Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels

Abstract

Benefits associated with lowered serum DHT levels after 5α-reductase inhibitor (5AR-I) therapy in men have contributed to a misconception that circulating DHT levels are an important stimulus for androgenic action in target tissues (e.g., prostate). Yet evidence from clinical studies indicates that intracellular concentrations of androgens (particularly in androgen-sensitive tissues) are essentially independent of circulating levels. To assess the clinical significance of modest elevations in serum DHT and the DHT/testosterone (T) ratio observed in response to common T replacement therapy, a comprehensive review of the published literature was performed to identify relevant data. Although the primary focus of this review is about DHT in men, we also provide a brief overview of DHT in women. The available published data are limited by the lack of large, well-controlled studies of long duration that are sufficiently powered to expose subtle safety signals. Nonetheless, the preponderance of available clinical data indicates that modest elevations in circulating levels of DHT in response to androgen therapy should not be of concern in clinical practice. Elevated DHT has not been associated with increased risk of prostate disease (e.g., cancer or benign hyperplasia) nor does it appear to have any systemic effects on cardiovascular disease safety parameters (including increased risk of polycythemia) beyond those commonly observed with available T preparations. Well-controlled, long-term studies of transdermal DHT preparations have failed to identify safety signals unique to markedly elevated circulating DHT concentrations or signals materially different from T.

Figure 1.

Metabolism pathways for deactivation of DHT to inactive glucuronides. Enzymes and genes associated with pathways are noted next to arrows. Relative thickness/size of arrows represents primary direction of reaction. Compiled from (6, 7, 8). 3α-DH, 3α-dehydrogenase; 3β-DH, 3β-dehydrogenase; HSD2, 17β-hydroxysteroid dehydrogenase type 2; HSD3, 17β-hydroxysteroid dehydrogenase type 3; HSD5, 17β-hydroxysteroid dehydrogenase type 5; HSD7, 17β-hydroxysteroid dehydrogenase type 7; HSD8, 17β-hydroxysteroid dehydrogenase type 8; HSD10, 17β-hydroxysteroid dehydrogenase type 10; HSD11, 17β-hydroxysteroid dehydrogenase type 11; SRD5A1, 5α-reductase type 1; SRD5A2, 5α-reductase type 2 (the 5α-reductase gene that predominates in androgen-sensitive tissue); SRD5A3, 5α-reductase type 3; UGT2, B7, UDP-glucuronyltransferase type 2 isozyme B7; UGT2, B15, UDP-glucuronyltransferase type 2 isozyme B15; UGT2, B17, UDP-glucuronyltransferase type 2 isozyme B17.

Figure 2.

Mean (± standard error of the mean) serum DHT and T response to transdermal DHT therapy over 24 months of treatment in middle-aged men. Shaded region of each graph represents normal ranges for DHT or T. To convert T and DHT to ng/dL, values must be divided by 0.0347 or 0.0345, respectively. Redrawn from Idan et al. (54).

Figure 3.

The classical and “back-door” pathways of androgen biosynthesis. In the classical pathway (solid gray arrow), C21 precursors (pregnenolone and progesterone) are converted to the C19 adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione by the sequential hydroxylase and lyase activities of CYP17A1. Circulating adrenal androgens [including dehydroepiandrosterone-sulfate (DHEA-S)] enter the prostate and can be converted to T by a series of reactions involving the activity of HSD3B, HSD17B, and aldo/keto reductase (AKR1C) enzymes. T is then converted to the potent androgen DHT by the activity of SRD5A. In the back-door pathway to DHT synthesis (short gray arrows), C21 precursors are first acted upon by SRD5A and the reductive 3α-hydroxysteroid dehydrogenase (3α-HSD) activity of AKR1C family members, followed by conversion to C19 androgens via the lyase activity of steroid 17α-monooxygenase (CYP17A) and subsequently to DHT by the action of HSD17B3 and an oxidative 3α-HSD enzyme. Redrawn from Mostaghel and Nelson (4).

Figure 4.

Results from REDUCE trial showing cancer risk vs baseline serum androgen concentration. Locally weighted scatterplot smoothing of serum levels of T and DHT at baseline and final cancer status after considering all biopsies during 4 years of the REDUCE trial. The overlapping circles on the top and bottom of the chart represent each individual case. Cancer risk with individuals overlapping circles of subjects with cancer were scored as 1, whereas subjects without cancer were scored as 0. Shaded regions of each graph depict eugonadal ranges for T and DHT. To convert T and DHT to ng/dL, divide by 0.0347 or 0.0345, respectively. Redrawn from Muller et al. (3).

Figure 5.

Regression graphs depicting the associations between levels of total and free DHT and ischemic stroke risk (Panel A), incident CVD risk (Panel B) and all-cause mortality risk (Panel C) in older normal men. Redrawn from Shores et al. (95, 96).

Figure 6.

Overview of the effects of DHT on various pathways in adipose tissues. + indicates upregulation, and – indicates downregulation of grouped genes. Collectively, DHT modulates several pathways involved in energy metabolism and promotes lipid use by multiple mechanisms. See original reference for list of full gene names. Redrawn from Bolduc et al. (170). acetyl-coA, acetyl co-enzyme A; FA, fatty acid; Lpl, lipoprotein lipase; NADPH, nicotinamide adenine dinucleotide phosphate.