Gender difference in insulin-like growth factor I response to growth hormone (GH) treatment in GH-deficient adults: Role of sex hormone replacement

GH production in healthy women is about thrice that in men. Yet insulin-lik e growth factor I (IGF-I) levels are similar, suggesting a lower responsivi ty 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 +/- so age , 37.2 +/- 13.8 yr; 44 women, mean +/- so age, 36.9 +/- 11.9 yr) with due a ttention to gender differences and to the effects of sex hormone replacemen t. 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), despit e 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 st atistically significant at all time points (P < 0.05-0.01). The IGF-I incre ase (Delta) per IU GH/day.kg over the 24-month period was about twice highe r in men than in women. Also calculated on a weight basis, rhGH responsivit y (rhGH responsivity = (Delta 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 si gnificantly higher than in nonestrogen-substituted women (P < 0.01 at t = 1 8 and 24 months, respectively). In women on estrogen substitution, rhGH res ponsivity plateaued from 6 months on, whereas in eugonadal women without es trogen substitution the responsivity for rhGH increased over time. In men, the reverse was true; rhGH responsivity increased over time in men on andro gen substitution, but plateaued in men without androgen substitution. The mechanisms underlying this gender difference are not known. Differentia l influences of estrogens and androgens on the expression of the GH recepto r 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 furth ers extends the data by demonstrating that this sex difference in GH respon sivity 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.