Pharmacological Reviews, Vol 19, 251-288, Copyright © 1967 by the American Society for Pharmacology and Experimental Therapeutics

CHLORPROMAZINE AND ENDOCRINE FUNCTION

¹ Department of Pharmacology, Medical Faculty, University of Utrechi, The Netherlands

This review surveys the influence of CPZ on pituitary activity. Analysis of the literature indicates that the tranquilizer affects pituitary activity only in amounts that exceed those necessary to induce psychodepressant effects in animal species. In these amounts CPZ appears to block the release of FSH and LH and to stimulate the release of prolactin. It inhibits the discharge of TSH and it stimulates the secretion of ACTH and growth hormone. In addition it seems to increase the release of MSH and ADH and it may block oxytocin-release. The influence of the phenothiazines on pituitary secretion depends on the amount of the drug given, the duration of the treatment and the circumstances, like environmental temperature, under which experiments are performed. The pituitary-gonadal axis of all pituitary functions seems to be most susceptible to the drug in animals and man. Clinically the most frequently observed endocrine dysfunction lies in the pituitary-gonadal axis since amenorrhea and galactorrhea are most commonly seen in female patients treated chronically with relatively high doses of the drug.

The locus of action of the drug with respect to pituitary activity must be sought in the brain, but extremely high doses of CPZ may antagonize the effect of pituitary hormones or the influence of the target hormones on their respective target tissues. In the brain CPZ may facilitate or inhibit structures that are involved in the control of pituitary secretions. Mesencephalic limbic and rhinencephalic limbic structures as well as the hypothalamus, which are known to be affected by CPZ and which are known to be involved in pituitary activity, should be regarded as the site of action of CPZ.

Some of the effects of CPZ on pituitary activity may be explained by its adrenergic blocking properties. This is based upon the concept that blockade of ovulation, stimulation of prolactin release, as well as MSH release induced by CPZ can be brought about also by depletion of catecholamines in the hypothalamus.

The effect of CPZ and related drugs on pituitary activity is complicated by the manifold actions of the phenothiazines in the body. Profound metabolic influences, hemodynamic effects, and marked disturbances in thermoregulation may affect pituitary secretion in a nonspecific manner. These considerations make it difficult to analyze the site of the action of the drug. This can be overcome if better methods become available to determine pituitary activity. It may then be possible to re-evaluate the effect of the phenothiazines on endocrine activity.

Only if direct measures to determine the respective pituitary hormones in the circulation are employed, and the effect of CPZ is assessed after a single injection or after chronic administration of the drug in various dosages and during various periods of time in animal and man under normothermic and hypothermic conditions, can the influence of CPZ and related drugs on endocrine activity be established with certainty.

Note:

The author wishes to thank Drs W. de Jong, Utrecht, G. P. van Rees, Leiden, E. Schönbaum, Toronto, P. G. Smelik, Utrecht, and B. van der Wal, Utrecht, for suggestions and criticism.

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