OBJECTIVES: Hypopituitary adults with growth hormone deficiency (GHD) have an increased cardiovascular mortality, although the mechanisms remain unclear. Endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailability, is a key early event in atherogenesis and is associated with increased vascular smooth muscle tone and arterial stiffening. DESIGN AND PATIENTS: In a randomized, double-blind, placebo-controlled study, we investigated the effects of GH replacement on endothelial function and large-artery stiffness in 32 GHD adults (19 males, 13 females) (age range 19-64 years) over a 6-month period. Thirty-two age- and sex-matched healthy controls were also studied. MEASUREMENTS: Endothelial function was assessed using ultrasonic wall tracking to measure flow-mediated dilatation (FMD) of the brachial artery. Large artery stiffness was assessed by pulse wave analysis of the radial artery pressure waveform, allowing determination of the corresponding central arterial pressure waveform and derivation of the augmentation index. Fasting lipid profiles, glucose and insulin were also measured. RESULTS: At baseline, FMD (mean±SD) was impaired in GH-deficient subjects vs. controls (3.4±2.3 vs. 5.7±2.0%,P < 0.0001), although endothelium-independent dilatation was similar. The augmentation index was higher in GH-deficient subjects vs. controls (23±12 vs. 14±14%, P < 0.01). GH-deficient subjects had higher LDL cholesterol (4.1±0.8 vs. 3.5±0.8 mmol/l, P < 0.01) and lower HDL cholesterol (1.1±0.3 vs. 1.4±0.4 mmol/l, P < 0.01). In GH-deficient subjects, there were inverse correlations between LDL cholesterol and FMD (r = -0.40, P < 0.05) and between FMD and the augmentation index (r = -0.58, P < 0.01). Regression analysis identified FMD as an independent predictor of the augmentation index (P < 0.0001). In comparison with baseline, GH replacement resulted in an increase in FMD (5.0<2.6 vs. 2.8±1.9%, P < 0.01). There were decreases in central aortic systolic pressure (117±15 vs. 123±17 mmHg, P < 0.01), diastolic pressure (82±10 vs. 86±8 mmHg, P < 0.01) and the augmentation index (22±8% vs. 26±10%, P < 0.05) despite unchanged brachial pressure indices. LDL cholesterol also decreased (3.5±0.8 vs. 4.2±0.8 mmol/l, P < 0.01). There were no significant changes in the placebo group. CONCLUSIONS: Adult GHD is associated with endothelial dysfunction and increased large-artery stiffness. An improvement in endothelial function and a reduction in arterial stiffness following GH replacement suggests an important therapeutic role for GH in reducing cardiovascular risk associated with adult GHD.