Endocrine effects of high-dose ketoconazole therapy in advanced prostatic cancer

Abstract

The endocrine effects of ketoconazole (400 mg orally every 8 h) were studied in 9 previously untreated patients with advanced prostatic cancer. Five of these patients were followed for 12 months. A rapid fall in the serum concentration of testosterone was noted in all patients studied. Minimal values were observed on day 4 of treatment but thereafter serum testosterone increased slowly. The effect of the drug on unbound testosterone was relatively more important, since sex hormone binding globulin increased markedly during treatment. An increase in progesterone and LH was observed in all patients. This suggests that ketoconazole limits the conversion of C21-precursors into androgens. This block is compensated in part by activation of the hypothalamo-hypophyseal feedback system. Urinary 17\ x=r eq-\ ketosteroids were decreased but 17-hydroxysteroids were unaffected by the treatment. In 5 patients followed monthly over a period of 12 months the mean testosterone concentration ranged from 69 ng/100 ml in one patient to 428 ng/100 ml in another. An excellent inverse correlation could be demonstrated between the mean serum concentration of testosterone and the mean concentration of ketoconazole. The change of serum dehydroepiandrosterone sulphate also correlated inversely with the mean ketoconazole level. Increased concentrations of oestradiol were noted in 2 patients with slight gynaecomastia. It is concluded that long-term suppression of androgen production can be realized by hi gh\ x=req-\ dose ketoconazole treatment and that the degree of suppression is proportional to the serum levels of the drug.

Ketoconazole: From an antimycotic to a drug for prostate cancer

“…The free testosterone fraction and saliva testosterone concentration closely reflected the changes in total plasma concentration Schurmeyer and Nieschlag, 19841, indicating that ketoconazole did not compete with testosterone's binding to the sex hormonebinding globulin (SHBG). In an investigation by Heyns et al [1985] during long-term therapy, SHBG increased with the result that free testosterone levels dropped even more markedly than total testosterone concentrations. Serum testosterone levels in or close to the castrate range could be maintained by 400 mg ketoconazole taken every 8 hr Trachtenberg, 1984al.…”

Active cell death in hormone-dependent tissues

“…These include anti-androgens which interfere with the steroid receptor mechanism [4][5][6]; compounds, such as ketoconazole and finasteride, which interfere with steroid metabolism [7][8][9][10][11]; and combination therapy using anti-androgens in combination with GnRH analogues, anti-prolactins [12][13][14][15][16][17][18] or aminoglutethimide [19]. Despite continued refinement in hormonal therapies, there has been a distressing lack of improvement in the disease-free interval or the overall five-year survival rate of patients with prostatic carcinoma [1,[20][21][22][23][24].…”

Ketoconazole as a Possible Universal Inhibitor of Cytochrome P-450 Dependent Enzymes: Its Mode of Inhibition

“…Up to the present, however, it is not known whether carcinogenic and tumor-promoting agents might be activated or inactivated in the tissue of humans as a result of the inhibition of cytochrome P-450dependent monooxygenases caused by the administration of ketoconazole. Therefore, great caution should be paid in prolonged administration of ketoconazole as a clinical therapeutic method including antiandrogenic therapy for prostatic cancer, even though recently such clinical trials have been carried out with favorable results (Trachtenberg, 1984a;Heyns et al, 1985).…”