Conversion of dihydrotestosterone to androstanediol glucuronide by female sexual skin.

Sexual skin biopsies from 13 normal women were obtained and minces/3-h studied after adding either [3H]dihydrotestosterone (DHT) or [3H]androstanediol (3 alpha diol) to RPMI-1640 medium in a Dubnoff apparatus. Unconjugated or conjugated androgens (after hydrolysis) were purified by three chromatography steps. Formation of 3 alpha diol and 3 alpha diol glucuronide (3 alpha diolG) was linear with time. The conversion of DHT to DHT17 beta G was only 4.4 +/- 0.5%/200 mg/3 h, while conversion to 3 alpha diol was 32 +/- 1.7%. The back conversion of 3 alpha diol to DHT was 30 +/- 3% and conversion to 3 alpha diolG was 4.5 +/- 1.25%. The product of the conversion separately measured of DHT to 3 alpha diol and 3 alpha diol to 3 alpha diolG was 1.5%, which is not very different than the overall conversion rate of DHT to 3 alpha diolG of 1.4%. This study indicates that the predominant path in this tissue is DHT in equilibrium 3 alpha diol----3 alpha diolG, rather than formation of DHT17 beta G and then 3 alpha reduction to 3 alpha diolG.

Production of 3 alpha-androstanediol glucuronide in human genital skin.

3 alpha-Androstanediol glucuronide (3 alpha diol-G) is produced extrasplanchnically and is a good clinical marker of androgen action in peripheral tissues. However, the direct formation of androgen glucuronides in peripheral sites such as skin has not been determined in man. Genital skin from 21 premenopausal women and 8 men and foreskin from 6 neonates were incubated with either [14C]testosterone [14C]dihydrotestosterone (DHT) to determine the production of DHT glucuronide and 3 alpha diol-G in skin. After hydrolysis of incubation medium with glucuronidase, followed by extraction and sequential chromatography, constant 3H to 14C ratios of 3 alpha diol confirmed the production of DHT glucuronide and 3 alpha diol-g. The conversion of DHT to 3 alpha diol-G was higher than the conversion from testosterone (P less than 0.05), and conversion was higher in men than in women. These data provide evidence for the direct formation of C19 steroid glucuronides by human skin.

Metabolic pathways for androstanediol formation in immature rat testis microsomes.

Metabolic routes from progesterone to androstanediol in washed rat testicular microsomes were investigated, with special emphasis on the importance of 4-ene-3-oxosteroids, as well as the effect of a minimal effective dose of human chorionic gonadotropin on these transformations. Incubation of equimolar concentrations of a mixture of [14C]progesterone and 17 alpha-hydroxy[3H]progesterone resulted in a large preference of 17 alpha-hydroxyprogesterone over progesterone as substrate for androstanediol formation. Incubation of [3H]progesterone together with [14C]androstenedione resulted in the inhibition of C-17,20-lyase and in a low 14C/3H ratio in androstanediol, indicating the preference of progesterone over androstenedione as substrate for androstanediol production. When a mixture of 17 alpha-hydroxy[3H]progesterone and [14C]androstenedione was incubated with the microsomes, a more than 8-fold preference of 17 alpha-hydroxyprogesterone as substrate for androstanediol production was found. The minimal dose of human chorionic gonadotropin stimulated testosterone production but inhibited androstanediol formation and effected, in some instances, a change in the metabolic routes. It is concluded that androstanediol is produced preferentially through 17-hydroxylated C-21 steroids, and also, to a lesser extent, through C-19 steroids.

Metabolism of testosterone to 17 beta-hydroxy-5 alpha-androstane-3-one and 5 alpha-androstane-3 alpha, 17 beta-diol in alveolar macrophages from rat lung--II. Effects of intratracheal instillation of 3.4 mumol K2Cr2O7.

Activity of the steroid 5 alpha-reductase in pulmonary alveolar macrophages from adult male rats has been investigated in vitro. Intratracheal instillation of 3.4 mumol K2Cr2O7 lowered the enzyme activity within 6 h, and the reduction was significant on the subsequent 2, 4 and 7 days. The activity of this enzyme was significantly decreased only 6 and 24 h after instillation when measured in the 800 g supernatant fraction of whole lung. Instillation of 3.4 mumol K2Cr2O7 increased serum levels of corticosterone. Serum levels of triiodothyronine and thyroxine decreased except for a transient increase 3 h after the K2Cr2O7 instillation. Subcutaneous administration of 200 micrograms dexamethasone/100 g b.wt, 200 micrograms/100 g b.wt of testosterone, 17 beta-hydroxy-5 alpha-androstane-3-one (5 alpha-DHT), dehydroepiandrosterone or corticosterone had no effect on the 5 alpha-reductase activity of the pulmonary alveolar macrophages within 12 h. The combined treatment with dexamethasone s.c. and intratracheal instillation of 3.4 mumol K2Cr2O7 reduced the steroid 5 alpha-reductase activity in the pulmonary alveolar macrophages to about 25% of controls. Measurement of the steroid 5 alpha-reductase activity in pulmonary alveolar macrophages as an index of lung damage when exposed to toxic material is discussed.

Synthesis of testosterone and 5 alpha-reduced androgens during initiation of spermatogenesis in the rat.

Numerous investigators demonstrated increased 5 alpha-reductase activity in testes of developing rats. The rapid in vitro metabolism of progesterone to 5 alpha-reduced androgens occurs at certain stages of testicular development. This was considered evidence for the conclusion that testosterone is primarily an intermediate rather than the final product in testes of immature rats. However, a discrepancy is noted when developmental patterns of circulating or intratesticular levels of androgens are compared with the patterns of accumulation of metabolites of progesterone in vitro. In blood and testicular tissue of 17-20 day old rats a testosterone peak has been reported, while in the in vitro studies such peak was not observed. In this study radiolabelled pregnenolone was utilized in vitro as a substrate, and a pattern of androgen formation similar to that observed in the in vivo studies was noted. A peak of androgen formation (testosterone and 5 alpha-androstanediol) was observed used prior to completion of the meiotic prophase. However, when testosterone was utilized as the substrate, no correlation between 5 alpha-reduction and completion of the meiotic prophase was detected. This suggests that the rise in testosterone may be associated with completion of the meiotic prophase. Investigation of the androgen metabolic pathways revealed the following age-related patterns: no change in 17 beta-hydroxysteroid dehydrogenase, activation of 5 alpha-reductase at 12 days of age, and activation of 3 alpha-hydroxysteroid dehydrogenase between 14 and 18 days of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased testicular 5 alpha-androstane-3 alpha, 17 beta-diol formation induced by treatment with [D-Ser (TBU) 6, des-Gly-NH2(10)] LHRH ethylamide in the rat.

While the intact male adult rats respond to LH with a predominant increase of testicular and plasma testosterone levels, the response to LH stimulation in animals treated with the LHRH agonist, [D-Ser(TBU) 6, des-Gly-NH2(10)] LHRH ethylamide is characterized by a major production of 5 alpha-androstane-3 alpha, 17 beta-diol. The marked increase of 5 alpha-androstane-3 alpha, 17 beta-diol levels in the presence of a 90% decrease of testosterone concentration strongly suggests that 5 alpha-reductase and 3 alpha-hydroxysteroid oxidoreductase activities are increased during testicular desensitization induced by treatment with the LHRH agonist.

[Androgen metabolism in prostate cancer: 3-hydroxysteroid dehydrogenase in relation to the grade of tumor differentiation (author's transl)]. / Androgenstoffwechsel im Prostatakarzinom: 3-Hydroxysteroid-Dehydrogenase-Aktivität in Abhängigkeit vom Tumordifferenzierungsgrad.

The peripheral zone of the prostate behaves as an androgen target organ, whereas the periurethral glands are under estrogenic stimulation. This anatomical-physiological situation explained in the past the endocrine dependence of prostatic carcinoma. Biochemical studies by Prout, however, showed that the response of prostate cancer to contrasexual measures correlates well with the activity of androgen-converting enzymes and with the grade of tumor differentiation. In this study the in vitro activity of 3-hydroxysteroid dehydrogenase (formation of androstanediols from dihydrotestosterone) was assessed in biopsy material of 8 highly differentiated adenocarcinomas and of 14 poorly differentiated tumors by a microassay technique. The results were compared with the enzyme activities obtained earlier from benign prostatic hyperplasia and normal prostatic tissue. In the different cell fractions (cytosol, microsomes) and with various cofactor supplementation, the enzyme activities in highly differentiated tumors strongly resembled those of adenomatous or normal prostate tissues, whereas a relative enzyme deficiency was present in poorly differentiated lesions. The pathophysiological and eventual clinical implications of these findings are discussed.

Metabolism of 5 alpha-androstane-3 beta,17 beta-diol to 17 beta-hydroxy-5 alpha-androstan-3-one and 5 alpha-androstan-3 alpha,17 beta-diol in the rat.

Significant metabolism of 5 alpha-androstane-3 beta,17 beta-diol to 17 beta-hydroxy-5 alpha-androstan-3-one was recorded in several tissues and organs from rats and humans. This bioconversion was further investigated in rat testis homogenates. 5 alpha-Androstane-3 beta,17 beta-diol was readily metabolized to 17 beta-hydroxy-5 alpha-androstan-3-one with NAD and/or NADP added as cofactors. When a NADPH generating system was included in the incubation, 5 alpha-androstane-3 beta,17 beta-diol was metabolized to 5 alpha-androstan-3 alpha,17 beta-diol. Only small amounts of 17 beta-hydroxy-5 alpha-androstan-3-one accumulated under the latter condition.