Growth hormone (GH) treatment causes salt and water retention, and this effect has been suggested to be mediated by activation of epithelial sodium channel (ENaC). Multi-system pseudohypoaldosteronism (PHA) is a salt wasting disease resulting from mutations in ENaC subunit genes. We examined effects of GH therapy for 12-21 months on the renin-angiotensin-aldosterone system (RAAS) in 12 children with idiopathic short stature (ISS) and a PHA patient with defective ENaC function and concomitant GH deficiency. On GH therapy (0.7 U/kg/week), plasma renin activity (PRA), serum aldosterone and insulin-like growth factor-I (IGF-I) levels were periodically determined every 1-3 months in all children. The PHA patient was studied for 6 yr during which time serum, urine, and sweat electrolytes and secretion rate were also examined before, on and off GH therapy. In the PHA patient, mean plasma aldosterone concentration, 7.7 nmol/l (278 ng/dl) before therapy (n=9) rose to 73 nmol/l (2650 ng/dl) 10 months after GH. PRA and IGF-I increased similarly, reaching a plateau between 8 and 12 months. Off GH, there was a decrease to pretreatment levels in 30 months. Aldosterone and PRA strongly correlated with IGF-I (r=0.66 and 0.67). GH therapy also improved the growth rate, and increased both sweat secretion rate and Na(+)/K(+) ratio. In children with ISS, aldosterone and IGF-I peaked 6-12 months after GH. Off GH their levels normalized in 3 months. These findings indicate that long-term GH activates the RAAS in both children with ISS and a PHA patient, and that this effect does not depend on a fully functional ENaC.