1. Regulation of pulsatile secretion of
growth hormone (GH) relies on hypothalamic neuronal loops, major transmitters involved in their operation are
growth hormone releasing hormone (GHRH) synthetized mostly in 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 manner. Other
neuropeptides synthetized in
ARC neurons, such as
galanin, or in
ARC interneurons, such as
neuropeptide Y (NPY), are able to modulate synthesis and release of GHRH and SRIH into the hypothalamohypophyseal portal system. 3. In addition, the hitherto uncharacterized endogenous
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
steroid hormones also affect the GHRH-SRIH balance; a differential distribution of sex
steroid receptors in the
ARC and the PVe is likely to account for the different pattern of GH secretion in male and female animals. 5.
Growth hormone itself is able to inhibit the amplitude of GH secretory episodes and to increase their frequency, by entering the brain (presumably by receptor-mediated internalization at the level of the choroid plexus) and acting subsequently on
ARC neurons. 6. At the pituitary level, major
neurotransmitters regulating GH cells act on receptors of the VIP/
PACAP/GHRH family and of the
somatostatin family, in particular, sst2 and sst3. Those are coupled to accumulation of cAMP as a second messenger. 7. In addition, patch-clamp experiments and measurement of intracellular Ca2+ indicate that GH cells present characteristic, GHRH-dependent, but self-maintained Ca2+ spikes and [Ca2+]i transients, which reflect adaptive mechanisms to constraints of episodic release. 8. Recent data on
transcription factors affecting GH gene expression and somatotrope differentiation are also summarized. 9. Regulation and differentiation of somatotropes also depend upon paracrine processes within the pituitary itself and involve
growth factors and several
neuropeptides, for instance,
vasoactive intestinal peptide,
angiotensin 2,
endothelin, and
activin. 10. Finally, characteristic changes occur in the GH secretory pattern under discrete, pathological conditions, such as abnormal growth and
dwarfism, diabetes, and
acromegaly, as well as during inflammatory processes.