The hypothalamicgrowth hormone axis

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Although the HPA and HPT axes have been more closely scrutinized in patients with psychiatric disorders, there is virtual universal agreement that the blunted growth-hormone response to a variety of provocative stimuli (particularly clonidine, an a 2-adrenergic agonist) in depressed patients is the most consistent finding in affective disorders research.(29) The mechanism underlying this phenomenon remains obscure, but it is of particular interest that, at least in some studies, it appears to persist upon recovery from depression, suggesting that it is a trait marker for depression vulnerability. There are reports of similar findings with other growth hormone-provocative stimuli, such as the use of apomorphine, desipramine, or levodopa. In addition, the blunted growth-hormone response to clonidine in depressed patients is particularly robust in those who have recently attempted suicide. Clearly, further work in this area is warranted, especially in the context of several reports of alterations in basal growth-hormone secretion in this disorder. The nature of this alteration is a reduction in the normal nocturnal rise in growth-hormone secretion, though this is not a universally agreed-upon finding. Alterations in growth-hormone secretion in other psychiatric disorders (particularly schizophrenia) have also been reported, though the results may have largely been due to long-term treatment of such patients with dopamine-receptor antagonists, antipsychotic drugs.

The secretion of growth hormone and the regulation of this axis are distinct from that of the other endocrine axes for several reasons. First, this is the one axis in which two hypothalamic-hypophysiotrophic hormones have unequivocally been shown to play a physiological role. The first discovered was somatostatin or growth hormone-inhibiting hormone, isolated from ovine hypothalamus in 19Z4. It is a tetradecapeptide, which contains a disulfide bridge linking the two cysteine residues. It is distributed in the CNS not only in cells of the periventricular nucleus of the hypothalamus, which projects to the median eminence, but in a variety of extrahypothalamic areas as well. Indeed, somatostatin is known to function as a CNS neurotransmitter and is of particular interest to psychiatrists because of its early involvement in the Alzheimer's disease process. Our group and others have documented the marked reduction in somatostatin concentrations in this dementing disorder.(28> In addition, somatostatin concentrations are markedly elevated in the basal ganglia of patients with Huntington's disease; (30) the pathological implications of this finding remain obscure. In contrast to the other peptide receptors described above in which one or at most two receptor subtypes have been identified, several distinct somatostatin receptor subtypes have now been structurally identified. Such diversity suggests the possibility of specific receptor-subtype agonists and antagonists as putative therapeutic agents.

Several years after the elucidation of the structure of somatostatin, the long-postulated growth hormone-releasing factor ( GHRF) was found in extracts of an ectopic tumour associated with acromegaly. It is a peptide containing 44 amino acids, and it has the most limited CNS distribution of all the hypothalamic-releasing hormones thus far studied. The vast majority of the peptide is found in the arcuate nucleus of the hypothalamus from where it projects nerve terminals to the median eminence. Unlike the other axes, the growth-hormone axis is also unique in not having a single target endocrine gland. Indeed, growth hormone does stimulate the release of somatomedin C from the liver and it also exerts direct effects on a variety of targets including bone and muscle. Most, but not all, investigators have reported a blunted growth-hormone response to GHRH in depressed patients, but the total number of patients studied pales in comparison to the TRH- and CRF-stimulation test data. There are no data published on somatomedin C responses to GHRH in depressed patients. No published studies are available in which GHRH concentrations or GHRH-mRNA expression have been studied in postmortem tissue of depressed patients and matched controls, an obvious study in view of the data reviewed above.

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