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Drug Metabolism and Disposition: the... Jul 2006We identified human UDP-glucuronosyltransferase (UGT) isoforms responsible for producing dihydrotestosterone (DHT) diglucuronide, a novel glucuronide in which the second... (Comparative Study)
Comparative Study
We identified human UDP-glucuronosyltransferase (UGT) isoforms responsible for producing dihydrotestosterone (DHT) diglucuronide, a novel glucuronide in which the second glucuronosyl moiety is attached at the C2' position of the first glucuronosyl moiety, leading to diglucuronosyl conjugation of a single hydroxyl group of DHT at the C17 position. Incubation of the DHT monoglucuronide with 12 cDNA-expressed recombinant human UGT isoforms and uridine 5'-diphosphoglucuronic acid resulted in a low but measurable DHT diglucuronidation activity primarily with UGT1A8, a gastrointestinal UGT, and to a lesser extent with UGT1A1 and UGT1A9. In contrast, the activity of DHT monoglucuronidation was high and was found in UGT2B17, UGT2B15, UGT1A8, and UGT1A4 in descending order. Among the 12 UGT isoforms tested, only UGT1A8 was capable of producing DHT diglucuronide from DHT. The kinetics of DHT diglucuronidation by microsomes from human liver and intestine fitted the Michaelis-Menten model, and the V(max)/K(m) value for the intestinal microsomes was approximately 4 times greater than that for the liver microsomes.
Topics: Animals; Dihydrotestosterone; Dogs; Glucuronosyltransferase; Humans; In Vitro Techniques; Intestines; Isoenzymes; Kinetics; Microsomes, Liver; Molecular Structure; Rats; Recombinant Proteins; UDP-Glucuronosyltransferase 1A9
PubMed: 16595710
DOI: 10.1124/dmd.106.009621 -
The Journal of Endocrinology Apr 1972
Distribution of 5 -dihydrotestosterone in the epididymis of bull and boar, and its concentration in rat epididymis after ligation of efferent testicular ducts, castration and unilateral gonadectomy.
Topics: Animals; Castration; Cattle; Chromatography, Gas; Dihydrotestosterone; Epididymis; Injections, Intramuscular; Ligation; Male; Rats; Spermatozoa; Swine; Testis; Testosterone; Tritium; Vas Deferens
PubMed: 5021265
DOI: 10.1677/joe.0.0530085 -
The Journal of Steroid Biochemistry and... Jun 1994Several substances with different inhibitory effects on adrenal steroid biosynthesis were investigated in patients with Cushing's syndrome. It has been shown that... (Review)
Review
Several substances with different inhibitory effects on adrenal steroid biosynthesis were investigated in patients with Cushing's syndrome. It has been shown that trilostane, a 3 beta-hydroxysteroid-dehydrogenase inhibitor, is not potent enough to block cortisol biosynthesis in patients with hypercortisolism. Aminoglutethimide inhibits side chain cleavage of cortisol synthesis, but it has been demonstrated that the blocking effect on cortisol secretion is not strong enough to normalize urinary cortisol excretion in patients with Cushing's disease. For metyrapone, an inhibitor of adrenal 11 beta-hydroxylase, promising results were reported for the treatment of Cushing's syndrome. However, the drug has several side effects and depending on the definition of the desired reduction of cortisol secretion a true remission was only found in a minority of patients. The antifungal drug ketoconazole in vitro predominantly blocks 17,20-desmolase (IC50 1 microM) and to a lesser extent 17 alpha-hydroxylase (IC50 10 microM) and 11 beta-hydroxylase (IC50 15-40 microM). Therefore, ketoconazole in vivo most potently suppresses androgen secretion and only to a lesser extent cortisol biosynthesis. Several therapeutic trials with ketoconazole treatment in patients with pituitary Cushing's disease showed various remission rates between 30 and 90%. In contrast, in almost all patients with benign, primary adrenal Cushing's syndrome cortisol levels were normalized. In patients with ectopic ACTH syndrome ketoconazole was effective in about 50% of all reported cases, while cortisol hypersecretion due to adrenocortical carcinoma was only rarely inhibited by ketoconazole. The main side effect of ketoconazole treatment was liver toxicity which occurred in 12% of all treated patients. In contrast to ketoconazole, the narcotic drug etomidate shows a strong inhibitory effect on 11 beta-hydroxylase (IC50 0.03-0.15 microM) but only a weak inhibition of 17,20 desmolase (IC50 380 microM). This correlates with in vivo studies where even low, non-hypnotic doses of etomidate induced a pronounced fall in serum cortisol levels in normals and in patients with Cushing's syndrome. However, its clinical use is limited by its mandatory intravenous application and its sedative effects. In conclusion, ketoconazole remains the only available steroid-inhibitory drug for a therapeutic trial in patients with Cushing's syndrome who cannot be treated definitively by surgery.
Topics: 3-Hydroxysteroid Dehydrogenases; Aminoglutethimide; Cushing Syndrome; Dihydrotestosterone; Etomidate; Humans; Ketoconazole; Metyrapone; Steroids
PubMed: 8043488
DOI: 10.1016/0960-0760(94)90267-4 -
Life Sciences 1989Dihydrotestosterone glucuronide (DHTG), a series of 5 alpha-bile acids, or allo-bile acids (3 alpha-hydroxy-5 alpha-cholanic acid, 3-keto-5 alpha-cholanic acid and 3...
Dihydrotestosterone glucuronide (DHTG), a series of 5 alpha-bile acids, or allo-bile acids (3 alpha-hydroxy-5 alpha-cholanic acid, 3-keto-5 alpha-cholanic acid and 3 beta-hydroxy-5 alpha-cholanic acid) and their normal bile acid analogues (3 alpha-hydroxy-5 beta-cholanic acid or lithocholate, 3-keto-5 beta-cholanic acid and 3 beta-hydroxy-5 beta-cholanic acid) were administered intravenously to female rats in order to determine their effects on bile flow. All agents caused a rapid and profound inhibition of bile flow which was dose-dependent. The logarithm of the dose vs the cholestatic response curve for DHTG, the allo-bile acids and lithocholate were all parallel. DHTG was the most potent congener and was two times more potent than 3-keto-5 alpha-cholanic acid and 5 times more potent than lithocholate. These data indicate that the glucuronic acid moiety and the trans configuration of the A and B rings of the steroid nucleus confer the greatest cholestatic potency.
Topics: Animals; Bile; Bile Acids and Salts; Dihydrotestosterone; Dose-Response Relationship, Drug; Female; Lithocholic Acid; Molecular Structure; Rats; Rats, Inbred Strains; Secretory Rate; Structure-Activity Relationship
PubMed: 2747415
DOI: 10.1016/0024-3205(89)90349-4 -
Endocrinology Dec 1983Dihydrotestosterone (DHT) concentration was measured in prostatic tissue obtained from castrate or intact beagles treated with androgens and/or estradiol-17 beta. Also...
Dihydrotestosterone (DHT) concentration was measured in prostatic tissue obtained from castrate or intact beagles treated with androgens and/or estradiol-17 beta. Also DHT concentration was measured in prostatic tissue of beagles ranging from 0.7-9.2 yr; some with and others without spontaneously occurring benign prostatic hyperplasia (BPH). Three major results were forthcoming. First, a linear, positive correlation was observed between prostatic weight and DHT concentration in castrated or intact beagles treated with 11 of 15 steroid hormone regimens. Four additional treatments including intact or castrated beagles treated with either DHT or 5 alpha-androstan-3 alpha,17 beta-diol alone resulted in high concentrations of prostatic DHT but not equally high prostatic weight. Thus, prostatic DHT concentration is not always tightly coupled with prostate weight in the beagle. Second, there was no significant (P greater than 0.25) difference in prostatic DHT concentration between dogs with histologically normal prostates and those with spontaneous BPH. Thus, contrary to earlier reports, the tissue concentration of DHT in dog prostatic hyperplasia is not supranormal. Third, there was a dramatic change in prostatic DHT concentration which peaked at 3.8 yr. We conclude that steroid hormone treatment regimens which caused elevated prostatic DHT concentrations did not always result in equally high prostatic weight in the beagle. Also, if androgens like DHT are related causally to BPH in the dog, they probably play a permissive rather than an inductive role in the disease process.
Topics: Aging; Androstane-3,17-diol; Animals; Castration; Dihydrotestosterone; Dogs; Male; Organ Size; Prostate; Prostatic Hyperplasia
PubMed: 6196180
DOI: 10.1210/endo-113-6-2004 -
Endocrine Research 2001Previous investigations in our laboratory have shown that testosterone implanted into the lateral septum in male rats increases LH and FSH secretion. However, it was...
Previous investigations in our laboratory have shown that testosterone implanted into the lateral septum in male rats increases LH and FSH secretion. However, it was unclear whether the effect of testosterone was direct via androgen receptor, or indirect via the estrogen receptor after conversion by aromatization to estradiol. To answer this question, we implanted either testosterone or the non-aromatizable androgen 5 alpha-dihydrotestosterone (DHT), into the lateral septum of adult male rats and measured plasma levels of LH and FSH by radioimmunoassay 2 days after implantation. Both testosterone and DHT significantly increased the plasma LH and FSH concentrations. Mean concentration of LH in control animals was 0.21 +/- 0.06 ng/ml, a figure that increased to 0.7 +/- 0.12 and 0.55 +/- 0.1 ng/ml after DHT or testosterone implantation respectively. Mean concentration of FSH in control animals was 1.5 +/- 0.3 ng/ml; this figure increased to 3 +/- 0.3 and 2.9 +/- 0.3 ng/ml after DHT or testosterone implantation. Neither plasma DHT (64.0 +/- 5.6 vs. 52 +/- 5 ng/100ml) nor plasma testosterone levels (4.1 +/- 0.38 vs. 3.3 +/- 0.18 ng/ml) were significantly affected by the implants. We conclude that androgens independently of conversion to estrogen acting in the lateral septum facilitates the release of LH and FSH.
Topics: Animals; Crystallization; Dihydrotestosterone; Drug Implants; Follicle Stimulating Hormone; Luteinizing Hormone; Male; Rats; Rats, Wistar; Septum Pellucidum; Testosterone
PubMed: 11428719
DOI: 10.1081/erc-100107167 -
Clinical Endocrinology Oct 1983We have studied clinical and endocrine parameters in a group (group A) of forth men referred to us because of persistent idiopathic gynaecomastia (of more than 18 months... (Clinical Trial)
Clinical Trial
We have studied clinical and endocrine parameters in a group (group A) of forth men referred to us because of persistent idiopathic gynaecomastia (of more than 18 months duration), before and during the administration of percutaneous dihydrotestosterone (DHT). The endocrine parameters (testosterone (T), 17 beta-oestradiol (E2), DHT, gonadotrophins (FSH and LH) and prolactin (PRL), were compared to those of control groups of 12 healthy men on DHT therapy (group B) and 10 on placebo (group C). Local administration of DHT was followed by the complete disappearance of gynaecomastia in 10 patients, partial regression in 19 and no change in 11 patients after 4 to 20 weeks of percutaneous DHT (125 mg twice daily). Before treatment the T + DHT/E2 ratio was significantly (P less than 0.001) lower in group A 244 +/- 21 (SEM) than in groups B and C (361 +/- 21) while T, DHT and E2 concentrations were all within the normal range. During DHT treatment plasma hormone levels were measured in 26 patients from group A: DHT levels increases significantly (day 0: 1.63 +/- 0.14 nmol/l; day 15: 12.8 +/- 1.6 nmol/l, P less than 0.001) while T and E2 levels fell significantly (T: day 0: 22.6 +/- 1.2 nmol/l; day 15: 11.0 +/- 1.5 nmol/l, P less than 0.001; E2: day 0: 110.5 +/- 7.12 pmol/l; day 15: 86.79 +/- 9.4 pmol/l, P less than 0.01). The T/E2 ratio decreased from 231 +/- 20 to 164 +/- 27 (P less than 0.05) while the T + DHT/E2 ratio increased significantly (P less than 0.02) to a normal mean value (day 15: 354 +/- 57).(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adolescent; Adult; Clinical Trials as Topic; Dihydrotestosterone; Estradiol; Gynecomastia; Humans; Injections, Subcutaneous; Male; Middle Aged; Testosterone
PubMed: 6354523
DOI: 10.1111/j.1365-2265.1983.tb00026.x -
General and Comparative Endocrinology Sep 2013The steroid hormone 5α-dihydrotestosterone (DHT) is one of the most physiologically important androgens in male vertebrates, with the exception of teleost fish, in...
The steroid hormone 5α-dihydrotestosterone (DHT) is one of the most physiologically important androgens in male vertebrates, with the exception of teleost fish, in which it is generally assumed that DHT does not play any major physiological role. However, this assumption is challenged by the fact that all the components involved in DHT biosynthesis and action are present and evolutionary conserved in teleost fish. In fact, testosterone (T) is converted into DHT by two isoforms of the enzyme steroid-5-alpha-reductase (5αR), and both 5αRs gene expression and enzymatic activity have been detected in several tissues of different teleost species, which also have an androgen receptor with high binding affinity to DHT. This body of evidence strongly suggest that DHT is synthesised by teleost fish. We investigated this hypothesis using the cyprinid fathead minnow (Pimephales promelas) as the experimental model. The study of the evolutionary and functional conservation of 5αRs in teleost fish was used to support the experimental approach, based on an ultrasensitive gas chromatography-tandem mass spectrometry (GC-MS/MS) method to identify and measure simultaneously T and DHT in fathead minnow biological fluids and tissues. The analyses were performed using plasma samples collected from both male and female adult fish and samples of testicular tissue collected from sexually mature males. Both T and DHT were identified and quantified in all the samples analysed, and in particular, the high concentrations of DHT quantified in the testes suggested that these organs are a likely site of synthesis of DHT in the teleost fathead minnow, as they are in mammals. These results may represent the basis for future studies aimed at elucidating the physiological role, if any, of DHT in teleost fish.
Topics: Animals; Cyprinidae; Dihydrotestosterone; Female; Gas Chromatography-Mass Spectrometry; Male
PubMed: 23831110
DOI: 10.1016/j.ygcen.2013.06.017 -
Physiology & Behavior Feb 1985The ability of dihydrotestosterone (DHT) to maintain androgen-sensitive target tissue and masculine sexual behavior was examined in castrated male rats and guinea pigs....
The ability of dihydrotestosterone (DHT) to maintain androgen-sensitive target tissue and masculine sexual behavior was examined in castrated male rats and guinea pigs. Silastic capsules filled with DHT amd implanted subdermally at the time of castration were found to stimulate epididymal tissue in a dose-dependent manner in both species. However, differences were found in the behavioral effectiveness of this steroid. Capsules containing sufficient DHT to maintain peripheral structures were effective in maintaining copulatory behavior of castrated guinea pigs, but not of the similarly treated rats.
Topics: Animals; Castration; Copulation; Dihydrotestosterone; Dose-Response Relationship, Drug; Epididymis; Guinea Pigs; Male; Rats; Sexual Behavior, Animal
PubMed: 4001193
DOI: 10.1016/0031-9384(85)90123-4 -
Journal of Animal Science Jul 1985Eight long-term ovariectomized pony mares were treated with either dihydrotestosterone (DHT) benzoate (400 micrograms/kg body weight) in safflower oil or an equivalent...
Eight long-term ovariectomized pony mares were treated with either dihydrotestosterone (DHT) benzoate (400 micrograms/kg body weight) in safflower oil or an equivalent amount of oil every other day for 21 d to determine the effects of DHT on follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations in blood samples drawn once daily and after administration of three successive injections of gonadotropin releasing hormone (GnRH). The GnRH injections were given at 4-h intervals on the day following the last DHT or oil injection. Treatment with DHT benzoate did not alter (P greater than .10) concentrations of FSH or LH in daily blood samples relative to controls. The FSH and LH response, assessed by areas under the GnRH curves, decreased (P less than .05) from the first to third injection of GnRH when averaged over both groups of mares. There was no effect of DHT treatment on FSH response to GnRH. There was an interaction (P less than .05) between treatment and GnRH injection for LH areas; areas decreased (P less than .05) for DHT-treated mares from the first to third GnRH injection but were unchanged for control mares. It seems that DHT alone cannot mimic the stimulatory effects of testosterone on FSH production and secretion as observed in previous experiments with ovariectomized and intact mares. Moreover, because intact mares have been shown previously to respond to DHT treatment with an increase in GnRH-induced FSH secretion, it appears that some mechanism is lost in long-term ovariectomized mares, making them unresponsive to DHT treatment.
Topics: Animals; Castration; Dihydrotestosterone; Female; Follicle Stimulating Hormone; Horses; Luteinizing Hormone; Pituitary Hormone-Releasing Hormones
PubMed: 3928567
DOI: 10.2527/jas1985.611240x