Howard D. Kolodny

Effect of Chlorpromazine on Serum Growth-Hormone Concentration in Man

Abstract Chlorpromazine, a commonly used tranquilizer of the phenothiazine group, was administered orally to 15 subjects in doses of 25 mg four times a day for one week. Fasting serum growth-hormone concentrations and growth-hormone responses to insulin stimulation were measured before and after the treatment period. Definite suppressive effects were found: fasting levels were decreased in 10 of 15 patients. At one and two hours after intravenous insulin injection the levels were lower in 13 of 14, and 10 of 15 subjects, respectively. The decrease was statistically significant during fasting (p<0.05), at one hour (p<0.005) and at two hours (p<0.05). These results warrant appraisal of phenothiazine derivatives as therapeutic adjuncts in chronic hypersecretion of growth hormone.

Prolactin and Breast Carcinoma

The recent findings regarding the possible relation of prolactin to human breast cancer are reviewed. Prolactin is a single-chain polypeptide hormone secreted by the anterior pituitary; it appears important to the development and growth of mammary tumors in mice and rats. Certain drugs (L-dopa, the ergot derivatives) inhibit the release of prolactin from the anterior pituitary and lower its serum concentration. Chlorpromazine and other phenothiazines block the synthesis, release, or action of prolactin-inhibiting factors leading to increased prolactin secretion. The midcycle serum estrogen elevation does not increase serum prolactin but often high doses of estrogen will. Mammary tumors in mice and rats appear different from those in human, being of alveolar origin while human tumors are thought to be ductal. Also, rodent cancers do not usually metastasize, even when large. About 40% of human breast cancers respond to endocrine therapy while in Sprague-Dawley rats induced mammary tumors are 80% hormone responsive. In mice hyperplastic nodules but not mammary cancers respond to horomone deprivation. Prolactin is a key hormone in the stimulation of hyperplastic nodules in mice and mammary tumors in rats. The effects of progesterone on these growths is not clear. Serum prolactin levels normally vary throughout the day. Levels are not different in cancer patients but certain families with high cancer rates have been shown to have higher than normal serum levels. Although prolactin receptors have been identified in mouse and rat mammary tissue and tumors and prolactin responsiveness of the tumors correlated with the number of such receptors, these receptors have not been identified in human breast cancer cells. Patients have responded to L-dopa with relief of bone pain and a 50% decrease in serum prolactin. Suppressing atypical precancerous lesions by depriving them of their hormonal support offers the best chance for preventing eventual development of breast cancer. In vitro determination of the presence of prolactin receptors in human breast tumor tissue may allow accurate prediction of response to endocrine ablation. Variations in prolactin receptors may account for response differences of breast tumors to different doses of estrogen. Near-zero prolactin levels following hypophysectomy in some patients have been correlated with clinical remissions. Combinations of drugs to reduce serum prolactin levels or antagonize the hormoness effect on the breast may be needed to obtain results.

Acromegaly treated with chlorpromazine. A case study.

Abstract Short-term therapy with chlorpromazine, medroxyprogesterone acetate and a combination of the two drugs was given to a young man with active acromegaly. Serial levels of serum growth hormone with the patient fasting and during six-hour oral glucose tolerance tests were determined before any treatment, during treatment and between treatment periods. There was a marked decrease in fasting levels by the 12th day of each treatment period. On the 10th day of chlorpromazine therapy the fasting level was still above normal, though decreased from the base-line level. On the 12th and 17th days of this therapy fasting concentrations were near the normal range. The clinical manifestations improved during the course of chlorpromazine therapy. The known pharmacologic effects of chlorpromazine suggest that the site of its action on growth-hormone suppression is the hypothalamus.

Use of l-dopa (l-dihydroxyphenylalanine) to stimulate ovulation

This study was prompted by previous experimental data which suggested that l -dopa may be useful clinically in treating anovulation and oligoamenorrhea due to hypothalamic-pituitary hypofunction of nonorganic origin. Six such patients, who had failed to respond to clomiphene therapy but who had previously ovulated and become pregnant following the administration of human pituitary gonadotropins, were treated with 2 Gm. of l -dopa daily for 3 months. There was no response in 3 patients. The remaining 3 patients showed evidence of increased gonadotropin and estrogen activity. However, follicular maturation did not reach the level necessary to trigger ovulation, even with the addition of human chorionic gonadotropin. These data indicated that in the manner used in this study l -dopa is not useful clinically in hypogonadotropism.