Blockade of endogenous growth hormone-releasing hormone receptors dissociates nocturnal growth hormone secretion and slow-wave sleep.

OBJECTIVES: A temporal association between non-rapid eye movement (NREM) sleep stages 3 and 4 and nocturnal augmentation of GH release was found long ago, yet the precise mechanism for this association has not been identified. It has been shown, however that pulsatile GHRH administration increases both slow-wave sleep (SWS) and GH. Based on these data, a role for GHRH as an inducer of SWS was proposed. To test this hypothesis, we have performed the corollary experiment whereby the action of endogenous GHRH has been antagonized. DESIGN: Healthy men (20-33 years old) had an infusion of GHRH antagonist ((N-Ac-Tyr(1), D-Arg(2)) GHRH-29 (NH(2))) or saline for a 12-h period, between 2100 and 0900 h. An i.v. bolus of GHRH was given at 0700 h and GH samples were drawn from 0700 to 0900 h to document the efficacy of GH suppression by the GHRH antagonist. METHODS: A limited montage sleep study was recorded from 2300 to 0700 h during each admission. Plasma GH concentrations were analyzed by the use of a sensitive chemiluminometric assay. RESULTS: Effectiveness of the GHRH antagonist was validated in all subjects by demonstrating 93+/-1.8% (P=0.012) suppression of GH response to a GHRH bolus. Polysomnography demonstrated that the percentage of SWS was not different when saline and GHRH antagonist nights were compared (P=0.607); other quantifiable sleep parameters were also unchanged. CONCLUSIONS: We conclude that endogenous GHRH is indispensable for the nocturnal augmentation of GH secretion, but that it is unlikely to participate in the genesis of SWS.

Sexual dimorphism of growth hormone (GH) regulation in humans: endogenous GH-releasing hormone maintains basal GH in women but not in men.

GH secretory patterns in humans are sexually dimorphic in terms of pulse regularity, amplitude of the diurnal rhythm, and magnitude of basal (trough) secretion. The neuroendocrine mechanisms of gender-specific GH regulation in humans are currently unknown, but the interpulse GH levels are generally assumed to be controlled by somatostatin. In rats, however, administration of antiserum to GHRH lowers GH interpulse levels in females but not males. In this study, using a competitive antagonist to GHRH in humans, we investigated whether endogenous GHRH has differential, gender-specific effects on the interpulse GH levels. Six healthy men and five healthy women (20-28 yr old) who were nonobese, did not smoke, and were on no medications known to influence GH secretion were studied. Each served as his or her own control during an infusion of GHRH antagonist or saline for a 27-h period. A control bolus of GHRH was given near the end of the infusion. In both sexes during GHRH antagonist infusion, mean GH, pulse amplitude, and GH response to GHRH decreased significantly, whereas pulse frequency remained unchanged. However, during the GHRH antagonist infusion, trough GH did not significantly change in men (P = 0.54) but significantly decreased in women (P = 0.008). Deconvolution analysis confirmed the lack of a significant change in basal secretion in men (P = 0.81) as opposed to women (P = 0.006). We conclude that sexual dimorphism in the neuroendocrine regulation of GH secretion in humans involves a differential role of endogenous GHRH in maintaining baseline GH.

Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels.

We studied plasma ghrelin and GH concentrations over a 24-h period in young healthy men and women and in patients with acromegaly. Healthy subjects were restudied after administration of GH-lowering agents, octreotide or GHRH antagonist. Ghrelin concentrations in women studied during the late follicular stage of the cycle were about 3-fold higher than in men. Suppression of GH secretion by GHRH antagonist did not alter ghrelin concentration profiles. In the presence of high GH levels (acromegaly), ghrelin levels were similar to those found in healthy men. Administration of somatostatin analog octreotide suppressed both GH and ghrelin concentration profiles. We conclude that: 1) ghrelin secretion is sexually dimorphic in humans, with women in the late follicular stage having higher levels than men; 2) ghrelin secretion is suppressed by somatostatin; and 3) GH has no influence over ghrelin secretion.