Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Circulating levels of cortisol, 17 alpha hydroxy progesterone and delta 4 androstenedione were analysed by specific radioimmunoassays in 11 patients with Cushing's disease before and at 2, 4, 6, 12 and 24# h following an oral dose of 400 mg ketoconazole. A significant fall in cortisol (26 - 79.6%, 59.8 +/- 18.7 SEM), delta 4 androstenedione (21.5 - 63.3%, 47.8 +/- 4.87) with a concomitant rise in 17 alpha hydroxy progesterone (113 - 218%, 116 +/- 11.43) were noted, suggesting inhibition of 17, 20 desmolase and 11 beta-hydroxylase enzymes in cortisol biosynthetic pathway.
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PMID:Circulating cortisol & related steroids following ketoconazole challenge in Cushing's disease. 240 36

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.
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PMID:Effects of high dose ketoconazole therapy on the main plasma testicular and adrenal steroids in previously untreated prostatic cancer patients. 294 57

In an attempt to determine whether the chronic administration of GnRH agonist (GnRH-A) has a direct inhibitory effect on testicular steroidogenesis in the human, the testes of four men with disseminated prostatic cancer who were treated with GnRH-A daily for at least 1 yr were assayed for intratesticular pregnenolone (5-pregnen-3 beta-ol-20-one), progesterone, dehydroepiandrosterone, 17 alpha-hydroxypregnenolone (5-pregnen-3 beta 17 alpha-diol-20-one), 17 alpha-hydroxyprogesterone, androstenedione, and testosterone (T). In addition, testicular 17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase enzyme activities of the delta 4 pathway were measured. These intratesticular steroids and enzyme activities from four GnRH-A-treated patients were compared to those in five men (controls) who were orchiectomized as the primary treatment for their disseminated prostatic cancer and in three other men who were treated for 3-12 months with GnRH-A daily but received, in addition to the daily GnRH-A, 1000 IUhCG, im, every other day for 3 days immediately before their salvage orchiectomy, which was performed when their disease progressed. In the control group, the delta 5-steroids, particularly dehydroepiandrosterone and pregnenolone, represented the majority of the intratesticular steroids. Compared to control values, all intratesticular steroids except delta 4-P (for which there was no difference) were significantly lowered by treatment with GnRH-A. Intratesticular T was reduced by 98% from 328 +/- 139 (+/- SEM) ng/g testis in the control group to 8 +/- 3 in the GnRH-A-treated group (P less than 0.01). The additional treatment with hCG for 3 days in the GnRH-A-treated group reversed the inhibition of all steroids to either control or above control levels, with intratesticular T rising to 1144 +/- 273 ng/g testis. A similar trend was found for all three enzymatic activities, i.e., GnRH-A alone inhibited each of the enzymatic activities, whereas the addition of hCG reversed this inhibition by GnRH-A. These data indicate that the chronic administration of GnRH-A to elderly men results in inhibition in both the delta 4 and delta 5 pathways, with a subsequent decrease in the intratesticular T concentration. The ability of exogenous hCG to reverse both the reduction in delta 4 and delta 5 intratesticular steroid content and the intratesticular enzyme activities induced by GnRH-A treatment supports the concept that GnRH-A does not have a direct inhibitory effect on testicular T biosynthesis.
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PMID:Lack of a direct effect of gonadotropin hormone-releasing hormone agonist on human testicular steroidogenesis. 302 29

The antifungal drug ketoconazole is known to inhibit testosterone biosynthesis and decrease serum testosterone concentrations. To assess whether the ketoconazole-induced reduction in serum testosterone might stimulate LH and FSH output in a manner suitable as a test of pituitary gonadotropin reserve, we gave normal men ketoconazole every 8 h for 1 week in dosages of 300-1200 mg/day. Ketoconazole administration caused a dose-dependent reduction in serum testosterone which correlated inversely with serum ketoconazole (r = -0.82; P less than 0.001). This fall in serum testosterone stimulated increases in serum LH and FSH which were maximal at a ketoconazole dose of 900 mg/day [LH increase, 127 +/- 27% (+/- SEM); FSH increase, 63 +/- 15%]. Ketoconazole tended to blunt the LH and FSH responses to LHRH. Ketoconazole increased serum 17-hydroxyprogesterone, reflecting blockade of 17,20-desmolase by the drug, while having inconsistent effects on serum estradiol. I conclude that ketoconazole administration for 1 week to normal men stimulates LH and FSH output in a fashion that makes it potentially suitable, after additional verification in subjects with normal and abnormal pituitary-testicular function, as a test of pituitary gonadotropin reserve.
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PMID:Ketoconazole-induced stimulation of gonadotropin output in men: basis for a potential test of gonadotropin reserve. 309 21

In an attempt to determine whether defective testicular testosterone (T) biosynthesis may be associated with a varicocele, an experimental study was performed in adult rats whereby a unilateral left varicocele was surgically created. At 2, 4, 8, and 12 wk following the creation of the varicocele, intratesticular T as well as the activities of three (17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase) of the five enzymes in the delta 4 pathway of testicular T biosynthesis were measured. Intratesticular T (ng/g testis +/- SEM) in the left testis decreased significantly from 121 +/- 21 in the control group to 59 +/- 8 in the two-wk varicocele group (p less than 0.01), and remained significantly suppressed throughout the experimental period. The T concentrations in the right testis paralleled those in the left in both the control and varicocele animals. At 2 wk following the creation of the varicocele, the activity (nmol/min/testis +/- SEM) of the 17,20-desmolase enzyme decreased significantly, from 115 +/- 8 in the left testis of control rats to 87 +/- 6 in the left testis of the varicocele animals (p less than 0.025), and remained low throughout the 12 weeks of the study. The activity of the 17 alpha-hydroxylase enzyme was significantly decreased at the 8th and 12th weeks of the study, while the 17 beta-hydroxysteroid dehydrogenase activity did not show any significant change during the study period. The enzyme activities in the right testis paralleled those in the left testis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of testicular testosterone biosynthesis following experimental varicocele in rats. 359 58

Serum concentrations of testosterone, 17-hydroxyprogesterone, estradiol and several other unconjugated and sulphated steroids were analyzed before and after a single dose of hCG in 6 power athletes, who had used high doses of testosterone and anabolic steroids for 3 months. The study was carried out 3 weeks after cessation of drug use, but the study subjects were still characterized by hypogonadotrophic hypogonadism. The mean concentrations of serum LH and FSH were 2.6 +/- 0.3 and 1.1 +/- 0.03 mIU/ml (mean +/- SEM), respectively, and the concentrations of several precursors and metabolites of testosterone were lower than those before drug use. In contrast, circulating concentrations of steroid sulphates were not decreased, with the exception of dehydroepiandrosterone sulphate. After hCG injection serum testosterone and 5 alpha-dihydrotestosterone concentrations increased significantly, whereas no increases in estradiol and 17-hydroxyprogesterone concentrations were observed. These results demonstrate that during transient hypogonadotrophism in adult men, the testicular responsiveness to a single injection of hCG is similar to that in prepubertal boys without any sign of steroidogenic lesion at the 17,20-desmolase step. Therefore, the appearance of the possibly estradiol-mediated inhibition at the level of C21-steroid side-chain splitting in testosterone biosynthesis seems to be dependent on priming by gonadotrophins.
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PMID:Testicular responsiveness to human chorionic gonadotrophin during transient hypogonadotrophic hypogonadism induced by androgenic/anabolic steroids in power athletes. 374 10

In an attempt to confirm where in the testosterone (T) biosynthetic pathway of the rat testis ketoconazole (KTZ) inhibits T production, rat testicular mince was incubated with either 10 micrograms/ml or 100 micrograms/ml KTZ in the presence and absence of hCG (1 IU), and intratesticular pregnenolone (delta 5P), progesterone (P), 17-alpha-hydroxyprogesterone (17 alpha-HP), androstenedione (A) and testosterone (T) were assayed. In the absence of hCG, 10 micrograms/ml KTZ was sufficient to reduce intratesticular T by 80%. At this concentration of KTZ, intratesticular 17 alpha-HP (ng/g testis, mean +/- SEM) increased from 0.3 +/- 0.1 to 1.3 +/- 0.2 (p less than 0.0025), whereas intratesticular A decreased from 84 +/- 7 to 17 +/- 1 (p less than 0.005). KTZ did not inhibit the conversion of P to 17 alpha-HP. From these data it was concluded that KTZ has its inhibitory effect on testosterone biosynthesis in the rat testis primarily at the step catalyzed by the 17,20 desmolase enzyme.
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PMID:Effect of in vitro ketoconazole on steroid production in rat testis. 383 56

The basal plasma levels of cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and testosterone were studied in 20 patients with advanced prostatic cancer receiving combined treatment with an LHRH agonist and an antiandrogen [5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl]-2 4-imidazolidinedione]. After 60 days of combined antihormonal therapy, plasma levels of testosterone decreased from 5.44 +/- 0.44 (SEM) to 0.136 +/- 0.052 ng/ml (2.5% of control). Somewhat unexpectedly, the plasma concentrations of the adrenal androgens DHEA and DHEA-S were reduced to 45 +/- 7 and 64 +/- 4% of control, respectively. The maximal reduction in plasma adrenal androgen levels occurred between 2 and 4 weeks of treatment. Whereas the increase in serum cortisol, 17-hydroxypregnenolone, and 17-hydroxyprogesterone concentrations 2 1/2 h after the injection of 0.25 mg human ACTH 1-24 was not affected by the combined treatment, the increment of DHEA and androstenedione after the same stimulus was reduced from 3.1 +/- 0.98 and 0.73 +/- 0.11 to 1.48 +/- 0.5 and 0.31 +/- 0.05 ng/ml, respectively. The reduced levels of serum DHEA and DHEA-S were not due to the LHRH agonist by itself, since similarly low levels of serum DHEA and DHEA-S were found in patients surgically castrated and receiving the same antiandrogen. These data suggest that treatment with an antiandrogen in castrated men inhibit the formation of adrenal androgens due to a blockade at the level of 17, 20-desmolase. The efficiency of the new combined antihormonal therapy (castration and antiandrogen) aimed at complete androgen neutralization in prostate cancer is thus further facilitated.
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PMID:Inhibition of basal and adrenocorticotropin-stimulated plasma levels of adrenal androgens after treatment with an antiandrogen in castrated patients with prostatic cancer. 608 97

The luteinizing hormone releasing hormone analog D-Trp6-Pro9-Net-LHRH (LHRHa) inhibits rat testicular testosterone secretion. To determine whether LHRHa decreases serum testosterone concentrations solely by inhibiting gonadotropin secretion or, in addition, by influencing directly testicular testosterone biosynthesis, we examined the effects of LHRHa on the activities of 5 key testicular steroidogenic enzymes. Thirty hypophysectomized, hOG treated rats were given either LHRHa (1 micrograms sc/day) or saline during 7 days. The LHRHa treated animals exhibited a significant decrease of serum testosterone when compared to the control group (498 +/- 37 ng/dl vs 2044 +/- 105 ng/dl, mean +/- SEM, P less than 0.001). 17-Hydroxyprogesterone serum levels were also decreased in the LHRHa treated rats (61 +/- 6 ng/dl vs 93 +/- 7 ng/dl, P less than 0.005), while serum progesterone levels were similar in both groups of animals. These changes in steroid concentrations were associated with decreases in the microsomal enzyme activities of 17-hydroxylase (37 +/- 9 vs 654 +/- 41 pmol/mg protein/min, P less than 0.001), 17,20-desmolase (103 +/- 9 vs 522 +/- 47 pmol/mg protein/min, P less than 0.001), 3 beta-hydroxysteroid dehydrogenase (1.7 +/- 0.02 vs 4.1 +/- 0.1 nmol/mg protein/min, P less than 0.001), aromatase (95 +/- 7 vs 228 +/- 6 pmol/mg protein/min, P less than 0.001) and 17-ketosteroid reductase (167 +/- 9 vs 290 +/- 18 pmol/mg protein/min, P less than 0.01) in the LHRHa treated animals. These findings indicate that LHRHa can inhibit directly rat testicular testosterone biosynthesis.
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PMID:Direct effect of the luteinizing hormone releasing hormone analog D-Trp6-Pro9-Net-LHRH on rat testicular steroidogenesis. 639 51

Testosterone biosynthesis by Leydig cells can be modulated by estradiol. This modulation appears to occur at the 17-hydroxylase and 17,20-desmolase stage. In this study we have examined the effects of estradiol and progesterone on the activities of the 17-hydroxylase (17-OH) and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) in rat ovarian tissue, to examine the hypothesis that estradiol may regulate these enzymes in the ovary as well as in the testis. Estradiol capsule implants produced a decrease in 17-OH activity (0.5 +/- 0.05 vs. 2.1 +/- 0.1 nmol/mg protein/min, mean +/- SEM, p less than 0.001), and an increase in 3 beta-HSD activity (15.5 +/- 0.9 vs 9.7 +/- 0.7 nmol/mg protein/min p less than 0.001). Progesterone injections produced a decrease in both 17-OH (0.9 +/- 0.1 vs. 2.3 +/- 0.2 p less than 0.005) and 3 beta-HSD (2.5 +/- .4 vs. 8.6 +/- 0.5; p less than 0.005) activities. We conclude that estradiol decreases 17-OH activity in the ovary as it does in the testis. This, coupled with an increase in 3 beta-HSD may explain the pre-ovulatory increase in progesterone seen in many species. Progesterone seems to decrease the steroidogenic activity of the ovarian tissue, perhaps offering an explanation for the gonadotropin resistance seen in corpus luteus bearing ovaries.
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PMID:The effects of estradiol and progesterone on rat ovarian 17-hydroxylase and 3 beta-hydroxysteroid dehydrogenase activities. 660 68


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