Beyond the Abstract - Potential prostate cancer drug target: Bioactivation of androstanediol by conversion to dihydrotestosterone, by James L. Mohler, MD, Mark A. Titus, PhD and Elizabeth M. Wilson, PhD


Conversion of androstanediol to DHT by 17b-hydroxysteroid dehydrogenase-6 is a new target for prostate cancer drug therapy

Morbidity associated with advanced prostate cancer continues even though encouraging efforts are underway to identify and administer drugs that target the androgen receptor (AR) and enzymes that catalyze the synthesis of its high affinity ligands. AR is activated by testosterone, the major circulating active androgen derived from the testis, or its more potent 5α-reduced metabolite, dihydrotestosterone (DHT). The persistence of intratumoral DHT despite removal of circulating testosterone by medical or surgical castration suggests that androgens continue to activate AR and drive prostate cancer recurrence and growth during androgen deprivation therapy. (1, 2)

In the classical pathway for DHT synthesis, testosterone is a major intermediate and 17a-hydroxylase/17,20-lyase (P450c17) -- the enzyme targeted for inhibition by abiraterone acetate -- catalyzes multiple steps in the conversion of cholesterol to DHT. Several 5a-reductase enzymes targeted for inhibition by finasteride and dutasteride convert testosterone to DHT. Temporary remediation by surgical or medical castration or by the administration of these androgen biosynthetic inhibitors support a reliance on AR for prostate cancer growth. Failure to achieve long-term benefit suggests a versatility of AR to remain active in the genetically unstable environment of prostate cancer cells.

Earlier work in marsupials highlighted a second pathway for DHT synthesis in which 17a-hydroxyprogesterone, androsterone and androstanediol are intermediates rather than testosterone. Several aldo-keto reductases such as AKR1C2 and AKR1C4 have 3a-hydroxysteroid dehydrogenase activity that catalyzes the reduction of 5α-dihydroprogesterone (5α-pregnane-3,20-dione) to 3a-hydroxydihydroprogesterone (allopregnanolone), followed by conversion to androsterone, androstanediol and DHT. This so-called backdoor pathway of DHT synthesis was shown recently to be required for fetal male sex development. (3) Naturally occurring mutations in AKR1C2 and AKR1C4 aldo-keto reductase genes caused severe under virilization in 46XY genetic males at birth. In contrast, expression of these enzymes is low in the adult testis, but AKR1C2 and AKR1C3 levels increase in castration-recurrent prostate cancer tissue. (4) The backdoor pathway also may be implicated in the in utero virilization of females with 21-hydroxylase deficiency who accumulate high levels of the 17a-hydroxyprogesterone intermediate.

A major oxidative enzyme responsible for the conversion of androstanediol to DHT is 17b-hydroxysteroid dehydrogenase-6 (17b-HSD-6), known also as retinol dehydrogenase (RODH) 3a-HSD. (5, 6) The presence of 17b-HSD-6 at higher levels in normal and malignant prostate cells compared to other cell types suggests that the synthesis of DHT from androstanediol is a normal function of the prostate. Injection of androstanediol into castrated immunodeficient mice bearing a castration-recurrent human prostate cancer xenograft demonstrated further the capacity of prostate cancer cells to synthesize DHT from androstanediol.

Persistence of testosterone and DHT in prostate cancer tissue during androgen deprivation therapy likely results from redundancy in the classical and backdoor biosynthetic pathways. Longer term effectiveness of drugs that inhibit 5α-reductase or 17a-hydroxylase/17,20-lyase activity may be improved by combination therapies that include inhibitors of 17b-HSD-6. On the other hand, redundancy in DHT metabolism makes this approach challenging. Complete elimination of prostate cancer tissue androgen in prostate cancer cells that have increased coactivator expression and AR phosphorylation may be required to inhibit transcriptional activity of the hypersensitive AR that responds to very low levels of androgen. Whether AR can drive prostate cancer recurrence and growth in the frank absence of tissue androgen remains to be established.



  1. Mohler JL, Gregory CW, Ford OH, Kim D, Weaver CM, Petrusz P, Wilson EM, French FS 2004 The androgen axis in recurrent prostate cancer. Clin. Cancer Res. 10:440–448
  2. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL 2005 Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin. Cancer Res. 11:4653–4657
  3. Flück CE, Meyer-Böni M, Pandey AV, Kempná P, Miller WL, Schoenle EJ, Biason-Lauber A 2011 Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation. Am. J. Hum. Genet. 89:201–218
  4. Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG, Balk SP 2006 Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 66:2815–2825
  5. Mohler JL, Titus MA, Bai S, Kennerley BJ, Lih FB, Tomer KB, Wilson EM 2011 Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res. 71:1486–1496
  6. Mohler JL, Titus MA, Wilson EM. 2011 Potential prostate cancer drug target: Bioactivation of androstanediol by conversion to dihydrotestosterone. Clin. Cancer Res.17(18):5844-9.


Written by:
James L. Mohler, MD, Mark A. Titus, PhD and Elizabeth M. Wilson, PhD as part of Beyond the Abstract on This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.


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