Divergent Effect of Endogenous and Exogenous Sex Steroids on the Insulin-Like Growth Factor I Response to Growth Hormone in Short Normal Adolescents

Abstract

The lower responsiveness to GH in women than in men is probably due to a divergent effect of gonadal steroids. It is unknown, however, how the progressive increase in sex steroid production that occurs during puberty affects this responsiveness. To compare the effects of puberty and sex steroid administration on responsiveness to GH, we used the IGF-I generation test, in which the peak IGF-I level 24 h after a single injection of GH (2 mg/m2) was studied in 117 healthy short subjects (56 females and 61 males). The subjects, aged 8-16 yr, were divided into four groups: prepuberty, early puberty, midpuberty, or pubertal delay. In the latter group, the IGF-I response was determined before and after priming with oral 17beta-estradiol in girls and im testosterone in boys. We also tested for an association between body composition (by dual energy x-ray absorptiometry) and the IGF-I response to GH. The IGF-I increment in response to GH (change in IGF-I from baseline) was correlated with the growth velocity sd score (P < 0.05). Progression throughout puberty was associated with an increase in both baseline IGF-I (P < 0.05) and the IGF-I increment in response to GH (P < 0.05), with no gender difference. Pubertal category (pre-, early, and midpuberty; P < 0.05) and fat percentage (P < 0.05) were the main positive predictors of the IGF-I increment in response to GH, expressed as micrograms per liter as well as sd score, independently of baseline IGF-I. After sex steroid priming, both the GH peak in response to insulin-induced hypoglycemia and baseline IGF-I were increased (P < 0.05, after vs. before sex steroid). However, the IGF-I increment in response to GH decreased after oral 17beta-estradiol (P < 0.05), whereas it was unchanged after testosterone administration. Endogenous gonadal steroid secretion appears to result in increased responsiveness to GH in peripubertal girls and boys. By contrast, exogenous estrogen and testosterone, respectively, produce a relative decrease and no change in responsiveness to GH in similar populations, possibly through the achievement of sex steroid concentrations exceeding physiological ranges for age. Fat percentage was a positive determinant of the responsiveness to GH, suggesting a link between the energy stores and the anabolic action of GH.

Serum IGF1 and insulin levels in girls with normal and precocious puberty

“…Although this may indicate a direct effect of sex steroid withdrawal, GH secretion seems to be suppressed in parallel with the decrease in the activity of the hypothalamic-pituitary-gonadal (HPG) axis during GNRHa treatment (32). Accordingly, the positive influence of pubertal progression and E 2 priming on secretion of GH during stimulation testing is well documented (33). Thus, these changes may be secondary to a possible concomitant suppression of GH secretion rather than primarily related to E 2 withdrawal.…”

Low-dose estrogen combined oral contraceptives may negatively influence physiological bone mineral density acquisition during adolescence

“…Studies in individuals with panhypopituitarism, in whom adequate replacement with both hormones had not been achieved, and in individuals with estrogen receptor defects or mutations of the aromatase gene, suggest a facilitative role of estrogen receptor-mediated processes on GH secretion and somatomedins production (26,27). Thus, estrogen action may be rather indirect through modulation of the GH-insulin-like growth factor 1 (IGF1) axis (28,29).…”

“…Thus, estrogen action may be rather indirect through modulation of the GH-insulin-like growth factor 1 (IGF1) axis (28,29). However, exogenous estrogen produces a relative decrease in responsiveness to GH in similar populations, possibly through the achievement of sex steroid concentrations exceeding physiological ranges for age (27). Estrogens stimulate proliferation and differentiation of osteoblasts and inhibit osteoblast apoptosis (30,31), and are involved in bone mineral accumulation namely at the endocortical bone surface (32).…”

DIAGNOSIS OF ENDOCRINE DISEASE: Limitations of the IGF1 generation test in children with short stature

“…More recently, physiological determinants of GH sensitivity and/or responsiveness have been described following the use of IGFGT in groups of normal individuals or normal individuals with short stature according to height, body mass index, gonadal steroid production and age (from prepuberty to menopause) (16,26,27,28).…”