Neuroendocrine regulation of pulsatile growth hormone secretion in the rat

Like other anterior pituitary hormones, GH is secreted in a pulsatile fashion. This secretory pattern is the result of a complex neuroendocrine control from the brain, integrating spontaneous endogenous rhythms, endocrine signalling from peripheral tissues and environmental stimuli. These factors act directly or through specific neural pathways on a hypothalamic command that associates both stimulatory (GHRH) and inhibitory (somatostatin) influences on somatotrope function. GH secretion exhibits striking sex differences in the rat, with a highly pulsatile pattern in males and a more continuous secretion in females. This species has, therefore, provided a good model system to study the regulatory mechanisms underlying GH pulsatility.
Hypothalamic growth hormone-releasing hormone (GHRH) is essential to maintain pulsatile GH secretion and somatotroph trophicity. Suppression of this stimulatory influence results in almost complete inhibition of GH release in both sexes, and in growth retardation which seems more severe in male animals. In both male and female rats, GH pulses are driven by concomitant surges of GHRH from the hypothalamic-ME axis into the hypophysial-portal circulation. In addition, GHRH contributes to elevated interpulse concentrations of GH in the female rat.
Somatostatin counteracts GHRH stimulatory effects on GH secretion. The actual rate of GH release from the somatotrophs will depend on the relative predominance of one of these two opposite influences. In the male rat, a marked somatostatin inhibitory tone maintains interpulse GH secretion to very low levels an prior interruption of this inhibition is necessary for the occurrence of a large GH surge. As opposed to this cyclic secretion in males, the hypothalamic release of somatostatin appears to be more constant and of intermediate amplitude in the female rat, allowing frequent and significant GH bursts in response to GHRH.
GH itself regulates its own secretion by modulating the synthesis and release of its hypothalamic-controlling peptides (inhibition of GHRH and stimulation of somatostatin). These feedback effects are exerted by GH directly (short-loop feedback) and/or by IGF-I produced by the peripheral tissues in response to GH (long-loop feedback). The sensitivity of GHRH- and somatostatin-producing neurons to GH autoregulation is more pronounced in male rats than in females. These differences might also contribute to the generation of the sex-specific pattern of GH secretion.
Several neurotransmitters and neuropeptides are important modulators of the somatotrope axis. In particular, galanin, a neuropeptide abundant in the hypothalamus and the median eminence, is aphysiological stimulator of GH release and is essential for the preservation of the high amplitude, low frequency GH pulse typically observed in male rats.
Finally, peripheral hormones and metabolic factors influence GH secretion. The presence of thyroid hormones and glucocorticoids in adequate amounts is necessary for normal pituitary GH synthesis and release. Gonadal hormones have also profound effects on GH pulstility in male and female animals. Testosterone stimulates GH pulse amplitude and maintains low basal levels of GH whereas estrogens elevate basal GH concentrations and diminish GH peaks under some conditions. The mechanisms underlying these effects are complex and not fully understood. They involve both activational effects of gonadal hormones on the adult hypothalamus and pituitary, and organizational effects of neonatally secreted sex steroid on the developing brain.
The physiological significance of GH secretory pulsatility has been investigates in hypophysectomised rats by stimulating different plasma patterns of GH. A masculine pattern was mimicked by giving GH in four daily sc injections, and a feminine pattern was stimulated by infusing the hormone continuously.
Pulstile GH administration is more effective than continuous hormonal infusion to promote somatic growth and stimulate tissue synthesis and secretion of IGF-I. On the other hand, constant and prolonged exposure to GH leads to an increase in the number of liver somatogenic receptors and in serum GH binding protein (GHPB) concentration, while intermittent GH delivery does not affect GH binding to liver membranes or serum GHBP. Thus, growth-promoting action of GH depends on GH pulses and is dissociated from its up-regulatory effect on GH binding sites at the target tissue level.
The mode of GH administration also influences other sexually differentiated hepatic characteristics, such as PRL receptor concentration and steroid metabolism. A “feminization” of the liver develops after exposure to constantly elevated GH levels, and a “masculinisation” of the liver is induced by repeated GH bursts. It appears, therefore, that the secretory pattern of GH in the rat determines, at least in part, some important sex-related differences including growth rate, the amount of liver GH and PRL receptors, and hepatic steroid metabolism.
there is some evidence that GH pulsatility is also of physiological relevance in human beings, and clinical trials have recently been undertaken to determine the frequency and timing of GH therapy that are optimal for growth promotion in GH-deficient children. This issue is all the more important as potential indications for GH administration are rapidly expanding and encompass now various medical and socio-economical problems, such as GH deficiency in adults, growth failure in absence of classical GH deficiency, severe catabolic sates, aging or increase in milk yield in cattle and in meat mass in farm animals. In all situations where GH treatment will prove to be beneficial, chronobiological studies, will be needed to determine the best mode of hormonal administration