Clinical Endocrinology (1997) 46, 473–481 The safety profile of GH replacement therapy in adults J. J. Chipman*, A. F. Attanasio§, M. A. Birkett§, P. C. Bates§, S. Webb² and S. W. J. Lamberts‡ * Eli Lilly & Co, Indianapolis, USA, §Lilly Research Centre, Windlesham, Surrey UK, ² Hospital Santa Cruz Y San Pablo, Barcelona, Spain and ‡ University Hospital Dijkzigt, Rotterdam, The Netherlands (Received 5 August 1996; returned for revision 27 September 1996; finally revised 4 November 1996; accepted 6 February 1997) Summary OBJECTIVE The benefits of GH replacement in GH- deficient adult patients are becoming accepted but the safety profile continues to be defined. The GH deficiency in adults may have arisen in either child- hood or during adult life and these two groups differ with regard to history of disease. The aim of the present report was to study differences in safety profile between these two groups during long-term replacement therapy with recombinant human GH (hGH). Possible factors which placed a patient at risk of experiencing an adverse event were also examined. PATIENTS AND DESIGN GH-deficient adult patients were randomized into two study protocols, differing only in age of onset of the GH deficiency syndrome. There were 98 patients with adult-onset and 67 patients with childhood-onset GH deficiency. Each study consisted of a 6-month double-blind placebo- controlled phase followed by an open-label hGH treat- ment phase. Glucose tolerance, incidence of treat- ment-emergent adverse events and relationship to IGF status were studied throughout the 36 months of treatment. RESULTS Human growth hormone-related adverse events were reported less commonly in childhood- onset patients compared with adult-onset patients. Adult-onset patients who continued into the open- label therapy phase reported an increased incidence of arthralgia, myalgia and paraesthesia. There were significant increases in fasting glucose with hGH therapy but values remained within the normal range. Hypertension was reported in 7 7% of adult-onset patients at 18 months of hGH, which was within the expected prevalence for the number of patients, but was not reported for any childhood-onset patients. Only in adult-onset patients were sufficient adverse events reported to enable analysis of risk factors. Patients reporting hGH-related adverse events were significantly heavier and, therefore, received more hGH. There was a significantly greater increase in IGF-I and IGFBP-3 in the first month in patients who experienced hGH-related adverse events compared with those who did not. CONCLUSION The risks of replacement therapy with hGH in GH-deficient adults varied with pathogenesis of disease; hGH-related adverse events occurred more frequently in patients with adult-onset com- pared with those with childhood-onset GH deficiency. In the adult-onset patients there was an increased risk of adverse events in heavier patients and those who had the greatest increases in IGF-I and IGFBP-3 at 1 month of therapy. GH deficiency in hypopituitary adults has been well character- ized in recent years (Lamberts et al., 1992; Rose ´n et al., 1995). The onset of GH deficiency in adults occurs either in childhood (childhood onset) or is acquired in adulthood (adult onset). As adults, these two populations differ with regard to their pathogenesis and history of disease. Patients with the adult- onset form of GH deficiency usually have acquired disease of pituitary or hypothalamic cause whereas the childhood-onset form is an idiopathic disease in the majority of the patients (Attanasio et al., 1997). The benefits of replacement therapy have been described extensively; however, the safety profile of replacement therapy continues to be defined as experience accumulates and dosage algorithms are refined. Since adults and children with GH deficiency differ with regard to pathogenesis of the disorder, concomitant chronic diseases, and requirements for human growth hormone (hGH) replacement therapy, endocrinologists might anticipate that the safety profile for GH-deficient adults may differ somewhat from the established safety profile for GH-deficient children treated with hGH. Furthermore, there may be differences in the safety profile between adult-onset and childhood-onset GH deficiency within the adult population. These possible safety profile differences among patients receiving hGH replacement therapy have been examined in the 473  1997 Blackwell Science Ltd Correspondence: A. F. Attanasio, Lilly Research Centre, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, UK. Fax: 01276 853588.