CONTEXT: The contribution of endogenous testosterone (TS) in the functional integrity of peripheral circulation in men was studied. OBJECTIVE: The objective of this study was to observe vascular reactivity in male congenital hypogonadal patients before and after prolonged exposure to normal TS levels. DESIGN: This was a longitudinal study in which, basically and after 6-month (range, 6-8 months) androgen treatment, we investigated forearm blood flow (strain-gauge plethysmography) changes induced by intraarterial acetylcholine (Ach), alone or in the presence of N(G)-monomethyl-l-arginine infusion, and by sodium nitroprusside. We also evaluated, by Doppler ultrasound, flow-mediated dilation of the brachial artery (BA) in response to reactive hyperemia (RH) and glyceryl trinitrate (GTN). SETTING: The studies were conducted at university referral centers for andrologic and blood pressure diseases. PATIENTS: Eight adult male Caucasian hypogonadal patients and nine healthy matched control subjects were studied. INTERVENTION: Intervention was TS enanthate (250 mg in 1 ml oily solution) by im injection every 3 wk. RESULTS: At baseline, BA diameter and RH, flow-mediated dilation, and GTN responses showed no difference between the two groups. TS therapy increased plasma total TS (P < 0.02) and reduced high-density lipoprotein (P < 0.01) and total cholesterol (P < 0.04). It did not affect vasodilation to sodium nitroprusside (355 +/- 47%), but it further reduced the vascular response to Ach (187 +/- 29%, P < 0.01 vs. baseline) and abolished the inhibition by N(G)-monomethyl-l-arginine on Ach (inhibition, 3.2%). Moreover, TS therapy decreased (P < 0.01) flow-mediated dilation, whereas it did not modify BA diameter and responses to RH and GTN. CONCLUSIONS: Hypogonadal patients show impaired vascular reactivity, including endothelial-dependent vasodilation due to reduced nitric oxide availability. TS administration further impairs nitric oxide availability in these patients.