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Growth Hormone‐Releasing Peptides

Cyril Y. Bowers

10.1002/cphy.cp070510

Source: Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth

Originally published: 1999

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Chemistry
1.1 Peptides
1.2 Peptides and Partial Peptides
1.3 Nonpeptides
2 Biological Actions
2.1 In Vitro
2.2 In Vivo
3 Mechanism of Action
3.1 Receptor
3.2 Postreceptor
4 Pharmacokinetics and Pharmacodynamics
5 Clinical Effects: 1989–1998
5.1 Synergism
5.2 Pulsatile Secretion, Desensitization, and Upregulation
6 Future Prospects
Figure 1. Figure 1.

Sequential reduction and optimization of the pseudopentapeptide 4a to the simple, low‐molecular‐weight compound 4g, which maintains high in vitro and in vivo potency. inip, isonipecotic acid; b, D2Nal; bda, butanediamine; nmb, N‐methyl‐D2Nal; bol, D‐2‐naphthylalanol; wol, D‐tryptophanol. Lower‐case letters denote D stereochemistry.

From McDowell et al. 93, with permission
Figure 2. Figure 2.

Structures of novel growth hormone secretagogues and L‐692, 428, the biologically inactive enantiomer of L‐692, 429.

From Smith et al. 124, with permission
Figure 3. Figure 3.

Comparative mean growth hormone; (GH) responses to a 1.0 μg/kg intravenous bolus of GHRNH[1–44]NH2, GHRP‐6, GHRP‐1, and GHRP‐2 in normal young men. Values are means and vertical bars indicate 1 SEM. AUC, area under curve; GHRH, growth hormone–releasing hormone; GHRP, growth hormone–releasing peptide.

From Bowers et al. 16, with permission
Figure 4. Figure 4.

Left: Predicted amino acid sequence of the growth hormone secretagogue receptor (GHS‐R). The amino acid sequences predicted for types Ia and Ib GSH‐R for swine and humans are shown. Identical residues are boxed. Conserved cysteine residues and the G protein coupled receptor signature sequence Glu‐Arg‐Tyr142, are shaded gray. Potential sites for N‐linked glycosylation (arrows) and phosphorylation (asterisks) are shown. TM, transmembrane domain. Right: Binding of [35S]MK‐0677 to crude membranes from COS‐7 cells transfected with human type la GHS‐R cDNA. A: Saturation isotherm (bottom: ▾, nonspecific binding; ▴, total binding; ▪, specific binding) and Scatchard analysis (top) of [35S]MK‐0677 binding (bound units are femtomoles per milligram of protein). B: Competition analysis (0.24 nM [35S]MK‐0677). Competition binding data were analyzed by a nonlinear regression curve‐fitting program (Prism V, version 2.0; Graph Pad Software, San Diego, CA). Results are means ± SEM of triplicate determinations; K1 values calculated using the formula K1 = Ka/1 + c/Ka.

From Howard et al. 71, with permission
Figure 5. Figure 5.

Evidence for expression of a growth hormone secretagogue (GHS‐R) in Xenopus oocytes. A: Oocytes were injected with poly (A)+ RNA (50 ng) from swine pituitaries, and membrane currents were recorded at −80 mV. Current traces for effects of 100 nM MK‐0677 (left) and 1 μM growth hormone–releasing peptide (GHRP)‐6 (right). Horizontal line indicates duration of ligand exposure. B and C: Aequorin bioluminescence responses to addition of 1μM MK‐0677 (upward arrows) recorded in oocytes injected with poly (A)+ RNA (17ng) from swine, human, or rat pituitary or rat hypothalamus and Gα11 cRNA (2 ng); background (no signal) is ∼30 counts per second (cps). D: Aequorin bioluminescence response to 1 μM MK‐0677 by an oocyte injected with GHS‐R clone 7–3. E: Electrophysiological response to 100 nM MK‐0677 by an oocyte injected with GSH‐R clone 7–3 (1 ng cRNA). Horizontal line indicates duration of ligand exposure.

From Howard et al. 71; with permission
Figure 6. Figure 6.

Comparison of growth hormone (GH) secretory responses to growth hormone–releasing peptide (GHRP‐2) after intravenous (iv), subcutaneous (sc), oral, or nasal administration of 1 μg/kg, 3 μg/kg, 300 μg/kg, and 15 μg/kg, respectively, in normal young men. Values are means ± SEM. Vertical lines represent one SEM. AUC, area under curve; IGF‐I, insulin‐like growth factor I (μg/l); BMI, body mass index (kg/m2).
Figure 7. Figure 7.

Serum concentration profiles for immunoreactive growth hormone–releasing peptide (GHRP‐2) (top) and growth hormone (GH) (bottom) following intravenous administration of 1 μg/kg GHRP‐2 to nine normal young men. Mean serum concentration of GHRP‐2 peaked at 8.5 ± 2.4 μg/l and then fell to 1.78 ± 0.14 μg/l at 30 min and to 0.32 ± 0.04 μg/l at 2h after injection. Mean serum concentration of GH rose from baseline values of 0.2–0.3 μg/l to peak at a mean concentration of 79 ± 33 μg/l 35 min. after GHRP‐2 injection, before falling to 10.5 ± 1.8 μg/l 2h after injection. Values are means ± SD.
Figure 8. Figure 8.

Growth hormone (GH) and growth hormone–releasing peptide (GHRP‐2) concentration time profiles obtained when 10 mg GHRP‐2 made up in various formulations was given orally on different occasions to the same five normal young men. Values are means ± SEM.
Figure 9. Figure 9.

Mean serum growth hormone (GH), Cortisol, and prolactin (PRL) levels in normal young men after oral administration of 600 μg/kg growth hormone–releasing peptide (GHRP‐1) and 300 μg/kg GHRP‐2. Values are means. Vertical lines represent one SEM. AUC, area under curve.
Figure 10. Figure 10.

Mean serum growth hormone (GH) levels in normal young men after intravenous bolus of growth hormone–releasing peptide (GHRP‐2), growth hormone–releasing hormone (GHRH), or GHRP‐2 + GHRH. Results demonstrate the marked synergism of 0.lμg/kg GHRP‐2 + 1.0 μg/kg GHRH and the lack of synergism of 1.0 μg/kg GHRP‐2 + 0.1μg/kg GHRH because the GH secretory responses obtained with the latter and with 1.0 μg/kg GHRP‐2 alone are the same. Values are means. Verticle lines represent one SEM. AUC, area under curve; BMI, body mass index (kg/m2); IGF‐I insulin‐like growth factor I (μg/l).
Figure 11. Figure 11.

Growth hormone (GH) secretory responses in normal young men given 10 μg/kg growth hormone–releasing peptide (GHRP‐2) subcutaneously or 1 μg/kg GHRP‐2 and 1μg growth hormone–releasing hormone (GHRH) intravenously. Results indicate that the two GH secretory responses are the same and that GHRP‐2 probably releases endogenous GHRH when given at high dosages. Values are means. Verticle lines represent one SEM. AUC, area under curve; BMI, body mass index (kg/m2). IGF‐I, insulin‐like growth factor (μg/l).
Figure 12. Figure 12.

Plasma growth hormone concentrations in nine normal men during intravenous saline (upper panel) or growth hormone–releasing peptide (GHRP‐6, lower panel) infusions from 0600 h on day 1 to 1800 h on day 2. At the times indicated by arrows, intravenous bolus injections of thyrotropin–releasing hormone (TRH, 50 μg), growth hormone–releasing hormone (GHRH, 1 μg/kg), and GHRP‐6 (1 μg/kg) were given. Values are means ± SEM.

From Jaffe et al. 73, with permission
Figure 13. Figure 13.

Growth hormone (GH) secretory responses to an acute intranasal dose of growth hormone–releasing peptide (GHRP‐2) (10 μg/kg) at zero time (•) and 6 months after daily intranasal administration of GHRP‐2 (5–15 μg/kg bid/tid) (▾)

From Pihoker et al. 105 with permission


Figure 1.

Sequential reduction and optimization of the pseudopentapeptide 4a to the simple, low‐molecular‐weight compound 4g, which maintains high in vitro and in vivo potency. inip, isonipecotic acid; b, D2Nal; bda, butanediamine; nmb, N‐methyl‐D2Nal; bol, D‐2‐naphthylalanol; wol, D‐tryptophanol. Lower‐case letters denote D stereochemistry.

From McDowell et al. 93, with permission


Figure 2.

Structures of novel growth hormone secretagogues and L‐692, 428, the biologically inactive enantiomer of L‐692, 429.

From Smith et al. 124, with permission


Figure 3.

Comparative mean growth hormone; (GH) responses to a 1.0 μg/kg intravenous bolus of GHRNH[1–44]NH2, GHRP‐6, GHRP‐1, and GHRP‐2 in normal young men. Values are means and vertical bars indicate 1 SEM. AUC, area under curve; GHRH, growth hormone–releasing hormone; GHRP, growth hormone–releasing peptide.

From Bowers et al. 16, with permission


Figure 4.

Left: Predicted amino acid sequence of the growth hormone secretagogue receptor (GHS‐R). The amino acid sequences predicted for types Ia and Ib GSH‐R for swine and humans are shown. Identical residues are boxed. Conserved cysteine residues and the G protein coupled receptor signature sequence Glu‐Arg‐Tyr142, are shaded gray. Potential sites for N‐linked glycosylation (arrows) and phosphorylation (asterisks) are shown. TM, transmembrane domain. Right: Binding of [35S]MK‐0677 to crude membranes from COS‐7 cells transfected with human type la GHS‐R cDNA. A: Saturation isotherm (bottom: ▾, nonspecific binding; ▴, total binding; ▪, specific binding) and Scatchard analysis (top) of [35S]MK‐0677 binding (bound units are femtomoles per milligram of protein). B: Competition analysis (0.24 nM [35S]MK‐0677). Competition binding data were analyzed by a nonlinear regression curve‐fitting program (Prism V, version 2.0; Graph Pad Software, San Diego, CA). Results are means ± SEM of triplicate determinations; K1 values calculated using the formula K1 = Ka/1 + c/Ka.

From Howard et al. 71, with permission


Figure 5.

Evidence for expression of a growth hormone secretagogue (GHS‐R) in Xenopus oocytes. A: Oocytes were injected with poly (A)+ RNA (50 ng) from swine pituitaries, and membrane currents were recorded at −80 mV. Current traces for effects of 100 nM MK‐0677 (left) and 1 μM growth hormone–releasing peptide (GHRP)‐6 (right). Horizontal line indicates duration of ligand exposure. B and C: Aequorin bioluminescence responses to addition of 1μM MK‐0677 (upward arrows) recorded in oocytes injected with poly (A)+ RNA (17ng) from swine, human, or rat pituitary or rat hypothalamus and Gα11 cRNA (2 ng); background (no signal) is ∼30 counts per second (cps). D: Aequorin bioluminescence response to 1 μM MK‐0677 by an oocyte injected with GHS‐R clone 7–3. E: Electrophysiological response to 100 nM MK‐0677 by an oocyte injected with GSH‐R clone 7–3 (1 ng cRNA). Horizontal line indicates duration of ligand exposure.

From Howard et al. 71; with permission


Figure 6.

Comparison of growth hormone (GH) secretory responses to growth hormone–releasing peptide (GHRP‐2) after intravenous (iv), subcutaneous (sc), oral, or nasal administration of 1 μg/kg, 3 μg/kg, 300 μg/kg, and 15 μg/kg, respectively, in normal young men. Values are means ± SEM. Vertical lines represent one SEM. AUC, area under curve; IGF‐I, insulin‐like growth factor I (μg/l); BMI, body mass index (kg/m2).



Figure 7.

Serum concentration profiles for immunoreactive growth hormone–releasing peptide (GHRP‐2) (top) and growth hormone (GH) (bottom) following intravenous administration of 1 μg/kg GHRP‐2 to nine normal young men. Mean serum concentration of GHRP‐2 peaked at 8.5 ± 2.4 μg/l and then fell to 1.78 ± 0.14 μg/l at 30 min and to 0.32 ± 0.04 μg/l at 2h after injection. Mean serum concentration of GH rose from baseline values of 0.2–0.3 μg/l to peak at a mean concentration of 79 ± 33 μg/l 35 min. after GHRP‐2 injection, before falling to 10.5 ± 1.8 μg/l 2h after injection. Values are means ± SD.



Figure 8.

Growth hormone (GH) and growth hormone–releasing peptide (GHRP‐2) concentration time profiles obtained when 10 mg GHRP‐2 made up in various formulations was given orally on different occasions to the same five normal young men. Values are means ± SEM.



Figure 9.

Mean serum growth hormone (GH), Cortisol, and prolactin (PRL) levels in normal young men after oral administration of 600 μg/kg growth hormone–releasing peptide (GHRP‐1) and 300 μg/kg GHRP‐2. Values are means. Vertical lines represent one SEM. AUC, area under curve.



Figure 10.

Mean serum growth hormone (GH) levels in normal young men after intravenous bolus of growth hormone–releasing peptide (GHRP‐2), growth hormone–releasing hormone (GHRH), or GHRP‐2 + GHRH. Results demonstrate the marked synergism of 0.lμg/kg GHRP‐2 + 1.0 μg/kg GHRH and the lack of synergism of 1.0 μg/kg GHRP‐2 + 0.1μg/kg GHRH because the GH secretory responses obtained with the latter and with 1.0 μg/kg GHRP‐2 alone are the same. Values are means. Verticle lines represent one SEM. AUC, area under curve; BMI, body mass index (kg/m2); IGF‐I insulin‐like growth factor I (μg/l).



Figure 11.

Growth hormone (GH) secretory responses in normal young men given 10 μg/kg growth hormone–releasing peptide (GHRP‐2) subcutaneously or 1 μg/kg GHRP‐2 and 1μg growth hormone–releasing hormone (GHRH) intravenously. Results indicate that the two GH secretory responses are the same and that GHRP‐2 probably releases endogenous GHRH when given at high dosages. Values are means. Verticle lines represent one SEM. AUC, area under curve; BMI, body mass index (kg/m2). IGF‐I, insulin‐like growth factor (μg/l).



Figure 12.

Plasma growth hormone concentrations in nine normal men during intravenous saline (upper panel) or growth hormone–releasing peptide (GHRP‐6, lower panel) infusions from 0600 h on day 1 to 1800 h on day 2. At the times indicated by arrows, intravenous bolus injections of thyrotropin–releasing hormone (TRH, 50 μg), growth hormone–releasing hormone (GHRH, 1 μg/kg), and GHRP‐6 (1 μg/kg) were given. Values are means ± SEM.

From Jaffe et al. 73, with permission


Figure 13.

Growth hormone (GH) secretory responses to an acute intranasal dose of growth hormone–releasing peptide (GHRP‐2) (10 μg/kg) at zero time (•) and 6 months after daily intranasal administration of GHRP‐2 (5–15 μg/kg bid/tid) (▾)

From Pihoker et al. 105 with permission
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Article Title: Growth Hormone‐Releasing Peptides
 

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Cyril Y. Bowers. Growth Hormone‐Releasing Peptides. Compr Physiol 2011, Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth: 267-297. First published in print 1999. doi: 10.1002/cphy.cp070510