Alpha-reduction Of Testosterone Research Articles

Role of the Alternate Pathway of Dihydrotestosterone Formation in Virilization of the Wolffian Ducts of the Tammar Wallaby,Macropus eugenii

Dihydrotestosterone in androgen target tissues is formed under most circumstances by the 5alpha-reduction of testosterone, but an alternate pathway involves the oxidation of androstanediol to dihydrotestosterone. To investigate the mechanism by which androgens virilize the Wolffian ducts in the tammar wallaby, [(3)H]progesterone was incubated with testes from d 10 and 19 pouch young, and radioactivity was recovered in testosterone and androstanediol at both ages. Analysis of the intermediates indicates that androstanediol was formed both from testosterone via 5alpha-reduction and 3alpha-keto reduction and directly from 5alpha-reduced progestogens. 5alpha-Reductase activity was high in minces of mesonephros/epididymis from d 6-21 pouch young. When minces of urogenital tract tissues from d 19 pouch young were incubated with [(3)H]testosterone, [(3)H]dihydrotestosterone, and [(3)H]androstanediol, dihydrotestosterone was the principal androgen formed in the mesonephros/epididymis, urogenital sinus, and urogenital tubercle, whereas androstanediol was the principal androgen formed by the testis. In intact pouch young studied between d 10 and 34, administration of the 5alpha-reductase inhibitor, 17beta-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5alpha-androstan-3-one, blocked virilization of the Wolffian ducts in males, and administration of androstanediol caused virilization of the Wolffian ducts in females. We conclude that dihydrotestosterone, largely formed in the tissue by the oxidation of androstanediol derived from the testes and also the 5alpha-reduction of testosterone, is responsible for Wolffian duct virilization in this species.

Androgen metabolism in the prostate of the finasteride-treated, adult rat: a possible explanation for the differential action of testosterone and 5 alpha-dihydrotestosterone during development of the male urogenital tract.

Previous work has clearly demonstrated that inhibition of 5 alpha-dihydrotestosterone (DHT) formation in vivo is not as effective as total androgen ablation (castration) in causing involution of the prostate. It is likely that this is due to the fact that testosterone is partially effective in maintaining androgen action. To provide insight into this observation, the androgenic metabolites of testosterone, androstenedione, and 5 alpha-DHT, were measured in prostate tissue and in blood of 5 alpha-reductase inhibitor (finasteride)-treated adult male rats. Finasteride treatment caused a significant decrease in prostatic DHT levels and a profound increase in prostatic testosterone and androstenedione levels. Similarly, circulating DHT levels were decreased in finasteride-treated rats (0.02 ng/ml compared with 0.05 ng/ml seen in control rats); and circulating androstenedione and testosterone levels were significantly elevated in finasteride-treated animals compared with controls. The in vitro effects of finasteride were assessed on the metabolism of [3H]testosterone in a tissue-slice assays. In the prostate, the inhibition of 5 alpha-reductase activity resulted not only in the decreased formation of 5 alpha-reduced metabolites (primarily DHT and 5 alpha-androstanedione), but also an increase in the 17-oxo metabolite androstenedione. In contrast, the tissues derived from the embryonic wolffian duct (seminal vesicle and epididymis) formed relatively low amounts of 17-keto steroids. Because DHT is a high affinity ligand for the androgen receptor and androstenedione shows very little, if any, affinity for the receptor, these studies suggest that 5 alpha-reduction of testosterone may be a mechanism to amplify androgen action in urogenital tissues such as the prostate by preventing catabolism of testosterone to the inactive androgen, androstenedione, at the site of hormone action.

5 alpha-reductase deficiency in patients with micropenis.

The enzyme 5 alpha-reductase (5 alpha R), by virtue of its peripheral 5 alpha-reduction of testosterone (T) to dihydrotestosterone (DHT), is believed to play a major role in the differentiation and the subsequent growth of the penis. However, recent studies have reported 5 alpha R deficiency (5 alpha RD) in patients with isolated micropenis and hypothesized that 5 alpha RD is not invariably associated with genital ambiguity. In Egypt, 5 alpha RD has been reported frequently among intersex patients. The aim of this study was to assess the role of 5 alpha RD in the development of micropenis among Egyptian patients with abnormal sexual development. The study included 29 patients who were categorized into three groups (isolated micropenis, 9 patients; microphallus with genital ambiguity, 11 patients; genital ambiguity with normal-sized phallus, 9 patients). Activity of 5 alpha R was assessed by estimating T/DHT ratios in the basal state in pubertal subjects and following human chorionic gonadotropin (HCG) stimulation test in prepubertals. The results showed that the incidence of 5 alpha RD was much higher in cases of ambiguous genitalia with micropenis (5 families out of 10, 50%) than in those with isolated microphallus (1/9, 11.1%) or those with ambiguous genitalia and normal-sized phallus (1/8, 12.5%). In conclusion, the study showed that isolated micropenis is a heterogeneous disorder and that 5 alpha RD, despite its relative prevalence in Egypt, has a minimal role in the aetiology. On the other hand, 5 alpha RD seems to correlate with penile length in intersex cases.

Clinical and Biochemical Parameters of Androgen Action in Normal Healthy CaucasianVersusChinese Subjects

Stimulation of androgen-sensitive hair follicles is mediated by dihydrotestosterone (DHT), which is formed in these tissues by 5 alpha-reduction of testosterone. A possible mechanism for increased body hair in some human populations might, therefore, be an increase in 5 alpha-reductase activity, resulting in elevated tissue levels of DHT. If present, this finding could have other important clinical implications, since the 5 alpha-reductase enzyme is pivotal in the pathophysiology of prostatic disease. To explore differences in clinical and biochemical parameters of androgen action, we conducted a study of 184 caucasian and Chinese subjects in whom we evaluated chest hair density and serum levels of androgen precursors and 5 alpha-reduced androgen metabolites. Differences in chest hair density were most notable in the men, in whom comparative mean chest hair scores (using a scale of 0-4) were 3.0 vs. 0.8 (P less than 0.0001), caucasian vs. Chinese. Levels of 5 alpha-reduced androgen products were also strikingly higher in the caucasian vs. Chinese subjects. Serum 3 alpha-androstanediol glucuronide levels (nanomoles per L) were 34.7 +/- 2.4 vs. 19.7 +/- 0.9 (P less than 0.001) for the men and 21.5 +/- 3.2 vs. 9.4 +/- 0.6 (P less than 0.001) for the women, and serum levels of androsterone glucuronide (nanomoles per L) were 179 +/- 26 vs. 107 +/- 7 (P less than 0.01) for the caucasian vs. Chinese men and 173 +/- 23 vs. 81 +/- 9 (P less than 0.001) for the women. Serum levels of total and bioavailable testosterone did not differ between the racial groups, but serum levels of the precursor androgens, dehydroepiandrosterone sulfate and androstenedione, were significantly higher in the caucasian vs. Chinese men, but not in the women. We conclude that increased serum levels of 5 alpha-reduced androgen metabolites in caucasians vs. Chinese subjects provide circumstantial evidence for a racial difference in 5 alpha-reductase activity and suggest a mechanism for the increased body hair observed in the caucasian men. Increased levels of precursor androgens may also play a role.

Hypogonadal impotence treated by transdermal testosterone

The transdermal therapeutic system for testosterone (TTS-T) (ALZA Corp.), applied to the scrotal skin for twenty-two hours daily, was tested for twelve weeks on 4 men with hypogonadal impotence; 2 of these men wore TTS-T for as long as twenty-six months. The 40 cm2 system delivered a daily dose of 2.8 +/- 0.16 (S.E.) mg (nominal dose 2.4 mg) and the 60 cm2 system delivered a dose of 3.99 +/- 0.24 mg (nominal dose 3.6 mg). Both systems promptly increased serum testosterone and dihydrotestosterone (DHT) to physiologic levels, restoring normal erectile activity with an increased frequency of ejaculation and a positive effect on both mood and energy. There were no changes in serum sex binding globulin and estradiol, prostate or breast size, hematologic or liver function measures, or urinary flow and frequency. There were no significant changes in serum cholesterol or low-density lipoproteins, but high-density lipoproteins tended to decline slightly. There were no dermatologic problems associated with the system. The tenfold increase in DHT over baseline levels was attributed to 5-alpha reduction of testosterone in the scrotal skin. The TTS-T is convenient, reliable, and mimics normal physiologic testosterone secretion and levels more closely than conventional methods of testosterone replacement.

5α-Metabolism in Finasteride-Treated Subjects and Male Pseudohermaphrodites with Inherited 5α-Reductase Deficiency

Male pseudohermaphrodites (MPHs) with inherited 5 alpha-reductase deficiency and decreased dihydrotestosterone production have a global defect in 5 alpha-metabolism affecting both C19 androgen metabolism and C21 steroid metabolism. However, the decreased 5 alpha-reduction of testosterone to dihydrotestosterone is the only impaired steroid conversion to have clinical consequences, e.g., ambiguous genitalia, impaired prostate differentiation and development, and decreased facial and body hair. The 5 alpha-steroid metabolite profile in the MPHs was compared with that of men with benign prostatic hyperplasia who were administered varying doses of the 5 alpha-reductase inhibitor finasteride. Finasteride was found to be a potent inhibitor of both C19 androgen and C21 5 alpha-steroid metabolism affecting both hepatic and peripheral 5 alpha-metabolism. The 5 alpha-steroid metabolite profile was strikingly similar to that of MPHs with inherited 5 alpha-reductase deficiency. The data suggest that a 5 alpha-reductase gene codes for an enzyme with affinity for multiple steroid substrates.

Precopulatory behaviour in the male hamster: effect of the 5 alpha-reductase inhibitor 17 beta-N,N-diethylcarbamoyl-4-aza-5 alpha-androstan-3-one.

Three independent components of hamster masculine behaviour (approaching, leaving and sniffing the female) have been shown to depend on both androgenic and oestrogenic action. The behavioural role of 5 alpha-reduced androgens was assessed by blocking 5 alpha-reduction of testosterone by means of 17 beta-N,N-diethylcarbamoyl-4-aza-5 alpha-androstan-3-one (4-MA) through slow-release silicone elastomer implants. Three dose levels of 4-MA were given to intact, sexually active males. The probability of approaching the female and the amount of sniffing directed to her were both decreased, while the probability of leaving the female was increased. Sniffing and the tendency to approach were affected at lower dose levels than was the tendency to leave. The higher dosage of 4-MA also abolished odour-based discrimination between females shown by normal males. These effects of 4-MA on behaviour were confirmed in castrated hamsters maintained on testosterone. The suppressive effects of 4-MA on behaviour were reversed by treatment with 5 alpha-dihydrotestosterone (DHT). We conclude that testosterone maintains sociosexual behaviour in part by conversion to its 5 alpha-reduced metabolites; components of this behaviour differ in their relative dependence on DHT. In this species, DHT is likely to be a behaviourally active metabolite of testosterone involved in the fine control of behaviour.

Control of 5 alpha-reduction of testosterone in neuroendocrine tissues of female rats.

An assay that involved generating [3H] dihydrotestosterone from [1 alpha,2 alpha-3H] testosterone by a microsomal preparation was developed to measure 5 alpha-reductase (5 alpha R) activity in brain and pituitary tissues of female rats. A major part of the activity was located within the microsomes and was linear, with protein concentrations ranging from 0.01 to 0.23 mg. The apparent Michaelis-Menten constants for pituitary and hypothalamic-preoptic areas were 2.37 and 2.69 microM respectively. Using this assay, we studied changes in 5 alpha R activity in brains and pituitaries of female rats ovariectomized 3 days prior to treatment and treated with either vehicle (oil) or estradiol benzoate (E2B, 10 micrograms/100 g of body weight). Groups of 5-17 animals were killed at 0, 12, 24, 48 and 72 h after treatment. In the pituitary gland, 5 alpha R activity 48 and 72 h after treatment was twice the value obtained at time 0 (p less than 0.05). A single injection of E2B maintained the 5 alpha R at pretreatment levels (p less than 0.05). The 5 alpha R values for intact females were significantly less than the values obtained from pituitaries of animals treated with estrogen (p less than 0.05). This probably indicates that the ovaries control 5 alpha R through mechanisms other than E2 secretion. In the preoptic area and the hypothalamus, ovariectomy did not produce marked elevations in 5 alpha R activity (p greater than 0.05). Thus, the responsiveness of the brain to estrogen treatment differed from the responsiveness of the pituitary. These results confirm the work of others on the effects of ovariectomy and estrogen treatment on 5 alpha R activity in the brain and pituitary. In addition, the data establish a time course for estrogen action that can be correlated with data on estrogen in the circulation. New data are also provided for understanding short-term effects of estrogen on the brain, effects that may be applicable to the control of gonadotropin secretion in rats.

The synthesis and metabolism of gonadal steroids in pouch young of the opossum, Didelphis virginiana.

We have measured steroid hormone biosynthesis from pregnenolone in ovaries and testes, aromatization of testosterone in gonads and peripheral tissues, and 5 alpha-reduction of testosterone in peripheral tissues of developing opossum pouch young. Sex of the newborn opossums is discernible grossly with development of the pouch in females and the scrotum in males approximately 10 days after birth. Differentiated endocrine function of ovaries and testes was demonstrable as soon as development of the pouch or scrotum was apparent. The testes synthesized testosterone, and ovaries aromatized androgens to estrogens as assessed by the conversion of [1 beta-3H] testosterone to 3H2O. This endocrine differentiation of the gonads occurs days or weeks before differentiation of the male and female urogenital tracts. As in other species, 5 alpha-reduction of [1 beta-3H] testosterone was high in urogenital sinus and urogenital tubercle. However, 5 alpha-reductase activity was highest in mesonephros and structures derived from the mesonephros. In wolffian and mullerian ducts of pouch young less than 10 days old, 5 alpha-reductase activity was greater than 50 pmol/h . mg protein and decreased by 19 days of age to approximately 3 pmol/h . mg protein, a pattern different than in eutherian mammals in which testosterone itself appears to mediate virilization of the wolffian ducts. These studies provide the framework for studies of the endocrine control of phenotypic sexual differentiation in the opossum.

Inhibition of luteinizing hormone (LH)-releasing hormone-induced secretion of LH in rat anterior pituitary cell culture by testosterone without conversion to 5 alpha-dihydrotestosterone.

The role of 5 alpha-reduction of testosterone in the inhibition of LH secretion was investigated in rat anterior pituitary cell cultures. Pituitary cells were preincubated with testosterone or dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) for 17 h and then with LHRH for an additional 4 h. Dihydrotestosterone was 6-fold more potent than testosterone in the inhibition of LHRH-induced LH release. Basal LH secretion was not affected by either androgen. The inhibition curves of testosterone and dihydrotestosterone were not shifted by the presence of the 5 alpha-reductase inhibitors 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA) and 17 beta-N,N-diisopropylcarbamoyl-4-aza-androstan-3-one (DIPA). Neither 4-MA nor DIPA alone had an effect on either basal or LHRH-induced LH release. When pituitary cells were incubated with [3H]testosterone for 17 h, the radioactivities were found to be unmetabolized testosterone (66.9 +/- 2.4%), dihydrotestosterone (13.3 +/- 0.5%), androstenedione (15.9 +/- 1.3%), 5 alpha-androstane-3,17-dione (2.8 +/- 0.3%), and 3 alpha (beta), 17 beta-androstanediol (less than 1%). In the presence of 4-MA or DIPA, 5 alpha-reduction of testosterone was completely inhibited; androstenedione was the only metabolite. Androstenedione was only 12% as potent as testosterone in the inhibition of LHRH stimulation of LH release, and conversion of [3H]androstenedione to testosterone and dihydrotestosterone did occur in these cells. When [3H]dihydrotestosterone was incubated with pituitary cells, the radioactivities were dihydrotestosterone (64.4 +/- 0%), 5 alpha-androstanedione (19.3 +/- 1%), 3 alpha (beta), 17 beta-androstanediol (7.7 +/- 1.7%), and unknown polar metabolites. 4-MA and DIPA had no effect on the metabolism of dihydrotestosterone. These results indicate that both testosterone and dihydrotestosterone inhibit LHRH-induced LH release and that this activity of testosterone does not depend on its 5 alpha-reduction.

Circadian rhythm of acid phosphatase activity in rat liver microsomes and dependence of NADH 5 alpha-reductase on phosphatase activity.

The specific activity of acid phosphatase in male and female rats follows a circadian rhythm. Preincubation of liver microsomes with testosterone led to an increase of phosphatase activity and a loss of circadian rhythm. NADH 5 alpha-reductase was inactivated by several animal and bacterial acid and alkaline phosphatases while the acid phosphatase from potatoes was ineffective. The extent of inhibition depends on the course of circadian rhythm of NADH 5 alpha-reductase activity. Preincubation of microsomes in the presence of testosterone inhibited the NADH 5 alpha-reduction of testosterone. No such inhibition was observed after preincubation of microsomes with progesterone.

Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

The in vivo biotransformations of drugs known to be metabolized by enzymes localized in the endoplasmic reticulum of liver can be greatly altered by diet in humans, as we have shown previously. Steroid hormones also are metabolized extensively by hepatic microsomal enzymes; therefore, we examined the possibility that testosterone and estradiol biotransformations, as assessed with radiolabeled tracer methods, could be influenced by dietary macronutrients. Normal males were fed a high-protein diet for 2 weeks, followed by a high-carbohydrate diet for an additional 2 weeks. The delta 4-5 alpha-reduction of testosterone was considerably diminished, while the cytochrome P-450-dependent hydroxylation of estradiol at the C2 position was substantially enhanced during ingestion of the high-protein diet as compared with the high-carbohydrate diet. These results indicate that dietary macronutrients can significantly alter major metabolic pathways for testosterone and estradiol in man. The mechanism by which reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-mediated oxidation of estradiol are produced by diets is not known. Similar changes in steroid delta 4-5 alpha-reduction and cytochrome P-450-dependent chemical oxidations have been observed in circumstances in which the mixed-function oxidase system in liver is induced by agents such as phenobarbital, hexachlorobenzene, dioxin, and polyhalogenated biphenyls. Thus, the alterations in steroid hormone metabolism produced by dietary macronutrients in man mimic those that can be produced by drugs and environmental chemicals.

Seminal plasma testosterone and dihydrotestosterone levels in men with varicoceles.

Testosterone (T) and dihydrotestosterone (DHT) were measured in the seminal plasma of men with varicoceles, azoospermic vasectomized men and men with normal seminal parameters. Testosterone levels were not different significantly in these groups of men. DHT concentrations and the DHT/T ratio were significantly lower than normal in men with varicoceles and sperm densities below 30 million/ml and the vasectomized men, but not different from normal in the men with varicoceles whose sperm densities were greater than 30 million/ml. In men whose sperm density and/or motility improved after varicocelectomy, there was an increase in seminal plasma DHT levels and the DHT/T ratio. When seminal parameters were not improved by varicocelectomy, there was no change in DHT levels or in the DHT/T ratio. It is concluded that men with varicoceles and sperm densities below 30 million/ml have a deficiency in the epididymal 5 alpha-reduction of testosterone.

Studies on the human epididymis: Partial characterization of 3.ALPHA.- and 3.BETA.-hydroxysteroid dehydrogenase, regional distribution of 5.ALPHA.-reductase and inhibitory effect of 4.DELTA.-3-oxosteroids on 5.ALPHA.-reductase.

When [4-14C]-5 alpha-dihydrotestosterone was incubated with the homogenate of human epididymis, 5 alpha-androstane-3 alpha, 17 beta-diol and 5 alpha-androstane-3 beta, 17 beta-diol were identified as major metabolites. The ratio of 3 alpha- to 3 beta-epimer in androstanediol formation was approximately 2.4. 5 alpha-Androstane-3, 17-dione was also identified as a minor metabolite. Among the subcellular fractions, both the human epididymal 3 alpha- and 3 beta-hydroxysteroid dehydrogenases were localized almost exclusively in the cytosol fraction (105,000 X g supernatant). Both enzymes had optimum pH at 7.5 and optimum temperature at 46 degrees C. NADPH was a more preferable cofactor than NADH for both dehydrogenases. The Michaelis constants (Km) of 3 alpha- and 3 beta-hydroxysteroid dehydrogenase for 5 alpha-dihydrotestosterone were similar and estimated as 8 X 10(-5) M, but the enzymes were unsaturable with the substrate under the conditions investigated, indicating low affinity and high capacity of both dehydrogenases for 5 alpha-dihydrotestosterone. The human epididymal 5 alpha-reductase revealed a regional difference in activity. The 5 alpha-reductase activity in the most proximal part of the head (ductuli efferentes) was one seventh to one tenth the activity in the remaining part of the epididymis which was constructed of ductus epididymis. Except for this finding, the activity of 5 alpha-reductase was highest in the head, then declined along the course to the tail portion. The 5 alpha-reductase for testosterone was competitively inhibited by delta 4-3-oxosteroids such as progesterone, 20 alpha-dihydroprogesterone, 17 alpha-hydroxyprogesterone, 4-androstenedione, 11-deoxycorticosterone, corticosterone and 11-deoxycortisol, which had inhibition constants (Ki) of 3.3 X 10(-9) M, 2.2 X 10(-9) M, 1.8 X 10(-8) M, 1.3 X 10(-8) M, 8.3 X 10(-9) M, 1.5 X 10(-7) M and 8.7 X 10(-8) M, respectively, suggesting the possibility that the 5 alpha-reduction of testosterone is regulated by other delta 4-3-oxosteroids.

INHIBITION OF STEROID 5α-REDUCTASE IN VIVO: EFFECT ON SUPPRESSION OF LUTEINIZING HORMONE AND STIMULATION OF ACCESSORY SEX ORGANS BY TESTOSTERONE IN THE ORCHIDECTOMIZED RAT

An inhibitor of 5 alpha-reductase, the 17 beta-carboxylic acid derivative of testosterone (testosterone-17 beta CA), has been used to evaluate the importance of the 5 alpha-reduction of testosterone in its action on the suppression of LH secretion in male rats. The potential of testosterone-17 beta CA to inhibit the formation of 5 alpha-dihydrotestosterone (DHT) was first demonstrated in vitro. When homogenates of hypothalami or anterior pituitary glands were incubated with [3H]Testosterone in the presence of a 50-fold excess of testosterone-17 beta CA, the formation of labelled DHT was inhibited by more than 80%. Adult male rats that had been castrated for 1-2 months were fitted with chronic intravenous catheters and implanted with silicone elastomer sheets: one group received one sheet, 0.5-2.0 cm2 in size containing 1.6% testosterone, a second group received one 50 cm2 sheet containing 1.6% testosterone-17 beta CA and a third group received two sheets, one sheet 50 cm2 in size containing 1.6% testosterone-17 beta CA and the second ranging in size from 0.5 to 2.0 cm2 and containing 1.6% testosterone. Blood was withdrawn daily from each rat over a 4-5 day period after implantation of the steroids and the level of LH in the plasma was measured by radioimmunoassay. The seminal vesicles and the ventral prostate gland were removed at autopsy on day 4 or 5; the weights of these organs were shown to have increased progressively as the size of the implant of testosterone increased. In contrast, the level of LH in the plasma was suppressed to a comparable extent by implants of testosterone between 0.6 and 2 cm2, whereas a 0.5 cm2 implant of testosterone had no effect. Implants of testosterone-17 beta CA alone did not influence the weight of the accessory organs or the level of LH. When testosterone-17 beta CA and testosterone were implanted together, the growth-promoting effect of the latter on the accessory sex organs was significantly reduced. The effectiveness of testosterone in suppressing the level of LH in the plasma of these animals was not influenced by the presence of testosterone-17 beta CA and in certain instances the level was raised.

Cellular Regulation of the Metabolism of Androgens in Rat Oral Mucosa. III. Activation of Δ4-3-ketosteroid-5α-A Ring Reductase Enzyme System by 5,5-Diphenylhydantoin

Systemic pretreatment of rats with diphenylhydantoin (DPH) or its addition into an in vitro assay increases 5alpha-reduction of testosterone by the oral mucosa. Enzyme kinetic studies showed that DPH binds to the enzyme and probably activates it by an allosteric mechanism.

Clinical, Endocrinological, and Enzymatic Characterization of Two Patients with 5α-Reductase Deficiency: Evidence that a Single Enzyme Is Responsible for the 5α-Reduction of Cortisol and Testosterone*

Two siblings with 46,XY male pseudohermapthroditism were demonstrated to have the phenotype characteristic of 5 alpha-reductase deficiency, namely normal testes and male Wolffian duct derivatives (epididymis, vas deferens, and seminal vesicle) terminating in a blind-ending vagina. Clitoromegaly was present at birth and increased further at the time of expected puberty. The diagnosis of 5 alpha-reductase deficiency was confirmed by demonstration of male levels of testosterone and testosterone precursors before and after hCG administration, elevated plasma testosterone to dihydrotestosterone and urinary etiocholanolone to androsterone ratios, and by in vitro studies indicating 5 alpha-reductase enzyme deficiency in the epididymis of one patient. Studies of control and mutant epididymal microsomes indicated that a single enzyme is responsible in the normal person for the 5 alpha-reduction of testosterone and cortisol (and probably other delta 4-3-ketosteroids as well) and that 5 alpha-reductase activity is undetectable for all substrates examined in the mutant. This finding explains why the formation of 5 alpha-reduced glucocorticoids is also defective in the disorder.

In vitro effects of oestrogen on 5alpha reduction of testosterone in hormone-dependent rat mammary carcinomata.

This regime was continued for a further14 days when the animals were sacrificedby exsanguination. No injection wasgiven on the day of sacrifice. Tumoursize was monitored throughout the studyby measuring with calipers the two majordiameters at right angles, and expressingthe size of the resulting multiple in

Der Stoffwechsel von ∆4-3-Oxosteroiden in der Rattenleber

The enzymatic reactions are described by which delta4-3-oxosteroids, specially testosterone, are inactivated in rat liver. The delta4-3-oxosteroid-5 alpha-reductase in liver microsomes was studied intensively and it was found that it is an enzyme system. The 5 alpha-reduction of testosterone with NADPH or with NADH depends upon different enzymes or enzyme systems.

Interference with the 5 α-Reductase System

The paper presents evidence indicating that, in an “in vitro” system, progesterone may interfere with the conversion of testosterone into its “active” metabolites (5 alpha-androstan-17 beta-ol-3-one, 5 alpha-androstan-3 beta, 17 beta-diol and 5 alpha-androstan-3 alpha, 17 beta-diol, etc.) both at the anterior pituitary and prostatic levels. Progesterone probably acts as a preferential substrate for the enzyme 5 alpha-reductase present in these structures. Other steroids are also active in diminishing the 5 alpha-reduction of testosterone in its target organs. Both corticoids and progestagens seem to be effective inhibitors for such a reduction. These observations open a new approach for developing anti-androgenic compounds.