Do reproductive hormones modify insulin sensitivity and metabolism in older men? A randomized, placebo-controlled clinical trial of recombinant human chorionic gonadotropin

Abstract

Objective: In order to assess the hormonal determinants of insulin sensitivity and related components of the metabolic syndrome, we evaluated the effect of subcutaneous recombinant human chorionic gonadotropin (r-hCG; Ovidrel) on insulin sensitivity, vascular reactivity, leptin, insulin-like growth factor-I (IGF-I) and lipids in ambulant, community dwelling men .60 years of age with serum testosterone # 15 nmol/l on two occasions. Design: Forty eligible men were randomized to receive 250 mg (5000 IU) r-hCG subcutaneously twice each week ðn ¼ 20Þ or placebo ðn ¼ 20Þ injections for 3 months, and all subjects (mean age 67 (range 60 -85) years) completed the study. Methods and results: Groups were well matched for height, weight, anthropometry and insulin sensitivity. Insulin sensitivity was assessed by homeostasis model (HOMA) and euglycemic hyperinsulinemic clamp at baseline and at the end of the treatment period in the first 30 men who did not have diabetes mellitus. Insulin sensitivity (HOMA and euglycemic clamp) or b cell function (HOMA) were not significantly changed by r-hCG despite a significant increase in lean body mass (,2 kg, P , 0:001) and reduced fat mass (, 1 kg, P , 0:05). Subcutaneous fat (skinfold measurements), abdominal girth and serum leptin all decreased and IGF-I tended to increase, but these changes were not significant. Recombinant hCG significantly reduced total and low density lipoprotein cholesterol, and triglycerides, but did not significantly alter high density lipoprotein cholesterol. Endothelial function (vascular reactivity) was not significantly worsened. We conclude that three-months of treatment with r-hCG demonstrates expected hormonal effects, improved lipids and did not worsen vascular endothelial function. Insulin sensitivity was not altered despite suggestive changes in body composition. Conclusions: These findings suggest short-term metabolic and cardiovascular safety and argue against an important role for androgens in the hormonal control of insulin sensitivity in older men.

Testosterone therapy increased muscle mass and lipid oxidation in aging men

“…In accordance with our findings, four placebo-controlled studies of testosterone therapy in aging men found no effect on insulin sensitivity using surrogate markers of insulin resistance such as the minimal model (Basu et al 2007;Nair et al 2006) and HOMA-IR (Svartberg et al 2008;Emmelot-Vonk et al 2008). Correspondingly, a placebo-controlled, double-blinded study of aging men treated with HCG therapy to increase endogenous testosterone serum levels showed no increase in insulin sensitivity measured by the euglycemic hyperinsulinemic clamp despite an increase in LBM (Liu et al 2003). On the other hand, two placebo-controlled, double-blinded studies have reported an increase in insulin sensitivity during testosterone therapy assessed by the euglycemic hyperinsulinemic clamp in obese middle-aged men, in whom no predefined cutoff level for testosterone was used (Marin et al 1992;Marin et al 1993).…”

Body composition, metabolic syndrome and testosterone in ageing men

“…74,75 Three randomized controlled trials (RCTs) in older men with low-normal serum testosterone have examined the effect of physiological androgen replacement on vascular reactivity. 42,76,77 No change in FMD was seen with 3 months of DHT 42 or hCG 76 or with 12 months of transdermal testosterone. 77 FMD was increased with short-term physiological and acute supraphysiological testosterone treatments in middleaged men with underlying coronary artery disease.…”

“…55 In ageing men, hCG administered for 3 months did not affect insulin sensitivity (as measured by euglycaemic clamp). 76 It is unclear as to whether changes in serum testosterone mediate insulin sensitivity independent of their effect on FM (specifically visceral fat). Comparison of data sets is difficult as those middle-aged men showing improved insulin sensitivity had higher FM and greater waist circumference at baseline 52 Body composition, metabolic syndrome and testosterone in ageing men CA Allan et al than the ageing men treated with hCG.…”

“…Comparison of data sets is difficult as those middle-aged men showing improved insulin sensitivity had higher FM and greater waist circumference at baseline 52 Body composition, metabolic syndrome and testosterone in ageing men CA Allan et al than the ageing men treated with hCG. 76 Furthermore, the middle-aged cohort had significant visceral fat loss with treatment, 52 and although total FM declined in the older men, there are no data regarding regional adipose tissue changes; 76 it is also possible that the duration of hCG treatment was insufficient. Although anabolic steroids (oxandrolone) demonstrate a significant reduction in abdominal fat, they have been associated with insulin resistance, thought to be mediated through hepatotoxicity.…”

A view of geriatrics through hormones. What is the relation between andropause and well-known geriatric syndromes?

“…A bidirectional relation is possible where obesity and hyperinsulinemia induce a decrease in T levels, which in turn have a negative effect on body composition and insulin levels. Conversely, as supported by a study by Liu et al [97] on non diabetic obese men, TRT has a positive effect of on insulin sensitivity. TRT also improved glycemic control in hypogonadal men with T2D [98].…”