Effect of somatostatin infusion on the somatotrope responsiveness to growth hormone-releasing hormone in patients with anorexia nervosa.

BACKGROUND: According to the existence in anorexia nervosa (AN) of peripheral growth hormone (GH) resistance, low circulating insulinlike growth factor I (IGF-I) levels may be coupled with GH hypersecretion; however, there is also evidence for alterations in the neural control of GH secretion. In fact, reportedly GH secretion is partially refractory to the inhibitory effect of muscarinic cholinergic antagonists as well as to the stimulatory effect of muscarinic cholinergic agonists, which act via opposite modulation of hypothalamic somatostatin (SS) release. Thus, somatostatinergic activity could be impaired in AN. This could be due to an impaired hypothalamic SS release or, alternatively, an altered somatotroph sensitivity to SS. METHODS: We studied in 10 women with AN in acute phase (AN, age, mean +/- SEM: 18.7 +/- 0.8 years) the effect of exogenous SS1-14 (25 and 75 micrograms/hour i.v., infused from +15 to +75 min), at doses that had previously been shown capable of increasing circulating SS levels within the physiological range, on the GH response to GH-releasing hormone (GHRH) (1 microgram/kg i.v. at 0 min). The same study protocol was performed in 8 normal age-matched women (NW, 22.9 +/- 1.0 years). RESULTS: In AN patients, IGF-I levels were lower (p < .01) than those in NW, while basal GH levels were similar in both groups. The GHRH-induced GH rise in AN was higher (p < .01) than that in NW. In AN, the exaggerated GH response to GHRH was inhibited to the same extent by both SS doses (p < .05) and became similar to that after GHRH alone in NW. In NW both 25 and 75 micrograms/hour SS decreased the GHRH-induced GH response; however, the inhibitory effect of the lower dose did not attain statistical significance, whereas the higher dose did (p < .02). During SS infusion, the GHRH-induced GH response in NW was persistently lower (p < .02) than that in AN. The percent inhibitory effect of SS on the somatotroph responsiveness to GHRH was similar in both groups at each dose. CONCLUSIONS: Our present findings demonstrate that the sensitivity of somatotroph cells to exogenous SS given at physiological doses is preserved in patients with AN. It is noteworthy that, during the infusion of physiological SS doses, the GH response to GHRH in AN overlaps on that to GHRH alone under physiological conditions. Thus, in AN, the sensitivity of somatotroph cells to SS apparently being preserved, an impairment of somatostatinergic neurons cannot be ruled out.

Involvement of brain catecholamines and acetylcholine in growth hormone hypersecretory states. Pathophysiological, diagnostic and therapeutic implications.

Secretion of growth hormone (GH) is excessive in acromegaly, but also in a number of other pathological states such as anorexia nervosa, insulin-dependent diabetes mellitus (IDDM), liver cirrhosis, depression, renal failure and GH-insensitivity syndrome. Abnormalities in the neuroendocrine control of GH secretion and/or a state of insensitivity to GH contribute to hypersecretion of GH in these states, with the possible exception of acromegaly, which appears to be a primary pituitary disease. GH hypersecretion may also occur in neonates or adolescents with tall stature, thus reflecting particular physiological or paraphysiological conditions. In the cohort of brain neurotransmitters, catecholamines and acetylcholine reportedly play a major role in the control of neurosecretory GH-releasing hormone (GHRH) and somatostatin (SS)-producing neurons, and hence GH secretion. Activation of alpha 2-adrenoceptors or of muscarinic cholinergic receptors in the hypothalamus stimulates GH release, probably through stimulation of GHRH and inhibition of SS release, respectively. Activation of dopamine receptors likewise stimulates GH release, while activation of beta-receptors inhibits GH release through stimulation of hypothalamic SS function. This review discusses the involvement of brain catecholamines and acetylcholine in GH hypersecretory states, including anorexia nervosa, acromegaly, IDDM, liver cirrhosis, depression, renal failure and GH insensitivity syndrome, with a view to providing a fuller understanding of their pathophysiology and, whenever possible, diagnostic and therapeutic implications.

Blockade of cholinergic muscarinic receptors by pirenzepine and GHRH-induced GH secretion in the acute and recovery phase of anorexia nervosa and atypical eating disorders.

In view of the important role played by the cholinergic system in the neural regulation of growth hormone (GH) secretion, the ability of pirenzepine, a selective antagonist of muscarinic cholinergic receptors, to blunt the GH response to GH-releasing hormone (GHRH) was studied in adolescent females with anorexia nervosa in the acute (AN-AP) five AN-AP patients, administration of GHRH 1-40 (1 microgram/kg IV) evoked a significantly higher GH response than in controls at established intervals, whereas in eight AN-RP and seven AED patients it was higher than in controls at only one (150-min) and two (150-min, 180-min) time intervals, respectively. In the AN-AP patients, pretreatment with pirenzepine (0.6 mg/kg IV) only partially blocked the GH response to GHRH, whereas in the same AN-AP patients tested during recovery, and in AN-RP and AED patients, the drug completely suppressed the GH response to GHRH, as it did in controls. In view of pirenzepine's mechanism of action, these findings are best explained by the existence in the hypothalamus of AN-AP patients of a cholinergic hypertone and/or a diminished somatostatinergic function. Evaluation of the clinical and hormonal characteristics of the anorectic patients studied would indicate that factors other than undernutrition and its biological consequences, which subside in the recovery stage of the disease and are not present in AED patients, contribute to the anomalous GH response pattern of AN-AP patients.

Effects of cholinergic muscarinic antagonist pirenzepine on GH response to GHRH 1-40 in patients with anorexia nervosa.

The effects of cholinergic muscarinic receptor antagonist pirenzepine on the GHRH-induced GH release were studied in 10 adolescent females with anorexia nervosa at different stages of the disease, in 5 adolescent females with eating disorders and in 5 normal adolescents. The patients were characterized according to psychological (DSM III-R), endocrinological (GnRH test), nutritional (Somatomedin-C, T3), and clinical (% IBW, duration of the amenorrhoea) criteria. On two separate occasions, each subject received an i.v. bolus injection of GHRH 1-40 (1 microgram/kg) alone or preceded by pirenzepine (0.6 mg/kg i.v. 5 min before GHRH 1-40). GHRH 1-40 injection induced a significantly (P less than 0.05) higher GH increase in the patients with anorexia nervosa at the acute stage as compared with the controls. Pirenzepine did not abolish opportunely the exaggerated GH response to GHRH 1-40 in anorectic patients at the acute stage unlike the control, who showed the blockade of GHRH-induced GH release by the cholinergic muscarinic antagonist (P less than 0.05). The anorectic adolescents at the non acute stage and the adolescents with eating disorders showed varying reductions of GH response; however, pirenzepine produced a blunted suppression of GHRH-induced GH increase as compared to the controls, which was not statistically significant. Somatomedin-C values were significantly (P less than 0.05) lower in anorectic patients at the acute stage as compared with controls. The abnormal activity of cholinergic system in anorectic patients, as our data show, could induce the GH hypersecretion through an inhibitory influence on the somatostatinergic function. The reduced somatomedin-C levels, a specific malnutrition index in anorectic patients, produce a modified feed-back on the hypothalamic site (somatostatin) and/or directly on the pituitary, following the GH hypersecretion.

Failure of glucose infusion to suppress the exaggerated GH response to GHRH in patients with anorexia nervosa.

The growth hormone (GH) response to GH-releasing hormone (GHRH) is characteristically exaggerated in anorexia nervosa (AN). Hyperglycemia suppresses the GH response to GHRH in normal subjects. To test whether this inhibitory action of hyperglycemia is preserved in AN, we performed a GHRH (GHRH 1-40, 1 micrograms/kg) test under basal conditions (saline infusion) and during steady-state hyperglycemia (200 mg/dl, induced by the intravenous administration of 8 mg/min.kg of glucose) in 6 adolescent girls with acute-stage AN (as diagnosed by psychopathological, hormonal, and nutritional criteria) and in 5 age-matched female controls. In control subjects, GHRH stimulated GH release during saline, but not glucose, infusion. In the anorectic patients, the GH response to GHRH was exaggerated during both saline infusion (2.97 +/- 0.79 versus 0.52 +/- 0.22 micrograms.120 min.ml-1, p less than 0.02) and under hyperglycemic conditions (4.61 +/- 0.56 versus 0.33 +/- 0.10, p less than 0.001). We conclude that the inhibitory action of hyperglycemia on GHRH-induced GH release is lost in the acute phase of AN.

Apparent free cortisol concentrations in patients with anorexia nervosa at different stages of the disease.

We have measured the total cortisol concentration (TC) and the apparent free cortisol concentration (AFCC) in plasma samples of 17 patients with anorexia nervosa (AN) at different stages of the disease, in basal conditions and after suppression test. We measured free cortisol values directly by a RIA method in dialyzed plasma samples after an equilibrium dialysis system. We have found significantly elevated TC and AFCC values in basal conditions and after suppression test only in the group of patients in the severe stage of the disease. In addition, a significant (p less than 0.05) correlation existed between percent loss of ideal body weight TC and AFCC values after suppression test. Our results suggest that the hypothalamus-pituitary-adrenal axis may be grossly impaired only in the severe stage of AN.