Finasteride Mechanism of Action: The Full Enzymatic Pathway Explained

What enzymatic step does finasteride block?

Finasteride blocks the conversion of testosterone to DHT by Type II 5-alpha-reductase. The label describes two isoenzymes. Type I is predominant in the sebaceous glands of most regions of skin, including the scalp, and in the liver, and is responsible for about one-third of circulating DHT. Type II is found mainly in the prostate, seminal vesicles, epididymides, hair follicles, and liver, and is responsible for two-thirds of circulating DHT [1].

Finasteride is a competitive and specific inhibitor of Type II, with about 100-fold selectivity over Type I in native scalp and prostate tissue. The label gives IC50 values of 4.2 nM for Type II and 500 nM for Type I [1]. Because the target is the enzyme rather than the androgen receptor, finasteride lowers the amount of DHT available to bind the receptor; it does not block the receptor itself [1]. In cultured genital skin fibroblasts from a patient with 5-alpha-reductase deficiency, DHT bound the human androgen receptor with about twice the affinity of testosterone [3].

How does finasteride interact with the enzyme?

Finasteride binds the Type II enzyme, and the inhibition is accompanied by reduction of finasteride to dihydrofinasteride and formation of an adduct with NADP+ [1]. The label describes a stable enzyme complex that turns over extremely slowly: the half-life is about 30 days for the Type II complex and 14 days for the Type I complex [1]. The plasma half-life is about 5 to 6 hours in men 18 to 60 and about 8 hours in men over 70, so the effect on DHT outlasts the time the drug stays in plasma [1].

How much does finasteride lower DHT?

The Propecia label states that a 1 mg tablet produces a rapid reduction in serum DHT, reaching 65% suppression within 24 hours [1]. A 42-day biopsy study of 249 men with androgenetic alopecia tested 0.01, 0.05, 0.2, 1, and 5 mg daily against placebo. At 1 mg, scalp skin DHT fell 64.1% and serum DHT fell 71.4%; at 5 mg, scalp DHT fell 69.4% and serum DHT fell 72.2%. Doses as low as 0.2 mg maximally decreased both scalp and serum DHT in that study [2].

What happens to testosterone and estradiol?

The label states that mean circulating testosterone and estradiol increased by approximately 15% compared with baseline, but remained within the physiologic range [1]. Finasteride has no affinity for the androgen receptor and no androgenic, antiandrogenic, estrogenic, antiestrogenic, or progestational effects [1].

How does DHT suppression translate into hair growth?

Androgenetic alopecia is caused by androgen-dependent miniaturization of scalp hair follicles, and scalp DHT is implicated as a contributing cause [6]. Finasteride lowers scalp and serum DHT, but the label states the relative contributions of these reductions to the treatment effect have not been defined [1].

In two 1-year trials, 1,553 men aged 18 to 41 with male pattern hair loss received finasteride 1 mg daily or placebo; 1,215 continued in blinded extensions for a second year. Hair count in a 1-inch (5.1 cm2) circle of vertex scalp was 107 hairs higher than placebo at 1 year and 138 higher at 2 years (P<0.001), with placebo-treated men continuing to lose hair [6]. The label says daily use for three months or more is generally necessary before benefit is observed, continued use is needed to sustain benefit, and withdrawal leads to reversal of effect within 12 months [1].

What does the same pathway do in the prostate?

The prostate is a Type II-rich tissue, and the Proscar label states that prostate development and enlargement depend on DHT. Type II 5-alpha-reductase converts testosterone to DHT in the prostate gland, liver, and skin, and DHT binds androgen receptors in the cell nuclei of these organs [7]. Proscar 5 mg is indicated for symptomatic benign prostatic hyperplasia in men with an enlarged prostate to improve symptoms, reduce the risk of acute urinary retention, and reduce the need for surgery [7]. The label also states Proscar is not approved for prevention of prostate cancer [7].

In the Proscar Long-Term Efficacy and Safety Study, 3,040 men with moderate to severe benign prostatic hyperplasia were randomized to 5 mg finasteride or placebo for 4 years. Surgery for benign prostatic hyperplasia was performed in 5% of the finasteride group versus 10% of placebo, a 55% reduction. Acute urinary retention occurred in 3% versus 7%, a 57% reduction. Mean symptom score fell 3.3 points with finasteride versus 1.3 with placebo (P<0.001), and prostate volume also decreased significantly [8].

Which tablet is approved for what?

Propecia is the 1 mg tablet, indicated for male pattern hair loss in men only and not indicated for women [4][1]. Proscar is the 5 mg tablet, indicated for benign prostatic hyperplasia [5]. The 42-day biopsy study found that 0.2 mg per day already maximally decreased scalp and serum DHT in the men tested, and 1 mg and 5 mg produced similar reductions [2]. The label's recommended hair-loss dose is one 1 mg tablet once daily; the benign prostatic hyperplasia dose is one 5 mg tablet once daily [1][7].

What finasteride does not do

Finasteride does not bind the androgen receptor [1]. It does not have androgenic, antiandrogenic, estrogenic, antiestrogenic, or progestational effects according to the label [1]. It does not appear to affect the cytochrome P450 system, and no clinically important interactions were identified with antipyrine, digoxin, propranolol, theophylline, or warfarin [1]. Finasteride itself is extensively metabolized in the liver mainly by CYP3A4 [1].

What the label says about PSA and pregnancy

Propecia lowered mean PSA from 0.7 to 0.5 ng/mL at month 12 in men aged 18 to 41, and the Proscar label says PSA falls about 50% within six months [1][7]. The label says any confirmed increase from the lowest PSA value while on treatment should be evaluated for prostate cancer, even if the value is still within the normal range for men not taking a 5-alpha-reductase inhibitor [1][7].

Pregnancy is a contraindication. The label says women who are or may be pregnant must not take finasteride and must not handle crushed or broken tablets because of the risk of abnormal external genitalia in a male fetus [1].