Finasteride History and Development: From Prostate Drug to Hair Loss Treatment

What exactly does finasteride block?

Finasteride is a competitive, specific inhibitor of type II 5-alpha reductase, the enzyme that converts testosterone into dihydrotestosterone (DHT) [3]. The type II isozyme sits mainly in the prostate, seminal vesicles, epididymides and hair follicles, and it accounts for about two-thirds of circulating DHT; finasteride binds it roughly 100 times more readily than the type I isozyme [3]. A single 1 mg tablet suppresses serum DHT by 65% within 24 hours, mean testosterone and estradiol rise by about 15% but stay within the normal range, and the drug has no affinity for the androgen receptor [3].

Finasteride does not occupy the androgen receptor; it blocks the conversion step upstream [3]. The label also notes that the genital abnormalities produced when pregnant animals are exposed to finasteride resemble those reported in male infants born with genetic 5-alpha reductase deficiency [3].

What was Proscar approved to treat?

Proscar, the 5 mg tablet, was approved on June 19, 1992, as a type 1 new molecular entity on priority review [1]. Its label covers symptomatic benign prostatic hyperplasia in men with an enlarged prostate: improving symptoms, reducing the risk of acute urinary retention, and reducing the risk of surgery including transurethral resection of the prostate and prostatectomy [4]. Proscar is also approved with the alpha-blocker doxazosin to reduce the risk of symptomatic BPH progression [4].

The 4-year Proscar Long-Term Efficacy and Safety Study randomized 3,040 men aged 45 to 78 with moderate to severe symptoms and an enlarged prostate [6][4]. Surgery for BPH was performed in 5% of the finasteride group versus 10% of the placebo group over four years, a 55% risk reduction (95% CI 41 to 65), and acute urinary retention developed in 3% versus 7%, a 57% reduction (95% CI 40 to 69) [6]. Mean symptom score fell 3.3 points on finasteride and 1.3 points on placebo [6].

When did the hair-loss version arrive?

Propecia, the 1 mg tablet, was approved on December 19, 1997 [2]. Drugs@FDA lists the approval type as 3, new dosage form [2]. The indication is male pattern hair loss in men only; the label states that efficacy in bitemporal recession has not been established and that the drug is not indicated for women [3]. HealthRX.com offers finasteride 1 mg tablets by prescription.

What did later research show about the 1 mg dose?

A scalp-biopsy study published in 1999 examined how different finasteride doses affected scalp and serum DHT [7]. In the study, 249 men with androgenetic alopecia had scalp biopsies before and after 42 days of finasteride at 0.01, 0.05, 0.2, 1 or 5 mg daily, or placebo [7]. Scalp DHT fell by 14.9%, 61.6%, 56.5%, 64.1% and 69.4% across those five doses (13.0% with placebo), and serum DHT fell by 49.5%, 68.6%, 71.4% and 72.2% at 0.05, 0.2, 1 and 5 mg [7]. The authors concluded that doses as low as 0.2 mg per day already maximally decreased both scalp and serum DHT in that study, and said the data supported hair-loss trials at doses between 0.2 and 5 mg [7].

What did the two pivotal hair-loss trials show?

The registration data behind the 1 mg dose were reported in 1998: two 12-month placebo-controlled trials in 1,553 men aged 18 to 41 with male pattern hair loss, with 1,215 men continuing into blinded second-year extensions [5]. Hair count in a 1-inch (5.1 cm2) circle of vertex scalp, starting from a baseline of 876 hairs, was 107 hairs higher than placebo at one year and 138 hairs higher at two years (P<0.001) [5]. Men on placebo continued to lose hair [5].

The Propecia label directs one 1 mg tablet once daily, with or without food, and says daily use for three months or more is usually needed before benefit is observed, continued use is recommended to sustain benefit, and withdrawal leads to reversal of effect within 12 months [3].

What did the Prostate Cancer Prevention Trial change?

The Prostate Cancer Prevention Trial, reported in 2003, randomized 18,882 men aged 55 or older with a normal digital rectal exam and a PSA of 3.0 ng/mL or lower to finasteride 5 mg or placebo for seven years [8]. Prostate cancer was detected in 18.4% of evaluable men on finasteride (803 of 4,368) versus 24.4% on placebo (1,147 of 4,692), a 24.8% relative reduction (95% CI 18.6 to 30.6) [8]. Gleason 7 to 10 tumors were more common on finasteride, at 6.4% versus 5.1% of men [8].

Both labels now carry the warning that 5-alpha reductase inhibitors may increase the risk of high-grade prostate cancer; the Propecia label reports Gleason 8 to 10 rates of 1.8% versus 1.1% in the trial and says the clinical significance for men taking 1 mg is unknown [3][4]. Proscar's limitation of use states that it is not approved for the prevention of prostate cancer [4].

A 2007 analysis examined whether finasteride's effects on tumor morphology or prostate size accounted for the excess of high-grade cancer. Prostates were smaller on finasteride (median 25.1 versus 34.4 cm3), and among men who had prostatectomy, biopsy identified high-grade disease present at prostatectomy in 69.7% versus 50.5% [9]. Follow-up published in 2013, with up to 18 years of observation, found no difference in overall survival: 15-year survival was 78.0% on finasteride and 78.2% on placebo, hazard ratio 1.02 (95% CI 0.97 to 1.08) [10].

How did the psychiatric and sexual wording in the labels change?

The June 2021 Propecia label listed postmarketing depression; on May 31, 2022 the FDA issued a Safety Labeling Change order under section 505(o)(4) of the FD&C Act citing new safety information on suicidal ideation and behavior, additional sexual dysfunction and psychoneurocognitive events, and supplement S-030, approved August 1, 2022, changed the wording to depression, suicidal ideation and behavior [11]. The labels describe these as voluntary postmarketing reports from a population of uncertain size, from which a causal relationship cannot reliably be established [3][4]. Neither Propecia nor Proscar carries a boxed warning [3][4].

The Propecia postmarketing section also lists sexual dysfunction that continued after discontinuation, including erectile dysfunction, libido, ejaculation and orgasm disorders, plus male infertility and poor seminal quality that improved after stopping in some reports [3].

What did the controlled trials show about sexual side effects?

Three 12-month controlled trials of Propecia (945 men on drug, 934 on placebo, aged 18 to 41) reported drug-related decreased libido in 1.8% versus 1.3%, erectile dysfunction in 1.3% versus 0.7% and ejaculation disorder in 1.2% versus 0.7% [3]. Overall, 3.8% of treated men had one or more of these versus 2.1% on placebo (p = 0.04), and the incidence of each fell to 0.3% or lower by year five [3]. A 2019 meta-analysis of 15 randomized placebo-controlled trials covering 4,495 men found a relative risk of sexual dysfunction of 1.57 (95% CI 1.19 to 2.08) with 5-alpha reductase inhibitors, and 1.66 (95% CI 1.20 to 2.30) for finasteride 1 mg [12]. A separate review of 34 finasteride hair-loss trials found that none had adequate safety reporting [13].

What about generic tablets and topical finasteride?

Finasteride is FDA-approved as oral tablets in both 1 mg and 5 mg strengths, as brand and generic products [2][1][3]. No topical or injectable finasteride is FDA-approved [3].

A topical spray has been tested in research. In a 24-week phase III trial at 45 European sites, 458 men with androgenetic alopecia were randomized; change in target-area hair count was 20.2 hairs with topical finasteride versus 6.7 with placebo (P<0.001), and the reduction in mean serum DHT was 34.5% with topical versus 55.6% with oral finasteride [14]. That product is not FDA-approved [3].

Was finasteride ever effective in women?

The label contraindicates finasteride in women who are or may be pregnant and says such women should not handle crushed or broken tablets, because of the risk of abnormal external genitalia in a male fetus [3]. In a 1-year randomized trial of 137 postmenopausal women aged 41 to 60 with androgenetic alopecia, hair count did not differ significantly between finasteride 1 mg and placebo, and both groups lost hair on the frontal and parietal scalp [15].

Timeline

• June 19, 1992: Proscar 5 mg approved for symptomatic BPH [1]
• December 19, 1997: Propecia 1 mg approved for male pattern hair loss [2]
• 1998: two 12-month hair-loss trials in 1,553 men reported [5]
• 1999: scalp biopsy dose study in 249 men [7]
• 2003: Prostate Cancer Prevention Trial, 18,882 men [8]
• 2007: pathology analysis of PCPT prostatectomy specimens [9]
• 2013: long-term survival follow-up [10]
• May 31, 2022 order and August 1, 2022 supplement S-030 adding suicidal ideation wording [11]
• 2022: 24-week phase III trial of topical finasteride in 458 men [14]