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Growth hormone replacement in adults: What dose?

Defining optimum replacement therapy requires the accurate measurement of a tissue marker specific for the hormone being prescribed. The assessment of thyroxine, oestrogen, and glucocorticoid replacement therapy has been bedevilled by a lack of accurate tissue markers and, when present, the lack of specificity in their measurement, e.g. bone mineral density. In contrast, for growth hormone there are clear physiological markers of its action in children, but determining the optimum dose regime for adults will prove a formidable challenge. In a child, linear growth provides a sophisticated integrated tissue marker of GH action. The greater availability of GH following its commercial biosynthetic production in 1985 led to a lively debate about the definition of GH deficiency/insufficiency and the ideal therapeutic regimen to promote optimal growth. It is now accepted that GH is as effective by subcutaneous as by intramuscular injection, that once daily injections promote growth more efficiently than thrice weekly, and that the dose may need to be increased during puberty (Jrargensen, 1991). The same assessment now needs to be repeated in adults; however, unlike children there is not the sensitive tissue marker of linear growth. The syndrome of adult GH-deficiency has recently been defined in this journal (Cuneo et al., 1992). The cardinal features are that patients have a depressed mood, abnormal body composition and lipid profile, reduced exercise capacity, decreased bone density, and may be more prone to cardiovascular death. A number of short-term controlled studies have now demonstrated that GH replacement therapy can improve mood and reverse some of the abnormal metabolic and physiological changes associated with adult GH-deficiency (Jrargensen et al., 1989; Salomon et al., 1989). Initial studies used dose regimens (2-3 IU/m*/day) based on those established in children: in some studies these doses have been associated with a high incidence of side-effects which were reduced when the dose was lowered (Salomon et al., 1989). Comparison of dose regimens between studies is complicated by the diversity with which dose regimens are reported-mg, pg, IU per m2 per kg body weight per day per week. We need a uniform method of dose assignment but a rough guideline is that for an average 70 kg man, 1 IU/m2/ day = 0.025 IU/kg/day = 0.01 mg/kg/day = 0.175 IU/kg/ week = 0-07 mg/kg/week. An initial approach to considering dose is to look at production rates in normal individuals. However, physiological GH secretion is pulsatile, increases at puberty, decreases after the age of forty, is greater in women during their fertile years, and is influenced by nutritional state. Studies are now required to define GH production rate throughout life and to relate this rate to body composition and metabolic parameters such as IGF-I levels, although a complicating issue is the lack of uniformity among assays for GH. The aim of replacement therapy is usually to mimic nature; however, the subcutaneous administration of GH imposes some restrictions on this. In children, daily injections promote more growth than thrice weekly and there are data showing that nitrogen retention is greater if the GH injection is given at night simulating normal physiology (Rudman et a!., 1973). Daily injections seem a reasonable compromise and have been adopted in most adult studies so far reported. It might also be argued that some of the changes of senescence are related to a decline in GH secretion and that GH replacement should not be reduced in the elderly if maximal benefit is sought (Lancet, 1991). Mraller and colleagues in this issue (Maller et al., 1993) have made the first important attempt to define a doseresponse to GH in ten GH deficient adults aged 21-39 years. The patients were treated with GH for 3 consecutive 4-week periods with the following doses of GH in fixed order: 1, 2 and 4 IU/m2/day. Serum IGF-I, IGFBP-3, insulin and lipid intermediates all increased and fat mass decreased in a dose dependent manner without plateau. Importantly, the study included age and sex matched controls. Based primarily on IGF-I and IGFBP-3 levels the authors conclude that a dose of 1-2 IU/mz/day is adequate. This dose is less than that used in previous studies of GH replacement. The goal of therapy is not only to maximize the benefits but also to minimize the risks. This is especially true of GH replacement therapy in adults where we know that long-term excessive GH levels result in acromegaly with an increase in morbidity and mortality. The characteristic feature of GH secretion in acromegaly is persistent elevation in GH levels without the trough or undetectable levels which are seen in normal individuals. The GH profile seen after a subcutaneous injection of G H gives a single peak with a prolonged elevation of GH similar to that seen in acromegaly. Patients receiving long-term G H therapy will need long-term followup to monitor body composition, cardiac risk factors, and the small but possible risk of increased malignancy (Ezzat & Melmed, 1991). It is now clear that GH plays an important role in adult metabolism and that GH replacement can benefit some