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PubMed1988

Effects of corticosterone on the negative feedback action of testosterone, 5 alpha-dihydrotestosterone and estradiol in the adult male rat.

Corticosterone acetate (10 mg/day) was administered to gonadectomized and adrenalectomized male rats bearing 5, 10 or 15 mm long testosterone filled silicone elastomer capsules. It was found that the serum testosterone levels induced by these capsules were not influenced by corticosterone treatment and that the weights of the prostates in the corticosterone treated rats were not different from their controls. In contrast, corticosterone acetate increased markedly the LH and FSH inhibitory effects of testosterone. Since several brain structures are able to convert testosterone into 17-beta-hydroxy-5-alpha-androstan-3-one (5-alpha-dihydrotestosterone) and/or estradiol, and these metabolites are probably involved in mechanisms controlling gonadotropin secretion, we studied also the effects of corticosterone on the feedback action of dihydrotestosterone and estradiol. 5 alpha-Dihydrotestosterone was administered by 5, 10 or 20 mm long elastomere capsules whereas estradiol was given by daily s.c. injections of 0.125, 0.25 or 0.50 micrograms estradiol benzoate. In the presence of corticosterone acetate the gonadotropin inhibitory action of testosterone, 5 alpha-dihydrotestosterone and estradiol increased more than 2 times.

Adrenalectomy↗
PubMed1985

Effects of neonatal castration or treatment with dihydrotestosterone on numbers of neurons in the rat superior cervical sympathetic ganglion.

There is a normal sexual dimorphism in the number of neurons in the rat superior cervical sympathetic ganglion (SCG), with adult males having more neurons in this ganglion than females. We confirm this finding here, report that this sex difference is not present at birth and that neonatal castration of males reduces the adult sex difference. These results indicate that perinatal levels of circulating testicular hormones play a role in regulating the numbers of neurons in the SCG. Treatment of neonatal rats with testosterone propionate or estradiol significantly increases the number of neurons in the SCG. To determine whether this effect is primary androgenic or estrogenic, the effects of dihydrotestosterone, on SCG neuron number were investigated. Dihydrotestosterone, unlike testosterone, is not aromatized to estradiol intracellularly. There was no difference in the number of neurons between animals injected from birth with vehicle or dihydrotestosterone. This difference in effects between dihydrotestosterone and testosterone suggests that the actions of testosterone may be via aromatization to estradiol, rather than action at an androgen receptor.

Animals↗
PubMed1981

Small doses of 5 alpha-dihydrotestosterone mimic the effects of 5 alpha-androstane-3 beta, 17 beta-diol on acid phosphatase activity in the adult rat prostate gland.

These studies were designed to further investigate whether 5 alpha-androstane-3 beta, 17 beta-diol was exerting unique effects on rat prostate acid phosphatase activity or could possibly be exerting its actions by a small peripheral conversion to 5 alpha-dihydrotestosterone. Intraperitoneal administration of 5 alpha-dihydrotestosterone in doses of 1 mg, 100 microgram or 50 microgram per day starting 7 days after castration led to the restoration of normal characteristics of acid phosphatase activity. However, when 5 alpha-dihydrotestosterone was given in a dose of only 25 microgram per day starting 7 days after castration, the changes in acid phosphatase activity were indistinguishable from those found when 5 alpha-androstane-3 beta, 17 beta-diol was administered in a dose of 2 mg per day. This suggests that the effects of 5 alpha-androstane-3 beta, 17 beta-diol can be explained by its conversion to small amounts of 5 alpha-dihydrotestosterone.

Acid Phosphatase↗
PubMed1980

Testosterone-sensitive neurones respond to oestradiol but not to dihydrotestosterone.

Testosterone is aromatized to oestradiol in the brain, and it has been suggested that its effects on the brain are produced by this metabolite. Oestradiol does indeed restore sexual behaviour in castrated rats, but is is much more effective if combined with a second metabolite, dihydrotestosterone. This may be because the two hormones have a synergistic effect on the brain; or because the central effect of oestradiol synergises with the peripheral effects of dihydrotestosterone (which include stimulation of penile development). Evidence that the corticomedial amygdala (CMA) and the preoptic area of the rat brain are both involved in the control of sexual behaviour led us to examine the neurones of the stria terminalis that connect the two. These neurones are hormone-sensitive; their absolute refractory period is lengthened by castration and reduced again by testosterone. So we have investigated the aromatization hypothesis further by examining the effect of oestradiol and dihydrotestosterone on these testosterone-sensitive neurones. Oestradiol has exactly the same effect as testosterone; dihydrotestosterone has no effect, whether it is given alone or in combination with oestradiol.

Amygdala↗
PubMed1989

The in vitro conversion of 3H androstenedione to testosterone and dihydrotestosterone in the adrenal gland of castrated male rat: influence of gonadal steroid administration.

In the present study we considered the effects of bilateral orchiectomy on the metabolism of androstenedione in the adrenal gland of the adult male rat. Adrenal glands of intact animals incubated in the presence of 3H androstenedione resulted in its conversion to testosterone and dihydrotestosterone (the two principal metabolites investigated). The value of the latter metabolite increased with the elapsing of time from castration despite the decrease of testosterone with respect to that observed in the sham operated rats of the same age. This effect is reversed in the presence of testosterone treatment with androstenedione and testosterone levels similar to those obtained in intact animals. Androstenedione adrenal metabolism is greatly lowered following the administration of dihydrotestosterone propionate, resulting in high substrate residue values with respect to untreated castrated rats. Contemporarily, testosterone metabolite value remains unchanged while the production of dihydrotestosterone is significantly lower. Finally a decrease of DHT was also encountered in the presence of estradiol benzoate. The above results clearly point to a progressive activation of the 5 alpha-reductase of the adrenal gland after castration utilizing androstenedione as substrate. The metabolic pathway leading to the production of dihydrotestosterone from androstenedione appears to be modulated differently following the administration of gonadal steroids.

Adrenal Glands↗
PubMed1987

Adult sheep blood metabolizes dihydrotestosterone to 5 alpha-androstane-3 alpha, 17 beta-diol and 5 alpha-androstane-3 beta, 17 beta-diol.

The metabolism of 5 alpha-dihydrotestosterone by adult sheep blood was investigated. Erythrocytes contain 3 alpha- and 3 beta-hydroxysteroid dehydrogenase activities. The mean rate of reduction of 5 alpha-dihydrotestosterone by erythrocytes established in 15-min incubations was 0.66 +/- 0.36 (s.d.) mumol ml-1 erythrocytes h-1 and at equilibrium after a 60-min incubation, 90.6 +/- 5.1% of the substrate was reduced. The reduction of 5 alpha-dihydrotestosterone was shown to be dependent upon extracellular glucose and the intracellular cofactor NADPH. The proportion of the two reduction products was determined at equilibrium after separation by paper partition, chromatography and favoured 5 alpha-androstane-3 alpha, 17 beta-diol (96.0%) to 5 alpha-androstane-3 beta, 17 beta-diol (4.0%). The identities and proportions of the two products were confirmed by recrystallization procedures. The fact that erythrocytes can significantly metabolize the androgen 5 alpha-dihydrotestosterone is evidence for the recognition of blood as a major component of steroid endocrine homeostasis in sheep.

Androstane-3,17-diol↗
PubMed1996

Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter.

Androgens repress expression of many genes, yet the mechanism of this activity has remained elusive. The cytokine, interleukin-6, is active in a variety of biological systems, and its expression is repressed by androgens. Accordingly we dissected the mechanism of androgen's ability to inhibit interleukin-6 expression at the molecular level. In a series of co-transfection assays, we found that 5alpha-dihydrotestosterone, through the androgen receptor, repressed activation of the interleukin-6 promoter, in part, by inhibiting NFkappaB activity. It did not appear that 5alpha-dihydrotestosterone inhibited NFkappaB by activating the androgen receptor to compete for the NFkappaB response element as we could not detect androgen receptor binding to the IL-6 promoter by DNase I footprinting assay. However, by electrophoretic mobility shift assay we found that 5alpha-dihydrotestosterone repressed formation of NFkappaB middle dotNFkappaB response element complex formation. In LNCaP prostate carcinoma cells, 5alpha-dihydrotestosterone achieved this effect through maintenance of IkappaBalpha protein levels in the face of phorbol ester, a stimulus that results in IkappaBalpha degradation. Finally, we confirmed that IkappaBalpha inhibits NFkappaB-mediated activation of the interleukin-6 promoter. These data suggest that maintenance of IkappaBalpha levels may represent the first identified mechanism for androgen-mediated repression of a natural androgen-regulated gene.

Cell Line↗
PubMed1985

Effects of intermittent pulsatile infusion of luteinizing hormone-releasing hormone on dihydrotestosterone-suppressed gonadotropin secretion in castrate rams.

The feedback effects of dihydrotestosterone (DHT) on gonadotropin secretion in rams were investigated using DHT-implanted castrate rams (wethers) infused with intermittent pulsatile luteinizing hormone-releasing hormone (LHRH) for 14 days. Castration, as anticipated, reduced both serum testosterone and DHT but elevated serum LH and follicle-stimulating hormone (FSH). Dihydrotestosterone implants raised serum DHT in wethers to intact ram levels and blocked the LH and FSH response to castration. The secretory profile of these individuals failed to show an endogenous LH pulse during any of the scheduled blood sampling periods, but a small LH pulse was observed following a 5-ng/kg LHRH challenge injection. Dihydrotestosterone-implanted wethers given repeated LHRH injections beginning at the time of castration increased serum FSH and yielded LH pulses that were temporally coupled to exogenous LHRH administration. While the frequency of these secretory episodes was comparable to that observed for castrates, amplitudes of the induced LH pulses were blunted relative to those observed for similarly infused, testosterone-implanted castrates. Dihydrotestosterone was also shown to inhibit LH and FSH secretion and serum testosterone concentrations in intact rams. In summary, it appears that DHT may normally participate in feedback regulation of LH and FSH secretion in rams. These data suggest androgen feedback is regulated by deceleration of the hypothalamic LHRH pulse generator and direct actions at the level of the adenohypophysis.

Animals↗
PubMed1990

Structure of 5 beta-dihydrotestosterone.

17 beta-Hydroxy-5 beta-androstan-3-one, C19H30O2, Mr = 290.45, orthorhombic, P2(1)2(1)2(1), a = 11.7821 (6), b = 21.2184 (8), c = 6.5322 (2) A, V = 1633.0 (2) A3, Z = 4, D chi = 1.181 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.58 mm-1, F(000) = 640, T = 293 K, R = 0.033 for 1849 unique observed reflections. The molecular conformation of 5 beta-dihydrotestosterone shows the strong bending typical of 5 beta-steroids: the bowing angle of the A ring, relative to the remainder of the steroid, is 65.1 degrees. Bowing shortens the distance between the terminal O atoms, O(3) and O(17), to 9.824 (2) A which is ca 1 A shorter than was observed in 5 alpha-dihydrotestosterone and testosterone. The effects of both the bowing and the shorter separation between O(3) and O(17) may explain a difference in the affinity of 5 beta-dihydrotestosterone for the dexamethasone binding site on membranes compared to that of the other two compounds. A unique conformational feature of 5 beta-dihydrotestosterone is the flattening of the A ring on the side containing the C(3)--C(4) bond; this may be due to the combination of the 3-oxo substitution and the 5 beta-configuration.

Chemical Phenomena↗
PubMed1980

Total and SHBG-bound testosterone and 5 alpha-dihydrotestosterone serum concentrations in normal elderly men and patients with benign prostatic hypertrophy before and after removal of the adenoma.

Serum testosterone, 5 alpha-dihydrotestosterone and their binding by sex hormone binding globulin (SHBG) were quantified in 10 patients with prostatic hypertrophy, before and after retropubic prostatectomy, and in an age-matched control group. Testosterone was significantly higher in the sera of the BPH patients. The SHBG-bound testosterone and 5 alpha-dihydrotestosterone were identical in both groups, but the fraction of testosterone and 5 alpha-dihydrotestosterone not bound to SHBG was higher in the group with BPH. Therefore patients with prostatic hypertrophy are exposed to increased androgen action. Prostatectomy did not lead to significant changes in serum testosterone, 5 alpha-dihydrotestosterone or their binding to SHBG.

Aged↗
PubMed1975

Inhibition of anterior pituitary estrogen-receptor complex formation by low-affinity interaction with 5 alpha-dihydrotestosterone.

A possible role for 5alpha-dihydrotestosterone in the anterior pituitary of the rat has been investigated by determining the influence of this androgen upon the binding 17beta-estrasiol to its cytoplasmic receptor. Under equilibrium binding conditions, both testosterone and 5 alpha-dihydrotestosterone are very poor competitors for the estrogen binding sites, as compared to estrogenic compounds. 5alpha-Dihydrotestosterone, however, inhibits the initial rate of formation of the estradiol-receptor complex in a concentration-dependent manner. Steroidal specificity of this incubation is indicated by the failure of progesterone to elicit the same effect. The androgen inhibition appears to involve low-affinity interaction with the estrogen receptor, since no high-affinity binding of 5alpha-dihydrotestosterone could be detected. Kinetic analysis indicated that the inhibition is competitive, involving interaction at the estrogen-binding site of the receptor.

Animals↗
PubMed1980

Supranormal nuclear content of 5 alpha-dihydrotestosterone in benign hyperplastic prostate of humans.

We investigated the concentration of nuclear and cytosolic 5 alpha-dihydrotestosterone and 3 alpha-androstanediol in benign prostatic hyperplasia (BPH) in men. The endogenous content of the androgens was quantitated by radioimmunoassay after isolation of the nuclear and cytosolic fractions by classical differential centrifugation techniques. The mean dihydrotestosterone content was about four-fold higher (P < .01) than normal in the nuclear fraction and two-fold higher (P = .05) in the cytosolic fraction in periurethral tissue from hyperplastic prostates. The mean 3 alpha-androstanediol values were approximately one-third of normal in both the nuclear (P < .01) and cytosolic (P < .01) fractions in glands with BPH. In BPH tissue the ratios of dihydrotestosterone to androstanediol content in both the nuclear and cytosolic fractions was significantly higher (P < .01) than the ratio in normal prostate. Our data suggest that elevated intranuclear dihydrotestosterone but not 3 alpha-androstanediol may be causally related to the development of BPH in aging men.

Aged↗
PubMed1986

Epidermal keratinocytes: a source of 5 alpha-dihydrotestosterone production in human skin.

The major products of testosterone, androstenedione, and progesterone metabolism by human epidermal keratinocytes are 5 alpha-reduced steroids, viz. 5 alpha-dihydrotestosterone, 5 alpha-androstanedione, and 5 alpha-dihydroprogesterone, respectively. The rates of metabolite formation by these cells were linear with incubation time up to 3 h. The apparent Km of keratinocyte 5 alpha-reductase was 1.3 microM for androstenedione and 1.5 microM for progesterone. 5 alpha-Reductase activity was found only in particulate subcellular fractions of a homogenate of epidermal keratinocytes when assayed with tritium-labeled progesterone as the substrate and NADPH as the cofactor. In addition to 5 alpha-reductase activity, other enzymatic activities found in epidermal keratinocytes were 17 beta-hydroxysteroid oxidoreductase and 3 beta-hydroxysteroid oxidoreductase. These enzymes were expressed in the formation of androstenedione from testosterone, testosterone from androstenedione, isoandrosterone from androstenedione, and 3 beta-hydroxy-5 alpha-pregnan-20-one from progesterone. The apparent Km of 17 beta-hydroxysteroid oxidoreductase for androstenedione in epidermal keratinocytes was 10 microM. When measured at weekly intervals, the rates of product formation from testosterone, androstenedione, or progesterone by cultured epidermal keratinocytes increased several-fold with advancing time in culture up to 3 weeks. The results of these studies suggest that epidermal keratinocytes are a major site of synthesis of biologically potent androgens in human skin, viz. testosterone from androstenedione and 5 alpha-dihydrotestosterone from testosterone. Skin is a target organ for 5 alpha-dihydrotestosterone action, and thus, the local formation of 5 alpha-dihydrotestosterone may play an important role in the regulation of proliferation and differentiation of keratinocytes.

Adult↗
PubMed1979

Effects of antiprostatic agents on 5alpha-dihydrotestosterone binding to rat hypophyseal and hypothalamic cytosol macromolecules.

The binding of 5alpha-dihydrotestosterone to the hypophyseal and hypothalamic cytosol macromolecules prepared from castrated male rats was observed. The effects of antiprostatic agents on 5alpha-dihydrotestosterone binding to both hypophyseal and hypothalamic cytosol macromolecules was examined. Cyproterone acetate and chlormadionone acetate showed the significant inhibiting effects on 5alpha-dihydrotestosterone binding to 7-8 S macromolecules of cytosol from both hypophysis and hypothalamus. SCH 13521 and AA 560 did also affect 5alpha-dihydrotestosterone binding to 7-8 S macromolecules of cytosol from both tissues.

Androgen Antagonists↗
PubMed1989

Maturational changes in steroidogenic enzyme activities metabolizing testosterone and dihydrotestosterone in two populations of testicular interstitial cells.

The present study examined changes in steroidogenic enzyme activities which metabolize testosterone or dihydrotestosterone between days 21-73 of maturation in Band 2 and Band 3 cells isolated by centrifugation of rat testicular interstitial cells on metrizamide density gradients. 5 alpha-reductase and 17 beta-hydroxysteroid dehydrogenase activities increased progressively in Band 2 and Band 3 cells between days 21-35 of maturation, then both enzyme activities declined to reach low levels in adult Band 2 and Band 3 cells. The significantly higher activities of both enzymes in Band 3, which contains a greater concentration of Leydig cells at each age, suggest their localization in Leydig cells. 5 alpha-androstane-3 alpha- and 3 beta-hydroxysteroid dehydrogenase activities increased in both Band 2 and Band 3 cells between days 21-50 of maturation and remained elevated; however, dihydrotestosterone was metabolized primarily to 5 alpha-androstane-3 beta,17 beta-diol in Band 2 cells, while 5 alpha-androstane-3 beta,17 beta-diol was the major metabolite of dihydrotestosterone in Band 3 cells. These studies suggest that testosterone accumulation during sexual maturation can be influenced by changing patterns of 5 alpha-reductase and 17 beta-hydroxysteroid dehydrogenase activities which metabolize testosterone, and of 5 alpha-androstane-3 alpha- and 3 beta-hydroxysteroid dehydrogenase activities which metabolize dihydrotestosterone in both Band 2 and Band 3 cells.

17-Hydroxysteroid Dehydrogenases↗
PubMed1992

5-alpha androstane diol stimulates the pituitary growth hormone responsiveness to growth hormone releasing hormone more effectively than testosterone or dihydrotestosterone in rats.

The effect of different androgens and estradiol on pituitary responsiveness to growth hormone releasing hormone was studied in intact and orchidectomized adult male Wistar rats, by injecting subcutaneously immediately after orchidectomy for two weeks with testosterone, dihydrotestosterone, 5-alpha androstane, 3-alpha,17 beta-diol or estradiol dissolved in olive oil (in doses of 0.2 or 2.0 mg.kg-1.day-1) or vehicle. Pituitary responsiveness was tested in pentobarbital anaesthetized rats by measuring growth hormone plasma levels at different times after administration of growth hormone releasing hormone (1-29) NH2. We found that: (a) High doses of testosterone, dihydrotestosterone and 5-alpha androstane, 3-alpha,17 beta-diol restored gonadotropin plasma concentrations and organ weights altered by orchidectomy; (b) both pituitary growth hormone content and concentration remained unaffected after orchidectomy or androgen replacement and decreased significantly after estradiol injection; (c) orchidectomy significantly reduced growth hormone-stimulated growth hormone releasing hormone secretion; (d) treatment with 5-alpha androstane,3-alpha,17 beta-diol increased more than testosterone or dihydrotestosterone both the peak concentration and the mean growth hormone secretion after growth hormone releasing hormone stimulation; (e) no differences were observed in the treatment with testosterone or dihydrotestosterone; (f) estradiol given at a dose of 0.2 mg.kg-1.day-1 increased pituitary responsiveness to growth hormone releasing hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstane-3,17-diol↗
PubMed1975

5alpha-dihydrotestosterone stimulation of human prostate in organ culture.

Explants of human benign hypertrophied prostate were cultured for 8 days. The effect of 5alpha-dihydrotestosterone on the morphology, DNA and glucose utilization of 14 cases was investigated. In four cases proliferation was clearly more extensive in the dihydrotestosterone-treated explants than in the controls. In six explants, there were no morphological differences between those cultured with or without dihydrotestosterone and in half of these, proliferation was present. Four explants were either necrotic or did not contain epithelial cells. The mean DNA content of the treated explants was higher than that of the controls (P smaller than 0.01). There was no significant difference in the rate of glucose utilization by the explants treated with dihydrotestosterone, and by the controls.

Cell Division↗
PubMed1981

Evidence that a placental factor other than androsterone or dihydrotestosterone inhibits oestrogen-induced lordosis behaviour in pregnant rats.

Daily administration of oestradiol benzoate, beginning 10 days after mating, stimulates lordosis behaviour in deciduomata-bearing pseudopregnant rats, but not in pregnant rats. The inhibition of this behaviour during pregnancy was not prevented by reducing the number of conceptuses to two, by removing the fetuses while leaving the placentas in utero, or by removing the ovaries and administering progesterone to prevent abortion. Removal of the uterus or fetuses and placentas on day 12, however, led to high levels of lordosis behaviour. Thus, it is likely that the placenta produces a factor which inhibits the behavioural responsiveness to oestrogen. Plasma levels of progesterone, androsterone and dihydrotestosterone were higher during the second half of pregnancy than in the second half of pseudopregnancy prolonged by uterine decidualization. The possible involvement of these steroids in the inhibition of lordosis behaviour was investigated by increasing their levels in deciduomata-bearing pseudopregnant rats and determining the effect on oestrogen-induced lordosis behavior. Little suppression of this behaviour was seen when the pseudopregnant rats were treated with progesterone or androsterone whereas treatment with dihydrotestosterone resulted in a significant inhibition of lordosis behavior. However, the dose of dihydrotestosterone required to do so resulted in high, non-physiological plasma levels of this steroid. No inhibition of lordosis behaviour was observed when dihydrotestosterone levels were approximately threefold those normally present in pregnant rats. It is concluded that none of these three steroids is primarily responsible for the suppression of lordosis behaviour during pregnancy.

Androsterone↗