations in elderly men. OBJECTIVE: The purpose of these studies was to assess sex steroid levels in a large cohort of older men. DESIGN: We conducted a cross-sectional cohort evaluation. SETTING: Community-dwelling men were studied at six academic medical centers in the United States. PARTICIPANTS: The Osteoporotic Fractures in Men Study is a prospective cohort of men aged at least 65 yr. In these studies, a randomly selected stratified subsample of 2623 participants was analyzed. MAIN OUTCOME MEASURES: We assessed levels of total and free testosterone and estradiol and SHBG. Results: Age was inversely associated with free testosterone and free estradiol levels (P for trend = 0.001 for both). Notably, at any age, there was substantial variation in levels of each hormone. Free testosterone levels were lower in men with greater body mass index, lower SHBG, and poorer self-reported health status and in those of Asian race. Free estradiol concentrations were lower in men with lower body mass index and higher SHBG levels. Free estradiol and free testosterone were modestly correlated (r = 0.20; P < 0.001), but at any level of free testosterone, there was considerable variation in free estradiol levels. CONCLUSIONS: This is the largest cohort of older men in which sex steroid levels are available, and it demonstrates that testosterone and estradiol, and their free fractions, tend to decline with age even among older men. However, substantial variation is also present. The relationships between sex steroid levels and their consequences in aging are likely to be complex.     

Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein-3: a cross-sectional study in healthy women

OBJECTIVE: Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index (BMI) with circulating androgens (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)), estrogens (estrone and estradiol), sex hormone-binding globulin (SHBG), IGF-I and IGF-binding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3. DESIGN AND METHODS: A cross-sectional analysis was performed using hormonal and questionnaire data of 620 healthy women (177 pre- and 443 post-menopausal). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk. RESULTS: In the pre-menopausal group, BMI was not related to androgens and IGF-I. In the post-menopausal group, estrogens, testosterone and androstenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre- and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to androgens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and androgens were observed. CONCLUSIONS: These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, androgens and SHBG appear to be related to each other in post-menopausal women.     

Associations of endogenous testosterone and SHBG with glycated haemoglobin in middle-aged and older men

Objective Low circulating levels of testosterone and sex‐hormone‐binding globulin (SHBG) are associated with increased cardiovascular risk in men. This association may be partially mediated through changes in glucose metabolism, but relatively few data are available on the relationship between sex hormones and markers of long‐term glycaemia. We assessed the associations of endogenous testosterone and SHBG with glycated haemoglobin (HbA_1c) in men. Design and subjects Cross‐sectional study of 1292 men from the Norfolk population of European Prospective Investigation into Cancer (EPIC‐Norfolk). Measurements Glycated haemoglobin, total testosterone (TT) and SHBG levels were measured, and free testosterone (FT) levels were calculated. Multiple linear regression models were used to assess the associations of TT, SHBG and FT with HbA_1c. Results Men with diabetes had lower testosterone and SHBG levels. In non‐diabetic men, HbA_1c levels were inversely associated with TT and calculated FT independently of age, body mass index, smoking, alcohol consumption and physical activity. The adjusted change in HbA_1c was 0·055 (95% CI 0·025; 0·085) per standard deviation (SD) decrease in TT and 0·041 (95% CI 0·010; 0·073) per SD decrease in calculated FT, respectively. SHBG levels were inversely associated with HbA_1c after multivariable adjustment (β = 0·038 per SD decrease (95% CI 0·004; 0·071)). Conclusions In middle‐aged and older men, low endogenous testosterone and SHBG levels are associated with glycaemia, even below the threshold for diabetes. Further studies are needed to determine the effects of interventions that raise testosterone levels in men having increased HbA_1c and subnormal testosterone levels.     

Association between hormones and metabolic syndrome in older Italian men

OBJECTIVES: To determine whether low levels of testosterone, sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and dehydroepiandrosterone sulfate (DHEAS) and high levels of cortisol and leptin would be associated with metabolic syndrome (MS). DESIGN: Cross-sectional. SETTING: Population-based sample of older Italian men. PARTICIPANTS: Four hundred fifty-two men aged 65 and older enrolled in the Invecchiare in Chianti (InCHIANTI) study. MEASUREMENTS: Complete data on testosterone, cortisol, DHEAS, SHBG, fasting insulin, IGF-1 and leptin. MS was defined according to Adult Treatment Panel III criteria. RESULTS: MS was present in 73 men (15.8% of the sample). After adjusting for confounders, total testosterone (P < .05) and log (SHBG) (P < .001) were inversely associated, whereas log (leptin) was positively associated with MS (P < .001). Independent of age, log (SHBG) was positively associated with high-density lipoprotein cholesterol (P < .05) and negatively associated with abdominal obesity (P < .001) and triglycerides (P < .001). Log (leptin) was significantly associated with each component of MS. Cortisol, DHEAS, free and bioavailable testosterone, and IGF-1 were not associated with MS. Having three or more hormones in the lower (for hormones lower in MS) or the upper (for hormones higher in MS) quartile was associated with three times the risk of being affected by MS (odds ratio = 2.8, 95% confidence interval = 1.3-6.9) (P = .005), compared with not having this condition. CONCLUSION: Total testosterone and SHBG are negatively and leptin is positively associated with MS in older men. Whether specific patterns of hormonal dysregulation predict the development of MS should be tested in longitudinal studies.     

Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromsø Study

OBJECTIVE: To test the hypothesis that lower endogenous testosterone levels are associated with higher blood pressure, left ventricular mass, and left ventricular hypertrophy. DESIGN: Population-based cross-sectional study. METHODS: Sex hormone levels, measured by immunoassay, anthropometric measurements and resting blood pressure were studied in 1548 men aged 25-84 Years; echocardiography was completed in 1264 of these men. Partial correlations and multiple regressions were used to estimate the associations between sex hormones, blood pressure and left ventricular mass by height. Analyses of variance and covariance were used to compare men with categorical hypertension and left ventricular hypertrophy. RESULTS: In age-adjusted partial correlations, total testosterone and sex hormone-binding globulin (SHBG) were each inversely associated with systolic blood pressure (SBP) (P<0.001). Men with categorical hypertension (SBP> or =140 or diastolic blood pressure (DBP)> or =90 mmHg) had lower levels of total and free testosterone and SHBG before (P<0.001, P=0.011 and P<0.001, respectively) and after (P<0.001, P=0.035 and P=0.002, respectively) adjusting for body mass index (BMI). Total testosterone and SHBG were each inversely associated with left ventricular mass (P<0.001), and men with left ventricular hypertrophy had significantly lower levels of total testosterone (P=0.042) and SHBG (P=0.006); these associations were no longer significant after adjusting for BMI. CONCLUSION: The results of the present study are consistent with the hypothesis that lower levels of testosterone in men are associated with higher blood pressure, left ventricular mass, and left ventricular hypertrophy. The reduced associations after adjusting for BMI suggest that the association of low testosterone levels with blood pressure and left ventricular mass is mediated by obesity.     

The independent effects of polycystic ovary syndrome and obesity on serum concentrations of gonadotrophins and sex steroids in premenopausal women

OBJECTIVE To investigate the basal levels of gonadotrophins and sex steroids, with special reference to the effects of obesity and body fat distribution, In premenopausal women, both those with polycystic ovary syndrome (PCOS) and those with normal ovaries and regular menstrual cycles. DESIGN Cross-sectional study. The separate effects of obesity (and body fat distribution and fasting Insulin levels) and PCOS on endocrine variables were evaluated by means of analysis of covariance. PATIENTS Sixty-seven women with anovulatory menstrual cycles and polycystic ovaries according to ultrasonography and 59 women with normal ovaries and regular cycles, both groups covering a wide range of body mass index (BMI, PCOS, 17·6-37·4, mean 25·7 kg/m²; controls, 18·8-40·9, mean 25·1 kg/m²). MEASUREMENTS Serum levels of gonadotrophins, sex steroid hormones, prolactin and GH obtained in the early follicular phase in the controls, fasting insulin levels, anthropometric measures (BMI, skinfolds, waist hip ratio). RESULTS Mean serum concentrations of LH, andro-stenedione, testosterone, the free androgen index (FAI; all P < 0·0001) and DHEAS (P < 0·01) were higher, and serum FSH (P < 0·01) and serum SHBG levels lower (P < 0·0001), in the PCOS group than in the controls. Women with PCOS had a more pronounced upper body fat distribution and higher fasting insulin levels than the controls. Independent of PCOS, BMI was positlvely associated with serum levels of FSH (P < 0·001) and negatively with levels of LH (P < 0·05), LH/FSH ratio (P < 0·0001), SHBG (P < 0·0001) and androstenedione (P < 0·01), whereas for levels of testosterone, FAI and DHEAS the impact of obesity differed significantly between the groups. Thus, in the PCOS group, testosterone levels (P < 0·05) and the FAI (P < 0·001) were positively associated with BMI, whereas they were constant throughout the entire range of BMI in the controls. DHEAS levels were positively associated with BMI in the PCOS group (P < 0·05) and negatively in the controls (P < 0·01). Measures of upper body fat were related to testosterone and FAI levels, independent of BMI. CONCLUSIONS Lower FSH levels were found in women with PCOS than during the early follicular phase of normally ovulating women, suggesting a role in anovulation in PCOS. Obesity itself exerted effects on endocrine variables, with the net result of a reduced LHIFSH ratio and lower serum levels of androstenedione and SHBG in both groups; obesity was associated with increased levels of DHEAS, testosterone and FAI exclusively in the women with PCOS. The results underline the endocrine impact of obesity and body fat distribution and the necessity of applying reference values of BMI matched subjects when establishing the endocrine profile of women with PCOS.     

The association of sex hormone levels with poor mobility, low muscle strength and incidence of falls among older men and women

OBJECTIVE: The objective of this study was to examine whether low levels of oestradiol and testosterone are associated with impaired mobility, low muscle strength and the incidence of falls in a population-based sample of older men and women. DESIGN: Cross-sectional population-based study, based on data of the Longitudinal Ageing Study Amsterdam (LASA), including 623 men and 663 women, aged 65-88 years. MEASUREMENTS: Serum levels of oestradiol, testosterone, albumin and sex hormone-binding globulin (SHBG) were measured. Physical performance, functional limitations and muscle strength were assessed, and a follow-up on falls was performed prospectively within 3 years. RESULTS: After adjustment for age, level of education, alcohol use, physical activity, chronic disease and body mass index (BMI), men in the highest quartile of the oestradiol/SHBG ratio had significantly higher physical performance scores than men in the lowest quartile (beta = 0.103). Serum levels of total testosterone were positively associated with muscle strength (beta = 0.085). Calculated bioavailable testosterone levels were positively associated with physical performance and muscle strength (beta = 0.128 and 0.109 respectively). No associations of oestradiol levels with mobility were seen in women. Levels of oestradiol and testosterone were not associated with falls. CONCLUSIONS: It can be concluded that low levels of sex hormones were associated with impaired mobility and low muscle strength in men, but not in women. Levels of sex hormones were not associated with the incidence of falls neither in men, nor in women.     

Obesity and testicular function

Obesity in men, particularly when central, is associated with lower total testosterone [TT], free testosterone [FT] and sex hormone-binding globulin [SHBG], and a greater decline in TT and FT with increasing age compared with lean men. Obesity-related conditions such as obstructive sleep apnea, insulin resistance and type 2 diabetes mellitus are independently associated with decreased plasma testosterone. Possible mechanisms include decreased LH pulse amplitude, inhibitory effects of oestrogen at the hypothalamus and pituitary and the effects of leptin and other peptides centrally and on Leydig cells. Obese men have reduced sperm concentration and total sperm count compared to lean men but sperm motility and morphology appear unaffected. The cause and effect relationships between low plasma androgen levels, obesity and the metabolic syndrome, and associated cardiometabolic risk remain unclear. While weight loss normalizes TT and FT in obese men, androgen replacement in the short term does not significantly improve cardiometabolic risk profile despite reducing fat mass.     

A strong association between biologically active testosterone and leptin in non-obese men and women is lost with increasing (central) adiposity

OBJECTIVE: In both humans and rodents, males have lower levels of leptin than females at any level of adiposity. Experimental data support the idea that testosterone exerts a negative influence on leptin levels. There are, however, major inconsistencies in available data concerning the possible association between androgenicity and leptin in humans. Reasons could be the influence of androgenicity on leptin production being dependent on body composition, and incomplete measures of biologically active testosterone levels. In the present study we have characterized the relationship between biologically active testosterone and leptin after careful stratification for gender and adiposity. DESIGN AND SUBJECTS: Healthy subjects (n=158; 85 men and 73 pre- and postmenopausal women) from the Northern Sweden MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) population were studied with a cross-sectional design. MEASUREMENTS: Anthropometric measurements (body mass index (BMI) and waist circumference) and oral glucose tolerance tests were performed. Circulating levels of leptin, insulin, testosterone, androstenedione, sex hormone-binding globulin (SHBG) and insulin-like growth factor-1 (IGF-1) were measured by radioimmunoassays or microparticle enzyme immunoassays. Apparent concentrations of free testosterone and non-SHBG-bound testosterone were calculated. RESULTS: After adjustments for age, BMI and insulin, leptin levels were inversely correlated to testosterone levels in non-obese men (r=-0.56, P<0.01) and obese women (r=-0.48, P<0.05). In contrast, leptin and testosterone correlated in a positive manner in non-obese women (r=0.59, P<0.01). Levels of SHBG were negatively associated with leptin in men with low waist circumference (r=-0.59, P<0.01). The following factors were associated with leptin in a multivariate model: low levels of biologically active testosterone and SHBG in men with low and medium waist circumference, insulin in men with high waist circumference, high levels of testosterone and insulin in non-obese women, and BMI in obese women. CONCLUSION: We conclude that low leptin levels are associated with androgenicity in non-obese men and women and that the direction of this association is dependent on gender and body fat distribution. Based on these results we suggest that the relation between testosterone and leptin contributes to the gender difference in circulating leptin levels. International Journal of Obesity (2001) 25, 98-105     

Relationship of leptin and sex hormones to bone mineral density in men

Sex hormones are strongly associated with bone mineral density (BMD) in adult humans. Leptin, a hormonal product of the OB gene, also appears to be associated with BMD, but results from previous studies are conflicting. Most of the studies in this area have been in women and apparently none have simultaneously analyzed the relationship of estradiol, testosterone, and leptin with BMD in healthy men. To address these issues, serum sex hormones, sex-hormone-binding globulin (SHBG), leptin, dehydroepiandrosterone sulfate (DHEAS), and insulin were measured in 50 apparently healthy men, 18-66 years of age. After controlling for age and body mass index (BMI), BMD correlated positively with estradiol ( p=0.007) and testosterone ( p=0.019), but negatively with leptin ( p=0.001). No significant correlations between BMD and SHBG, DHEAS, or insulin were observed. In multiple regression analysis with age, BMI, estradiol, testosterone, and leptin as the independent variables, only age ( p<0.05), BMI ( p<0.001), and leptin ( p=0.004) were significantly related to BMD. These findings suggest that in men, leptin may have an important negative relationship with BMD.     

Changes in sex hormone-binding globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome

Background: Mild hypoandrogenism in men, usually defined by low levels of testosterone, is a peculiar feature of abdominal obesity that independently predicts the development of insulin resistance and diabetes mellitus. Little is known about the short‐ and long‐term effects of weight loss on sex steroids in abdominally obese men, however. Objectives: We assessed the effect of rapid weight loss and sustained weight maintenance on the plasma concentrations of testosterone and other sex hormones in 58 abdominally obese men (age, 46.3 ± 7.5 years; body mass index, 36.1 ± 3.8 kg/m²; waist girth, 121 ± 10 cm) with the metabolic syndrome. Results: The men lost on average 16.3 ± 4.5 kg during a 9‐week very low‐calorie diet (VLCD) and maintained 14.3 ± 9.1 kg weight loss after a 12‐month maintenance period (vs. baseline, p < 0.001). Sex hormone‐binding globulin (SHBG) increased from 27.6 ± 11.9 to 48.1 ± 23.5 nmol/l during the VLCD but decreased to 32.6 ± 12.9 nmol/l during weight maintenance, which was still higher than at baseline (p < 0.001). Free testosterone (fT) increased from 185 ± 66 to 208 ± 70 pmol/l (p = 0.002) during the VLCD and remained high after 1 year of weight maintenance (212 ± 84 pmol/l, p = 0.002). Total testosterone levels followed a pattern intermediate between fT and SHBG. Plasma estradiol and dehydroepiandrosterone sulphate concentrations changed only transiently or not at all. Conclusions: Rapid weight loss with successful weight maintenance in abdominally obese men with the metabolic syndrome brings about a sustained increase in fT levels. The dramatic increase in SHBG attenuated initially during weight maintenance but remained elevated. These findings may be important with regard to prevention of progressive metabolic decompensation and cardiovascular disease associated with obesity and the metabolic syndrome.     

Insulin-like growth factor-binding protein-3 is associated with the presence and extent of coronary arteriosclerosis

Aging is associated with the progression of arteriosclerosis and the decline of several endocrine functions. We therefore investigated the association of coronary arteriosclerosis with hormones, the serum concentrations of which change during aging. Coronary angiograms of 189 men <70 years old were evaluated by 3 semiquantitative score systems to estimate the extent of focal and diffuse vessel wall alterations. Fasting sera were analyzed for levels of glucose, lipids, thyroid-stimulating hormone, insulin, insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), dehydroepiandrosterone sulfate (DHEAS), testosterone, and sex hormone-binding globulin (SHBG). After adjustment for age, body mass index, and waist-to-hip ratio, 92 patients with >/=1 stenoses >70% differed from 97 patients without such focal lesions by higher serum levels of glucose, total and LDL cholesterol, and apolipoprotein (apo) B, as well as by lower serum levels of IGFBP-3. Multivariate analyses revealed significant and independent correlations of all 3 coronary scores with LDL cholesterol (or apoB) and IGFBP-3; of 2 coronary scores with age, glucose, and insulin; and of 1 score with IGF-I. No significant correlations existed for waist-to-hip ratio (or body mass index) and DHEAS (or testosterone or SHBG). IGFBP-3 explained 9% to 14% and 3.5% to 10% of the variances of focal and diffuse lesions, respectively. In conclusion, IGFBP-3 and, with much less strength and consistency, insulin and IGF-I, but not markers of hypothyroidism, adrenopause, and andropause, have statistically significant and independent associations with coronary arteriosclerosis in men.     

Effect of obesity and body fat distribution on sex hormones and insulin in men

To investigate the relationship between body fat distribution, sex hormones, and hyperinsulinemia in male obesity, we examined 52 obese men (body mass index [BMI], 35.0 +/- 6.1, mean +/- SD) and 20 normal-weight controls. Their waist to hip circumference ratio (WHR), which was used as an index of fat distribution, was 0.985 +/- 0.052 and 0.913 +/- 0.061 (P less than .005), respectively. Compared with controls, obese men presented significantly lower levels of total (357 +/- 132 v 498 +/- 142 ng/dL; P less than .005) and free testosterone (14.2 +/- 2.9 v 17.1 +/- 2.6 pg/mL; P less than .05) and sex hormone-binding globulin (SHBG; 41.7 +/- 31.9 v 66.2 +/- 18.6 nmol/L; P less than .001) without any significant difference on the other sex steroid or on gonadotropin concentrations. Fasting and glucose-stimulated insulin and C-peptide levels were significantly higher in obese than in controls, and in obese with the WHR value greater than 0.97 (corresponding to the distribution median) than in those with WHR lower or equal to 0.97. BMI was negatively correlated with testosterone (P less than .005), free testosterone (P less than .01), and SHBG (P less than .001) and positively with fasting (P less than .001) and glucose-stimulated (P less than .005) C-peptide concentrations, whereas no relationship was found between these variables and WHR values. On the contrary, WHR was significantly correlated with fasting and post-glucose insulin levels (P less than .05), but not with those of sex steroids.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endogenous sex hormones, blood pressure change, and risk of hypertension in postmenopausal women: The Multi-Ethnic Study of Atherosclerosis

ObjectiveSex steroid hormones have been postulated to involve in blood pressure (BP) regulation. We examine the association of endogenous sex hormone levels with longitudinal change of BP and risk of developing hypertension in initially normotensive postmenopausal women.MethodsWe conducted prospective analysis among 619 postmenopausal women free of hypertension at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Change of BP and development of incident hypertension were assessed during a mean of 4.8 years follow-up.ResultsAfter adjusting for age, race/ethnicity, and lifestyle factors, baseline serum estradiol (E₂), total and bioavailable testosterone (T), dehydroepiandrosterone (DHEA) were each positively associated and sex-hormone binding globulin (SHBG) was inversely associated with risk of hypertension. Additional adjustment for body mass index eliminated the associations for E₂ and T but only attenuated the associations for DHEA and SHBG. The corresponding multivariable hazard ratios (95% CIs) in the highest quartile were 1.28 (0.83–1.97) for E₂, 1.38 (0.89–2.14) for total T, 1.42 (0.90–2.23) for bioavailable T, 1.54 (1.02–2.31) for DHEA, and 0.48 (0.30–0.76) for SHBG. Adjustment for fasting glucose, insulin, and C-reactive protein further attenuated the association for DHEA but not for SHBG. Associations of sex hormones with longitudinal BP change were similar.ConclusionIn postmenopausal women, higher endogenous E₂, T, and DHEA and lower SHBG were associated with higher incidence of hypertension and greater longitudinal rise in BP. The associations for E₂, T, and DHEA were mostly explained by adiposity, while the association for SHBG was independent of measures of adiposity, insulin resistance, and systemic inflammation.