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TESTOSTERONE SUPPLEMENTATION BLUNTS GROWTH HORMONE AUTONEGATIVE FEEDBACK INHIBITION
By Karl Hoffman
Consider the following apparent paradox: When exogenous recombinant human growth hormone (rhGH) is administered to humans, natural growth hormone (GH) secretion is blunted in a dose dependent fashion (1,2). This is thought to happen for two reasons. First, increased GH levels in the blood lead to an increase in the secretion of the hypothalamic hormone somatostatin, which blocks GH secretion. that is normally stimulated by the naturally occurring hormone Growth Hormone Releasing Hormone (GHRH). Secondly, GH administration induces the hepatic production of IGF-1, which also acts in a negative feedback manner to suppress GH secretion. Yet when supraphysiological doses of testosterone are administered to humans, GH levels increase with no apparent negative autofeedback. This is rather surprising and the topic of the study discussed here (3).
Before proceeding, recall that GH is secreted by the pituitary in both a continuous, so called basal mode, and in a pulsatile mode superimposed on basal secretion.
The study group involved 13 healthy men who were given 200 mg IM of testosterone enanthate (Te) over three consecutive weeks, or placebo. On the day of the test the men were administered an i.v. infusion of both rhGH and the GH-releasing peptide (GHRP)-2.
Serum GH concentrations were measured in each 10-min sample interval in duplicate by using 22-kDa rhGH as assay standard. rhGH is manufactured as the pure 20kDa isoform of GH. In contrast, the body produces both the 20kDa and 22kDa isoforms. Administered rhGH can be distinguished from naturally produced GH by assaying the 22kDa isoform.
The outcomes measured were pulsatile GH release (the summed mass of GH secreted above basal), basal (nonpulsatile) secretion, and total (combined basal and pulsatile) GH production.
Summarizing the effects, Te (compared with placebo, Pl) supplementation 1) elevated basal GH secretion by 1.9-fold and 2) augmented pulsatile GH secretion by 2.4-fold and total (sum of basal and pulsatile) GH release by 2.3-fold. In the Pl condition, a single pulse of rhGH, suppressed basal, pulsatile, and total GH secretion by 2.6-fold, 2.3-fold, and 2.5-fold respectively. Te administration followed by an iv pulse of rhGH: 1) elevated otherwise inhibited basal GH secretion and nadir GH concentrations by 2.7-fold and 3.3-fold, respectively, and 2) did not mute autosuppression of pulsatile or total GH release (both < 1.2-fold effect).
To summarize the effects of Te on GH secretion, Te supplementation in normal middle-aged and older men stimulates basal and pulsatile GH secretion, attenuates rhGH-induced suppression of basal GH secretion, and facilitates initial recovery of GH concentrations from autonegative feedback.
Earlier clinical studies reported that GHRH and GHRP-2 elevate, and somatostatin and octreotide repress, both pulsatile and basal GH release (4,5,6). The latter outcome allows the hypothesis that Te opposes feedback inhibition of basal GH secretion by amplifying stimulation by GHRH, or potentially ghrelin/GHRP, and/or by reducing suppression by somatostatin. The precise physiological implications of increased basal GH secretion are not clear. Animals have been much better studied, and in these cases a combination of sex-steroid-specific control of somatostatin and GHRH outflow appear to be the leading candidates for the changes in GH caused by testosterone.
So, disappointingly we do not yet have a concrete answer to our original question of how testosterone maintains elevated GH levels without GH induced negative feedback returning our artificially elevated GH levels to their pre-testosterone baseline. But the authors certainly have narrowed the field to a few perhaps testable hypotheses. For example, antisera that block the receptors for growth hormone secretagogues like ghrelin have recently been developed (7) and, if functional in humans, could potentially test the viability of the postulate that testosterone elevates GH by increasing levels of ghrelin.
Also of interest, the authors briefly note in passing that "Mechanistically, nonaromatizable androgens stimulate hypothalamic somatostatin gene expression in the adult rodent". Again, if this effect holds in humans it would explain why nonaromatizing androgens generally do not elevate GH in humans, since as we have discussed, somatostatin blocks the release of GH from the pituitary.
References
Giustina A, Veldhuis JD Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human.1998 Endocr Rev 19:717–797
Mueller EE, Locatelli V, Cocchi D Neuroendocrine control of growth hormone secretion. 1999 Physiol Rev 79:511–607
Veldhuis JD, Evans WS, Iranmanesh A, Weltman AL, Bowers CY Short-term testosterone supplementation relieves growth hormone autonegative feedback in men. J Clin Endocrinol Metab. 2004 Mar;89(3):1285-90.
Iranmanesh A, South S, Liem AY, Clemmons D, Thorner MO, Weltman A, Veldhuis JD Unequal impact of age, percentage body fat, and serum testosterone concentrations on the somatotrophic, IGF-I, and IGF-binding protein responses to a three-day intravenous growth hormone-releasing hormone pulsatile infusion in men. Eur J Endocrinol 1998 139:59–71
Shah N, Evans WS, Bowers CY, Veldhuis JD 1999 Tripartite neuroendocrine activation of the human growth-hormone (GH) axis in women by continuous 24-hour GH-releasing peptide (GHRP-2) infusion: pulsatile, entropic, and nyctohemeral mechanisms. J Clin Endocrinol Metab 1999 84:2140–2150
Mulligan T, Jaen-Vinuales A, Godschalk M, Iranmanesh A, Veldhuis JD Synthetic somatostatin analog (octreotide) suppresses daytime growth hormone secretion equivalently in young and older men: preserved pituitary responsiveness to somatostatin’s inhibition in aging. J Am Geriatr Soc 1999 47:1422–1424
Shuto Y, Shibasaki T, Wada K, Parhar I, Kamegai J, Sugihara H, Oikawa S, Wakabayashi I Generation of polyclonal antiserum against the growth hormone secretagogue receptor (GHS-R): evidence that the GHS-R exists in the hypothalamus, pituitary and stomach of rats. Life Sci. 2001 Jan 19;68(9):991-6.
By Karl Hoffman
Consider the following apparent paradox: When exogenous recombinant human growth hormone (rhGH) is administered to humans, natural growth hormone (GH) secretion is blunted in a dose dependent fashion (1,2). This is thought to happen for two reasons. First, increased GH levels in the blood lead to an increase in the secretion of the hypothalamic hormone somatostatin, which blocks GH secretion. that is normally stimulated by the naturally occurring hormone Growth Hormone Releasing Hormone (GHRH). Secondly, GH administration induces the hepatic production of IGF-1, which also acts in a negative feedback manner to suppress GH secretion. Yet when supraphysiological doses of testosterone are administered to humans, GH levels increase with no apparent negative autofeedback. This is rather surprising and the topic of the study discussed here (3).
Before proceeding, recall that GH is secreted by the pituitary in both a continuous, so called basal mode, and in a pulsatile mode superimposed on basal secretion.
The study group involved 13 healthy men who were given 200 mg IM of testosterone enanthate (Te) over three consecutive weeks, or placebo. On the day of the test the men were administered an i.v. infusion of both rhGH and the GH-releasing peptide (GHRP)-2.
Serum GH concentrations were measured in each 10-min sample interval in duplicate by using 22-kDa rhGH as assay standard. rhGH is manufactured as the pure 20kDa isoform of GH. In contrast, the body produces both the 20kDa and 22kDa isoforms. Administered rhGH can be distinguished from naturally produced GH by assaying the 22kDa isoform.
The outcomes measured were pulsatile GH release (the summed mass of GH secreted above basal), basal (nonpulsatile) secretion, and total (combined basal and pulsatile) GH production.
Summarizing the effects, Te (compared with placebo, Pl) supplementation 1) elevated basal GH secretion by 1.9-fold and 2) augmented pulsatile GH secretion by 2.4-fold and total (sum of basal and pulsatile) GH release by 2.3-fold. In the Pl condition, a single pulse of rhGH, suppressed basal, pulsatile, and total GH secretion by 2.6-fold, 2.3-fold, and 2.5-fold respectively. Te administration followed by an iv pulse of rhGH: 1) elevated otherwise inhibited basal GH secretion and nadir GH concentrations by 2.7-fold and 3.3-fold, respectively, and 2) did not mute autosuppression of pulsatile or total GH release (both < 1.2-fold effect).
To summarize the effects of Te on GH secretion, Te supplementation in normal middle-aged and older men stimulates basal and pulsatile GH secretion, attenuates rhGH-induced suppression of basal GH secretion, and facilitates initial recovery of GH concentrations from autonegative feedback.
Earlier clinical studies reported that GHRH and GHRP-2 elevate, and somatostatin and octreotide repress, both pulsatile and basal GH release (4,5,6). The latter outcome allows the hypothesis that Te opposes feedback inhibition of basal GH secretion by amplifying stimulation by GHRH, or potentially ghrelin/GHRP, and/or by reducing suppression by somatostatin. The precise physiological implications of increased basal GH secretion are not clear. Animals have been much better studied, and in these cases a combination of sex-steroid-specific control of somatostatin and GHRH outflow appear to be the leading candidates for the changes in GH caused by testosterone.
So, disappointingly we do not yet have a concrete answer to our original question of how testosterone maintains elevated GH levels without GH induced negative feedback returning our artificially elevated GH levels to their pre-testosterone baseline. But the authors certainly have narrowed the field to a few perhaps testable hypotheses. For example, antisera that block the receptors for growth hormone secretagogues like ghrelin have recently been developed (7) and, if functional in humans, could potentially test the viability of the postulate that testosterone elevates GH by increasing levels of ghrelin.
Also of interest, the authors briefly note in passing that "Mechanistically, nonaromatizable androgens stimulate hypothalamic somatostatin gene expression in the adult rodent". Again, if this effect holds in humans it would explain why nonaromatizing androgens generally do not elevate GH in humans, since as we have discussed, somatostatin blocks the release of GH from the pituitary.
References
Giustina A, Veldhuis JD Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human.1998 Endocr Rev 19:717–797
Mueller EE, Locatelli V, Cocchi D Neuroendocrine control of growth hormone secretion. 1999 Physiol Rev 79:511–607
Veldhuis JD, Evans WS, Iranmanesh A, Weltman AL, Bowers CY Short-term testosterone supplementation relieves growth hormone autonegative feedback in men. J Clin Endocrinol Metab. 2004 Mar;89(3):1285-90.
Iranmanesh A, South S, Liem AY, Clemmons D, Thorner MO, Weltman A, Veldhuis JD Unequal impact of age, percentage body fat, and serum testosterone concentrations on the somatotrophic, IGF-I, and IGF-binding protein responses to a three-day intravenous growth hormone-releasing hormone pulsatile infusion in men. Eur J Endocrinol 1998 139:59–71
Shah N, Evans WS, Bowers CY, Veldhuis JD 1999 Tripartite neuroendocrine activation of the human growth-hormone (GH) axis in women by continuous 24-hour GH-releasing peptide (GHRP-2) infusion: pulsatile, entropic, and nyctohemeral mechanisms. J Clin Endocrinol Metab 1999 84:2140–2150
Mulligan T, Jaen-Vinuales A, Godschalk M, Iranmanesh A, Veldhuis JD Synthetic somatostatin analog (octreotide) suppresses daytime growth hormone secretion equivalently in young and older men: preserved pituitary responsiveness to somatostatin’s inhibition in aging. J Am Geriatr Soc 1999 47:1422–1424
Shuto Y, Shibasaki T, Wada K, Parhar I, Kamegai J, Sugihara H, Oikawa S, Wakabayashi I Generation of polyclonal antiserum against the growth hormone secretagogue receptor (GHS-R): evidence that the GHS-R exists in the hypothalamus, pituitary and stomach of rats. Life Sci. 2001 Jan 19;68(9):991-6.
