HYPOTHALAMIC AND HYPOPHYSEAL REGULATION OF GROWTH-HORMONE SECRETION

1. Regulation of pulsatile secretion of growth hormone (GH) relies on hypothalamic neuronal loops, major transmitters involved in their oper ation are growth hormone releasing hormone (GHRH) synthetized mostly i n arcuate nucleus (ARC) neurons, and somatostatin (SRIH), synthetized both in hypothalamus periventricular (PVe) and ARC neurons. 2. Neurons synthetizing both peptides can inhibit each other in a reciprocal man ner. Other neuropeptides synthetized in ARC neurons, such as galanin, or in ARC interneurons, such as neuropeptide Y (NPY), are able to modu late synthesis and release of GHRH and SRIH into the hypothalamohypoph yseal portal system. 3. In addition, the hitherto uncharacterized endo genous ligand of the recently cloned growth hormone releasing peptide receptor, expressed mostly in the ARC, triggers GH release, presumably by actions on ARC interneurons. 4. Thyroid, gonadal, and adrenal ster oid hormones also affect the GHRH-SRIH balance; a differential distrib ution of sex steroid receptors in the ARC and the PVe is likely to acc ount for the different pattern of GH secretion in male and female anim als. 5. Growth hormone itself is able to inhibit the amplitude of GH s ecretory episodes and to increase their frequency, by entering the bra in (presumably by receptor-mediated internalization at the level of th e choroid plexus) and acting subsequently on ARC neurons. 6. At the pi tuitary level, major neurotransmitters regulating GH cells act on rece ptors of the VIP/PACAP/GHRH family and of the somatostatin family, in particular, sst2 and sst3. Those are coupled to accumulation of cAMP a s a second messenger. 7. In addition, patch-clamp experiments and meas urement of intracellular Ca2+ indicate that GH cells present character istic, GHRH-dependent, but self-maintained Ca2+ spikes and [Ca2+](i) t ransients, which reflect adaptive mechanisms to constraints of episodi c release. 8. Recent data on transcription factors affecting GH gene e xpression and somatotrope differentiation are also summarized. 9. Regu lation and differentiation of somatotropes also depend upon paracrine processes within the pituitary itself and involve growth factors and s everal neuropeptides, for instance, vasoactive intestinal peptide, ang iotensin 2, endothelin, and activin. 10. Finally, characteristic chang es occur in the GH secretory pattern under discrete, pathological cond itions, such as abnormal growth and dwarfism, diabetes, and acromegaly , as well as during inflammatory processes.