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Pulsatile GH Secretion vs Sustained Elevation: The Critical Distinction
Growth hormone secretion in healthy physiology follows an ultradian rhythm. Discrete pulses occurring every 3–5 hours, with the largest amplitude pulse occurring 60–90 minutes after sleep onset. This pulsatility is regulated by the alternating secretion of GHR
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- Growth hormone secretion in healthy physiology follows an ultradian rhythm. Discrete pulses occurring every 3–5 hours, with the largest amplitude pulse occurring 60–90 minutes after sleep onset. This pulsatility is regulated by the alternating secretion of GHRH (stimulatory) and somatostatin (inhibitory) from the hypothalamus. Exogenous GH administration disrupts this rhythm entirely, creating a sustained pharmacological elevation that suppresses endogenous pituitary output through negative feedback at the hypothalamic level (increased somatostatin, decreased GHRH).
- MK-677 preserves pulsatility because it amplifies existing pulses rather than replacing them. When GHRH is released and somatostatin tone is low (permissive window), MK-677-occupied GHSR1a receptors synergise with GHRH signalling to produce a larger GH pulse than would occur with GHRH alone. During somatostatin-dominant periods, MK-677 cannot override the inhibitory tone. The pulse is still suppressed. This is why MK-677 does not cause the hypothalamic-pituitary axis suppression seen with exogenous GH: the regulatory feedback loops remain intact.
- A 2008 study published in Growth Hormone & IGF Research compared 24-hour GH secretion profiles in subjects receiving MK-677 25mg daily versus placebo. The MK-677 group showed a 60% increase in mean 24-hour GH AUC (area under the curve), but pulse frequency remained unchanged. What increased was pulse amplitude. IGF-1 levels, synthesised in the liver in response to GH, rose by 72% and remained elevated throughout the dosing period without tachyphylaxis over 12 months of continuous use.