Pituitarygrowth Hormone Axis

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Growth hormone (GH) is synthesized and secreted from somatotrophs located in the anterior pituitary. Its release is unique in that it is controlled by two peptide hypothalamic hypophysiotropic hormones, growth hormone-releasing factor (GHRF) and somatostatin (SRIF). SRIF, also known as growth hormone-release-inhibiting hormone (GHIH), was first isolated from ovine hypothalamus in 1974. It is a tetradecapeptide, containing a disulfide bridge linking the two cysteine residues. It is released predominantly from the periventricular and the PVN of the hypothalamus and inhibits GH release. SRIF has a wide extrahypothalamic distribution in brain regions, including the cerebral cortex, hippocampus and amygdala.

GHRF was characterized and sequenced in 1981, after considerable difficulty, from extracts of an ectopic tumour associated with acromegaly. GHRF is a 44-amino-acid peptide and has the most limited CNS distribution of all the hypothalamic-releasing hormones so far identified. GHRF-containing neurons are concentrated in the arcuate nucleus of the hypothalamus and stimulate the synthesis and release of GH. Dopamine, norepinephrine and serotonin innervate GHRF-containing neurons to modulate GH release. Both GHRF and SRIF are released from the median eminence into the hypothalamo-hypophyseal portal system, where they act on somatotrophs in the anterior pituitary to regulate GH release. The GH axis is unique in that it does not have a single target endocrine gland; instead, GH acts directly on targets including bone, muscle and liver. GH also stimulates the release of somatomedin from the liver and insulin-like growth factors. GH shows pulsatile release, with highest release occurring around the time of sleep onset and extending into the first non-REM period of sleep [117].

GH release response to a variety of stimuli, including l-DOPA, a dopamine precursor [118], apomorphine, a centrally active dopamine agonist [110], and the serotonin precursors l-tryptophan [119] and 5HTP [120], has been demonstrated. Several findings indicate dysregulation of GH secretion in depression. Studies have demonstrated a blunted nocturnal GH surge in depression [121], whereas daylight GH secretion seems to be exaggerated in both unipolar and bipolar depressed patients [122]. A number of studies have also demonstrated a blunted GH response to the a-adrenergic agonist clonidine in depressed patients [123, 124]. Siever et al. [125] demonstrated that the blunted GH response to clonidine was not related to age or sex, and this study provided evidence that the diminished GH response to clonidine may be secondary to decreased a2-adrenergic receptor sensitivity in depression. Using a GHRF stimulation test, our group later demonstrated a slight exaggeration of GH response to GHRH in depressed patients compared to controls, although this difference was mainly attributable to 3 of the 19 depressed patients, who exhibited markedly high GH responses to GHRF [126]. Others, however, have reported a blunted GH response to GHRH in depressed patients. Thus, it is unclear whether the blunted GH response to clonidine seen in depression is due to a pituitary defect in GH secretion, further implying the existence of a sub-sensitivity of a-adrenergic receptors in depression, or to a GHRH deficit. Recently, a diminished GH response to clonidine was demonstrated in children and adolescents at high risk for major depressive disorder. In the light of evidence demonstrating GH dysregulation in childhood depression [127], the blunted GH response seen in high-risk adolescents may represent a trait marker for depression in children and adolescents [128]. Arguably, the blunted GH response to clonidine seen in depression may be the most reproducible and specific finding in the biology of affective disorders.

A GHRH stimulation test has also been developed and employed in depressed patients. Two groups have shown a blunted GH response to GHRH in depressed patients [129-131]. However, Krishnan et al. [126,132] found minimal differences in serum GH response to GHRH between depressed and control patients. A comprehensive review of GHRH stimulation tests in depression, anorexia nervosa, bulimia, panic disorder, schizophrenia and Alzheimer's disease concluded that the results of this test are not consistent and in some cases are contradictory [133]. Factors including the variability of GHRH-stimulated GH among controls, lack of standard outcome measures, and age and gender-related effects may account for some of this variability. Further studies using GHRH will help develop a standard stimulation test to clarify further the response to GHRH in depression and other psychiatric disorders.

Several studies have demonstrated decreased SRIF levels in the CSF of patients suffering from depression [134,135], dementia, schizophrenia [136] and Alzheimer's disease [98,137]. SRIF concentrations are also markedly elevated in the basal ganglia of patients with Huntington's disease [138], though the implications of this finding are unknown. SRIF also inhibits the release of both CRF and ACTH [139-141], indicating a direct interaction between the GH and HPA axes. No published studies measuring GHRH concentration and GHRH mRNA expression have been conducted in post-mortem tissue from depressed patients and matched controls, which, in view of the evidence presented here, is of interest. Similarly, CSF studies of GHRH are lacking.

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