Extensive expertise in endocrinology: UK stance on adult GH replacement: the economist vs the endocrinologist.

In the UK, through the use of a forced economic model, endocrinologists are in the curious position of offering GH replacement to some patients with severe GH deficiency (GHD) but withholding it from other patients with even more severe GHD. This approach is counter-intuitive to endocrine practice in treating endocrine deficiency states. For all other endocrine deficiencies, one would opt for treating those with the most severe biochemical evidence of deficiency first. If this endocrine approach was applied to adult GH replacement in an era of rationing, one would start with the GHD patients with a pathologically low IGF1 level. Given that the prevalence of subnormal IGF1 levels in a GHD population is age-dependent, this would result in GH replacement being offered to more young adult onset (AO) GHD and childhood onset GHD adults, and less often to middle-aged and elderly AO GHD adults. This in itself has the added advantage that the skeletal benefits appear more real in the former cohort of patients.

Growth hormone: current and future therapeutic applications.

The increased availability of growth hormone (GH) in the mid-1980s, as a result of advances in recombinant DNA techniques, has allowed research into the use of this hormone at physiological dosage, as replacement therapy for adults with GH deficiency (GHD) and at pharmacological dosages as a possible therapeutic agent, for a number of disease states. GHD adults have increased body fat and reduced muscle mass and consequently, reduced strength and exercise tolerance. In addition, they are osteopenic, have unfavourable cardiac risk factors and impaired quality of life. In these individuals, replacing GH reverses these anomalies, although it may not alter the reduced insulin-sensitivity. A proportion of adults with GHD perceive a dramatic improvement in their well-being, energy levels and mood following replacement. GH has protein and osteoanabolic, lipolytic and antinatriuretic properties. GH has been considered for the therapeutic treatment of frailty associated with ageing, osteoporosis, morbid obesity, cardiac failure, major thermal injury and various acute and chronic catabolic conditions. Initial small, uncontrolled studies for many of these clinical problems suggested a beneficial effect of GH, although, later placebo-controlled studies have not observed such dramatic effects. Furthermore, with a recent publication demonstrating an approximate 2-fold increase in mortality in critically ill patients receiving large doses of GH, the use of GH should remain in the realms of replacement therapy and research, until there are significant advances in our understanding.

The assessment of growth hormone status in normal young adult males using a variety of provocative agents.

OBJECTIVE: In adults, there are few data regarding GH responses to provocative stimuli other than insulin-induced hypoglycaemia. We have compared the GH response to four different growth hormone secretagogues and placebo in normal healthy adult males. DESIGN: This was a prospective, randomized, placebo-controlled study in 18 normal male subjects. After an overnight last, an intravenous cannula was inserted into the arm of each subject and a blood sample was taken for GH at -30, -15, and 0 minutes. Four provocative agents (intravenous insulin 0.2 IU/kg; intravenous arginine 20 g/m2 as an infusion over 30 minutes; oral clonidine, either 100 or 200 micrograms; intramuscular glucagon 1 mg) and placebo were administered to each subject in a randomized manner on different days. Further blood samples were taken at 15-minute intervals for 180 minutes for GH estimation. RESULTS: The median (range) GH peak response for each agent was insulin 107.7 (28.1-200) mU/l; arginine 22.3 (3.1-72.9) mU/l; glucagon 42 (11.8-200) mU/l; 100 micrograms clonidine 7.2 (< 1-22.2) mU/l; 200 micrograms clonidine 8.2 (1.1- 88) mU/l and placebo 2.4 (< 1-30.2) mU/l. The peak GH response to insulin-induced hypoglycaemia (ITT) was significantly greater than for any other agent (P < 0.0001). The peak GH response to glucagon was significantly greater than for arginine (P < 0.05), clonidine at 100 and 200 micrograms (P < 0.01) and placebo (P < 0.01). The peak GH response following administration of arginine was significantly greater than for clonidine 100 and 200 micrograms (P < 0.05), and placebo (P < 0.01). The peak GH response following clonidine 200 micrograms was not significantly greater than following clonidine 100 micrograms (P = 0.38) or placebo. On an individual basis two, six and 15 of 18 subjects failed to achieve a peak GH level of > 20 mU/l to glucagon, arginine and clonidine respectively. In complete contrast only one subject achieved a peak response of less than 40 mU/l (28.1 mU/l) to ITT. CONCLUSIONS: The most profound GH release is seen after insulin-induced hypoglycaemia. Glucagon appears to be more effective at inducing GH release than arginine. Clonidine at a dose of 100 or 200 micrograms is no more effective than placebo.

Characteristics of adults who wish to enter a trial of growth hormone replacement.

OBJECTIVE: It is possible that the degree of perceived well-being may influence the decision of an adult with GH deficiency to receive GH replacement. We have therefore sought factors which influenced whether or not such a patient wished to enter a study of GH replacement. DESIGN: Biochemical, anthropometric and demographic characteristics, and well-being, of patients who chose to enter a 12-month study of GH replacement at Christie Hospital NHS Trust were compared with those of patients who declined to enter the study. PATIENTS: Sixty-five adults with GH deficiency who entered a study of GH replacement and 33 adults with GH deficiency who were approached but who declined to enter the study. MEASUREMENTS: The two groups of patients were compared according to sex, age, height, weight, body mass index, peak serum GH response to provocative testing, estimated duration of GH deficiency, whether GH deficiency was of childhood or adult onset, presence or absence of additional pituitary hormone deficiencies, aetiology of GH deficiency, previous therapeutic interventions, employment status, marital status and living arrangement (65 entered vs 33 declined to enter). Well-being or distress was measured using the Nottingham Health Profile (NHP) (65 entered vs 20 declined to enter) and the Psychological General Well-being Schedule (PGWBS) (33 entered vs 19 declined to enter). RESULTS: Those who entered the study had significantly higher scores on the energy (P = 0.03) and emotional reaction (P = 0.02) subsections and on the total score (P = 0.04) of the NHP, indicating greater distress, and had a significantly lower score (P = 0.009) on the vitality subsection of the PGWBS, again indicating greater distress. Those who entered the study had a significantly lower prevalence of non-functioning pituitary adenoma (P = 0.02) but there was no other difference in biochemical, anthropometric or demographic characteristics between the two groups. CONCLUSION: Adults who enter a study of GH replacement exhibit greater distress on questionnaire assessment than those who decline to enter such a study. This bias must be considered when interpreting studies of the effect of GH replacement on well-being in adults.

Management of idiopathic growth hormone deficient patients during puberty.

Boys with idiopathic GH deficiency, treated with hGH and entering spontaneous puberty, have an onset of puberty and peak height velocity (PHV) at a late chronological age but normal bone age. PHV occurs at G3 with testicular volumes of 6-12 ml. The size of PHV and the height gain after G2 are similar to those of a normal delayed adolescent. In contrast, idiopathic GH deficient girls have an onset of puberty and PHV nearer to a normal chronological age and at an early bone age. PHV occurs at B2 and its size and the height gain after B2 are similar to those of normal girls. The length of time of pubertal growth is shorter in both GH deficient boys and girls. Very late induction of puberty in idiopathic GH deficient boys results in psychosocial damage and in bodily disproportion. It is suggested that induction of puberty be considered no later than 14.5 years in boys and 13.5 years in girls with the use of low-dose sex steroids. The decision to induce puberty should be taken to avoid psychosocial problems and be independent of proof of associated gonadotrophin deficiency. In GH deficient girls with early puberty, therapies to delay puberty may be considered. There are theoretical grounds for increasing the GH dose given during puberty, but present dose-response studies fail to include controls for important biological variables and are so far inconclusive. Cost-effectiveness is an important consideration. Increasing the frequency of injections probably improves the growth effect for a given dose of GH.