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PubMed2006

Association between the dihydrotestosterone level in the prostate and prostate cancer aggressiveness using the Gleason score.

PURPOSE: To our knowledge the association between dihydrotestosterone in the prostate and prostate cancer aggressiveness has not yet been elucidated. We analyzed dihydrotestosterone levels in the prostate and Gleason score in patients diagnosed with clinically localized prostate cancer. MATERIALS AND METHODS: A total of 81 patients with suspected prostate cancer underwent prostate biopsy. Serum samples were collected before biopsy. Dihydrotestosterone levels in prostatic tissue and serum were analyzed using liquid chromatography/electrospray ionization-mass spectrometry after polar derivatization. RESULTS: A total of 47 patients were diagnosed with stages T1 to T3N0M0 prostate cancer and 34 were diagnosed with no malignancy. Of the 47 patients 32 had a Gleason score of 6 or less and 15 had a score of 7 to 10. Dihydrotestosterone in prostatic tissue in patients with Gleason score 7 to 10 disease was significantly lower than in those with Gleason score 6 or less disease (p = 0.025). Gleason score correlated with the testosterone-to-serum dihydrotestosterone ratio (rs = 0.329, p = 0.038). CONCLUSIONS: Patients with Gleason score 7 to 10 prostate cancer have low dihydrotestosterone in the prostate, although there were no significant differences between patients with Gleason score 7 to 10 vs 6 or less prostate cancer with respect to serum androgens. Low dihydrotestosterone in cases of aggressive prostate cancer is probably sufficient to activate androgen receptor expression and propagate tumor growth.

Aged↗

PubMed1989

Dihydrotestosterone regulates plasma sex-hormone-binding globulin in prepubertal males.

Plasma levels of sex-hormone-binding globulin (SHBG) in man are known to be regulated up and down by oestradiol and testosterone, respectively. To determine whether testosterone reduces SHBG level directly or via its conversion into dihydrotestosterone before puberty, the changes of plasma SHBG, testosterone, oestradiol and dihydrotestosterone following human chorionic gonadotrophin stimulation are studied in ten 5 alpha-reductase-deficient and in six normal prepubertal boys. Three main observations provide evidence that dihydrotestosterone plays a major role in SHBG regulation. (1) Basal plasma SHBG in 5 alpha-reductase-deficient is higher than in normal boys (P less than 0.1). (2) Circulating SHBG fails to decrease (P greater than 0.1) after human chorionic gonadotrophin stimulation despite striking elevation of plasma testosterone in 5 alpha-reductase deficiency where negligible dihydrotestosterone response occurs. This is in contrast to normal boys where SHBG is significantly reduced (P less than 0.01) after stimulation. (3). In normal boys the magnitude of plasma dihydrotestosterone response to human chorionic gonadotrophin correlates with that of SHBG (r = 0.72) more than testosterone does versus SHBG (r = 0.36). It is concluded that dihydrotestosterone decreases SHBG concentration in plasma of prepubertal boys. At least part of the observed decrease in SHBG following testosterone administration in earlier reports must have occurred after its conversion to dihydrotestosterone.

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

PubMed1976

Dihydrotestosterone binding by cultured human fibroblasts. Comparison of cells from control subjects and from patients with hereditary male pseudohermaphroditism due to androgen resistance.

Dihydrotestosterone binding was measured in culture fibroblasts from 14 control subjects and from 12 patients with five different types of hereditary male pseudohermaphroditism. Two assays of binding were used--an intact monolayer assay and density gradient centrifugation of cell extracts. In the intact monolayer assay of normal cells the uptake of [3H]dihydrotestosterone consisted of two components. The first was a high affinity component that exhibited saturation at approximately 1 nM dihydrotestosterone. The second was a low affinity component that was not saturable with concentrations of steroid up to 5 nM. Twice the number of high affinity binding sites were present in fibroblasts grown from genital skin (foreskin, labia majora, and scrotum) as from nongenital sites (37 vs. 14 fmol/mg protein). In the density gradient assay in 5-10% sucrose, the major peak of dihydrotestosterone binding was in the 8S region in low molarity buffer and in the 4S region in 0.5 M KCl. High affinity binding was normal in cells from two patients with familial incomplete male pseudohermaphroditism, type 2, an autosomal recessive defect in which dihydrotestosterone formation is deficient, and in cells from a patient with male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency, an autosomal recessive defect of testosterone synthesis. High affinity binding was low by both methods in fibroblasts from five patients with complete testicular feminization. Furthermore, binding by both methods was also low in cells from three subjects with familial incomplete male pseudohermaphroditism, type 1, a presumed X-linked recessive disorder of androgen resistance, and in fibroblasts grown from a subject with the incomplete form of testicular feminization. The finding that dihydrotestosterone binding is abnormal in two forms of hereditary androgen resistance in addition to complete testicular feminization suggests either that these disorders are the result of allelic mutations affecting the function of the androgen-binding protein or that normal dihydrotestosterone binding requires the participation of more than one gene product.

Binding Sites↗

PubMed1975

Direct evidence on incorporation of the receptor into the nuclei of rat ventral prostate in the form of the complex with dihydrotestosterone.

Cytosol 9S receptor was prepared from the supernatant fluid at 105,000 X g of rat prostate homogenates by a Sephadex G-100 gel chromatography, and was labeled with 131I. The 131I-labeled 9S receptor retained the activity of forming a complex with 3H-dihydrotestosterone, similarly to the intact cytosol receptor, when examined by a sucrose density gradient centrifugation. When the 131I-labeled cytosol 9S receptor was incubated with isolated prostatic nuclei in the presence of 3H-dihydrotestosterone, it was found that the 131I-labeled receptor was directly incorporated into the nuclei in a form of the complex bound to 3H-dihydrotestosterone. 131I-Labeled receptor-3H-dihydrotestosterone complex which was incorporated into the nuclei was extracted with 0.5 M KCl solution, and the nuclear complex sedimented with a velocity of 5S. The incorporation of 131I-labeled receptor-3H-dihydrotestosterone complex into the nuclei increased along with the raised temperature of incubation, whereas association of the complex with the chromatin reached maximum at 35 degrees C and then decreased gradually beyond this temperature. In the time course study, either the incorporation of the complex into the nuclei or the association with the chromatin reached the maximal levels within 10 min and leveled off up to 60 min. On the other hand, 131I-labeled serum protein was far less efficiently incorporated into the nuclei than the radioiodinated 9S receptor, and association of the serum protein with the chromatin was limited to a very little extent. The 131I-labeled 9S receptor-dihydrotestosterone complex associated with the chromatin was found to be preferably distributed into the non-histone protein as well as the DNA itself of the chromatin. The radioactivity lost by dehistonization of the chromatin was almost negligible. Furthermore, the cytosol 9S receptor fraction bound to 3H-dihydrotestosterone was purified about 100 fold by the two consecutive column chromatographies. The partially purified receptor fraction which was labeled with radioiodine incorporated mostly into non-histone protein and DNA fractions.

Animals↗

PubMed1976

Effect of prolactin, growth hormone and insulin on the uptake and binding of dihydrotestosterone to the cultured rat ventral prostate.

The effects of prolactin, growth hormone and insulin on the total uptake and specific binding of tritiated dihydrotestosterone in the cultured rat ventral prostate were examined. In similiar conditions prolactin and insulin act synergistically with testosterone on the macromolecule synthesis of the prostate, but have no effect on the conversion of testosterone to dihydrotestosterone. The total uptake of tritiated dihydrotestosterone to the tissues was slightly, but not statistically significantly, increased by prolactin, insulin and growth hormone. The majority of the radioactive dihydrotestosterone in the tissue was in free form or very loosely bound. None of these three hormones altered the binding of tritiated dihydrostestosterone to the cytoplasmic receptors. Non-radioactive dihydrotestosterone, cyproterone and cyproterone acetate in 1000 fold excess strongly decreased the binding of tritiated dihydrotestosterone to the cytoplasmic reseptors and to the nuclei. That part of the binding, which was inhibited by the hormones was considered to represent the specific binding to the receptors. Insulin stimulated both the specific and the unspecific uptake of dihydrostestosterone to the nuclei. Prolactin only stimulated the specific uptake to the nuclei while growth hormone had no effect. Autoradiography of the nuclear fraction indicated a firm binding of tritiated dihydrotestosterone to the nuclei. The radioactivity of the other contaminating cell components in this fraction appeared to be negligible.

Animals↗

PubMed1980

[A study of the effect of dihydrotestosterone on cultured human fibroblasts--with special reference to the hormone effect on the synthesis of proteins, collagen and DNA in fibroblasts (author's transl)].

Fibroblasts grown from abdominal and vulvar skin from normal women were tested for their dihydrotestosterone binding activity. Fibroblasts from either source had 8S cytoplasmic dihydrotestosterone receptors as confirmed by sucrose gradient analysis and the concentration of dihydrotestosterone binding sites and the apparent dissociation constant were 21.6 +/- 1.1 fmoles/mg protein and 0.50 +/- 0.028 nM, respectively, for fibroblasts from abdominal skin and 35.9 +/- 1.7 fmoles/mg protein and 0.24 +/- 0.015 nM, respectively, for fibroblasts from vulvar skin. The dihydrotestosterone binding activity was greater in fibroblasts from vulvar skin than from abdominal skin (P less than 0.01). Fibroblasts formed dense monolayers were treated with various concentrations of dihydrotestosterone (10, 100, 1,000 ng/ml) for six days and were assessed for hormone effect. The production of proteins was elevated in fibroblasts from either source with a slightly greater hormonal response occurring in fibroblasts from vulvar skin than from abdominal skin. Collagen production was elevated significantly in fibroblasts from vulvar skin but only marginally in fibroblasts from abdominal skin. The synthesis of DNA was not affected in fibroblasts from either source. These results than response to dihydrotestosterone was greater in fibroblasts with a higher hormone binding activity may reflect the hormone effect being mediated through dihydrotestosterone receptors.

Cells, Cultured↗

PubMed2002

Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia.

The development of human benign prostatic hyperplasia (BPH) clearly requires a combination of testicular androgens and the ageing process. Although the role of androgens as the causative factor for human benign prostatic hyperplasia is debated, they undoubtedly play, at least, a permissive role. The principal prostatic androgen is dihydrotestosterone. Although not elevated in human benign prostatic hyperplasia, dihydrotestosterone levels in the prostate remain at a normal level with ageing, despite a decrease in the plasma testosterone. Dihydrotestosterone (DHT) is generated by a reduction in testosterone. Two isoenzymes of 5alpha-reductase have been discovered. Type 1 is present in most tissues in the body where 5alpha-reductase is expressed, and is the dominant form in sebaceous glands. Type 2 5alpha-reductase is the dominant isoenzyme in genital tissues, including the prostate. Finasteride is a 5alpha-reductase inhibitor that has been used to treat BPH and male-pattern baldness. At doses used clinically, its major effect is to suppress type 2 5alpha-reductase, because it has a much lower affinity for the type 1 isoenzyme. Finasteride suppresses DHT by about 70% in serum and by as much as 85%-90% in the prostate. The remaining DHT in the prostate is likely to be the result of type 1 5alpha-reductase. The suppression of both 5alpha-reductase isoenzymes with GI198745 results in greater and more consistent containment of serum dihydrotestosterone than that observed with a selective inhibitor of type 2 5alpha-reductase. Physiological and clinical studies comparing dual 5alpha-reductase inhibitors, such as GI198745, with selective type 2, such as finasteride, will be needed to determine the clinical relevance of type 1 5alpha-reductase within the prostate. There have been two large, international multicentre, phase III trials published documenting the safety and efficacy of finasteride in treating human benign prostatic hyperplasia. Combining these two studies, randomised, controlled data are available for 12 months. Non-controlled extension of these data from a subset of patients, who elected to continue on the drug for 3, 4 and 5 years, are also available. Long-term medical therapy with finasteride can reduce clinically significant endpoints, such as acute urinary retention or surgery. According to the meta-analysis of six randomised, clinical trials with finasteride, finasteride is most effective in men with large prostates. A more effective dual inhibitor of type 1 and 2 human 5alpha-reductase may lower circulating dihydrotestosterone to a greater extent than finasteride and show advantages in treating human benign prostatic hyperplasia and other disease states that depend on dihydrotestosterone. A clinical evaluation of potent dual 5alpha-reductase inhibitors may help to define the relative roles of human type 1 and 2 5alpha-reductase in the pathophysiology of benign prostatic hyperplasia and other androgen-dependent diseases.

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

PubMed1989

Activation of sexual behavior in male rats by combined subcutaneous and intracranial treatments of 5 alpha-dihydrotestosterone.

When given peripherally, 5 alpha-dihydrotestosterone, the major androgenic metabolite of testosterone, is relatively less effective than testosterone in activating sexual behavior of castrated male rats. In order to test the possible central nervous system effects of dihydrotestosterone more directly, we castrated Long-Evans rats, gave them a behaviorally subthreshold dose of dihydrotestosterone placed subcutaneously in Silastic capsules (ScDHT), and then additionally treated the rats with intracranial implants of crystalline dihydrotestosterone (IcDHT, N = 12), testosterone (IcT, N = 12), or cholesterol (IcCHOL, N = 10) placed in the medial preoptic area. The peripheral ScDHT treatment maintained sexual organ weights of castrated males at levels comparable to those of intact males, but did not in itself significantly activate mating behavior. The addition of IcT or IcDHT to this treatment regimen significantly increased the number of males displaying mounting behavior, intromissions, and ejaculatory behavior (P less than 0.05) compared to males with IcCHOL implants. There were no significant differences between the group given IcT and the group given IcDHT. Results of this study support the hypothesis that the nonaromatizable androgen 5 alpha-dihydrotestosterone can act in the rat brain to influence male sexual behavior. In addition, these data lead us to suggest that the relative ineffectiveness of dihydrotestosterone versus testosterone when given systemically may reflect differences in bioavailability of these hormones to the brain following such treatment.

Animals↗

PubMed1983

Characteristics of the cytoplasmic and nuclear dihydrotestosterone receptors of human thymic tissue.

Dihydrotestosterone receptor was prepared from both the cytoplasm and nucleus of human thymic tissue. Human cytoplasmic and nuclear dihydrotestosterone receptor possessed a KA greater than 1.0 and by competition assay was highly specific for dihydrotestosterone. Human thymic cytoplasmic dihydrotestosterone receptor prepared in standard buffer sedimented on 5-20% sucrose gradients in the 4s region but human thymic cytoplasmic dihydrotestosterone receptor prepared in buffer containing sodium molybdate (10 mM) sedimented in the 7s region on 5-20% sucrose gradients. It is concluded that the human thymic dihydrotestosterone receptor is similar to classic androgen receptor.

Adolescent↗

PubMed1991

Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5 alpha-reductase.

Dihydrotestosterone, the primary mediator of prostate growth, is synthesized in target tissues from the circulating androgen testosterone through the action of steroid 5 alpha-reductase (EC 1.3.99.5). The expression of 5 alpha-reductase and the level of 5 alpha-reductase messenger RNA in rat ventral prostate are regulated by androgens. To determine whether this control is mediated by dihydrotestosterone or testosterone, we investigated the effect of finasteride, a potent inhibitor of steroid 5 alpha-reductase, on the expression of 5 alpha-reductase in the prostate. The administration of finasteride to intact rats for 7 days caused a 55% decrease in prostate weight and an 87% decrease in 5 alpha-reductase enzyme activity. Furthermore, the restoration of prostate growth after castration and the enhancement in 5 alpha-reductase enzyme activity and 5 alpha-reductase messenger RNA level by testosterone administration were blocked by finasteride, whereas the inhibitor had no effect on dihydrotestosterone-mediated increases in 5 alpha-reductase activity or messenger RNA level. These findings indicate that dihydrotestosterone itself controls prostate growth and 5 alpha-reductase activity. They further suggest that prostate growth is controlled by a feed-forward mechanism by which formation of trace amounts of dihydrotestosterone induces 5 alpha-reductase, thereby increasing dihydrotestosterone synthesis and triggering a positive developmental cascade.

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

PubMed1983

Plasma and salivary androstenedione and dihydrotestosterone in women with hyperandrogenism.

Sensitive radioimmunoassays (RIA) have been developed to measure salivary and plasma androstenedione and dihydrotestosterone levels in normal women, women with polycystic ovaries (PCO) and idiopathic hirsutism, and patients on antiandrogen therapy. There was a highly significant correlation (r = 0.92, P less than 0.001) between the concentration of androstenedione in saliva and the unbound concentration in plasma. The unbound plasma androstenedione was measured in the dialysate by RIA and ranged from 6.0-10.4% of the total concentration. Salivary and plasma androstenedione levels in patients with PCO (185 +/- 72 pg/ml (n = 11) and 3262 +/- 814 pg/ml (n = 12) respectively) and in those with hirsutism (151 +/- 110 pg/ml (n = 25) and 2177 +/- 1096 pg/ml (n = 25) were significantly higher than levels in normal women (78 +/- 30 pg/ml (n = 18) and 787 +/- 355 pg/ml (n = 18). A good correlation (r = 0.82, P less than 0.001) was also found between salivary and unbound plasma dihydrotestosterone concentrations. Salivary and plasma dihydrotestosterone levels in patients with PCO (8.2 +/- 3.3 pg/ml (n = 9) and 167 +/- 45 pg/ml (n = 11) respectively and hirsutism (6.0 +/- 2.1 pg/ml (n = 14) and 176 +/- 69 pg/ml (n = 17) were significantly higher than levels in normal women (4.5 +/- 1.3 pg/ml (n = 17) and 90 +/- 44 pg/ml (n = 16), although there was a large overlap between groups. A similar decrease was observed in salivary and plasma androstenedione levels after treatment with cyproterone acetate (CA) and ethinyl oestradiol (EE) for 3 months. Plasma dihydrotestosterone levels remained elevated in 47% of treated women whereas only 21% of cases had raised salivary dihydrotestosterone levels. It is concluded that, as with testosterone salivary androstenedione and dihydrotestosterone measurements give a good reflection of their biologically active levels in normal, hyperandrogenic and CA + EE treated women.

Adolescent↗

PubMed2005

Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer.

PURPOSE: Prostate cancer eventually recurs during androgen deprivation therapy despite castrate levels of serum androgens. Expression of androgen receptor and androgen receptor-regulated proteins suggests androgen receptor activation in recurrent prostate cancer. Many groups have pursued mechanisms of ligand-independent androgen receptor activation but we found high levels of testicular androgens in recurrent prostate cancer tissue using RIA. EXPERIMENTAL DESIGNS: Prostate specimens from 36 men were procured preserving blood flow to prevent ischemia and cyropreserved immediately. Recurrent prostate cancer specimens from 18 men whose cancer recurred locally during androgen deprivation therapy and androgen-stimulated benign prostate specimens from 18 men receiving no hormonal treatments were studied. Tissue levels of testosterone and dihydrotestosterone were measured in each specimen using liquid chromatography/electrospray tandem mass spectrometry. Testosterone and dihydrotestosterone levels were compared with clinical variables and treatment received. RESULTS: Testosterone levels were similar in recurrent prostate cancer (3.75 pmol/g tissue) and androgen-stimulated benign prostate (2.75 pmol/g tissue, Wilcoxon two-sided, P=0.30). Dihydrotestosterone levels decreased 91% in recurrent prostate cancer (1.25 pmol/g tissue) compared with androgen-stimulated benign prostate (13.7 pmol/g tissue; Wilcoxon two-sided, P < 0.0001) although dihydrotestosterone levels in most specimens of recurrent prostate cancer were sufficient for androgen receptor activation. Testosterone or dihydrotestosterone levels were not related to metastatic status, antiandrogen treatment, or survival (Wilcoxon rank sum, all P > 0.2). CONCLUSIONS: Recurrent prostate cancer may develop the capacity to biosynthesize testicular androgens from adrenal androgens or cholesterol. This surprising finding suggests intracrine production of dihydrotestosterone and should be exploited for novel treatment of recurrent prostate cancer.

Aged↗

PubMed1976

Effect of some synandrogens and antiandrogens on the conversion of testosterone to dihydrotestosterone in the cultured rat ventral prostate.

The actions of prolactin, insulin and cortisol on the conversion of testosterone to dihydrotestosterone in the cultured rat ventral prostate were examined in conditions in thich they have been demonstrated to act synergistically with testosterone on the macromolecule synthesis of the prostate. On the other hand oestradiol, progesterone and cyproterone were tested similarly in conditions where they have been shown to be effective antiandrogens. The metabolism of testosterone to dihydrotestosterone was found to be extremely rapid and approximately 70% of the radioactive steroids in the tissue was dihydrotestosterone from 5 min onwards, but only insignificant amounts of dihydrotestosterone were found in the culture medium during the first hour. Physiological concentrations of the synandrogens did not alter the metabolism of testosterone or the accumulation of the steroids into the tissue. Oestradiol, progesterone and unlabelled testosterone in a 500-fold concentration markedly reduced th e conversion of tritiated testosterone to dihydrotestosterone while cyproterone and dihydrotestosterone had no effect. The possible role of other hormones in the alteration of testosterone metabolism in the target organs as the mechanism of synandrogenic or antiandrogenic action is discussed.

Animals↗

PubMed1975

The influence of serum on the uptake, conversion and action of dihydrotestosterone in rat prostate glands in organ culture.

The influence of serum on the uptake, conversion and action of dihydrotestosterone in relation to the sex steroid binding protein, TeBG, has been investigated in rat ventral prostates in organ culture. The organs were incubated with (1,2-3H)dihydrotestosterone in: (1) serum-free medium, (2) horse serum, foetal and newborn bovine serum of (3) human male and human pregnancy serum. With all sera the uptake of dihydrotestosterone fell with rising serum concentration, at first steeply and then more gradually. At the same concentration, the uptake was significantly lower in explants incubated with human pregnancy serum than in those kept with human male serum. The conversion of dihydrotestosterone to androstanediol followed the same pattern and less androstanediol was formed in the presence of pregnancy serum. Since pregnancy serum contains higher amounts of TeBG than male serum, the lowered uptake suggests that only the free hormone was available to the target organ. Addition of unlabelled dihydrotestosterone resulted in a higher uptake than that measured in explants incubated with the labelled steroid only. The effect of the human sera on uptake and conversion was correlated with the androgenic activity of dihydrotestosterone applied at physiological concentrations and expressed as the percentage of secretory columnar cells present. The degree of maintainance closely corresponded to the uptake of the hormone. In serum-free medium, the number of columnar cells approached the values found in vivo, with male serum their number, though reduced, was still substantial, with pregnancy serum it was extremely low. It is concluded that the amounts of TeBG present in serum regulate the supply of the hormone to the target tissue and thus control its biological action.

Androstanes↗

PubMed1975

Distribution of testosterone and 5alpha-dihydrotestosterone in rat epididymis and their concentrations in efferent duct fluid.

5alpha-Dihydrotestosterone concentrations were found to be appreciably higher in the proximal portion of the rat epididymis than in the distal portion. Following ligation of the efferent ducts of a testis, the 5alpha-dihydrotestosterone concentration diminished in the proximal half but not in the distal half of the epididymis. Epididymal fluid and spermatozoa were washed out from minces of epididymal tissue. The numbers of spermatozoa present in the wash fluid and in the homogenate of washed minces of epididymal tissue were used as measures for the amounts of epididymal fluid present in these fractions. Of the total amount of 5alpha-dihydrotestosterone (30-2 ng/g tissue) in the proximal portion, 20-5 ng were localized in the epididymal fluid, whereas of the total amount of 5alpha-dihydrotestosterone (8-6 ng/g tissue) in the distal portion, 2-8 ng were found in the epididymal fluid. The amounts of testosterone present in the fluids of both proximal and distal portions were 1-2 ng/g tissue. In contrast to the epididymal fluid, efferent duct fluid had a high concentration of testosterone (28-8 ng/ml) and a low concentration of 5alpha-dihydrotestosterone (1-9 ng/ml). These data suggest that the fluid surrounding the spermatozoa in the testis and the epididymis contains a high concentration of androgen and that as the fluid moves from the testis to the epididymis there is a clear change in the ratio of testosterone to 5alpha-dihydrotestosterone.

Animals↗

PubMed1975

Dihydrotestosterone formation in cultured human fibroblasts. Comparison of cells from normal subjects and patients with familial incomplete male pseudohermaphroditism, Type 2.

The conversion of [1,2-3H]testosterone to [3H]dihydrotestosterone has been assessed in fibroblast monolayers grown from skin biopsies of foreskin, scrotum, and various nongential skins from 31 control men who varied in age from newborn to 25 years and three 46,XY subjects with hereditary male pseudohermaphroditism. Under the standardized conditions utilized in this study, the rate of dihydrotestosterone formation was greater in fibroblasts grown from genital skin (foreskin and scrotum) passages exhibit the same differentiation in dihydrotestosterone formation as the skin from which the fibroblasts were grown. Furthermore, 5alpha-reductase, the enzyme that converts testosterone to dihydrotestosterone, exhibits apparent similar substrate specificity in control foreskin fibroblasts and in the foreskin itself. Fibroblasts grown from the foreskin of two patients with familial incomplete male pseudohermaphroditism, type 2, an autosomal recessive disorder of phenotypic sexual differentiation, showed a marked deficiency in the capacity to form dihydrotestosterone. In contrast, fibroblasts grown from the scrotum of one 46,XY male with familial incomplete male pseudohermaphroditism, type 1, an apparent X-linked disorder of phenotypic sexual differentiation, formed dihydrotestosterone at a normal rate.

Adolescent↗

PubMed1985

Correlation of androgen-responsiveness of Shionogi mouse mammary carcinoma cell lines with binding of dihydrotestosterone to nuclear envelopes.

Purified nuclear envelopes have been isolated from an androgen-responsive and two androgen-unresponsive cell lines of the Shionogi mouse mammary carcinoma. The binding of dihydrotestosterone to nuclear envelope fractions isolated from the three variant cell lines is correlated with the androgen-responsiveness of the cell line. Nuclear envelopes prepared from the two androgen-unresponsive cell lines did not bind dihydrotestosterone specifically following incubation with radioactive dihydrotestosterone from 2.5 to 45.0 nM at 20 degrees C for 18 h. Under the same binding conditions, nuclear envelopes prepared from the androgen-responsive cell line demonstrated saturable, specific binding of dihydrotestosterone. Scatchard analysis revealed a class of binding sites with an apparent Kd of 14.2 nM and a maximum binding capacity of 28.7 fmol/mg protein. Proteinase and heat treatments resulted in the complete loss of androgen-binding activity, whereas DNAase treatment resulted in the loss of 38% of the binding activity. The binding sites were specific for dihydrotestosterone. Testosterone was only a weak competitor and estradiol did not compete. Extraction with concentrations of KCl up to 1.0 M did not result in loss of androgen binding.

Animals↗

PubMed1985

Dihydrotestosterone inhibits fibroblast-pneumonocyte factor-mediated synthesis of saturated phosphatidylcholine by fetal rat lung cells.

Dihydrotestosterone has previously been found to inhibit pulmonary surfactant production in vivo. In the present study, we have investigated the effects of this androgen on the fetal lung fibroblast and type II cell in culture. Addition of 1 X 10(-8) M cortisol to organotype cultures stimulates the synthesis of radiolabelled saturated phosphatidylcholine; however, preincubation of such cultures with 1 X 10(-8) M dihydrotestosterone completely blocks cortisol stimulation of saturated phosphatidylcholine synthesis without affecting basal activity. Cortisol treatment of fetal lung fibroblasts stimulates the production of fibroblast-pneumonocyte factor; pre-treatment with dihydrotestosterone blocks this stimulation. Fibroblast-pneumonocyte factor stimulates the synthesis of saturated phosphatidylcholine by type II pneumonocytes; this effect is also blocked by dihydrotestosterone pre-treatment. I conclude that dihydrotestosterone blocks cortisol-inducible saturated phosphatidylcholine synthesis by inhibiting the production and activity of fibroblast-pneumonocyte factor in vitro.

Animals↗