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 if 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 weeks 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 (HOMA-IR), Matsuda insulin sensitivity index (ISI)), and insulin secretion (corrected insulin response). Serum cortisol, leptin, adiponectin, free fatty acids, interleukin-6 (IL-6), C reactive protein (CRP), and tumor necrosis factor alpha (TNF-)) levels were also measured.

Results: BMI 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), HOMA-IR increased from 1.07 ± 0.2 to 1.4 ± 1.01 (P < 0.005), and ISI 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), while 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 BMI or leptin levels suggest that sex steroids modulate insulin sensitivity in the absence of apparent or detectable changes in body composition.