title: Effects of high dose ketoconazole therapy on the main plasma testicular and adrenal steroids in previously untreated prostatic cancer patients.
abstract: 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.
mesh_terms: D019326:17-alpha-Hydroxyprogesterone; D000305:Adrenal Cortex Hormones / Q000097:blood*; D000368:Aged; D000728:Androgens / Q000097:blood*; D000735:Androstenedione / Q000097:blood; D003345:Corticosterone / Q000097:blood; D003350:Cortodoxone / Q000097:blood; D003687:Dehydroepiandrosterone / Q000097:blood; D003900:Desoxycorticosterone / Q000097:blood; D006801:Humans; D006908:Hydroxyprogesterones / Q000097:blood; D007654:Ketoconazole / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D011374:Progesterone / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013739:Testosterone / Q000097:blood
chemical_list: D000305:Adrenal Cortex Hormones; D000728:Androgens; D006908:Hydroxyprogesterones; D013739:Testosterone; D000735:Androstenedione; D003900:Desoxycorticosterone; D003687:Dehydroepiandrosterone; D011374:Progesterone; D019326:17-alpha-Hydroxyprogesterone; D007654:Ketoconazole; D003345:Corticosterone; D003350:Cortodoxone