3α-Androstanediol Kinetics in Man

Kinouchi, Toshi; Horton, Richard

doi:10.1172/jci107802

Cited by 56 publications

(23 citation statements)

References 23 publications

(20 reference statements)

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“…In man, secreted testosterone is peripherally converted into DHT and 3adiol by nongonadal tissues and a majority of both androgens in blood are derived from secreted testosterone (11,12). The importance of these observations was increased when it became clear that DHT conversion did not occur in muscle (13), and we have demonstrated that both DHT and 3adiol are derived from conversion in extrasplanchnic tissue (14).…”

mentioning

confidence: 70%

“…[14C]testosterone and [3H]3adiol were given by constant infusion over a 2-h period as described (11,12 for correction of losses and the plasma extracted with solvent as described (14). The dried extracts were then chromatographed on a celite column (18), collecting testosterone, DHT, and 3adiol fractions.…”

Section: Methodsmentioning

confidence: 99%

“…The conversion ratios (testosterone-DHT, DHT-3adiol, and 3adiol-DHT) were determined as described (11,12) as the ratio of counts in plasma as product and precursor steroid.…”

Section: Methodsmentioning

confidence: 99%

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Alteration in the metabolism of dihydrotestosterone in elderly men with prostate hyperplasia.

Morimoto¹,

Edmiston²,

Horton³

1980

J. Clin. Invest.

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A B S T R A C T In vivo androgen kinetics were determined in six young (21-49 yr) and elderly men (62-77 yr) with prostate hyperplasia (BPH). Steadystate infusions of [14C]testosterone and [3H]androstanediol (3adiol) were given, which allowed determination of the conversions testosterone -* dihydrotesterone (DHT) ti 3adiol. These infusions also yield metabolic clearance data which, together with measurement of nonisotopic steroid levels, yield estimations of blood production rates. The production rate for testosterone was 6.04±+1.66 vs. 3.69+±0.62 mg/d, whereas the production rate for 3adiol was 319±57 and 193+34 ,tg/d (P < 0.05 both groups). The irreversible conversion rate of testosterone to DHT was 3.1+0.4 and 3.5±0.9% (NS). The back conversion of 3adiol to DHT was high (68+25 vs. 81±+17, NS) indicating that 3adiol might cause BPH as a result of conversion to DHT in vivo. The conversion of DHT to 3adiol is reduced in the elderly group (15.8±2.6 and 6.3+1.4, P < 0.001). Since DHT formation in the prostate is a key event in development of BPH and blood DHT appears to be a measure of extrasplanchnic sexual target tissue activity, our in vivo studies suggest that the tissue increase in DHT may result from reduced metabolism and the activity of 3a-oxidoreduction favors the oxidative pathway in elderly men.

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confidence: 70%

Section: Methodsmentioning

confidence: 99%

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Alteration in the metabolism of dihydrotestosterone in elderly men with prostate hyperplasia.

Morimoto¹,

Edmiston²,

Horton³

1980

J. Clin. Invest.

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“…RIA measurements of 5α-androstan-3α,17β-diol glucuronide levels revealed that this metabolite was also present at background levels in the sera of type 2-deficient and type 1-and 2-deficient mice. This steroid is produced from DHT by reductive 3α-hydroxysteroid dehydrogenases, and its presence in the plasma of humans is directly proportional to the level of DHT (34)(35)(36). Inasmuch as these findings translate to the mouse, the absence of 5α-androstan-3α,17β-diol glucuronide from the knockout animals suggests that circulating levels of DHT are, in fact, very low or absent.…”

Section: Discussionmentioning

confidence: 96%

Unexpected Virilization in Male Mice Lacking Steroid 5α-Reductase Enzymes

et al. 2001

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Mice lacking steroid 5α-reductase 1 and 2 were produced by gene targeting and breeding. Male mice without 5α-reductase 2 or without both enzymes had fully formed internal and external genitalia and were fertile, but had smaller prostates and seminal vesicles than controls. T accumulated to high levels in the reproductive tissues of the mutant mice. DHT administration increased seminal vesicle and coagulating gland weights in mice deficient in 5α-reductase 2 and increased the weights of the prostate, seminal vesicle, and coagulating gland in animals deficient in both enzymes. An inhibitor of both 5α-reductases (GI 208335X) decreased prostate and coagulating gland weights of control mice, but had no effect in those lacking 5α-reductase 1 and 2. Castration reduced the sizes of these tissues in animals of all genotypes. Androgen-dependent gene expression was decreased in the seminal vesicles of mice lacking one or more 5α-reductases and was restored by administration of T or DHT. Female mice missing both enzymes exhibited parturition and fecundity defects similar to those of animals without 5α-reductase 1. We conclude that T is the only androgen required for differentiation of the male urogenital tract in mice and that the synthesis of DHT serves largely as a signal amplification mechanism.The formation of the human male phenotype requires T and DHT, which act through the AR to direct the virilization of different genital anlagen (1). T is necessary for differentiation of the Wolffian ducts into the seminal vesicles, epididymes, and ejaculatory ducts, whereas DHT is needed for the differentiation of the urogenital sinus and genital tubercle into the prostate, urethra, penis, and scrotum. The involvement of distinct androgens in these two developmental pathways is most clearly evidenced in patients with defects in the formation of T or DHT. Mutations that decrease the synthesis of T affect both developmental pathways, as T serves as a metabolic precursor of DHT (2). In contrast, a decrease in the synthesis of DHT is associated only with defects in the virilization of the urogenital sinus and genital tubercle (3,4). Studies in male rats with pharmacological inhibitors support a two-androgen model of phenotypic sexual differentiation in this species (5-7); however, it is not clear whether the requirement for T and DHT in the formation of the male phenotype extends across the mammalian class or why this need exists. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe conversion of T to DHT is catalyzed by steroid 5α-reductase, a membrane-bound enzyme that uses NADPH as a cofactor to reduce the Δ 4,5 bonds of various substrates (8).There are two 5α-reductase genes, and their encoded proteins, designated type 1 and type 2, share approximately 50% sequence identity (9). The enzymes have divergent biochemical and pharmacological properties, and they exhibit different tissue-specific and cell typespecific expression patterns that reflect their biological roles. For example, t...

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“…Studies in the rat, dog, marsupial and human also indicate that circulating 3α-diol can be oxidized back to 5α-DHT (Orlowski et al, 1983;Walsh and Wilson, 1976;DeKlerk et al, 1979;Jacobi et al, 1977; Liehy et al, 2001;Shaw et al, 2000;). In fact 50% of an administered dose of 3α-diol in humans was converted to 5α-DHT within the prostate, indicating that the back conversion is significant in androgen action (Horst et al, 1975;Kinouchi and Horton 1974). Backdoor pathways to 5α-DHT using 3α-diol as a precursor have been proposed in which the production of DHT "by-passes" the formation of Δ 4 -androstene-3,17-dione and testosterone, (Auchus, 2004).…”

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confidence: 99%

Pre-receptor regulation of the androgen receptor

Penning

Jin

Rižner

et al. 2008

Molecular and Cellular Endocrinology

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The human androgen receptor (AR) is a ligand activated nuclear transcription factor and mediates the induction of genes involved in the development of the male phenotype and male secondary sex characteristics, as well as the normal and abnormal growth of the prostate. We have identified the pair of hydroxysteroid dehydrogenases (HSDs) that regulate ligand access to the AR in human prostate. We find that type 3 3α-HSD (aldo-keto reductase (AKR)1C2) catalyzes the NADPH dependent reduction of the potent androgen 5α-dihydrotestosterone (5α-DHT) to yield the inactive androgen 3α-androstanediol (3α-diol). We also find that RoDH like 3α-HSD (RL-HSD) catalyzes the NAD + dependent oxidation of 3α-diol to yield 5α-DHT. Together these enzymes are involved in the pre-receptor regulation of androgen action. Inhibition of AKR1C2 would be desirable in cases of androgen insufficiency and inhibition of RL-HSD might be desirable in benign prostatic hyperplasia. KeywordsHydroxysteroid dehydrogenase; aldo-keto reductase; short chain dehydrogenase; benign prostatic hyperplasia; prostate cancer Pre-receptor regulation of steroid hormone actionSteroid hormone receptors [androgen receptor (AR), estrogen receptor, progesterone receptor, glucocorticoid receptor (GR), and mineralocorticoid receptor (MR)] are ligand-activated nuclear receptors (Carcon-Jurica et al., 1990;Evans, 2005). The activated receptors bind to hormone response elements on hormone responsive genes resulting in gene expression in target tissues (Truss and Beato, 1993). Ligand specific conformational changes on the receptor determine the recruitment of co-activators and co-repressors in a tissue specific manner, and as a result tissue specific effects on gene transcription can be observed (Shibata et al., 1997). This is the pharmacological basis for the mechanism of action of selective steroid receptor modulators (especially partial agonists). Often the co-activators and co-repressors are involved in chromatin remodeling and act as histone-acetyl transferases and histone-deacetylases (Liu et al., 1999). Thus multiprotein complexes determine changes in gene transcription mediated by nuclear receptor ligands and the rational design of therapeutics targeting these complexes is challenging. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Another level of steroid receptor regulation involves the control of steroid ligands for their respective nuclear receptors. This pre-receptor regulation for steroid hormone action was first documented with the type 2 and type 1 11β-hydroxysteroid dehydrogenases (HSDs) (Funder et al., 1988;Wh...

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3α-Androstanediol Kinetics in Man

Cited by 56 publications

References 23 publications

Alteration in the metabolism of dihydrotestosterone in elderly men with prostate hyperplasia.

Alteration in the metabolism of dihydrotestosterone in elderly men with prostate hyperplasia.

Unexpected Virilization in Male Mice Lacking Steroid 5α-Reductase Enzymes

Pre-receptor regulation of the androgen receptor

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