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Acute Sex Steroid Withdrawal Reduces Insulin Sensitivity in Healthy Men with Idiopathic Hypogonadotropic Hypogonadism

Reproductive Endocrine Unit of the Department of Medicine (M.A.Y., A.A.D., N.P., E.H., F.J.H.) and Department of Biostatistics and General Clinical Research Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Frances J. Hayes, MB, FRCPI, Reproductive Endocrine Unit, Massachusetts General Hospital, Bartlett Hall Extension 511, Boston, Massachusetts 02114. E-mail: fhayes{at}partners.org.

Context: Evidence suggests that testosterone (T) influences insulin sensitivity in men. The mechanism of this effect is unclear but is thought to involve changes in body composition.

Objective: The aim of this study was to determine whether acute sex steroid withdrawal decreases insulin sensitivity in young, healthy men with idiopathic hypogonadotropic hypogonadism (IHH).

Design: This was a 2-wk prospective study.

Setting: The study was conducted at a General Clinical Research Center.

Patients: Twelve men with IHH (age 40.8 ± 2.8 yr) were studied: 1) on hormone replacement with normal T levels and 2) 2 wk after discontinuing therapy.

Main Outcome Measures: Each evaluation comprised a 75-g oral glucose tolerance test with assessment of insulin sensitivity (fasting insulin levels, homeostatic model assessment for insulin resistance, and Matsuda insulin sensitivity index) and insulin secretion (corrected insulin response). Serum cortisol, leptin, adiponectin, free fatty acids, IL-6, C-reactive protein, and TNF- levels were also measured.

Results: Body mass index was unchanged (27.1 ± 1.1 to 27.2 ± 1.1 kg/m²). Serum T levels decreased from 529 ± 65 to 28 ± 8 ng/dl (P < 0.00005). Fasting insulin levels increased from 4.9 ± 0.7 to 6.2 ± 0.6 µU/ml (P = 0.005), homeostatic model assessment of insulin resistance increased from 1.07 ± 0.2 to 1.4 ± 1.01 (P < 0.005), and insulin sensitivity index decreased from 11.0 ± 2.3 to 7.5 ± 0.7 (P < 0.05). There was a trend for fasting glucose levels to increase, 86.7 ± 1.3 to 90.8 ± 1.7 mg/dl (P = 0.09). IL-6 levels increased from 1.2 ± 0.2 to 2.4 ± 0.5 pg/ml (P < 0.01), whereas TNF- levels decreased from 1.0 ± 0.1 to 0.6 ± 0.1 pg/ml (P < 0.05). No other significant changes were observed.

Conclusions: 1) Acute sex steroid withdrawal reduces insulin sensitivity in young healthy IHH men. 2) The acuity of the hypogonadism and absence of changes in body mass index or leptin levels suggest that sex steroids modulate insulin sensitivity in the absence of apparent or detectable changes in body composition.