5-alpha-reductase
Testosterone

Stimulatory effect of insulin on 5alpha-reductase type 1 (SRD5A1) expression through an Akt-dependent pathway in ovarian granulosa cells., 2010

Kayampilly PP, Wanamaker BL, Stewart JA, Wagner CL, Menon KM.

Endocrinology. 2010 Oct;151(10):5030-7. Epub 2010 Sep 1.

Metabolism of testosterone to 5-dihydro-testosterone

Metabolism of testosterone to 5-dihydrotestosterone is essential for initiation of the differentiation and development of the urogenital sinus into the prostate. Differentiation of male external genitalia (penis, scrotum and urethra) also strongly depends on the conversion of testosterone to 5-dihydrotestosterone in the urogenital tubercle, labioscrotal swellings and urogenital folds (9).
The irreversible conversion of testosterone to 5-dihydrotestosterone is catalyzed by the microsomal enzyme 5-alpha reductase. It converts testosterone into more potent Dihydrotestosterone (DTH).
There are two isoenzymes, steroid 5-alpha reductase 1 and 2 (SRD5A1 and SRD5A2):

1. Enzyme 5-reductase type 2 (SRD5A2) is NADPH dependent (10) figure 3.
   • The cDNA of the gene for 5-reductase type 2 codes for a protein of 254 amino acid residues with a predicted molecular mass of 28,398 Dalton (11) .
     The NH2-terminal part of the protein contains a subdomain supposedly involved in testosterone binding, while the COOH-terminal region is involved in NADPH-binding (12) .
   • The gene is located on chromosome 2 at locus 2p23. Elucidation of the organization of the 5-reductase type 2 gene revealed 5 coding exons (11) .
   • The enzyme has a pH optimum at pH 5.5 in broken cell preparations, but may function optimally in the native state in intact cells at neutral pH and has an apparent Km for testosterone of 4-50 nM. The apparent Km for NADPH is 3-10 <61549>M. High expression of 5-reductase type 2 is observed in prostate tissue.
   • Mutations and deletions in the 5-reductase type 2 gene have been found to be the molecular basis for the syndrome of 5-Reductase type 2 deficiency (12) .
2. The 5-reductase type 1 (SRD5A1) isozyme, also catalyzing the conversion of testosterone to 5-dihydrotestosterone, differs from the type 2 isozyme in its amino acid composition, kinetics, biochemical properties, substrate specificity, tissue distribution and pH optimum (10, 13 ).
   • The type 1 enzyme is not involved in androgen dependent male sexual differentiation.
   • The 5-reductase type 1 cDNA codes for a protein of 259 amino acid residues with a predicted molecular mass of 29,462 Dalton (13) . The gene is located on chromosome 5 at locus 5p15 (10).
   • The apparent Km for testosterone is 1-5 mM and for NADPH 3-10 mM. The expression of 5-reductase type 1 in prostate tissue is relatively low.
   • Male mice with a disruption of the 5-reductase type 1 gene have a normal phenotype and are fertile. However, female mice with a null allele, have a severe parturition defect, suggesting a role of 5-reduced androgens synthesized by the type 1 isozyme normal female physiology (14) .

The difference in pH optima between 5-reductase type 1 and type 2 enzymes can be used diagnostically for the differential assessment of the individual isoenzymes in genital skin fibroblasts of patients with the syndrome of 5-reductase deficiency ( 12 , 10).

Figure 3. Metabolism of Testosterone to 5a-Dihydrotestosterone by the enzyme 5a-Reductase type 2 (SDR5A2).

• 10. Russell DW., and Wilson JD. (1994) Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem 63, 25-61.
• 11. Andersson S., Berman DM., Jenkins EP., and Russell DW. (1991) Deletion of steroid 5 alpha-reductase 2: gene in male pseudohermaphroditism. Nature 354, 159-161.
• 12. Wilson JD., Griffin JE., and Russell DW. (1993) Steroid 5 alpha-reductase 2 deficiency. Endocr Rev 14, 577-593.
• 13. Andersson S., Bishop RW., and Russell DW. (1989) Expression cloning and regulation of steroid 5 alpha-reductase, an enzyme essential for male sexual differentiation. J Biol Chem 264, 16249-16255.
• 14. Mahendroo MS., Cala KM., and Russell DW. (1996) 5 alpha-reduced androgens play a key role in murine parturition. Mol Endocrinol 10, 380-392.

BJU Int. 2010 Nov;106(10):1444-51. doi: 10.1111/j.1464-410X.2010.09714.x.
5-α-Reductase inhibitors for prostate cancer chemoprevention: an updated Cochrane systematic review. 2010
Wilt TJ, Macdonald R, Hagerty K, Schellhammer P, Tacklind J, Somerfield MR, Kramer BS.

Minneapolis VA Center for Chronic Disease Outcomes Research, Minneapolis, MN 55417, USA. tim.wilt@va.gov
Abstract
OBJECTIVE: • To estimate the benefits and harms of 5-α-reductase inhibitors (5-α-RIs) in preventing prostate cancer.

MATERIALS AND METHODS: • We searched MEDLINE and the Cochrane Collaboration Library through June 2010 to identify randomized trials. • We included articles if they examined 5-α-RI vs control, were ≥ 1 year in duration and provided clinical outcomes. • Our primary outcome was prostate cancer period-prevalence 'for-cause'.

RESULTS: • Eight studies met inclusion criteria but only the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events were designed to assess the impact of 5-α-RIs on prostate cancer period-prevalence. The mean age of enrolees was 64 years, 92% were White, and mean PSA level was 3.1 ng/mL. For-cause prostate cancers comprised 54% of all cancers detected in placebo-controlled studies. • Compared with placebo, 5-α-RI resulted in a 25% relative risk (RR) reduction in prostate cancers detected for-cause [RR 0.75, 95% confidence interval (CI) 0.67-0.83; 1.4% absolute risk reduction (3.5% vs 4.9%)]. One BPH trial reported that the risk of prostate cancers detected for-cause was significantly reduced with dutasteride and combined dutasteride plus tamsulosin compared with tamsulosin monotherapy. • Six trials vs placebo assessed prostate cancers detected overall. There was a 26% RR reduction favouring 5-α-RI [RR 0.74, 95% CI 0.55-1.00; 2.9% absolute risk reduction (6.3% vs 9.2%)]. There were reductions across categories of age, race and family history of prostate cancer. • One placebo-controlled trial of men that investigators considered at greater risk for prostate cancer (based on age, elevated PSA level and having a previous suspicion of prostate cancer leading to a prostate biopsy) reported that dutasteride did not reduce prostate cancers detected for-cause based on needle-biopsy but did reduce risk of overall incident prostate cancer detected by biopsy by 23%[RR 0.77, 95% CI 0.70-0.85; absolute reduction 16.1% vs 20.8%]. There were reductions across age, family history of prostate cancer, PSA level, and prostate volume subgroups. • Incidences of erectile dysfunction, ejaculate volume, decreased libido, and gynaecomastia were greater with 5-α-RI vs placebo.

Prague Med Rep. 2009;110(3):222-30.
Finasteride treatment and neuroactive steroid formation.

Dusková M, Hill M, Hanus M, Matousková M, Stárka L.

Institute of Endocrinology, Prague, Czech Republic.

Finasteride is the 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostate hyperplasia and androgenetic alopecia. The 5alpha-reductase is enzyme responsible for the reduction of testosterone to dihydrostestosterone, progesterone to dihydroprogesterone and deoxycorticosterone to dihydrodeoxycorticosterone, steroids modulating the action of gamma-aminobutyric acid on GABA receptors. These neuroactive steroids possess anticonvulsant, antidepressant and anxiolytic effects. The objective of the study was to determine the effect of finasteride therapy on a broad steroid spectrum in men with benign prostate hyperplasia. A group of 20 men with benign prostate hyperplasia was involved in the present study. Finasteride in the daily dose of 5 mg/day was administrated for 4 months. In all individuals, their hormonal profile of steroid hormones was determined before and after 4 months lasting finasteride treatment. Finasteride treatment resulted in a significant decrease all alpha-reduced and increase of most 5beta-reduced metabolites of testosterone and progesterone as well as in an increase of 7alpha-hydoxyderivatives, which are known as neuroactive steroids acting by modulation of GABAA and NMAD receptors in the brain. In the course of finasteride treatment the decrease of the concentration of circulating steroids with known inhibitory activity on GABA-ergic excitation in the brain is very probably an important factors contributing to the development of the symptoms of depression seen in some isolated cases of finasteride administration.