Growth hormone (GH) or somatotropin is another stress-sensitive neuroendocrine system. GH is synthesized by the anterior pituitary, and although it can be used as an endpoint in itself for neuroendocrine research in psychiatry, its predominant use is as a marker of the integrity of the noradrenergic system following challenge. The hypothalamic-pituitary-somatotrophic (HPS) axis is under complex regulatory control that is not yet fully understood since cross-species variations in GH
regulation make it difficult to extrapolate to humans from animal studies. It is well established, however, that the final common pathways for control of GH release from the pituitary are hypothalamic growth hormone-releasing hormone (GHRH) (stimulation) and somatostatin (inhibition). The wide variety of metabolic, endocrine, and neural influences that alter GH secretion do so primarily through effects on GHRH and/or somatostatin. Neural influences may be mediated by noradrenergic, cholinergic, dopaminergic, 7 aminobutyric acid (GABA)-ergic, and serotonergic neurotransmission. Clear physiological regulatory roles, however, have only been well documented in humans for noradrenergic and cholinergic inputs. Dopamine, serotonin, and GABAergic drugs can alter GH release but do so in contradictory ways, depending on the experimental paradigm, leaving their roles as GH regulatory agents uncertain at present (Devesa et al. 1992; Muller 1987). In humans, GH is released by acute stress, but is suppressed by chronic stress. Chronic psychosocial stress in children can result in growth arrest and even short stature and delayed puberty. A variety of other endocrine, metabolic, and physiological factors can influence GH release, although the mechanisms by which they do so are not clear. Factors that can inhibit GH release include free fatty acids (Penalva et al. 1990) and, most importantly for this review, CRH (Corsello et al. 1992) and glucocorticoids (del Balzo et al. 1990; Giustina and Wehrenberg 1992). Studies by Wiedemann et al. (1991) examined GH secretion in healthy control subjects given hourly pulses of ACTH (1L g) or h-CRH (10 L'g) between 9 a.m. and 6 p.m. to induce hypercortisolemia. They found an increase in the number of GH pulses and amount of GH secreted during the daytime but did not find an increase in the total 8 a.m. to 3 a.m. GH secretion because of blunted nighttime secretion. This pattern is similar to that seen in depressed patients (Mendlewicz et al. 1985) who have increased daytime GH secretion and reduced sleep-related GH secretion, suggesting a similar mechanism may occur in depressed patients. However, our own studies of 26 premenopausal women with major depression and 26 age- and menstrual-cycle-day-matched control women examining 10-minute secretion of GH for 24 hours found no changes in GH secretion (Amsterdam et al. 1989).
Current evidence suggests that the normal episodic GH secretory pattern is shaped by an alternating rhythm of GHRH and somatostatin release (Plotsky and Vale 1985), which has been called the hypothalamic-somatotroph rhythm (HSR) (Devesa et al. 1992). This is not a regular alternation but consists rather of four to eight short pulses of GH secretion distributed irregularly over a 24-hour period, the largest one occurring shortly after the onset of sleep. The significant role of somatostatin in shaping the HSR is evidenced by its persistence in the face of a constant GHRH infusion (Hulse et al. 1986; Vance et al. 1985). The intrinsic HSR, in turn, appears to shape the response to exogenous GHRH (Devesa et al. 1989, 1990, 1991a, 1992; Tannenbaum and Ling 1984). The response is greatest if GHRH is given while plasma GH is rising or near the peak of a pulse, presumably indicating that somatostatin is suppressed. The GH response is minimal if GHRH is given while plasma GH is low and stable, presumably indicating predominance of the somatostatin effect. Currently available human data therefore suggest that clonidine exerts a major effect on GH release via suppression of somatostatin-mediated inhibition.
It appears that cholinergically mediated suppression of somatostatin plays a significant role in regulating nocturnal GH release (Ghigo et al. 1990; Mendelson et al. 1978; Peters et al. 1986). Factors that can enhance GH release include estrogen (Devesa et al. 1991b; Ho et al. 1987), thyroid-releasing hormone, vasoactive intestinal peptide, hypoglycemia, sleep, exercise, and stress (Devesa et al. 1992; Muller 1987; Uhde et al. 1992). Finally, GH exerts a negative feedback inhibition of its own secretion (Devesa et al. 1992; Muller 1987). It appears to act at the level of the hypothalamus and/or median eminence to stimulate somatostatin release (Devesa et al. 1992). It may also inhibit GHRH release (Devesa et al. 1992). GH also stimulates the production of somatomedin-C/insulin-like growth factor 1 (IGF-1) in peripheral tissues, including liver. Somatomedin-C in turn has a dual inhibitory feedback effect. It directly suppresses GH secretion at the pituitary level and stimulates somatostatin release at the hypothalamic level (Devesa et al. 1992). Levels of somatomedin-C correlate positively with, and can be used to infer, systemic GH levels during the past 8-12 hours (Copeland et al. 1980; Ross et al. 1987; Vance et al. 1985). Measurement of somatomedin-C levels thus can provide another means of evaluating the overall functional status of the HPS axis.
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