Activation of the Somatotropic Axis by Testosterone in Adult Men: Evidence for a Role of Hypothalamic Growth Hormone-Releasing Hormone

Abstract

Testosterone (T) is known to affect the growth hormone (GH) axis. However, the mechanisms underlying the activation of GH secretion by T still remain to be clarified. Available data in animals and humans have shown that withdrawal of somatostatin (SRIH) infusion induces a GH-releasing hormone (GHRH)-mediated rebound release of GH, and there is accumulating evidence that SRIH infusion withdrawal may be a useful test to probe the GHRH function in vivo. With the aim of investigating whether the stimulatory effect of androgens on GH release in man could be accounted for by activation of the hypothalamic GHRH tone, we evaluated the plasma GH response to SRIH withdrawal in 10 patients aged 29.6 ± 2.4 years (mean ± SEM), diagnosed with hypergonadotropic hypogonadism, before and after a 6-month replacement therapy with T enanthate (250 mg every 3 weeks, i.m.), and in 10 healthy men, aged 26.7 ± 2.8 years. To verify whether the modulation of GH secretion by T could also be mediated through changes in SRIH tone and/or pituitary releasable pool, we examined GH secretory responses to combined GHRH and L-arginine (ARG) in the same individuals. Basal plasma concentrations of GH (0.48 ± 0.11 µg/l) and IGF-I (23.79 ± 1.83 nmol/l) were significantly lower in untreated hypogonadal patients than in healthy men, and significantly increased after T replacement therapy (GH 1.13 ± 0.28 µg/l; IGF-I 28.71 ± 1.46 nmol/l). The mean ΔGH peak after SRIH withdrawal recorded in untreated hypogonadal men (2.65 ± 0.86 µg/l) was significantly (p < 0.05) lower than that observed in healthy men (6.53 ± 1.33 µg/l) and significantly increased after T replacement therapy (5.52 ± 1.25 µg/l). The GH responses to GHRH combined with ARG (a functional SRIH antagonist) were not significantly different between healthy men and untreated hypogonadal patients, and were not significantly affected by T treatment. Plasma T and estradiol (E₂) levels significantly correlated with ΔGH peak after SRIH withdrawal in healthy men and in T-treated hypogonadal patients, whereas in untreated patients they did not. No significant correlation was found between GH areas under the curve after GHRH + ARG test and T and E₂ plasma levels in either healthy men or in hypogonadal patients (both before and after T replacement). These findings are consistent with the view that in humans the stimulatory action of T on the GH axis appears to be mediated at the hypothalamic level primarily by promoting GHRH function.

Long-term testosterone supplementation augments overnight growth hormone secretion in healthy older men

“…Similar results were observed in hypogonadal men after 24 wk of T replacement therapy (250 mg im every 3 wk) (5). As a consequence, other studies (5,34) have suggested that the stimulatory action of T may involve promoting GHRH release from the hypothalamus rather than potentiating its action at the level of the pituitary. In addition, T therapy in healthy older men is known to attenuate feedback inhibition by GH and IGF-I (42).…”

“…However, in healthy older men, high doses of T have been reported not to amplify the maximal stimulatory effect of simultaneous infusion of L-arginine, GHRH, and GH-releasing peptide on GH release (45). Similar results were observed in hypogonadal men after 24 wk of T replacement therapy (250 mg im every 3 wk) (5). As a consequence, other studies (5,34) have suggested that the stimulatory action of T may involve promoting GHRH release from the hypothalamus rather than potentiating its action at the level of the pituitary.…”

Determinants of GH-releasing hormone and GH-releasing peptide synergy in men

“…Data from 18 studies in hypogonadal or normal men (n ϭ 149 subjects total) indicate that parenteral T supplementation increases mean GH concentrations by a weighted-mean effect size [standard deviations (SDs)] of 1.8 (7,8,12,17,18,25,30,32,37,39). In women, the effect size of age on GHRH/GHRP-2 stimulation was 1.2 SDs (38).…”

Growth hormone receptor modulators

“…Testosterone enhances the secretion of GH [120], an effect mediated at the hypothalamic level by stimulation of GH releasing hormone [121]. Thus, one mechanism how testosterone regulates GH system is through stimulation of GH secretion by testosterone.…”