A Comparative Study of the Conversion of Testosterone to 17β-Hydroxy-5α-androstan-3-one (Dihydrotestosterone) by Prostate and Epididymis

Gloyna, Robert E.; Wilson, Jean D.

doi:10.1210/jcem-29-7-970

Cited by 286 publications

(100 citation statements)

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“…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). This work indicates that DHT and 3adiol production measured in the circulation may be a reflection of events occurring in sexual target tissue.…”

mentioning

confidence: 70%

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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mentioning

confidence: 70%

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

Morimoto¹,

Edmiston²,

Horton³

1980

J. Clin. Invest.

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“…Principal cells are the major cell type of this tissue (Trasler et al 1988) and are particularly sensitive to androgen removal (Moore & Bedford 1979a,b). The major circulating androgen testosterone is metabolized by 5a-reductases into the potent androgen 5a-dihydrotestosterone (DHT; Gloyna & Wilson 1969, Monsalve & Blaquier 1977, Robaire et al 1977. Androgens mediate their effects by diffusing through the plasma membrane and binding to intracellular androgen receptors (ARs).…”

Section: Introductionmentioning

confidence: 99%

Androgens activate mitogen-activated protein kinase via epidermal growth factor receptor/insulin-like growth factor 1 receptor in the mouse PC-1 cell line

Hamzeh¹,

Robaire²

2011

Journal of Endocrinology

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Androgens are the primary regulators of epididymal structure and functions. In the classical view of androgen action, binding of androgen to the intracellular androgen receptor (AR) produces the receptor-steroid complex that has high affinity for DNA response elements and regulates the transcription of target genes. In this study, we demonstrate that in epididymal cells, 5a-dihydrotestosterone (DHT) can cause an alternative and rapid response that is independent of AR-DNA interactions and is mediated by activation of signaling pathways through the AR. We examined changes in AKT and extracellular signal-regulated protein kinases (ERK1/2) activation at early time points after DHT supplementation in the mouse proximal caput epididymis-1 cell line. DHT had no significant effect on AKT activation at any time point. However, DHT activated the ERK pathway as early as at 1 min, the pathway remained activated at 10 min, but activation was not sustained at later time points. Interestingly, ERK activation was blocked by hydroxyflutamide (HF), indicating that early ERK activation was an AR-mediated response. DHT phosphorylates steroid receptor co-activator (SRC) kinase, and this activation was required for the ERK response. EGFR and IGF1R were downstream of SRC, and these two receptors together contributed to enhance ERK and cAMP response elementbinding protein (CREB) phosphorylation. We postulate that this rapid action of androgen may ultimately act to modulate the transcription of genes regulated by AR in the nucleus. These results support the hypothesis that DHT can activate a pathway involving the sequential activation of MEK, ERK1/2, and CREB through the EGFR/IGF1R in an epididymal cell line.

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“…More specifically, several studies have clearly shown that the primary androgen acting in this tissue is dihydrotestosterone (DHT) (Gloyna & Wilson 1969, Tindall et al 1972, Orgebin-Crist et al 1976, Turner et al 1984. 5a-Reductase (EC 1.3.1.22) is the enzyme that catalyzes the conversion of testosterone to DHT.…”

Section: Introductionmentioning

confidence: 99%

Region-specific expression of androgen and growth factor pathway genes in the rat epididymis and the effects of dual 5α-reductase inhibition

Henderson¹,

Cooke²,

Robaire³

2006

Journal of Endocrinology

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Dihydrotestosterone (DHT) is the primary androgen acting in the epididymis, the site of sperm maturation. Previously, we showed that the treatment of male rats with PNU157706, an inhibitor that acts on both isoforms of 5a-reductase to prevent DHT formation, has effects on the expression of genes implicated in processes that create the optimal luminal microenvironment required for sperm maturation, and on sperm maturation itself. However, signaling pathways involved in regulating or mediating DHT actions in the epididymis remain largely unknown. The goals of this study were to determine the expression profiles of potential signaling systems in the epididymis and assess their DHTdependence using two different dual 5a-reductase inhibitors. Rats were untreated or gavaged with vehicle, 10 mg/kg per day PNU157706 or 32 mg/kg per day FK143 for 28 days and epididymal gene expression was analyzed. Gene array analysis revealed analogous effects of FK143 on overall epididymal gene expression when compared with previous PNU157706 studies. Quantitative RT-PCR analysis of the expression of the 5a-reductase isozymes, androgen receptor, and members of the IGF, FGF, TGF, and VEGF families revealed novel region-specific expression profiles in the epididymis that were differentially affected by 5a-reductase inhibition; the two inhibitors had parallel effects. Specifically, in proximal regions, 5a-reductase 1, androgen receptor, and TGF-b1 expression increased after treatment, while in distal regions expression of IGF-I, IGFBP-5, IGFBP-6, and FGF-10 decreased. These results provide insight into epididymal signaling mechanisms and indicate potential candidates acting either upstream or downstream of DHT to regulate and/or mediate its actions in the epididymis.

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A Comparative Study of the Conversion of Testosterone to 17β-Hydroxy-5α-androstan-3-one (Dihydrotestosterone) by Prostate and Epididymis

Cited by 286 publications

References 1 publication

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

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

Androgens activate mitogen-activated protein kinase via epidermal growth factor receptor/insulin-like growth factor 1 receptor in the mouse PC-1 cell line

Region-specific expression of androgen and growth factor pathway genes in the rat epididymis and the effects of dual 5α-reductase inhibition

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