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Growth Hormone Therapy in GH-Deficient Adults: The Problem of the Dose¹

Institute of Endocrinology IInd University of Naples Naples, Italy

We read with great interest the paper by Johannsson et al. (1), recently published in JCEM about the effects on bone structure and metabolism of 2 yr of growth hormone (GH) therapy and the recent paper by the same group (2) on the cardiac effects of prolonged GH treatment in GH deficient adults (GHDA). However, we believe there are certain important considerations. Beside the beneficial effects of this therapy, the patients showed several adverse effects. Among these, there were features seen in acromegaly such as the increase of biochemical bone markers (Osteocalcin, PICP, and ICTP) after 2 yr. of GH treatment, "After 2 yr of treatment, these markers were still elevated ... Similarly increased bone turnover has been observed in ... longstanding acromegaly, indicating that bone turnover remains elevated during years of GH exposure" (1). Moreover, prolonged GH treatment caused an increase of some heart dimensions as seen in patients with active acromegaly (2). The authors concluded suggesting caution against the use of GH therapy in such patients, as already suggested in a previous paper by Valcavi et al. (3), also in your Journal "cardiac hypertrophy might develop during chronic GH treatment" (3).

In 1989, Salomon et al. (4) suggested that the GH doses they had used were higher than necessary. They based this opinion on excessively elevated IGF1 levels and on many adverse effects after GH treatment. About 4 yr later, we were able to show that the use of GH for 6 months in adult patients with GH deficiency, at doses three times lower than those used up to that point, caused a normalization of body composition, heart structure, and function (but not of bone metabolism and structure) without any adverse effects (5). Another reason for choosing this dose was to take into account the physiological decrease of GH secretion in adulthood. We also recently showed a normalization of bone metabolism and an improvement of bone structure, always without any adverse effects, using the same dose for a longer period (12 months) (6).

Thus, we believe it is more correct to start with the lowest GH doses, as also suggested by de Boer, Blok, and van der Veen’s study (7), increasing the doses if necessary during the treatment, in particular in the absence of IGF1 level normalization.

The protocol of the above mentioned works (1, 2, 3) called instead for low initial doses, increasing after 1 month of therapy without taking into account the individual response of patients. After a variable period they were compelled to decrease the dose because of adverse effects or high levels of IGF1.

Is it necessary to use such high doses, in view of the exposure to a high amount of GH and the related risk of mortality from cardiovascular and respiratory disease (8, 9) and malignancy (10)? We must not make the conditions to create another disease, while seeking to correct a deficit of GH secretion.

Hormonal replacement therapy has to have the aim of normalizing the majority of the altered parameters with the lowest useful dose able to mimic the physiological hormone secretion, without causing important adverse effects.

Lower doses also improve the cost to benefit ratio, since GHDA patients have to undergo this therapy for their whole lives. In view of this, a thrice weekly injection, suggested by our protocol, would be better to ameliorate the compliance of the patients.

Footnotes

¹ Address correspondence to: Giovanni Amato, via Orsi 33, 80128 Naples, Italy.

Received October 29, 1996.

References

1. Johannsson G, Rosén T, Bosaeus I, Sjöström L, Bengtsson B-. 1996 Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency. J Clin Endocrinol Metab. 81:2665–2873.[Abstract/Free Full Text]
2. Johannsson G, Bengtsson B-, Andersson B, Isgaard J, Caldahl K. 1996 Long-term cardiovascular effects of growth hormone treatment in GH-deficient adults. Preliminary data in a small group of patients. Clin Endocrinol (Oxf). 45:305–314.[Medline]
3. Valcavi R, Gaddi O, Zini M, Iavicoli M, Mellino U, Portioli I. 1995 Cardiac performance and mass in adults with hypopituitarism: effects of one year of growth hormone treatment. J Clin Endocrinol Metab. 80:659–666.[CrossRef][Medline]
4. Salomon F, Cuneo RC, Hesp R, Sonksen PH. 1989 The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med. 321:1797–1803.
5. Amato G, Carella C, Fazio S, et al. 1993 Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab. 77:1671–1676.
6. Amato G, Izzo G, La Montagna G, Bellastella A. 1996 Low dose recombinant human growth hormone normalizes bone metabolism and cortical bone density and improves trabecular bone density in growth hormone deficient adults without causing adverse effects. Clin Endocrinol (Oxf). 45:27–32.[CrossRef][Medline]
7. De Boer H, Blok G-J, van der Veen EA. 1995 Clinical aspects of growth hormone deficiency in adults. Endocr Rev. 16:63–86.[CrossRef][Medline]
8. Wright AD, Hill DM, Lowy C, Fraser TR. 1970 Mortality in acromegaly. Q J Med. 39:1–16.[Abstract/Free Full Text]
9. Alexander L, Appleton D, Hall R, Ross WM, Wilkinson R. 1980 Epidemiology of acromegaly in the Newcastle region. Clin Endocrinol (Oxf). 12:71–79.[Medline]
10. Ezzat S, Melmed S. 1991 Are patients with acromegaly at increased risk for neoplasia? J Clin Endocrinol Metab. 72:245–249.[Medline]

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