Molecular biology and regulation of the hypothalamic hormones

Over the past twenty years, each of the five major hypothalamic releasing or release-inhibiting hormones has been sequenced and its gene structure determined. With the use of molecular biological techniques, such as in situ hybridization, Northern blot analysis or gene constructs for in vitro or in vivo transfection studies--together with 'traditional' neuroendocrinological techniques, such as immunocytochemistry, radio-immunoassay and portal vessel cannulation--investigators have been able to address major issues in neuroendocrine regulation. Several common themes have emerged: messenger RNA expression is uniformly present in neurons that are immunopositive for the specific hypothalamic hormone. Steady state RNA levels within the hypophysiotropic neuron groups are either increased or reduced by changes in specific target hormones that conform to predictions based on previous physiological data. Regulation by the requisite peripheral hormone is exquisitely anatomically specific and is not evident in extrahypophysiotropic regions. Determining the receptor or genetic basis of this specificity is a major focus of current research. Clarifying the apparently lesser role of afferent neural pathways to the hypothalamus in regulating releasing hormone mRNA levels is also an important challenge. Clinically, the measurement of levels of releasing hormones in the peripheral circulation appears to be of limited usefulness, except in rare cases of ectopic GRH or CRH secretion. For diagnostic purposes, each of the releasing hormones has specific utility in amplifying the release and measurement of pituitary hormones, both to clarify the overall physiological activity of the hypothalamic-pituitary-target hormone axis and to further define the anatomic locus of any underlying disturbance. The usefulness of somatostatin as a diagnostic tool is presently limited, but the development of SS receptor antagonists might have significant impact in future clinical investigation. The molecular mechanisms of action of the hypothalamic hormones have been separated into those whose receptor-effector function is mediated by the cAMP-adenylate cyclase pathway(s), GRH and CRH, and those working through the phosphoinositide-protein kinase C cascade, GnRH and TRH. Each of the hormone receptors is coupled to intermediary G proteins, somatostatin uniquely to the inhibitory subclass. The mechanisms responsible for sensitization (priming) or desensitization are not fully understood but are presumably related to receptor down regulation and protein phosphorylation.(ABSTRACT TRUNCATED AT 400 WORDS)