BACKGROUND: Adult growth hormone deficiency (AGHD) is associated with fatigue, tiredness and myalgias, which improve after initiating recombinant human GH (rhGH) therapy. AIM: To conduct an extensive neuromuscular investigation of patients with AGHD in an attempt to explain their neuromuscular symptoms. PATIENTS AND METHODS: Twenty adult patients (11 males) with untreated GHD of whom 10 were childhood-onset (CO) underwent a prospective neurological protocol, including physical examination and a neurophysiological study that comprised sensory and motor neurography, repetitive stimulation, electromyogram (EMG) and interference pattern analysis (IPA). In the first seven patients (four CO), a biceps muscle biopsy was also performed for histochemical analysis and Western blot, and investigation of signal transducers and activators of transcription (STATs)-1 and -3 and the two isoforms STAT-5a and -5b. RESULTS: Neuromuscular examination, sensory and motor neurography and repetitive stimulation were normal in 20/20 patients. Fourteen [seven CO and seven adult-onset (AO)] of the 20 patients had abnormal EMG and/ or IPA suggestive of a neurogenic involvement. In those seven patients with initially abnormal results, who also remained on regular rhGH for at least 1 year, repeated IPA was normal in six and improved in the remaining patient (P = 0.004). The biceps muscle biopsy disclosed abnormal groupings in the seven cases tested, indicative of a neurogenic pattern. No changes in skeletal muscle STAT-1 and -3 were seen compared to controls, but a marked increase in both STAT-5 isoforms was observed in all seven patients. CONCLUSION: Skeletal muscle of patients with both adult-onset and childhood-onset adult GH deficiency shows a neuromuscular dysfunction, indicated by the muscle biopsy and the neurophysiological study, which in the subgroup of treated patients responds positively to rhGH therapy. The results obtained suggest that the STAT-5 signal transduction pathway in muscle is abnormal in adult GH deficiency.