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PubMed1970

Dihydrotestosterone in prostatic hypertrophy. II. The formation and content of dihydrotestosterone in the hypertrophic canine prostate and the effect of dihydrotestosterone on prostate growth in the dog.

Three types of studies have been performed in immature, mature, and hypertrophic prostate glands of the dog. First, the concentrations of testosterone and dihydrotestosterone have been measured in the three types of gland. Dihydrotestosterone was the predominant hormone recovered in all prostates studied and was present in approximately five times higher concentration in the hypertrophic as compared to the other types of dog prostate. Second, pharmacological doses of dihydrotestosterone were administered to castrated dogs for 9 months and resulted in a distinct acceleration of prostatic growth as compared to testosterone treatment. Third, the rates of formation and degradation of dihydrotestosterone were measured in normal and hypertrophic tissue and were found to be essentially the same. These observations suggest that dihydrotestosterone accumulation may be causally linked to the development of canine prostatic hypertrophy. However, the mechanism by which dihydrotestosterone accumulates in the prostate remains to be determined.

Aging↗
PubMed1970

Dihydrotestosterone in prostatic hypertrophy. I. The formation and content of dihydrotestosterone in the hypertrophic prostate of man.

To explore the relation between androgens and prostatic hypertrophy in man, the concentrations of testosterone, dihydrotestosterone, and androstenedione and the rate of conversion of testosterone to dihydrotestosterone have been measured in normal and hypertrophic prostate tissue. First, a double isotope derivative technique was adapted for the measurement of tissue androgen content in 15 normal and 10 hypertrophic prostates. Although there was no significant difference in the content of androstenedione and testosterone between the two types of tissue, the content of dihydrotestosterone was significantly greater in the hypertrophic tissue (0.60 +/-0.10 mug/100 g) than in the normal glands (0.13 +/-0.05 mug/100 g). Second, a regional study was performed in three normal prostates and four glands with early hypertrophy, and it was demonstrated that the dihydrotestosterone content was two and three fold greater in the periurethral area where prostatic hypertrophy usually commences than in the outer regions of the gland. Finally, the rate of conversion of testosterone to dihydrotestosterone has been measured under standardized conditions in tissue slices from 4 normal and 20 hypertrophic prostates. There was no significant difference in the rate of dihydrotestosterone formation between the two types of gland (6.0 +/-0.8 and 7.8 +/-0.5 mumumoles/15 mg of tissue per hr). While the mechanism by which dihydrotestosterone accumulation occurs remains unexplained, it is possible that the local accumulation of dihydrotestosterone may be involved in the pathogenesis of prostatic hypertrophy in man.

Adolescent↗
PubMed1972

The metabolism of testosterone and dihydrotestosterone in an androgen-dependent tumour. A possible correlation between dihydrotestosterone and tumour growth in vivo.

The effects of dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one) and testosterone on the growth of the androgen-dependent Shionogi SC-115 tumour in mice have been compared and the metabolites in the tumour arising from each steroid have been identified. After the transfer of SC-115 tumour cells to castrated male mice, treatment of the recipients with dihydrotestosterone produced a striking proliferative response that enabled earlier tumour detection and led to a higher tumour incidence than obtained with testosterone. At short intervals after the intravenous injection of 200muCi of [1,2-(3)H]testosterone the amounts of radioactivity in tumour, muscle and seminal vesicles were almost equal. The metabolism of [1,2-(3)H]testosterone in tumour and muscle was slight in comparison with the extensive metabolism in seminal vesciles. Whereas up to 7% of the total neutral steroid recovered from whole tumour tissue and isolated nuclei was in the form of [1,2-(3)H]dihydrotestosterone, the amount of this compound in the corresponding preparations from seminal vesciles was several times greater. When the metabolism of [1,2-(3)H]dihydrotestosterone in tumour tissue was studied, it was found that more than 60% of the total neutral steroid in both cytoplasm and nuclei consisted of [1,2-(3)H]dihydrotestosterone. Thus much higher intracellular concentrations of dihydrotestosterone occurred with the administration of this steroid than with testosterone. Tumour cell proliferation was suppressed by oestradiol and the amount of androgen in nuclei was significantly decreased by high doses of this hormone.

Androstanes↗
PubMed1982

Percutaneous absorption of 5 alpha-dihydrotestosterone in man. I. Plasma androgen and gonadotrophin levels in normal adult men after percutaneous administration of 5 alpha-dihydrotestosterone.

The distribution of 5 alpha-dihydrotestosterone to the blood following application of a solution of this androgen to the skin in a hydro-alcoholic gel was studied in order to evaluate the adequacy of the percutaneous route in correcting androgen deficiencies. In 14 adult men, daily percutaneous administration of 5 alpha-dihydrotestosterone (125 mg in 5 g gel) increases, on the average, 4 to 5 times its initial concentration in plasma. On the 14th day of treatment, repeated evaluations of plasma 5 alpha-dihydrotestosterone, between 2 and 21 h after final administration of gel, demonstrated the stability of diurnal 5 alpha-dihydrotestosterone levels and showed the regular distribution of the steroid from a presumably cutaneous reservoir. Plasma 5 alpha-androstane-3 alpha,17 beta-diol levels evolve parallel to those of 5 alpha-dihydrotestosterone. Plasma testosterone and luteinizing hormone, on the contrary, decrease considerably. No variation of follicle-stimulating-hormone is observed during treatment. The percutaneous absorption represents an interesting method for administration of a natural androgen in men, particularly because one avoids the deleterious effects of supra-physiological levels in the liver achieved with oral administration.

Adult↗
PubMed1982

Percutaneous absorption of 5 alpha-dihydrotestosterone in man. II. Percutaneous administration of 5 alpha-dihydrotestosterone in hypogonadal men with idiopathic haemochromatosis; clinical, metabolic and hormonal effectiveness.

The particularities of percutaneous absorption of a natural androgen, 5 alpha-dihydrotestosterone, were evaluated in substitutive androgen therapy in masculine hypogonadism. Nine men presenting idiopathic haemochromatosis complicated by severe hypogonadism were treated with percutaneous administration of 5 alpha-dihydrotestosterone (125 mg/day) for 5 months. Plasma levels of 5 alpha-dihydrotestosterone and 5 alpha-androstane-3 alpha, 17 beta-diol are greatly increased by treatment (from 0.86 to 18.39 nmol/l and 0.16 to 3.40 nmol/l, respectively). There is no modification of testosterone and oestradiol-17 beta. Double blind study demonstrated the direct stimulating effect of 5 alpha-dihydrotestosterone on sexual behaviour and psychism. Hepatic and metabolic tolerance was excellent in these patients, despite the preceding deleterious effects of the iron excess. The percutaneous route is original, practical and improves the androgen therapy of hypogonadism in men.

Adult↗
PubMed1990

The synthesis and testing of E-17 alpha-(2-iodovinyl)-5 alpha-dihydrotestosterone and Z-17 alpha-(2-iodovinyl)-5 alpha-dihydrotestosterone as gamma-emitting ligands for the androgen receptor.

Two iodinated steroids, E-17 alpha-(2-iodovinyl)-5 alpha-dihydrotestosterone and Z-17 alpha-(2-iodovinyl)-5 alpha-dihydrotestosterone were synthesized in a search for a gamma-emitting androgen that binds with high affinity to the androgen receptor. Such compounds would be extremely useful research tools for studies of androgen responsive tissues and as in vivo probes of androgen responsive tumors such as prostate cancer. These 17 alpha-iodovinyl steroids were synthesized because many 17 alpha-substituents do not interfere markedly with binding to the androgen receptor and because similar analogs of other steroids, estrogens and progestins, have been shown to have the requisite properties for ligands to those receptors. Both of these potential ligands were tested for their ability to compete with [3H]R1881 for binding to the androgen receptor in cytosols from prostate, hypothalamus and pituitary. The relative binding affinities ranged between 5 and 20%, depending upon the tissue and steroid. In order to test the two ligands directly, they were both synthesized labelled with 125I and tested for binding to the androgen receptor in prostatic cytosol and in vivo for specific concentration in androgen responsive tissues. While there was considerable binding in the prostatic cytosol, it was not specific because 5 alpha-dihydrotestosterone did not compete. Likewise in the in vivo experiment there was no evidence for androgen receptor mediated concentration of the tracers. While on the basis of relative binding affinity, these 2 steroids appeared to be good candidates for androgen receptor ligands, neither were useful for this purpose. These results contribute new information which will be valuable in the design of other gamma-emitting androgens and emphasises that, in this process, other factors such as metabolism and nonspecific binding must be considered.

Animals↗
PubMed1984

The effect of 5 alpha-dihydrotestosterone and 5 beta-dihydrotestosterone on erythropoiesis of the newt, Triturus cristatus carnifex (Laur.).

The erythropoietic effects of 5 alpha-dihydrotestosterone (5 alpha-DHT) and 5 beta-dihydrotestosterone (5 beta-DHT) were compared in the newt, Triturus cristatus carnifex (Laur.). In normal animals, 5 beta-DHT was more active than 5 alpha-DHT in increasing the number of circulating erythrocytes. In animals rendered completely anemic, only 5 beta-DHT was effective. The biochemical parameters of delta-aminolevulinic acid synthase and delta-aminolevulinic acid dehydratase of new basophilic erythroblasts, and incorporation of labeled glycine into heme and globin of new polychromatic erythroblasts were enhanced by 5 beta-DHT. The results are discussed with reference to a direct erythropoietin-independent action of 5 beta-DHT on erythroid stem cells.

5-Aminolevulinate Synthetase↗
PubMed1995

Synthesis of 11 beta-[18F]fluoro-5 alpha-dihydrotestosterone and 11 beta-[18F]fluoro-19-nor-5 alpha-dihydrotestosterone: preparation via halofluorination-reduction, receptor binding, and tissue distribution.

We have prepared 11 beta-fluoro-5 alpha-dihydrotestosterone (11 beta-F-DHT, 1) and 11 beta-fluoro-19-nor-5 alpha-dihydrotestosterone (11 beta-F-19-nor-DHT, 2) in order to investigate the properties of these new androgens labeled with fluorine-18 as potential androgen receptor (AR)-based imaging agents for prostate cancer. These compounds were synthesized in 6 steps from hydrocortisone and in 13 steps from 1,4-androstadiene-3,11,17-trione, respectively. Relative binding affinities (RBA) of 11 beta-F-DHT and 11 beta-F-19-nor-DHT to AR are 53.1 and 75.3 (R1881 = 100), respectively, the latter being the highest reported among fluorine-substituted androgens. The fluorination step, which involves addition of halogen fluoride across the 9(11)-double bond, followed by reductive dehalogenation at the 9 alpha-position has been adapted to introduce a fluorine-18-label at the 11 beta-position of DHT and 19-nor-DHT. The two high-affinity F-18-labeled ligands [18F]-1 and [18F]-2 were evaluated in vivo, in tissue distribution studies using diethylstilbestrol-pretreated mature male rats. 11 beta-F-DHT shows high prostate uptake and selective prostate to blood and prostate to muscle uptake ratios, the latter two ratios increasing from 5 and 8 at 1 h to 12 and 19 at 4 h postinjection. Moreover, this compound has low uptake in bone, displaying the lowest in vivo defluorination among all androgens labeled with fluorine-18 tested so far. The in vivo properties of 11 beta-F-DHT in rats are thus favorable for imaging of prostate cancer. On the other hand, 11 beta-F-19-nor-DHT shows low prostate uptake with low selectivity and high uptake in liver, kidney, and bladder. Even though this ligand has the highest RBA and undergoes little metabolic defluorination, it appears to suffer from rapid metabolism in vivo. Therefore, it is apparent that the biodistribution properties of androgens are affected by their structure and metabolism as well as by their RBA.

Animals↗
PubMed1975

Sexual behaviour in castrated rabbits treated with testosterone, oestradiol, dihydrotestosterone or oestradiol in combination with dihydrotestosterone.

Sexual behaviour and the function of the accessory sexual glands were studied in castrated rabbits injected with testosterone benzoate (TB), oestradiol benzoate (OEB), dihydrotestosterone benzoate (DHTB) or OEB in combination with DHTB. Testosterone benzoate (1 mg daily for 90 days) stimulated the sexual behaviour more than any of the other steroids. The combination of OEB (0-33 mg) and DHTB (1 mg) was no more effective than either of these steroids given alone. The function of the accessory sexual glands was stimulated to a level comparable to that of intact animals given TB. Dihydrotestosterone benzoate was, however, not very effective in this respect. Oestradiol benzoate alone or in combination with DHTB caused hypertrophy and very low secretory activity of the seminal vesicles. These results suggest that testosterone itself is active both in the brain and in the accessory sexual glands in rabbits. This is in contrast to the rat, in which aromatization to oestradiol in the brain and reduction to DHT in the periphery seems to be important.

Animals↗
PubMed1979

Percentage binding of testosterone and dihydrotestosterone and unbound testosterone and dihydrotestosterone in rabbit maternal and fetal plasma during sexual organogenesis.

The percentages of bound testosterone (17 beta-hydroxy-4-androsten-3-one; T) and dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one; DHT) and their unbound concentrations were determined in pregnant rabbits and their fetuses from the 18th day of gestation to birth. T and DHT were also measured in fetal testes. In the testis, the total T/total DHT ratio, very high at 22 days (73.7 +/- 15.2), decreased until birth (6.7 +/- 0.8). In male fetuses the concentrations of total and unbound circulating T and DHT were always low and did not show any peak during sexual organogenesis. The percent binding of T (from 73.0 +/- 0.5 to 77.6 +/- 0.6) and DHT (from 76.5 to 83.7 +/- 1.1) in fetuses were similar in both sexes and significantly lower than those measured in mothers (T: from 87.2 +/- 0.6 to 91.6 +/- 0.9; DHT: from 87.3 +/- 0.9 to 93.8 +/- 0.9).

Animals↗
PubMed1997

MK-386, an inhibitor of 5alpha-reductase type 1, reduces dihydrotestosterone concentrations in serum and sebum without affecting dihydrotestosterone concentrations in semen.

Two isozymes (types 1 and 2) of 5alpha-reductase (5alphaR; EC 1.3.99.5), with differential tissue distribution, catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT) in humans. This study examined sequentially increasing oral doses of MK-386 (4,7beta-dimethyl-4-aza-5alpha-cholestan-3-one), an azasteroid that specifically inhibits the human 5alphaR1 isozyme in vitro. Finasteride, a selective inhibitor of 5alphaR2, was included for comparison. One hundred men were evaluated in a double blind, randomized, placebo-controlled, sequential, increasing dose, parallel group trial. Ten to 20 subjects received MK-386, and 2 to 5 received placebo in each of 6 panels. In 1 panel, 10 subjects received finasteride (5 mg), and 5 received placebo. Treatments were given once daily for 14 days, except in 1 panel in which MK-386 was administered 10 mg twice daily for comparison to 20 mg daily. Serum, sebum, and semen DHT concentrations and serum and sebum T concentrations were measured before and after treatment. The mean changes from baseline on day 14 for serum DHT after placebo and 0.1, 0.5, 5, 20, and 50 mg MK-386 were 6.9%, 4.6%, -2.7%, -1.2%, -14.1% (P < 0.05 vs. placebo), and -22.2% (P < 0.05 vs. placebo), respectively. No significant alterations in serum T were observed after any dose of MK-386. Serum DHT fell 65.8% from the baseline 14 days after finasteride treatment (P < 0.05 vs. placebo). The mean changes from baseline on day 14 in sebum DHT were 5.0%, 3.0%, -25.4% (P < 0.05 vs. placebo), -30.1% (P < 0.05 vs. placebo), and -49.1% (P < 0.05 vs. placebo) for the placebo and 0.5, 5, 20, and 50 mg MK-386 groups, respectively. Finasteride also reduced sebum DHT, but to a lesser extent (- 14.9%; P < 0.05 vs. placebo). Reciprocal increases in sebum T concentration were noted at doses of 5 mg or more of MK-386, but not with finasteride. The mean reduction in semen DHT with 5 mg finasteride was approximately 88% (P < 0.01 vs. placebo); no significant change in semen DHT was noted with 20 or 50 mg MK-386. Serum 3alpha-androstanediol glucuronide values were also reduced after the 20- and 50-mg MK-386 treatments in parallel with the changes in serum DHT. No meaningful changes were observed in serum LH after MK-386 treatment. MK-386 was generally well tolerated by all subjects; reversible aspartate aminotransferase/alanine aminotransferase elevations were observed in two subjects at the 50-mg dose. The differential responses in serum, sebum, and semen DHT concentrations associated with MK-386 and finasteride treatments are consistent with those changes anticipated for selective inhibitors of the human 5alphaR isozymes. Dose-dependent suppression of sebum DHT by a 5alphaR1 inhibitor suggests the potential utility of such compounds in the treatment of acne.

5-alpha Reductase Inhibitors↗
PubMed1979

Concentration of dihydrotestosterone and 3 alpha-androstanediol in naturally occurring and androgen-induced prostatic hyperplasia in the dog.

Previous studies have suggested that dihydrotestosterone accumulation in the prostate may be involved in the pathogenesis of prostatic hyperplasia in man and dog. However, the fact that the administration of 10 mg dihydrotestosterone/d to castrated, mongrel dogs (0.5 mg/kg body wt) causes little growth in the prostate, whereas identical doses of 3alpha- androstanediol regularly induce prostatic hyperplasia (> 14 g weight) has raised the possibility that the dihydrotestosterone accumulation may be the result rather than the cause of the pathology. To investigate the mechanism of this phenomenon, we measured the levels of dihydrotestosterone and 3alpha-androstanediol in prostates from 75 dogs. In both naturally occurring and 3alpha-androstanediol-induced prostatic hyperplasia, the levels of dihydrotestosterone were high (>5 ng/g), whereas in immature glands and glands from dihydrotestosterone-treated animals, levels were similar (2.1 and 2.6 ng/g, respectively). 3alpha-Androstanediol levels were no different in animals treated with dihydrotestosterone or 3alpha-androstanediol.Therefore, because exogenous 3alpha-androstanediol is a better precursor of prostatic dihydrotestosterone than exogenous dihydrotestosterone itself, the effects of treatment with larger doses (2.5 mg/kg per d) of dihydrotestosterone and 3alpha-androstanediol for 12 wk were examined. In these amounts, dihydrotestosterone was as effective as 3alpha-androstanediol in inducing the development of prostatic hyperplasia and in elevating prostatic dihydrotestosterone concentration. Because dihydrotestosterone accumulates in spontaneous prostatic hyperplasia, because the administration of sufficient amounts of dihydrotestosterone to the castrated dog can induce the development of prostatic hyperplasia, and because 3alpha-androstanediol induces the development of hyperplasia via conversion to dihydrotestosterone, we conclude that accumulation of dihydrotestosterone is the cause of canine prostatic hyperplasia.

Androstenediols↗
PubMed1972

Metabolic clearance rate and blood production rate of testosterone and dihydrotestosterone in normal subjects, during pregnancy, and in hyperthyroidism.

The metabolic clearance rate (MCR) and blood production rate (BP) of testosterone (T) and dihydrotestosterone (DHT), the conversion of plasma testosterone to plasma dihydrotestosterone, and the renal clearance of androstenedione, testosterone, and dihydrotestosterone have been studied in man. In eight normal men, the MCR(T) (516+/-108 [SD] liters/m(2)/day) was significantly greater than the MCR(DHT) (391+/-71 [SD] liters/m(2)/day). In seven females, the MCR(T) (304+/-53 [SD] liters/m(2)/day) was also greater than the MCR(DHT) (209+/-45 [SD] liters/m(2)/day) and both values were less than their respective values in men (P < 0.001). In men the conversion of testosterone into dihydrotestosterone at 2.8+/-0.3% (SD) was greater than that found in females, 1.56+/-0.5% (SD) (P < 0.001). In five pregnant females the MCR(T) (192+/-36 [SD] liters/m(2)/day), the MCR(DHT) (89+/-30 [SD] liters/m(2)/day) and the conversion of testosterone into dihydrotestosterone (0.72+/-0.15%) (SD) were significantly less than the values found in nonpregnant women. In five females with hyperthyroidism, the MCR for testosterone and dihydrotestosterone were similar to those observed in pregnant females, but the conversion of testosterone into dihydrotestosterone (2.78+/-1.7%) (SD) was greater, and similar to that found in men. In men the production of dihydrotestosterone was 0.39+/-0.1 (SD) mg/day, 50% being derived from the transformation of plasma testosterone. In women the production of DHT was 0.05+/-0.028 (SD) mg/day, only 10% coming from testosterone. During pregnancy, the production of testosterone and dihydrotestosterone are similar to that in normal women. In three patients with testicular feminization syndrome (an adult with hyperthyroidism and two children) these two MCRs were greatly reduced compared to the normal females, but the conversion of testosterone into dihydrotestosterone was in the limits of normal male rangeIn the normal subjects the renal clearance of androstenedione was greater than that of testosterone and dihydrotestosterone. Less than 20% of the dihydrotestosterone and less than 10% of the androstenedione in the urine is derived from the plasma dihydrotestosterone and androstenedione.

17-Ketosteroids↗
PubMed1999

Possible role of Ca2+ channels in the vasodilating effect of 5beta-dihydrotestosterone in rat aorta.

It has previously been shown that the androgen, 5beta-dihydrotestosterone (17beta-hydroxy-5beta-androstan-3-one, 5beta-DHT), is able to produce an endothelium-independent vasodilating effect in rat aorta. The present study analyzed the mechanisms underlying the above vasodilator effect of 5beta-dihydrotestosterone, with particular emphasis on verifying a possible interaction with GABA(A) receptors, beta-adrenoceptors and Ca2+ channels. Rat aortic rings without endothelium were isometrically recorded. 5Beta-dihydrotestosterone produced a concentration-dependent relaxation on the contractions induced by noradrenaline (NA; 0.3 microM) or K+ (KCl; 60 mM), with the latter being more sensitive to 5beta-dihydrotestosterone-induced relaxation than the former; the concentration-response curves showed that 5beta-dihydrotestosterone is significantly more potent than 17beta-estradiol(1,3,5(10)-estratrien-3,17beta-diol) to induce vasodilatation. The vasodilating effect of 5beta-dihydrotestosterone on noradrenaline-induced contraction was resistant to blockade by the GABA(A) receptor antagonists, picrotoxin or bicuculline, and the beta-adrenoceptor antagonist, propranolol, a finding that excludes an interaction of the steroid with GABA(A) receptors and beta-adrenoceptors. Interestingly, the contractions evoked by calcium in depolarized tissues were substantially inhibited by 5beta-dihydrotestosterone, implying that this steroid could be an endogenous calcium channel blocker; consistent with this finding, 5beta-dihydrotestosterone was able to relax tissues precontracted with the calcium channel opener, Bay K 8644. Moreover, although the rings precontracted with noradrenaline and potassium were almost equipotently relaxed by 5beta-dihydrotestosterone. Nifedipine was more potent than 5beta-dihydrotestosterone to block the potassium-induced contraction, but the steroid was more effective than nifedipine to prevent noradrenaline-induced contraction. The above results suggest that 5beta-dihydrotestosterone causes relaxation of rat aorta by acting directly on the membrane of smooth muscle cells; this non-genomic action may be explained in terms of a blockade of voltage- and receptor-dependent calcium channels, a mechanism that restricts the availability of extracellular calcium in the contractile machinery.

Animals↗
PubMed2004

The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer.

PURPOSE: The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue is not clearly known. Changes in dihydrotestosterone levels in the prostatic tissue during androgen deprivation therapy in the same patients have not been reported. We analyzed dihydrotestosterone levels in prostatic tissue before and after androgen deprivation therapy. EXPERIMENTAL DESIGN: A total of 103 patients who were suspected of having prostate cancer underwent prostatic biopsy. Sixty-nine patients were diagnosed as having prostate cancer whereas the remaining 34 were negative. Serum samples were collected before biopsy or prostatectomy. Dihydrotestosterone levels in prostatic tissue and serum were analyzed using liquid chromatography/electrospray ionization-mass spectrometry after polar derivatization. In 30 of the patients with prostate cancer, dihydrotestosterone levels in prostatic tissue were determined by performing rebiopsy or with prostate tissues excised after 6 months on androgen deprivation therapy with castration and flutamide. RESULTS: Dihydrotestosterone levels in prostate tissue after androgen deprivation therapy remained at approximately 25% of the amount measured before androgen deprivation therapy. Dihydrotestosterone levels in serum decreased to approximately 7.5% after androgen deprivation therapy. The level of dihydrotestosterone in prostatic tissue before androgen deprivation therapy was not correlated with the serum level of testosterone. Serum levels of adrenal androgens were reduced to approximately 60% after androgen deprivation therapy. CONCLUSIONS: The source of dihydrotestosterone in prostatic tissue after androgen deprivation therapy involves intracrine production within the prostate, converting adrenal androgens to dihydrotestosterone. Dihydrotestosterone still remaining in prostate tissue after androgen deprivation therapy may require new therapies such as treatment with a combination of 5alpha-reductase inhibitors and antiandrogens, as well as castration.

5-alpha Reductase Inhibitors↗
PubMed1990

Pharmacokinetics and pharmacodynamics of testosterone enanthate and dihydrotestosterone enanthate in non-human primates.

The pharmacokinetics and pharmacodynamics of testosterone enanthate and dihydrotestosterone-enanthate were compared in orchidectomized cynomolgus monkeys (Macaca fascicularis) and in intact GnRH agonist-suppressed rhesus monkeys (Macaca mulatta). Following a single im injection of 32.8 mg testosterone enanthate or 32.7 mg dihydrotestosterone-enanthate, i.e. 23.6 mg of pure steroid, in the orchidectomized cynomolgus monkeys, serum testosterone and dihydrotestosterone levels rose to 400 and 800% of baseline, respectively, within 24 h. Androgen levels remained in that range for 3-5 days followed by a continuous decline until baseline values were attained after 4-5 weeks. The areas under the testosterone- and dihydrotestosterone-curves did not differ significantly 2290 +/- 340 (dihydrotestosterone-enanthate) vs 2920 +/- 485 (testosterone-enanthate) suggesting that similar amounts of steroid had been released from the respective ester preparation. Mean half-life estimates of the terminal elimination phase were 4 and 7 days for testosterone-enanthate and dihydrotestosterone-enanthate, respectively. In a second experiment rhesus monkeys received, at 4-weekly intervals, sc implantation of a biodegradable polylactic:polyglycolide rod loaded with the GnRH agonist buserelin. The last injection was given during week 20. GnRH agonist treatment suppressed serum bioactive LH, testosterone and dihydrotestosterone levels, testicular size, sperm production, and seminal carnitine content. The ejaculatory response to electrostimulation and the masturbatory behaviour were abolished. Testosterone or dihydrotestosterone injections at the same doses as above were given in week 10, 14, 17 and 20 of GnRH agonist treatment. Serum testosterone and dihydrotestosterone levels were stimulated 9- and 4-fold, respectively. Mean half-life estimates for testosterone-enanthate and dihydrotestosterone were 5 and 7 days, respectively. Both ester preparations completely restored the ejaculatory response, ejaculate size, masturbatory behaviour, and seminal carnitine levels. In conclusion, androgen substitution with dihydrotestosterone-enanthate, in equivalent doses, is as effective as testosterone-enanthate in restoring reproductive functions in hypogonadal monkeys.

Androgens↗
PubMed1982

Mechanisms of action of androgens and antiandrogens: effects of antiandrogens on translocation of cytoplasmic androgen receptor and nuclear abundance of dihydrotestosterone.

The effects of antiandrogens on the translocation of androgen receptor and the accumulation of nuclear dihydrotestosterone in rat ventral prostate were investigated. Using an isotope-exchange assay and radioimmunoassay it was found that 1 hr after the injection of 70 nmol of dihydrotestosterone into 1-day castrated rats, 19,000 +/- 2.350 (mean +/- SE) receptor molecules and 99,300 +/- 8,200 molecules of dihydrotestosterone were recovered per nucleus. When equivalent doses of antiandrogens were substituted for dihydrotestosterone only 0-1,500 receptor molecules were translocated. After injection of antiandrogens followed 1 hr later by injection of dihydrotestosterone, the inhibition of translocation given by the reduction in the mean numbers of molecules of receptor and dihydrotestosterone, respectively, was as follows: 17 beta-estradiol (0, 0); megestrol acetate (2000, 0); diethylstilbestrol (6000, 4000); cyproterone acetate (5500, 27000); flutamide (10000, 29000); R2956 (10000, 28000). With the exception of the effect of cyproterone acetate on receptor translocation, the reductions produced by the latter three antiandrogens were all statistically significant (P less than 0.5). Since less than 20% of the dihydrotestosterone in the nucleus is bound to receptor in dihydrotestosterone-treated rats, and since the concentrations of receptor and dihydrotestosterone are unequally affected by some antiandrogens, we infer that the nuclear abundance of dihydrotestosterone may be regulated in part through nonreceptor-mediated processes.

Androgen Antagonists↗