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PubMed1976

Rapid and intensive conversion of 5alpha-androstane-3alpha, 17beta-diol into 5alpha-dihydrotestosterone in the male rat anterior pituitary: in vivo and in vitro studies.

The in vivo and in vitro metabolism of (3H)-5alpha-androstane-3lapha,17beta-diol by the male rat anterior pituitary was studied. A rapid and intensive conversion of 5alpha-androstane-3alpha, 17beta-diol into 5alpha-dihydrotestosterone was demonstrated, since following a 30 min. incubation time, 73% of the recovered radioactivity were constituted by 5alpha-dihydrotestosterone. Studies on the subcellular distribution of steroids showed that 5alpha-dihydrotestosterone was the main steroid recovered except from the 105,000 X g pellet. From in vivo and in vitro experiments it was concluded that the transformation of 5alpha-dihydrotestosterone into 5alpha-androstane-3alpha, 17beta-diol was a reversible process, and that this last steroid could exert its biological action mainly via 5alpha-dihydrotestosterone.

Androgens↗
PubMed1992

Testosterone and 5 alpha-dihydrotestosterone interact differently with the androgen receptor to enhance transcription of the MMTV-CAT reporter gene.

Testosterone and its 5 alpha-reduced derivative 5 alpha-dihydrotestosterone exert different actions in the male during embryogenesis and in postnatal life. Nevertheless the two hormones bind to the same intracellular androgen receptor, and genetic and endocrinological studies in the Tfm mouse suggest that the actions of both hormones are mediated by this single receptor. Previous studies indicate that dihydrotestosterone binds more tightly to the androgen receptor but that the Bmax of binding of the two hormones is the same. To determine whether these differences in binding parameters could explain the mechanism by which the two hormones exert different physiological actions via the same receptor, we introduced a plasmid encoding the androgen receptor cDNA and a reporter plasmid encoding MMTV-CAT into Chinese hamster ovary cells. These cells do not express endogenous androgen receptor and do not convert testosterone to dihydrotestosterone. Therefore, it was possible to examine the relation between the concentration of each of the steroids and reporter gene expression. Both hormones enhanced CAT activity, but dihydrotestosterone was approximately 10 times as potent (half maximal of 0.018 nM) as testosterone (half maximal of 0.2 nM); the maximal activity achieved was the same for the two androgens. These findings are nearly identical to the apparent Kd values for the interaction of the two hormones with the androgen receptor. Although testosterone and dihydrotestosterone may influence the expression of other genes differently, these findings are compatible with a model system in which the differential effects can be explained as a consequence of different binding affinities to the receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

5-alpha-Dihydroprogesterone↗
PubMed1990

Androstenedione is an important precursor of dihydrotestosterone in the genital skin of women and is metabolized via 5 alpha-androstanedione.

Androgen action is largely determined by the formation of dihydrotestosterone in target tissues. In women, androstenedione is the major precursor of dihydrotestosterone production in female genital skin. The present study was initiated to determine whether androstenedione is converted to dihydrotestosterone primarily via testosterone or 5 alpha-androstane-3,17-dione (5 alpha-androstanedione), and to examine the pathway of androstenedione metabolism in genital skin. Genital skin was obtained from 9 normal premenopausal women and 2 normal men. Each tissue was incubated with [3H]androstenedione in RPMI-1640 medium for 1 h at 37 degrees C in 95% O2/5% CO2. The metabolites were separated and purified by paper partition and thin-layer chromatography. The conversions of androstenedione to 5 alpha-androstanedione and to androsterone were similar (10.45 +/- 1.46 and 11.04 +/- 2.04%/200 mg tissue), and were approx. 12, 8 and 23 times higher than the conversion of androstenedione to testosterone, dihydrotestosterone and 5 alpha-androstane-3 alpha,17 beta-diol, respectively. The male samples showed a similar pattern of metabolism. These data indicate that 5 alpha-androstanedione is the most important intermediate in the conversion of androstenedione to dihydrotestosterone. The data also confirm the importance of 5 alpha-reductase activity over that of 17 beta-hydroxysteroid oxidoreductase activity in the expression of androgen action in women.

Adult↗
PubMed2004

The proliferative effects of 5-androstene-3 beta,17 beta-diol and 5 alpha-dihydrotestosterone on cell cycle analysis and cell proliferation in MCF7, T47D and MDAMB231 breast cancer cell lines.

Epidemiological studies suggest that precursor steroids are implicated in the aetiology of breast cancer. However, our understanding of the role of precursor steroids in breast cancer is complicated by fact that there are many precursor steroids, which are metabolically inter-related and have divergent proliferative activities on the growth of breast cancer cell lines. In this study the proliferative affects of 5 alpha-dihydrotestosterone and 5-androstene-3 beta,17 beta-diol, which may be considered true metabolites acting at a tissue level, on MCF7, T47D and MDAMB231 breast cancer cell lines have been examined by a flow cytometric technique. DNA cell cycle analysis demonstrates that 5-androstene-3 beta,17 beta-diol stimulates the proliferation of hormone-dependent cell lines at physiological levels by an oestrogen receptor mediated mechanism whereas 5 alpha-dihydrotestosterone does not affect the proliferation of MCF7 and T47D cell lines at physiological levels over short (48 h) incubations. Both 5 alpha-dihydrotestosterone and 5-androstene-3 beta,17 beta-diol stimulate proliferation of hormone-dependent cell lines at pharmacological levels via and interaction with the oestrogen receptor. In long (6-9 days) incubations both 5 alpha-dihydrotestosterone and 5-androstene-3 beta,17 beta-diol inhibit the 17 beta-oestradiol induced proliferation of MCF7 and T47D cell lines, however, 5 alpha-dihydrotestosterone inhibits while 5-androstene-3 beta,17 beta-diol stimulates basal proliferation. These cell line studies suggest a model for the role of precursor steroids in pre- and postmenopausal breast cancer.

Anabolic Agents↗
PubMed1981

Radioimmunoassay measurements of nuclear dihydrotestosterone in rat prostate. Relationship to androgen receptors and androgen-regulated responses.

The concentration of dihydrotestosterone was measured by radioimmunoassay in nuclear and cytoplasmic extracts from rat ventral prostates. In the regenerating prostates of castrated rats treated with dihydrotestosterone for 4 days, the nuclear concentration of this steroid increased from approx. 70nM to 800nM as a linear function of the injected dose, whereas the cytoplasmic concentration remained relatively constant (70-130nM). Isotope-exchange measurements of nuclear androgen receptors by using [3H]methyltrienolone indicated that, although the concentration of nuclear dihydrotestosterone was several-fold higher than the concentration of androgen receptors, they were logarithmically related. The recruitment of prostatic cells into the growth fraction and the stimulation of 5 alpha-reductase activity were more directly correlated to the nuclear concentration of androgen receptors than to the total nuclear concentration of dihydrotestosterone. Maximal restoration of a specific isoenzyme of acid phosphatase ws achieved when approx. 2000 androgen receptors were present in the prostatic nuclei; higher concentrations of nuclear androgen receptors were associated with decreased amounts of this enzyme. Hence the results imply, first, that the total amount of dihydrotestosterone accumulated by nuclei is not a direct consequence of carrier-mediated transport by androgen receptors, and, secondly, that, whereas acid phosphatase may be differentially controlled by androgens in the regenerating prostate, increases in the amount of cell proliferation and 5 alpha-reductase activity directly parallel increases in the nuclear concentration of androgen receptors.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2006

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.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1984

Behavioural and morphological effects of 5 alpha-dihydrotestosterone and oestradiol-17 beta in the prepubertally castrated boar.

Three groups of 5 prepubertally castrated boars received twice weekly subcutaneous injections from 16 to 28 weeks of age of 5 alpha-dihydrotestosterone propionate (1 mg/kg), oestradiol-17 beta dipropionate (0.1 mg/kg), or a combination of the two steroids. The pigs were tested each week for sexual behaviour with an oestrogen-treated ovariectomized gilt. 5 alpha-Dihydrotestosterone did not induce copulatory behaviour whereas oestradiol initiated mounting, although this behaviour was not maintained. However, the combined hormonal treatment induced the full pattern of copulation, including ejaculation, in 4/5 pigs. Oestrogen-treated animals also showed champing and salivation. None of the pigs treated with 5 alpha-dihydrotestosterone showed lordosis when exposed to a mature boar. Increases in the size of the penis, the ischio- and bulbocavernosus muscles, seminal vesicles and bulbourethral glands were produced by 5 alpha-dihydrotestosterone, and, with the exception of the penis, this hypertrophy was further enhanced by additional treatment with oestradiol. Increases in the weight of the prostate and muscular urethra were due mainly to the effects of oestrogen; this steroid caused extensive development of fibromuscular tissue and also increased mammary teat length. In the submaxillary salivary glands, synergism between 5 alpha-dihydrotestosterone and oestradiol resulted in hypertrophy of the serous cells.

Animals↗
PubMed1977

Sexual behaviour of neonatally castrated rats injected during infancy with oestrogen and dihydrotestosterone.

Male rats were castrated on the day of birth (day 1) and injected with either testosterone, dihydrotestosterone, a synthetic oestrogen (RU 2858 + dihydrotestosterone, or oil from days 1 to 5. The aromatizable androgen, testosterone, and RU 2858 suppressed both cyclic gonadotrophin secretion, indicated by the absence of corpora lutea from implanted ovarian grafts, and the behavioural response to oestradiol benzoate + progesterone injections in adulthood. The 5alpha-reduced androgen, dihydrotestosterone alone did not affect gonadotrophin secretion or female receptive behaviour, but like testosterone, it increased penis development in response to testosterone propionate, and this was positively correlated with copulatory efficiency, i.e. the ratio of intromission to mount frequencies. Nevertheless, ejaculation only occurred among animals that had received testosterone or RU 2858 + dihydrotestosterone. The results support the concept that during the preinatal period, neural conversion of androgens to oestrogens is important both for the suppression of female gonadotrophin secretion and behaviour patterns as well as for the organization of male behaviour patterns. The 5alpha-reduction of unsaturated C19-steriods to dihydrotestosterone in peripheral tissues is also required to complete the development of the male genital tract.

Animals↗
PubMed1991

Treatment of lichen sclerosus with topical dihydrotestosterone.

Lichen sclerosus typically affects the vulva of postmenopausal women. Because serum levels of dihydrotestosterone are low in women with vulvar lichen sclerosus and because dihydrotestosterone is an effector androgen in vulvar skin, this double-blind cross-over study assessed five women with vulvar lichen sclerosus to determine the response to treatment with dihydrotestosterone. Objective gross and microscopic improvement in lichen sclerosus accompanied sustained treatment with topical dihydrotestosterone, but not with vehicle alone. However, there was no change in symptoms (itching and dyspareunia) in these women, although dihydrotestosterone did improve some of the features of vulvar lichen sclerosus and may represent a new treatment for this disease.

Administration, Cutaneous↗
PubMedDate not supplied

Effect of dihydrotestosterone on rat liver alcohol dehydrogenase activity.

Castration was previously demonstrated to result in an increase in liver alcohol dehydrogenase and in rates of ethanol elimination in male rats. In this study, the effect of dihydrotestosterone, which is a more potent androgen than testosterone in the rat, was determined on liver alcohol dehydrogenase and ethanol elimination in the castrated rat. Dihydrotestosterone was found to be a substrate of liver alcohol dehydrogenase in the reductive direction and a competitive inhibitor of ethanol oxidation by the enzyme. Also, the administration of a single dose of dihydrotestosterone inhibited liver alcohol dehydrogenase 4 hr after the injection, but this effect was not persistent at later intervals following injection. This transient in vivo inhibition of liver alcohol dehydrogenase was associated with a delay in ethanol elimination. The microsomal ethanol-oxidizing enzyme system was found to play no role in the changes in ethanol elimination observed after castration and dihydrotestosterone administration since its activity remained unchanged. These studies provide further evidence of an effect of androgenic steroids on liver alcohol dehydrogenase activity and ethanol metabolism.

Alcohol Dehydrogenase↗
PubMed1995

Induction of benign prostatic hyperplasia in intact dogs by near-physiological levels of 5 alpha-dihydrotestosterone and 17 beta-estradiol.

Benign prostatic hyperplasia was induced in mongrel dogs treated for 60 days with one silastic implant containing 17 beta-estradiol and four containing 5 alpha-dihydrotestosterone. The condition was characterized by (1) a marked increase of the stromal elements, particularly the stromal septa between the individual glands, (2) a slight increase in prostatic volume, and (3) a morphology that resembled spontaneous complex benign prostatic hyperplasia in the dog. Other groups of animals that remained untreated or received only 17 beta-estradiol or only 5 alpha-dihydrotestosterone did not develop this condition. Prostate volumes decreased by 14% in the estrogen-treated dogs, whereas they increased in the androgen-treated animals by 6% compared to pretreatment prostate volumes. The morphology of the epithelium of the prostates of androgen-treated animals was not different from that of controls despite the increase in prostate volume. The serum 17 beta-estradiol and 5 alpha-dihydrotestosterone concentrations were increased from 25 +/- 2 (mean +/- SEM) and 256 +/- 42 pg/mL, respectively, in control dogs to 52 +/- 37 and 562 +/- 37 pg/mL, respectively, in the dogs treated with the hormone combination. Thus, hormone concentrations were two- to three-fold higher than control values, and the ratio of estradiol-17 beta to 5 alpha-dihydrotestosterone was increased by up to 19%. These data demonstrate that treatment of dogs with low levels of estrogen and androgen may be an excellent model for the study of spontaneous complex benign prostatic hyperplasia in aging men.

Analysis of Variance↗
PubMed1996

Semiautomated method for the quantitation of plasma or sera androstenedione, testosterone, and dihydrotestosterone in population studies.

A method is presented that analyzes quantitatively and reproducibly the androgens testosterone, androstenedione, and dihydrotestosterone from human sera or plasma. The chromatographic separation step generates an unattended throughput of one preparative separation per hour. Controls are built into the method to account for changing chromatographic conditions that otherwise result in shifts in retention characteristics. Separation factors for the three androgens are as follows (mean +/- standard deviation): alpha = 1.23 +/- 0.011 between androstenedione and testosterone and alpha = 1.38 +/- 0.025 between testosterone and dihydrotestosterone. Sensitivities of the method are androstenedione 5 pg, testosterone 3 pg, and dihydrotestosterone 14 pg. A study of procedural losses associated with initial sample processing, a validation, and application to two sample sets which demonstrates the methods utility for the analysis of hypoandrogenic populations (postmenopausal women) and hyperandrogenic groups (prostate cancer patients) is also reported. The precision for replicate aliquots of control plasma is androstenedione and testosterone = 5-11% CV and dihydrotestosterone = 10-20% CV.

Adult↗
PubMed1988

Localization and identification of nuclear radioactivity in the pituitary gland and genital tract after administering 3H-testosterone, 3H-dihydrotestosterone, or 3H-estradiol to male rhesus monkeys.

Target cells for testosterone, dihydrotestosterone, and estradiol in the pituitary gland and genital tract of the male primate were localized by thaw-mount autoradiography, and high performance liquid chromatography was used to identify the metabolites of these steroids in cell nuclei. Castrated rhesus monkeys were injected with 3H-testosterone, 3H-dihydrotestosterone, or 3H-estradiol and killed 60 min later. In the anterior pituitary gland, fewer cells were labeled and less radioactivity was taken up by cell nuclei following the administration of either 3H-testosterone (4% of pars distalis cells and 5 dpm/micrograms DNA) or 3H-dihydrotestosterone (5% of cells and 13 dpm/micrograms DNA) than following the administration of 3H-estradiol (43% of cells and 214 dpm/micrograms DNA). Most of the radioactivity in nuclei was in the form of the unmetabolized parent compound (78-94%). In prostate, seminal vesicles, and penis, 3H-dihydrotestosterone was the predominant form of nuclear radioactivity following both 3H-testosterone (67-90%) and 3H-dihydrostestosterone (94-97%) administration, and both androgens labeled epithelial and smooth muscle cells. In contrast, 3H-estradiol was taken up in unchanged form, by cell nuclei of the genital tract and it labeled connective tissue fibroblasts, but not epithelial cells. Thus, the distributions of target cells for androgens and estrogens were clearly different in all these tissues, and the uptake of testosterone resembled that of its androgenic rather than that of its estrogenic metabolite.

Animals↗
PubMed1985

Human male sexual functions do not require aromatization of testosterone: a study using tamoxifen, testolactone, and dihydrotestosterone.

This study was designed to examine whether testosterone needs to be converted to estradiol in order to exert fully its effects on sexuality in the human male. Administration of the estrogen receptor antagonist tamoxifen and the aromatase inhibitor testolactone were without effect on parameters of sexual functions. Replacement of testosterone substitution therapy of agonadal men by dihydrotestosterone was likewise not associated with any change of sexual functioning. Administration of dihydrotestosterone to eugonadal men led to a transient increase of nocturnal sexual dreams and erections and irritability, waning after 3-4 weeks of dihydrotestosterone administration. It is concluded that aromatization of testosterone is not required and that dihydrotestosterone maintains sexual functions in the adult male with an established sex life.

Adult↗
PubMed1984

Specific 5 alpha-dihydrotestosterone receptor and 5 alpha-reductase activity in human amniotic fluid cells.

A macromolecular component which specifically binds tritium-labeled-dihydrotestosterone is present in cultured amniotic fluid cells. The androgen-binding complex is characterized by a 3.6S sedimentation coefficient, an apparent dissociation constant of 1 nmol/L, a mean binding capacity of 243 +/- 140 fmol/mg of DNA, and a specificity for testosterone and dihydrotestosterone. Similar properties have been reported for the androgen receptor of the fetal genital skin fibroblast, which suggests that the tritium-labeled-dihydrotestosterone-binding component in amniotic fluid cells is the androgen receptor. Amniotic fluid cell monolayers incubated with serum-free medium containing testosterone are able to transform testosterone into dihydrotestosterone. The 5 alpha-reduced product has been characterized by thin-layer chromatography and capillary column gas-liquid chromatography. Androgen receptors and 5 alpha-reductase activity are expressed in amniotic fluid cells. The prenatal diagnosis of 5 alpha-reductase deficiency or complete androgen insensitivity syndrome (testicular feminization) is thus theoretically possible and obviously prenatal testing would be indicated in the family at high risk.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1985

Does dihydrotestosterone induce atresia in the hypophysectomized immature female rat treated with pregnant mare's serum gonadotropin?

This study was originally designed to test the hypothesis that the binding of luteinizing hormone in granulosa cells decreases with atresia. The hypophysectomized immature female rat that was primed with pregnant mare's serum gonadotropin and treated with dihydrotestosterone was used as a model for atresia. Histochemical analysis of acid phosphatase was used as a marker for atresia and topical autoradiography with iodine 125-labeled human chorionic gonadotropin for binding of luteinizing hormone. Histologically, there was no significant difference in atresia, acid phosphatase, or 125I-labeled human chorionic gonadotropin binding in antral follicles between control animals given pregnant mare's serum gonadotropin and animals treated with pregnant mare's serum gonadotropin and dihydrotestosterone. Assessment of the total follicular population, however, showed that dihydrotestosterone at dosages of 1 and 5 mg/kg resulted in decreases in atresia of 48% and 58%, respectively. Although these data disprove our hypothesis, they strongly suggest that dihydrotestosterone decreases follicular atresia by increasing the number of small preantral follicles.

Acid Phosphatase↗
PubMed1986

Depression of alcohol dehydrogenase activity in rat hepatocyte culture by dihydrotestosterone.

Hepatocytes harvested from castrated rats retained a higher alcohol dehydrogenase (EC 1.1.1.1) activity than hepatocytes harvested from normal rats during 7 days of culture. Dihydrotestosterone (1 microM) decreased the enzyme activity, after 2 and 5 days of culture, in hepatocytes from castrated and control animals respectively. Dihydrotestosterone decreased the enzyme activity to similar values in both groups of hepatocytes by the end of 7 days of culture. Testosterone (1 microM) had no effect on the enzyme activity in normal hepatocytes and only a transitory effect in decreasing the enzyme activity in hepatocytes from castrated animals. The increases in alcohol dehydrogenase activity after castration and their suppression by dihydrotestosterone were associated with parallel changes in the rate of ethanol elimination. Additions of substrates of the malate-aspartate shuttle or dinitrophenol did not modify ethanol elimination. These observations indicate that dihydrotestosterone has a direct suppressant effect on hepatocyte alcohol dehydrogenase and that the enzyme activity is a major determinant of the rate of ethanol elimination.

Alcohol Dehydrogenase↗
PubMed1982

Binding of testosterone, 5 alpha-dihydrotestosterone and 5 alpha-androstane (3 alpha- and 3 beta-), 17 beta-diols to serum proteins in the rat.

Experiments with polyacrylamide gel electrophoresis at steady state conditions, indicated that testosterone, 5 alpha-dihydrotestosterone, 3 alpha-androstanediol and 3-beta-androstanediol bound only to albumin in rat serum. The extent of binding of several C19-steroids to serum proteins was measured in rat blood utilizing equilibrium dialysis. The values for the adult male rat were as follows (mean +/- SEM): testosterone 78.3 +/- 0.4% 5 alpha-dihydrotestosterone 81.8 +/- 0.4%, 3 alpha-androstanediol 95.5 +/- 0.1%; 3 beta-androstanediol 95.2 +/- 0.1%. The values for the latter two are significantly higher than those for the first two which in turn differ significantly from each other. The values for adult female and castrated male serum samples were not significantly different from those of the normal male. The results obtained for the extent of binding of C19-steroids in a 5-g% albumin solution (which is similar to male rat serum albumin concentration) did not differ significantly from values for serum indicating that the binding in the latter is due primarily to albumin. The KA's for C19-steroid binding to albumin were: testosterone 2.22 X 10(4)l/mol; 5 alpha-dihydrotestosterone 3.46 X 10(4)l/mol; 3 alpha-androstanediol 1.36 X 10(5)l/Mol and 3 beta-androstanediol 1.20 XC 10(5)l/mol. When correlated to our previously reported metabolic clearance rats (MCR) it was concluded that binding to serum proteins does not account for the significant difference between the MCR for testosterone and 5 alpha-dihydrotestosterone but may account for the lower MCR's for the 3 alpha- and 3 beta-androstanediols.

Androstane-3,17-diol↗