Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial.
CONTEXT:Dehydroepiandro-sterone (DHEA) administration has been shown to reduce accumulation of abdominal visceral fat and protect against insulin resistance in laboratory animals, but it is not known whether DHEA decreases abdominal obesity in humans. DHEA is widely available as a dietary supplement without a prescription. OBJECTIVE: To determine whether DHEA replacement therapy decreases abdominal fat and improves insulin action in elderly persons. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial conducted in a US university-based research center from June 2001 to February 2004. PARTICIPANTS: Fifty-six elderly persons (28 women and 28 men aged 71 [range, 65-78] years) with age-related decrease in DHEA level. INTERVENTION: Participants were randomly assigned to receive 50 mg/d of DHEA or matching placebo for 6 months. MAIN OUTCOME MEASURES: The primary outcome measures were 6-month change in visceral and subcutaneous abdominal fat measured by magnetic resonance imaging and glucose and insulin responses to an oral glucose tolerance test (OGTT). RESULTS: Of the 56 men and women enrolled, 52 underwent follow-up evaluations. Compliance with the intervention was 97% in the DHEA group and 95% in the placebo group. Based on intention-to-treat analyses, DHEA therapy compared with placebo induced significant decreases in visceral fat area (-13 cm2 vs +3 cm2, respectively; P = .001) and subcutaneous fat (-13 cm2 vs +2 cm2, P = .003). The insulin area under the curve (AUC) during the OGTT was significantly reduced after 6 months of DHEA therapy compared with placebo (-1119 muU/mL per 2 hours vs +818 muU/mL per 2 hours, P = .007). Despite the lower insulin levels, the glucose AUC was unchanged, resulting in a significant increase in an insulin sensitivity index in response to DHEA compared with placebo (+1.4 vs -0.7, P = .005). CONCLUSION: DHEA replacement could play a role in prevention and treatment of the metabolic syndrome associated with abdominal obesity.
JAMA. 2004 Nov 10;292(18):2243-8
The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men.
Testosterone has immune-modulating properties, and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNFalpha, IL-1beta, and IL-6 and potentiate the expression of the antiinflammatory cytokine IL-10. We report a randomized, single-blind, placebo-controlled, crossover study of testosterone replacement (Sustanon 100) vs. placebo in 27 men (age, 62 +/- 9 yr) with symptomatic androgen deficiency (total testosterone, 4.4 +/- 1.2 nmol/liter; bioavailable testosterone, 2.4 +/- 1.1 nmol/liter). Compared with placebo, testosterone induced reductions in TNFalpha (-3.1 +/- 8.3 vs. 1.3 +/- 5.2 pg/ml; P = 0.01) and IL-1beta (-0.14 +/- 0.32 vs. 0.18 +/- 0.55 pg/ml; P = 0.08) and an increase in IL-10 (0.33 +/- 1.8 vs. -1.1 +/- 3.0 pg/ml; P = 0.01); the reductions of TNFalpha and IL-1beta were positively correlated (r(S) = 0.588; P = 0.003). In addition, a significant reduction in total cholesterol was recorded with testosterone therapy (-0.25 +/- 0.4 vs. -0.004 +/- 0.4 mmol/liter; P = 0.04). In conclusion, testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol. Twenty of these men had established coronary disease, and because total cholesterol is a cardiovascular risk factor, and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque, these properties may have particular relevance in men with overt vascular disease.
J Clin Endocrinol Metab. 2004 Jul;89(7):3313-8
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/m(2); 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.
Diabetes Obes Metab. 2004 May;6(3):208-15
Use of 5-alpha-reductase inhibitors in the prevention of prostate cancer.
5-alpha-reductase inhibitors are now in widespread use for the treatment of benign prostatic hyperplasia (BHP) and these molecules have recently come under the spotlight in prostate cancer. Their peripheral “hormonal” action inducing reduced intraprostatic DHT synthesis seems to involve them in this hormone-dependant disorder. Finasteride evaluated in the treatment of BPH (PLESS study) was found to have a preventive effect on the incidence of cancer and this activity was assessed in a specific trial (PCPT study). Nevertheless, in the latter randomized study with a 7-year follow-up period, a reduction in the global incidence of the number of cases of cancers was associated with an increase in the number of high-grade cancers. A slight reduction in prostate cancer was also noted in the studies with dutasteride in BPH (ARIA3001, ARIA3002 and ARIB3003). An international multicenter study (REDUCE) is currently being conducted to confirm the preventive value of this molecule which has a more complete activity than finasteride with its inhibitory action on the two 5-alpha-reductase iso-enzymes, and may therefore have a clearer efficiency and rule out the risk of onset of high-grade cancer.
Ann Urol (Paris). 2004 Dec;38 Suppl 2:S35-42
Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study.
BACKGROUND:Overt hypothyroidism has been found to be associated with cardiovascular disease. Whether subclinical hypothyroidism and thyroid autoimmunity are also risk factors for cardiovascular disease is controversial. OBJECTIVE: To investigate whether subclinical hypothyroidism and thyroid autoimmunity are associated with aortic atherosclerosis and myocardial infarction in postmenopausal women. DESIGN: Population-based cross-sectional study. SETTING: A district of Rotterdam, The Netherlands. PARTICIPANTS: Random sample of 1149 women (mean age +/- SD, 69.0 +/- 7.5 years) participating in the Rotterdam Study. MEASUREMENTS: Data on thyroid status, aortic atherosclerosis, and history of myocardial infarction were obtained at baseline. Subclinical hypothyroidism was defined as an elevated thyroid-stimulating hormone level (>4.0 mU/L) and a normal serum free thyroxine level (11 to 25 pmol/L [0.9 to 1.9 ng/dL]). In tests for antibodies to thyroid peroxidase, a serum level greater than 10 IU/mL was considered a positive result. RESULTS: Subclinical hypothyroidism was present in 10.8% of participants and was associated with a greater age-adjusted prevalence of aortic atherosclerosis (odds ratio, 1.7 [95% CI, 1.1 to 2.6]) and myocardial infarction (odds ratio, 2.3 [CI, 1.3 to 4.0]). Additional adjustment for body mass index, total and high-density lipoprotein cholesterol level, blood pressure, and smoking status, as well as exclusion of women who took beta-blockers, did not affect these estimates. Associations were slightly stronger in women who had subclinical hypothyroidism and antibodies to thyroid peroxidase (odds ratio for aortic atherosclerosis, 1.9 [CI, 1.1 to 3.6]; odds ratio for myocardial infarction, 3.1 [CI, 1.5 to 6.3]). No association was found between thyroid autoimmunity itself and cardiovascular disease. The population attributable risk percentage for subclinical hypothyroidism associated with myocardial infarction was within the range of that for known major risk factors for cardiovascular disease. CONCLUSION: Subclinical hypothyroidism is a strong indicator of risk for atherosclerosis and myocardial infarction in elderly women.
Ann Intern Med. 2000 Feb 15;132(4):270-8