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Gender Difference in Insulin-Like Growth Factor I Response to Growth Hormone (GH) Treatment in GH-Deficient Adults: Role of Sex Hormone Replacement

Department of Internal Medicine, Division of Endocrinology (J.P.T.S., G.F.F.M.P., A.R.M.M.H., A.G.H.S.), and Department of Chemical Endocrinology (C.G.J.S.), University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands

Address correspondence and requests for reprints to: J. P. T. Span, M.D., University Hospital Nijmegen, St. Radboud, Department of Internal Medicine, Division of Endocrinology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: J.Span{at}aig.azn.nl

GH production in healthy women is about thrice that in men. Yet insulin-like growth factor I (IGF-I) levels are similar, suggesting a lower responsivity to GH in women. In untreated GH-deficient adults, basal IGF-I levels are reportedly lower in females than in males, and the therapeutic recombinant human GH (rhGH) dose required to achieve optimal IGF-I levels is higher in the former, suggesting a pivotal role of estrogens on rhGH requirement in GH-deficient patients. We, therefore, analyzed our 2-yr data on the effect of rhGH on serum IGF-I in 77 GH-deficient patients (33 men, mean ± SD age, 37.2 ± 13.8 yr; 44 women, mean ± SD age, 36.9 ± 11.9 yr) with due attention to gender differences and to the effects of sex hormone replacement. Of the 44 women, 33 had estrogen substitution. Of the 33 men, 23 were on androgen replacement. Patients (11 premenopausal women and 10 men) not on hormonal replacement were eugonadal.

Basal IGF-I levels in untreated GH-deficient women were significantly lower than in men (8.8 ± 0.7 nmol/L vs. 12.2 ± 0.9 nmol/L; P < 0.01), despite similar basal GH levels. The daily rhGH dose per kg body weight required to normalize IGF-I in women was higher than in men, the difference being statistically significant at all time points (P < 0.05–0.01). The IGF-I increase () per IU GH/day·kg over the 24-month period was about twice higher in men than in women. Also calculated on a weight basis, rhGH responsivity (rhGH responsivity = (IGF1(nmol/L)/dose (IU/day/kg)) was higher in men than in women at all time intervals (P < 0.05–0.01).

Estrogen replacement in women significantly increased rhGH requirement. The rhGH dose per kg body weight required in estrogen-substituted women was significantly higher than in nonestrogen-substituted women (P < 0.01 at t = 18 and 24 months, respectively). In women on estrogen substitution, rhGH responsivity plateaued from 6 months on, whereas in eugonadal women without estrogen substitution the responsivity for rhGH increased over time. In men, the reverse was true; rhGH responsivity increased over time in men on androgen substitution, but plateaued in men without androgen substitution.

The mechanisms underlying this gender difference are not known. Differential influences of estrogens and androgens on the expression of the GH receptor gene and IGF-I messenger RNA may be operative.

The present study confirms short-term data published in the literature on a sex difference in rhGH dose requirement in GH-deficient patients. It furthers extends the data by demonstrating that this sex difference in GH responsivity persists and changes during the 24 months of the study. Moreover, it shows that estrogen replacement blunts the IGF-I response to rhGH in women, whereas in men with androgen substitution the responsivity increases over time, thus bearing a risk of undertreatment in women and overtreatment in men.

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