R. J. Santen

Effect of very high dose D-leucine6-gonadotropin-releasing hormone proethylamide on the hypothalamic-pituitary testicular axis in patients with prostatic cancer.

Potent synthetic analogs of gonadotropin-releasing hormone produce parodoxical antireproductive effects when administered chronically. These compounds are minimally toxic and may exhibit no plateau of the dose-response curve even at very high doses. These considerations served as the basis for our systematic evaluation of [D-leucine6-desarginine-glycine-NH2(10)]gonadotropin-releasing hormone (GnRH-A) proethylamide in the very high dose range (i.e., 10-fold larger amounts than previously used). In rats given the analog for 12 wk, prostate, testis, and seminal vesicle weights were suppressed to a greater extent with 200 micrograms q.d. than with 40 micrograms q.d. (P less than 0.01 prostate, less than 0.01 testis, less than 0.01 seminal vesicles), indicating dose-response effects in the very high dose range. 200 micrograms of [D-Leu6-des-Gly-NH2(10]-GnRH-A consistently suppressed leutinizing hormone (LH) values at 6 and 12 wk (basal 71 +/- 9.5; 6 wk 34 +/- 3.8; 12 wk 28 +/- 5 ng/ml) whereas 40 micrograms suppressed LH variably (basal 33 +/- 3.8; 6 wk 17 +/- 3.9; 12 wk 32 +/- 5.2). Testosterone fell to 15 +/- 2.4 and 19 +/- 2.0 ng/100 ml in response to 200 micrograms q.d. and to 27 +/- 6.4 and 22 +/- 7.4 ng/100 ml with the 40-micrograms dose. These findings in the rodent prompted treatment of stage D prostate cancer patients with similarly high doses of [D-Leu6-des-Gly-NH2(10)]-GnRH-A. After treatment for 11 wk with 1,000 or 10,000 micrograms/d of the analog, testosterone and dihydrotestosterone levels transiently rose and then fell into the surgically castrate range (testosterone 19 +/- 4.4 ng/100 ml [D-Leu6-des-Gly-NH2(10)]-GnRH-A vs. surgically castrate 11 +/- 0.9 ng/100 ml, P = NS; dihydrotestosterone 15 +/- 1.7 ng/100 ml GnRH-A vs. surgically castrate 15 +/- 4.1 ng/100 ml. P = NS). However, unlike the chronic stimulatory effect on the pituitary at lower doses, very high dose therapy resulted in profound suppression of plasma and urine LH. Plasma levels fell to the limit of assay detectability, whereas the more sensitive urinary assay detected prepubertal levels of excretion (i.e., 64 +/- 8.4 mlU/h). The highly sensitive rat interstitial cell testosterone bioassay for LH also demonstrated a marked decline in LH to undetectable levels in 17/19 subjects. Clinical results with [D-Leu6-des-Gly-NH2(10)]-GnRH-A simulate those achieved by surgical castration in men with prostatic cancer as suggested by available preliminary data.

The effect of growth hormone on the Leydig cell response to chorionic gonadotrophin in boys with hypopituitarism.

Eleven boys with growth hormone (hGH) deficiency received human chorionic gonadotrophin (hCG) stimulation tests for the assessment of Leydig cell function before, during, and after 1 year of treatment with somatotrophin. Two patients entered puberty during the course of the study protocol. Analysis of the data in nine prepubertal boys revealed an augmentation of testosterone (T) responses to hCG in the presence of hGH. In six of these individuals in whom dihydrotestosterone (DHT) was determined, a similar augmentation in responsiveness of this steroid was found in the presence of hGH. Three prepubertal boys exhibited poor T responses to the basal hCG test with only partial improvement following hGH. In man growth hormone may be an important permissive factor in Leydig cell activity during periods of changing testicular function such as occur in utero or during puberty.

Clinical and Biochemical Effect of Aminoglutethimide in the Treatment of Advanced Prostatic Carcinoma

Treatment of male patients with advanced prostatic carcinoma and disease progression after initial endocrine therapy frequently is unsatisfactory. However, approximately 20 per cent of these patients respond to surgical adrenalectomy or hypophysectomy, indicating continued hormonal responsiveness. A total of 25 previously castrated men with stage D carcinoma received 1,000 mg. aminoglutethimide and 40 mg. hydrocortisone daily. The patients were evaluated using the criteria of the National Prostatic Cancer Project. One patient has had a complete response and is in remission after 275 weeks of therapy. A partial response was noted in 4 patients, while the disease was objectively stable in 6. Pre-treatment testosterone and dihydrotestosterone levels were measured in 9 of 25 patients and were significantly reduced statistically during aminoglutethimide therapy (p less than 0.01). Response and drug toxicity are discussed.

Actions of calcium ions and a calcium-influx blocker on basal and TRH- and GnRH-stimulated hormone release in patients with pituitary adenomas

We investigated the influence of calcium ions on the secretion of anterior pituitary hormones basally and in response to exogenous hypothalamic releasing factors in 6 men with pituitary tumors. To this end, concentrations of LH, FSH, TSH, growth hormone and prolactin were measured in blood collected at 10-min intervals basally and during a continuous infusion of combined TRH (2 μg/min) and GnRH (1 μg/min). Study sessions were randomized to iv saline, calcium, or diltiazem infusions or oral diltiazem administration. Our results indicate that in contrast to responses in normal men, iv calcium injections do not suppress circulating prolactin concentrations in patients with prolactin-secreting pituitary tumors. Moreover, neither oral diltiazem administration for one week nor acute iv diltiazem infusion suppressed the hyperprolactinemia of tumor patients. However, there were significant effects of drug and calcium treatments on serum concentrations of FSH, GH and testosterone, but not LH or TSH. Moreover, during GnRH-TRH stimulation, there were significant differences in LH, TSH, and testosterone responses in tumor patients compared to normal men. In summary, iv calcium infusion was associated with invariant basal release of anterior pituitary tumoral hormones in patients with pituitary adenomas. However, there were significant differences in the GnRH/TRH-stimulated release of certain anterior pituitary hormones in tumor patients compared to normal men in response to iv calcium and the calcium-channel antagonist, diltiazem.