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Letters to the Editor |
Sahlgrenska University Hospital S-413 45 Göteborg, Sweden
Until now, all treatment trials with growth hormone (GH) in GH-deficient adults have administrated GH according to body weight or body surface and ignored the presence of an individual responsiveness to GH, as recently reported by us in this journal (1). This rationale of dosing GH is not physiological because GH secretion is higher in fertile women than in young men (2), lower in adiposity, and decreases with increasing age (3). Thus, patients with higher body weight, independent of age and gender have received the highest doses of GH, which in turn has resulted in high frequency of side-effects in these patients (4, 5). This may explain why some trials comprising young and mostly lean adults have reported no or few side-effects (6, 7).
In our more recent paper (8), persistent levels above baseline of markers reflecting bone formation and bone resorption are interpreted by Dr. Amato, in the accompanying letter, as adverse effects of GH treatment. It is true that acromegalic patients have increased bone turnover. In contrast, adults with GH deficiency may have low bone turnover (9). We, however, suggest that the increased overall remodeling rate is a prerequisite for the increase in bone mineral content and density (BMD) observed in our trial. A change towards normal occurred in terms of BMD, and the continuing of the increased positive remodeling balance may result in more patients obtaining normal BMD during more prolonged GH treatment. Amato et al. demonstrated in a recent trial that cortical bone density normalized in nine young GH-deficient adults, aged 25–34 yr, using 70 µg/kg per week of GH (10). Their dose level was 20% lower than the target dose of GH used in our trial but, in fact, 28% higher than the daily dose of GH given in our study after 2 yr (8). Moreover, Amato et al. demonstrated an increase and a normalization of both serum insulin-like growth factor I and osteocalcin (10) in response to GH therapy, but after discontinuation of treatment, both markers returned to baseline levels, which were lower in the GH-deficient subjects than in the control group. Thus, the persistent increase of biochemical bone markers in our study should not be interpreted as a side-effect of GH treatment but merely as an increase in bone remodeling.
Dr. Amato cited another recent trial of ours (11), which indicates that the therapeutic window with GH in terms of heart structure and function is probably not as wide as has been thought, particularly during long-term replacement. However, direct extrapolation of data from acromegalic patients to GH-deficient patients with GH therapy seems inappropriate, as the production rate of GH in acromegaly far exceeds the ordinary GH replacement dose.
We agree that, in context of the current experience and knowledge of previous protocols, increasing the dose of GH without any consideration of the individual response to GH is not rational. Hormonal replacement should mimic the normal physiology to minimize the risk of side-effects in the life-long GH replacement in adults. We should therefore consider individual responsiveness and also be aware of the difference between patterns of GH under normal conditions and during subcutaneous administration. When studying long-term benefits and the safety of GH replacement in adults with GH deficiency, we should emphasize the incipient risks of cardiovascular disease (11, 12) and of neoplasia in particular, because the most common cause of GH deficiency in adults is pituitary or peripituitary tumors.
The rationale for GH dosage is, at present, to consider individual responsiveness to GH. As no optimal marker for physiological replacement is available, we have suggested that the initial dose of GH should be low and then increased individually according to the combination of clinical response, normalization of serum insulin-like growth factor-I concentration, and body composition (4, 13).
Footnotes
1 Address all correspondence to: Gudmundur Johannsson, MD, Research Center
for Endocrinology and Metabolism, Sahlgrenska University Hospital,
Göteborg, Sweden S-413 45. 
Received December 12, 1996.
References
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