5-alpha-reductase deficiency and finasteride
The enzyme 5-alpha-reductase converts testosterone into dihydrotestosterone (DHT), a more potent androgen (male sex hormone), inside target tissues.
Remember
When the enzyme that makes DHT is underactive, testosterone is normal but DHT is low, so DHT-dependent tissues such as the prostate and facial and body hair show reduced androgen effects. Finasteride lowers DHT by blocking the enzyme while testosterone is still made.
Memory aid
testosterone is the message sent round the body and DHT is the amplified version made where it is needed
Use the picture to recall that the enzyme makes the stronger form of the hormone inside the tissue that needs it, not in the gland that makes testosterone.
Testosterone is the main androgen in the blood. In some target tissues (the tissues that receive the hormone), the enzyme 5α-reductase converts it into dihydrotestosterone (DHT), a more potent androgen. DHT acts through the same androgen receptor (the protein inside target cells that androgens bind to) and gives a stronger signal through it.
The enzyme acts inside the target tissue rather than in the gland that makes the hormone. Testosterone itself is enough for muscle development and voice deepening. DHT is needed for the prostate, the external genitalia (the outer sex organs) and male-pattern facial and body hair.
So when 5α-reductase is deficient, muscle and voice changes are normal, but DHT-dependent features lag behind. Classically, the external genitalia are also affected from birth, and puberty brings only partial virilisation (male-type development). The usual cause is a mutation in the SRD5A2 gene (the type 2 form of the enzyme). It occurs in a genetic male with a 46,XY karyotype (the usual male chromosome pattern). Serum testosterone is normal or even raised, while DHT is low.
Finasteride and dutasteride are 5α-reductase inhibitors, so they reduce DHT formation while testosterone is still made. Finasteride is used in benign prostatic hyperplasia (non-cancerous enlargement of the prostate) and in male-pattern baldness. Dutasteride is also used in benign prostatic hyperplasia. Sexual side effects can occur.
The classic confusion is between enzyme blockers and receptor blockers. Bicalutamide, flutamide and cyproterone acetate block the androgen receptor instead, so blocking the receptor does not stop DHT being made (cyproterone acetate also suppresses testicular androgen production). Finasteride reduces the supply of DHT, whereas the receptor blockers cut the signal.
Key facts
- Enzyme
- 5α-reductase converts testosterone to the more potent dihydrotestosterone (DHT) in target tissues.
- Hormone levels in deficiency
- serum testosterone is normal or even raised while DHT is low.
- DHT-dependent features
- the prostate, the external genitalia and male-pattern facial and body hair.
- Testosterone alone
- muscle development and voice deepening can occur with testosterone alone.
- Genetics
- the usual cause is a mutation in the SRD5A2 gene (the type 2 form of the enzyme), inherited in an autosomal recessive way, meaning both copies of the gene are affected.
- Finasteride and dutasteride
- they inhibit 5α-reductase, so less testosterone is converted to DHT.
- Uses of finasteride
- benign prostatic hyperplasia (non-cancerous enlargement of the prostate) and male-pattern baldness.
Exam traps
- Bicalutamide does not inhibit 5α-reductase. It is an antagonist at the androgen receptor, so DHT is still made but cannot act on its receptor.
- Aromatase also acts on testosterone, but its product is an oestrogen, not a stronger androgen, so it does not amplify androgen action.
- Failure of the Leydig cells (the testosterone-producing cells of the testes) would give a low serum testosterone. If serum testosterone is normal, as in 5α-reductase deficiency, the problem lies in how the hormone is activated, not in how it is made.
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