Long vs Short Acting Compounds GH Secretory Pattern and Hormonal Specificity

In clinical studies, single doses of growth hormone secretagogues, given intravenously, intranasally, or orally have resulted in a dramatic elevation in serum GH levels (to approx 40-70 ng/mL) (38-45) accompanied by modest post-dose increases in serum cortisol (mediated by ACTH) and prolactin (46,47). Since growth hormone and prolactin secreting cells are derived from the same embryonic lineage, stimulation of prolactin can

Growth Hormone Adaptive Demands
Fig. 3. Serum samples were collected every 10 min from each of three normal subjects during 24-h saline or GHRP-6 (1 pg/kg ■ h, iv) infusions. Samples were analyzed for GH by immunoradiometric assay. Adapted from Huhn et al. (34).

occur if lactotrophs and/or somatomammotrophs in the pituitary expressed the secreta-gogue receptor. The mechanism of stimulation of ACTH is less clear. Although a direct stimulation of ACTH by the secretagogues is possible, there is no evidence that corticotrophs express the secretagogue receptor.

Continuous infusion of short acting peptide secretagogues results in a different GH profile than that observed after single bolus doses. Huhn et al. (34) administered a 24-h iv infusion of GHRP-6 to healthy young men and observed increased pulsatile GH secretion during the infusion. These investigators noted an increase in the number of GH pulses, as well as in the pulse height and interpeak nadir GH concentration (Fig. 3). Since MK-0677 is a long-acting GHRP-mimetic that is orally active (11), such a compound might be expected to have an effect similar to that of an infusion. In a double-blind placebo controlled crossover design, Copinschi et al. (48) dosed nine healthy young males with MK-0677 or placebo orally once daily for 7 d. An increase in GH pulse

Fig. 4. Healthy elderly subjects were treated with MK-0677 2 mg (n = 10), 10 mg (n = 12) or 25 mg (n = 10), or placebo (n = 10) daily at 10-11 pm. Subjects underwent serial sampling every 20 min for 24 h for GH at baseline and after 14 d of treatment (geometric mean ± geometric SE). Serum IGF-I levels were obtained at baseline and post-treatment (geometric mean ± geometric SE). *, p < 0.05 from baseline. Adapted from Chapman et al. (37).

Fig. 4. Healthy elderly subjects were treated with MK-0677 2 mg (n = 10), 10 mg (n = 12) or 25 mg (n = 10), or placebo (n = 10) daily at 10-11 pm. Subjects underwent serial sampling every 20 min for 24 h for GH at baseline and after 14 d of treatment (geometric mean ± geometric SE). Serum IGF-I levels were obtained at baseline and post-treatment (geometric mean ± geometric SE). *, p < 0.05 from baseline. Adapted from Chapman et al. (37).

frequency, but not in amount of GH secreted, was observed. Chapman et al. (37) performed a double-blind placebo controlled study with the same compound in healthy elderly men and women with somewhat different results. Subjects were dosed daily with MK-0677 (or placebo). GH was measured every 20 min for 24 h prior to treatment and after two weeks. In the MK-0677 treated subjects, increases in GH peak amplitude, peak area, and interpeak nadir were observed, but no difference in peak number was detected (Figs. 4 and 5). Serial samples were also collected for determination of cortisol and prolactin levels. There was no change in serum cortisol levels or diurnal cortisol secretory pattern compared to baseline or to placebo-treated controls (37). However, a modest (approx 20%) increase in mean serum prolactin levels was seen in elderly subjects after 2 wk of treatment with MK-0677. This increase was well within the physiologic range, and was not associated with clinical signs or symptoms of hyperprolactinemia. The

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Fig. 5. Twenty-four hour GH concentrations from a 69-yr-old man before and after 14 daily doses of MK-0677 10 mg. Blood was collected every 20 min from 8 am until 8 am.

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Fig. 5. Twenty-four hour GH concentrations from a 69-yr-old man before and after 14 daily doses of MK-0677 10 mg. Blood was collected every 20 min from 8 am until 8 am.

apparent inconsistency between the former two studies (34,48) and the latter one (37) may be related to the different GH assays employed. Chapman et al. employed a highly sensitive chemiluminescent GH assay with a lower limit of detection of0.002 ng/mL. The apparent increase in GH peak number reported in the former two studies may be owing to the inability to detect very small peaks at baseline that subsequently have detectable magnitude after treatment. In addition, an increased interpeak nadir, which contributes to an increase in mean 24-h GH secretion, may not be appreciated in less sensitive assays. Based on infusion studies as well as on data from Chapman et al. using MK-0677, it appears that continuous exposure to a secretagogue results in upregulation of the endogenous GH pulsatile profile without perturbing the underlying pulse frequency generator.

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