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Increasing Insulin Resistance Is Associated with a Decrease in Leydig Cell Testosterone Secretion in Men

Reproductive Endocrine Unit (N.P., M.H., A.A.D., E.V., M.Y., F.J.H.), Department of Medicine (D.E.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Surgery, University of Massachusetts Medical Center (D.E.), Worcester, Massachusetts 01655

Address all correspondence and requests for reprints to: Dr. Frances J. Hayes, Reproductive Endocrine Unit, BHX 511, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: fhayes{at}partners.org.

Insulin resistance is associated with low testosterone (T) levels in men, the mechanism of which is unclear. Thus, the aim of this study was to evaluate the hypothalamic-pituitary-gonadal axis in men with a spectrum of insulin sensitivity. Twenty-one men (aged 25–65 yr) had a glucose tolerance test and assessment of insulin sensitivity using a hyperinsulinemic-euglycemic clamp. Insulin sensitivity, expressed as the M value (milligrams per kilograms^–1 per minute^–1), was calculated from the glucose disposal rate during the final 30 min of the clamp. Eighteen subjects had blood sampling every 10 min for 12 h to assess LH pulsatility. Hypogonadism was then induced with a GnRH antagonist, followed by sequential stimulation testing with GnRH (750 ng/kg, iv) and human chorionic gonadotropin (hCG; 1000 IU, im) to assess pituitary and testicular responsiveness, respectively. Nine subjects had normal glucose tolerance, nine had impaired glucose tolerance, and three had diabetes mellitus. There was a positive relationship between M and T levels (r = 0.46; P < 0.05). No relationship was seen between M and parameters of LH secretion, including mean LH levels, LH pulse amplitude, LH pulse frequency, and LH response to exogenous GnRH administration. In contrast, a strong correlation was observed between M and the T response to hCG (r = 0.73; P < 0.005). Baseline T levels correlated with the increase in T after hCG administration (r = 0.47; P < 0.05). During the clamp, T levels increased from a baseline level of 367 ± 30 to 419 ± 38 ng/dl during the last 30 min (P < 0.05). From these data we conclude that insulin resistance is associated with a decrease in Leydig cell T secretion in men. Additional studies are required to determine the mechanism of this effect.

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