Effects of high-dose ketoconazole and dexamethasone on ACTH-stimulated adrenal steroidogenesis in orchiectomized prostatic cancer patients.

The effects of high-dose ketoconazole (i.e. 400 mg every 8 h) therapy on adrenal steroidogenesis were investigated in 7 patients with advanced prostatic cancer who no longer responded to orchiectomy. An ACTH challenge was performed before and on days 14 and 28 of high-dose ketoconazole treatment. During the last 14 days, dexamethasone (0.5 mg twice daily) was administered together with ketoconazole. High-dose ketoconazole alone lowered the basal levels of the androgens by 49-66%. It almost completely inhibited their stimulation by ACTH, whereas plasma progesterone was doubled. Basal cortisol was only slightly lowered, but the response to ACTH stimulation was markedly blunted. Basal and stimulated plasma aldosterone remained unaffected. Both basal and stimulated 11-deoxycortisol, 11-deoxycorticosterone, and, to a lesser extent, corticosterone rose more markedly after ketoconazole than after placebo. The basal and stimulated plasma adrenal androgen levels were further reduced after combined ketoconazole-dexamethasone treatment, whereas plasma corticosterone, 11-deoxycortisol, and 11-deoxycorticosterone were lowered in the same way as cortisol. Aldosterone and progesterone profiles were similar to those observed under high-dose ketoconazole, but plasma 17 alpha-hydroxyprogesterone increased more markedly than after high-dose ketoconazole alone. These results demonstrate that high-dose ketoconazole lowers plasma androgen levels in orchiectomized patients and partly inhibits the gluco- and mineralocorticoid syntheses, especially after ACTH-stimulation. The addition of dexamethasone does not only correct the possible consequence of the impairment of the cortisol production by high-dose ketoconazole, but it further reduces the androgen levels and lowers the plasma concentrations of most precursors, for instance 11-deoxycorticosterone, which has some physiological mineralocorticoid activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of high dose ketoconazole therapy on the main plasma testicular and adrenal steroids in previously untreated prostatic cancer patients.

In vitro, ketoconazole has been shown to block testicular and adrenal 17,20-lyase, which converts progestins to androgens. At higher concentrations, it also inhibits 11 beta-hydroxylase, 20,22-desmolase and 17 alpha-hydroxylase. To determine the differential hormonal effects of a 2-week ketoconazole high-dose therapy, the plasma levels of 10 major androgens, gluco- and mineralocorticoids were measured in 14 previously untreated patients with metastatic prostate cancer. Within 24 h, plasma testosterone fell from 14.6 +/- 1.4 nmol/l (mean +/- SEM) to 3.7 +/- 0.7 nmol/l. Thereafter, it decreased to about 2.5 nmol/l and remained at that level. Plasma androstenedione and dehydroepiandrosterone decreased more gradually, respectively from 3.1 +/- 0.4 nmol/l to 0.64 +/- 0.17 nmol/l and from 6.6 +/- 1.0 nmol/l to 2.82 +/- 0.55 nmol/l (on day 14). In contrast, 17 alpha-hydroxyprogesterone and progesterone rose respectively 2- and 5-fold. Plasma cortisol and aldosterone levels remained unchanged whereas 11-deoxycorticosterone and 11-deoxycortisol rose by factors of 14 and 6.7 respectively. Plasma corticosterone also increased, but to a much lesser extent (3-fold). These results demonstrate that ketoconazole high dose therapy blocks mainly the 17,20-lyase of both adrenal and testis. In addition it inhibits mitochondrial 11 beta-hydroxylase to a lesser extent. The inhibition of 20,22-desmolase also seems to be of little clinical relevance. However, since clinical or laboratory symptoms suggestive of hypo-adrenalism have been reported in a small minority of patients, replacement therapy should be considered in such cases.

Effect of a single administration of ketoconazole on total and physiologically free plasma testosterone and 17 beta-oestradiol levels in healthy male volunteers.

The effect of a single oral dose of 400 mg ketoconazole, given as an 80 mg/ml suspension, on total and physiologically free (i.e. non-sex hormone-bound) testosterone and 17 beta-oestradiol has been investigated in 6 healthy male volunteers. The two steroids fell to nadir levels of 18 and 60% of their respective initial concentrations 6 hours after drug intake, and then completely recovered. Although in vitro slight displacement of testosterone from the sex-hormone binding globulin, by high doses of ketoconazole was found, the physiologically free concentration of testosterone in vivo was closely correlated with that of the total hormone, suggesting that there is no direct interference with sex-hormone binding globulin in vivo. Plasma LH and FSH were not significantly modified by treatment. The effect of ketoconazole on plasma oestradiol levels was less pronounced and was not clearly related to a block of the aromatase system, as reported in vitro.