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Modulation of Cortisol Metabolism by Low-Dose Growth Hormone Replacement in Elderly Hypopituitary Patients¹

Department of Endocrinology (A.A.T., S.M.S.), Christie Hospital, Manchester M20 4BX; Department of Endocrinology (J.P.M.), St. Bartholomew’s and The Royal London School of Medicine and Dentistry, London EC1A 7BE; and Department of Clinical Biochemistry (N.F.T.), Kings College Hospital, London SE5 9RS, United Kingdom

Address correspondence and requests for reprints to: Dr. Andy Toogood, Department of Endocrinology, Christie Hospital, Manchester, M20 4BX, United Kingdom.

Abstract

11 ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) functions as a net reductase converting cortisone to cortisol. GH inhibits 11ß-HSD1, resulting in a shift in cortisol metabolism favoring cortisone, an observation that may have significance in patients with ACTH deficiency who are unable to compensate for such changes. We have studied the effect of three doses of GH replacement (0.17, 0.33, and 0.5 mg each given for 12 weeks in ascending order) on cortisol metabolism in nine patients, aged 62–70 yr, with hypopituitarism who were receiving fixed doses of oral hydrocortisone.

Serum insulin-like growth factor I levels rose in a dose-dependent manner over the course of the study. Fat mass decreased significantly at 24 weeks (P = 0.02), a change that was maintained at 36 weeks. Fasting serum insulin levels did not change significantly over the course of the study.

The ratio of urine cortisol to cortisone metabolites (Fm/Em) fell significantly at 12 weeks (GH dose, 0.17 mg/day) from 1.32 (0.91–2.20) at baseline to 1.08 (0.89–2.11) (P < 0.05). Although it did not fall further as the dose of GH was increased, the reduction in the Fm/Em ratio persisted at 24 weeks (GH dose, 0.33 mg/day), 1.09 (0.8–2.11) (P < 0.05 vs. baseline), and 36 weeks (GH dose, 0.5 mg/day), 1.19 (0.82–2.31) (P < 0.05 vs. baseline). The Fm/Em ratio did not correlate with serum insulin-like growth factor I, fat mass, or fasting insulin levels at any time during the study.

This study confirms the inhibitory effect of GH on 11ß-HSD1 but has shown that the effect occurs maximally at very low GH doses and is not mediated indirectly by change in circulating insulin. Patients with partial or total ACTH deficiency, in whom cortisol replacement is suboptimal, may be at risk of the clinical manifestations of cortisol deficiency when they are commenced on GH therapy.

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