ESTROGEN AND TESTOSTERONE, BUT NOT A NONAROMATIZABLE ANDROGEN, DIRECTNETWORK INTEGRATION OF THE HYPOTHALAMO-SOMATOTROPE (GROWTH HORMONE)-INSULIN-LIKE GROWTH-FACTOR-I AXIS IN THE HUMAN - EVIDENCE FROM PUBERTALPATHOPHYSIOLOGY AND SEX-STEROID HORMONE REPLACEMENT

Activation of the gonadotropic and somatotropic axes in puberty is mar ked by striking amplification of pulsatile pulsatile neurohormone secr etion. In addition, each axis, as a whole, constitutes a regulated net work whose feedback relationships are Likely to manifest important cha nges at the time of puberty. Here, we use the regularity statistic, ap proximate entropy (ApEn), to assess feedback-activity within the somat otropic (hypothalamo-pituitary/GH-insulin-like grow-th factor I) axis indirectly. To this end, we studied pubertal boys and prepubertal girl s or boys with sex-steroid hormone deficiency treated short-term with estrogen, testosterone, or a nonaromatizable androgen in a total of 3 paradigms. First, our cross-sectional analysis of 53 boys at various s tages of puberty or young adulthood revealed that mean ApEn, taken as a measure of feedback complexity, of 24-h serum GH concentration profi les is maximal in pre-and mid-late puberty, followed by a significant decline in postpubertal adolescence and young adulthood (P-=0.0008 by ANOVA). This indicates that marked disorderliness of the GH release pr ocess occurs in mid-late puberty at or near the time of peak growth ve locity, with a return to maximal orderliness thereafter at reproductiv e maturity. Second, oral administration of ethinyl estradiol for 5 wee ks to 7 prepubertal girls with Turner's syndrome also augmented ApEn s ignificantly (P = 0.018), thus showing that estrogen per se can induce greater irregularity of GH secretion. Third, in 5 boys with constitut ionally delayed puberty, im testosterone administration also significa ntly increased ApEn of 24-h GPI time series (P = 0.0045). In counterpo int, 5 alpha-dihydrotestosterone, a nonaromatizable androgen, failed t o produce a significant ApEn increase (P > 0.43). We conclude from the se three distinct experimental contexts that aromatization of testoste rone to estrogen in boys, or estrogen itself in girls, is Likely the p roximate sex-steroid stimulus amplifying secretory activity of the GH axis in puberty. In addition, based on inferences derived from mathema tical models that mechanistically Link increased disorderliness (highe r ApEn) to network changes, we suggest that sex-steroid hormones in no rmal puberty modulate feedback within, and hence network function of, the hypothalamo-pituitary/GH-insulin-like growth factor I axis.