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Although the hypothalamus functions as a temporal pattern generator of growth hormone releasing factor (GRF), the pituitary plays major dynamic roles in amplifying and modulating this pattern. First, in response to continued application of GRF, the pituitary somatotrophs rapidly desensitize and this process is important in shaping the pulsatile profile of growth hormone (GH) secretion. Second, the pituitary can amplify a pulsatile output of GRF from the hypothalamus. This may seem unnecessary given the possibility of generating a larger signal directly from the hypothalamus; however, the amplification is nonlinear (the dose-response curve of the pituitary to releasing factors is sigmoidal when plotted on a semilog scale). The nonlinearity is partly a result of short-term desen-sitization at the pituitary, which contributes to terminating secretory episodes, leading to a stereotyping of both pulse amplitude and duration, as well as ensuring a minimum interpulse interval. Furthermore, the pituitary coordinates a number of inputs from the hypothalamus and elsewhere.

The secretion of growth hormone in the rat is sexually dimorphic. In both sexes secretion is pulsatile, but in males the pulses are larger, less frequent, and arise from a lower interpulse baseline than in females (1). That pulsatile GH secretion fuels faster growth has been demonstrated both in animals deficient in growth hormone and in animals experimentally deprived of hypothalamic GRF (2-4). In the male rat, pulses occur

From: Human Growth Hormone: Research and Clinical Practice Edited by: R. G. Smith and M. O. Thorner © Humana Press Inc., Totowa, NJ

at intervals of about 3 h, and since the growth-promoting effects of pulsatile GH administration appear to saturate at about nine pulses per day, the physiological pattern of growth hormone secretion appears to be optimally efficient. Pulses of growth hormone secretion derive from episodic secretion of GRF, but growth hormone secretion is also regulated by the secretion of somatostatin (5-8).

Somatostatin (SRIF) inhibits the secretion of growth hormone, and although acting at a separate receptor, acts as a functional GRF antagonist in that in the presence of somatostatin the growth-hormone releasing ability of GRF is attenuated; both the GRF receptor and the somatostatin receptor are G protein-linked receptors, and activation of these receptors produces opposing effects upon intracellular calcium and cAMP levels and on calcium entry, in particular, through L-type channels. The sexually dimorphic patterns of growth hormone secretion in the rat appear to derive from sexually dimorphic behavior of the somatostatin neurons, possibly reflecting the sexually dimorphic expression of androgen receptors by these neurons (9). In the male rat, GRF and soma-tostatin are probably released alternately to produce peaks and troughs of growth hormone release, respectively, whereas in the female, somatostatin is released more continuously. However, inferring the nature of the hypothalamic signals from the pituitary response is not simple because the pituitary responsiveness to releasing factors is variable. Variability arises from the interactions of the hypothalamic factors with each other from desensitization of the pituitary during sustained exposure to probably either factor, from actions of the hypothalamic factors on the synthesis of growth hormone, and in the case of somatostatin, a dramatic "off" effect when somatostatin is removed, reflected by an increase of basal release in the absence of GRF and a sensitization to GRF (10,11).

Application of artificial growth hormone secretagogues also promotes GH release in a similar dose-dependent manner by different receptors (12), and there is evidence in vivo of synergism between the two stimulants in the sense that GH release is in total greater when GRF and secretagogue are applied together than the sum of the releases when they are applied separately.

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