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Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science (A.B.S., S.H., I.S.-H., L.W., R.S., S.B.), Los Angeles, California 90059; Oklahoma Medical Research Foundation (P.A.), Oklahoma City, Oklahoma 73104; University of Southern California School of Medicine (T.A.B., R.B.), Los Angeles, California 90059; and Harbor-University of California-Los Angeles Medical Center (N.B.), Torrance, California 90502
Address all correspondence and requests for reprints to: Shalender Bhasin, M.D., University of California School of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059. E-mail: sbhasin{at}ucla.edu
The effects of T supplementation on insulin sensitivity, inflammation-sensitive markers, and apolipoproteins remain poorly understood. We do not know whether T’s effects on plasma lipids, apolipoproteins, and insulin sensitivity are dose dependent, or whether significant anabolic effects can be achieved at T doses that do not adversely affect these cardiovascular risk factors. To determine the effects of different doses of T, 61 eugonadal men, 18–35 yr of age, were randomly assigned to 1 of 5 groups to receive monthly injections of long-acting GnRH agonist to suppress endogenous T secretion and weekly injections of 25, 50, 125, 300, or 600 mg T enanthate for 20 wk. Dietary energy and protein intakes were standardized. Combined administration of GnRH agonist and graded doses of T enanthate resulted in nadir T concentrations of 253, 306, 542, 1345, and 2370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Plasma high density lipoprotein cholesterol and apolipoprotein A-I concentrations were inversely correlated with total and free T concentrations and were significantly decreased only in the 600 mg/wk group (change in high density lipoprotein cholesterol: -8 ± 2 mg/dl; P = 0.0005; change in apolipoprotein A-I: -16 ± 2 mg/dl; P = 0.0001). Serum total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, triglycerides, apolipoprotein B, and apolipoprotein C-III were not significantly correlated with T dose or concentration. There was no significant change in total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, triglycerides, apolipoprotein B, or apolipoprotein C-III levels at any dose. The insulin sensitivity index, glucose effectiveness, and acute insulin response to glucose, derived from the insulin-modified, frequently sampled, iv glucose tolerance test using the Bergman minimal model, did not change significantly at any dose. Circulating levels of C-reactive protein were not correlated with T concentrations and did not change with treatment in any group. Significant increments in fat-free mass, muscle size, and strength were observed at doses that did not affect cardiovascular risk factors.
Over a wide range of doses, including those associated with significant gains in fat-free mass and muscle size, T had no adverse effect on insulin sensitivity, plasma lipids, apolipoproteins, or C-reactive protein. Only the highest dose of T (600 mg/wk) was associated with a reduction in plasma high density lipoprotein cholesterol and apolipoprotein A-I. Long-term studies are needed to determine whether T supplementation of older men with low T levels affects atherosclerosis progression.
This work was supported by a research grant from the NIA (1RO1-AG-14369-01). Additional support was provided by Grants 1RO1-DK-49296-01 and 1RO1-DK-59627-01, FDA Grant (ODP001397), Clinical Trials Unit Grant U01-DK-54047, Research Centers for Minority Institutions Clinical Research Infrastructure Initiative P20-RR-11145, RCMI Grants G12-RR-03026 and U54-RR-14616, and General Clinical Research Center Grant MO1-RR-00425.
Abbreviations: AIRG, Acute insulin response to glucose; CRP, C- reactive protein; DI, glucose disposition index; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; SG, glucose effectiveness index; SI, insulin sensitivity index; VLDL-C, very low density lipoprotein cholesterol.
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