In all species studied thus far, including man, growth hormone (GH) secretion is pulsatile. Using sensitive GH assays and frequent blood sampling over extended periods of time, it has been shown that in normal humans, plasma GH fluctuates over an approximately 1000 fold range: between 0.01 and 30-40 xg/L. These wide fluctuations are not haphazard, but rather tightly organized into discrete secretory pulses and long periods of secretory quiescence. Alterations in GH pulsatility are seen in a variety of physiological and pathological circumstances, including puberty, aging, menstrual cycle, obesity, starvation, growth delay and acromegaly. Even more importantly, the biological efficiency of GH and its tissue specificity depend on the mode of pulsatile GH presentation to the tissues.
Administration of GH to hypophysectomized animals in either continuous or pulsatile pattern differentially affects the induction of GH-dependent parameters. Moreover, some biological actions of GH are preferentially modulated by the magnitude and duration of the steady, interpulse GH levels, whereas others require frequent and transiently-high GH pulses. Thus, it is not only the total amount of GH presented to the peripheral tissues, but also the pattern of its pulsatile secretion that is important for the ultimate effect. Over the past 20 years, several research groups have directed major efforts aimed at identifying the discrete neuroendocrine components responsible for the regulation of GH pulsatility. Cnicial for these research endeavors were the identifications of the hypothalamic and the peripheral regulators of GH synthesis and secretion, GH-releasing hormone (GHRH), somatostatin (SRIH) and insulin growth factor-I (IGF-I). More recently the existence of yet another GH stimulant, tentatively labeled GHS (Growth Hormone Secretagogue) has been postulated. The discovery of GHRH and SRIH allowed for the development of physiologic techniques to study their roles in GH secretion. Such techniques, including immuno neutralization of GHRH and SRIH, and direct sampling of hypophysial-portal blood, attributed to GHRH the role of the primary releaser of OH and to SRIH the role of the inhibitor that controls the interpulse GH levels and the amplitude of GH pulses.
Recent discovery of hypothalamic and pituitary receptors for a still unidentified GHS peptide introduced further complexity to the system. Since this putative compound apparently possesses both GHRH-releasing and anti-SRIH properties, it would be ideally suited to be the primary regulator of GH pulsatility. Another level of complexity in the study of GH regulation is the heterogeneity of the models. Conclusions derived from one species may not be applicable to another species. Recently, Dutour performed a careful review of the existing data regarding the mechanisms of GH pulsatility. They stressed the unique features of GH neuroregulation in the rat on the one hand and in humans and sheep on the other hand. It is likely that a model different from the rat will be needed in the future to obtain the detailed biochemical and pharmacological data needed to explain GH pulsatihty in humans. In this review we shall attempt to present the existing data on the relative roles of GHRH, SRIH and the putative GHS as the hypothalamic regulators of GH pulsatility, with the emphasis on the humans.
A wide variety of in vivo animal studies have supported the central role of GHRH in the production of GH pulses. Animals with experimentally-induced hypothalamic lesions and humans with organic illnesses of the hypothalamus have absent or severely impaired GH secretion. This is especially true with regards to the pulsatile component. Administration of GHRH in these GHRH-deficient models invariably restored GH pulsatility and promoted somatic growth. However, hypothalamic lesioning is too crude to pinpoint the precise neuroendocrine component of GH dysregulation. More selective and specific models, such as GHRH immunoneutralization, blockade of GHRH action by a receptor antagonist, or destruction of the GHRH-containing neuronal bodies in the arcuate nucleus by neonatal monosodium glutamate (MSG), all confirmed the crucial role of GHRH in the generation of GH pulsatility in animal models. Moreover, direct measurement of hypophysial-portal GHRH concentration in sheep has shown that the majority of GH pulses are preceded or accompanied by simultaneous GHRH pulses.
Although SRIH secretory patterns were also pulsatile, there was no correlation between GH and SRIH pulses. Taken together, these data attribute to GHRH the crucial role of the actual GH pulse generator, with SRIH playing only a secondary role, possibly as a modulator of GH pulse amplitude. Understandably, the methodologies used in animals such as immunoneutralization of GHRH or direct pituitary-portal sampling are impractical in humans. We have therefore approached this problem pharmacologically, blocking the GHRH receptor to investigate the role of endogenous GHRH in the generation of GH pulsatility in humans. The compound used is a specific and selective GHRH antagonist (GHRH-ant) both in vitro and in vivo. We first showed that a single intravenous bolus dose of GHRH-ant 400 ag/kg blocked the pituitary response to exogenous GHRH in a time-dependent manner, suppressing the GH response by 95% at 60 minutes and 4% at 24 hours. The same bolus dose of GHRH-ant suppressed the nocturnal GH release by 75%. Failure to more completely suppress nocturnal GH secretion could have been due to either a non-GHRH mechanism accounting for some of the nocturnal GH pulsatility, or waning efficacy of GHRH-ant due to rapid clearance. In a subsequent experiment, we administered GHRH-ant as a continuous IV infusion following the loading bolus at 2200 h.
Nocturnal pulsatile GH secretion in young healthy men was suppressed by almost 90%, confirming the exquisite importance of endogenous GHRH for the generation of pulsatile GH secretion in humans. The neuroendocrine genesis of pharmacologically-induced GH pulses is unknown. Acute provocative stimuli of GH have been used for more than 30 years as diagnostic tools in investigating potential GH deficiency. Theoretically, these stimuli elicit GH release either through an acute discharge of hypothalamic GHRH or through acute suppression of SRIH secretion.
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