Melatonin and psychiatry

Melatonin (5-methoxy-N-acetyltryptamine) is a lipidsoluble derivative of 5-hydroxytryptamine, which is produced clinically via the pineal gland under the influence of sympathetic neural tone governed by diurnal variation in light exposure. Melatonin secretion is maximal with the onset of darkness and it controls diurnal rhythms (i.e., temperature and sleep) and the seasonal Zeitgebar involving reproductive behavior, the seasonal pelt, and pigmentation. The complicated patterns of these relationships between pituitary-hypophyseal, light exposure, and the pineal gland that may be mediated by melatonin have been discussed in a number of reviews (1-13). These observations have resulted in a recent conference on melatonin in humans (14) where melatonin diurnal and seasonal rhythms have been shown to be a factor in sleep and seasonal affective disorders. Recent observations suggest that melatonin deserves clinical trial to enhance or modify response in hormonally sensitive tumors and to determine if melatonin’s impact on chronobiologic control can improve the circadian

Melatonin: a rediscovered antitumor hormone? Its relation to surface receptors; sex steroid metabolism, immunologic response, and chronobiologic factors in tumor growth and therapy.

An in vitro stimulatory effect of indoleamines on aldosterone biosynthesis in the rat.

Sex-dependent effect of melatonin on the secretory activity of rat and hamster adrenal gland in vitro.

The in vitro effects of 13 indole compounds on the synthesis of glucocorticoids and of adrenal androgens in sheep adrenal glands has been studied from 11-deoxycortisol as a precursor. This work demonstrates the activating effect of some indole compounds on 11 beta-hydroxylase and 17,20-desmolase and the inhibitory effect of most of them on 11 beta-hydroxysteroid dehydrogenase. Three categories could be distinguished: 1) compounds without any effect (5-hydroxytryptophan, 5-hydroxytryptamine); 2) compounds moderately increasing (10-30% as compared with controls) cortisol yields (tryptamine, melatonin, 6-hydroxymelatonin, 5-methoxytryptophol, indomethacin); and 3) compounds markedly increasing (80-100%) cortisol yields (5-methoxyindole acetic acid, 5-hydroxyindole acetic acid, 2-methylindole, 5-hydroxytryptophol, N-acetyl-5-hydroxytryptamine). In fact, since most of the studied indoles reduced 11 beta-hydroxysteroid dehydrogenase activity, the actual activation of cortisol synthesis was four to five times less. Lastly, all the studied compounds, but melatonin, increased the activity of 17,20 desmolase as seen from 11 beta-hydroxyandrostenedione and 11-ketoandrostenedione yields. The possible in vivo effects of the indoles for therapeutic use needs further studying.

Activity of melatonin and other pineal indoles on the in vitro synthesis of cortisol, cortisone, and adrenal androgens.

The effects of melatonin and an aqueous extract of bovine pineal glands on adrenal function were studied in pinealectomized, ovariectomized and hypophysectomized rats. Melatonin (50 µg i.p., twice daily for 1 week) stimulates adrenal 5α-reductase activity in intact animals and after ovariectomy. A corresponding enhancement in the secretion of the principal 5α-reduced metabolites of corticosterone (B), dihydrocorticosterone (DHB) and tetrahydrocorticosterone (THB), occurs in vivo. As a result, proportional output of B declines. In contrast, an aqueous pineal extract (360 mg bovine pineal tissue/day for 1 week) fails to alter reductase activity or to produce the secretory changes associated with increased reductive metabolism of B. Melatonin also stimulates adrenal reductase activity in hypophysectomized rats. The results suggest that melatonin is a potential contributor to the physiologic regulation of adrenal steroidogenesis.

T.F. Ogle

Papers

Effects of Melatonin and an Aqueous Pineal Extract on Adrenal Secretion of Reduced Steroid Metabolites in Female Rats