Finasteride Side Effects: Incidence Rates Across Clinical Trials

The 1 mg hair-loss trials: 3.8% versus 2.1%

Three controlled trials of 12 months enrolled 945 men on finasteride 1 mg and 934 on placebo, all aged 18 to 41 with male pattern hair loss [1]. Adverse experiences judged possibly, probably or definitely drug-related were 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% [1]. Pooled, 36 of 945 men (3.8%) reported one or more of these versus 20 of 934 (2.1%), a difference the label reports as p=0.04 [1]. Discontinuation because of a drug-related sexual event was 1.2% versus 0.9% [1].

Two further details from the same program. The incidence of each of those events fell to 0.3% or lower by the fifth year of treatment [1]. And a self-administered sexual function questionnaire at month 12 found statistically significant differences in favor of placebo in 3 of 4 domains — sexual interest, erections, and perception of sexual problems — with no significant difference on overall satisfaction with sex life [1].

The finasteride 1 mg tablet is the dose studied in the male pattern hair-loss trials [1].

PLESS at 5 mg: year one, then years two to four

The Proscar Long-Term Efficacy and Safety Study ran 4 years in 3,040 men aged 45 to 78 with symptomatic BPH and an enlarged prostate, 1,524 on finasteride 5 mg and 1,516 on placebo [2]. Year-one rates: impotence 8.1% versus 3.7%, decreased libido 6.4% versus 3.4%, decreased volume of ejaculate 3.7% versus 0.8%, ejaculation disorder 0.8% versus 0.1%, breast enlargement 0.5% versus 0.1%, breast tenderness 0.4% versus 0.1%, and rash 0.5% versus 0.2% [2].

In years 2 to 4, impotence and decreased libido occurred at the same rates in both groups: 5.1% versus 5.1% and 2.6% versus 2.6% [2]. Decreased ejaculate volume was reported by 1.5% on finasteride versus 0.5% on placebo, ejaculation disorder by 0.2% versus 0.1%, breast enlargement by 1.8% versus 1.1% and breast tenderness by 0.7% versus 0.3% [2]. The label states there was no significant difference between groups in the incidences of impotence, decreased libido and ejaculation disorder during years 2 to 4 [2]. Over the full 4 years, 3.7% (57 men) on finasteride and 2.1% (32 men) on placebo stopped treatment because of a sexual adverse reaction [2].

MTOPS: finasteride alone and with doxazosin

MTOPS randomized 3,047 men to Proscar 5 mg (n=768), doxazosin (n=756), the combination (n=786) or placebo (n=737) for 4 to 6 years [2]. Drug-related rates by arm — placebo, doxazosin, finasteride, combination — were: decreased libido 5.7%, 7.0%, 10.0% and 11.6%; abnormal ejaculation 2.3%, 4.5%, 7.2% and 14.1%; impotence 12.2%, 14.4%, 18.5% and 22.6%; gynecomastia 0.7%, 1.1%, 2.2% and 1.5% [2]. The label notes that abnormal ejaculation on combination therapy was comparable to the sum of the two monotherapies, and that MTOPS was not specifically designed to make statistical comparisons between groups for reported adverse experiences [2].

Why the 1 mg and 5 mg percentages are not the same

The dose differs (1 mg versus 5 mg) and so does the population: men 18 to 41 with hair loss in the Propecia trials, men 45 to 78 with BPH in PLESS [1][2]. Placebo rates differ too — erectile dysfunction 0.7% on placebo in the 1 mg trials versus 3.7% in year one of PLESS [1][2].

Pooled across 15 trials: a 1.57-fold relative risk

A 2019 systematic review and meta-analysis pooled 15 randomized, double-blind, placebo-controlled trials covering 4,495 men treated for androgenetic alopecia with finasteride 1 mg/day or dutasteride 0.5 mg/day [3]. The 5-alpha reductase inhibitors as a group carried a 1.57-fold risk of sexual dysfunction (95% CI 1.19 to 2.08); finasteride alone 1.66 (1.20 to 2.30); dutasteride 1.37 (0.81 to 2.32), which was not statistically significant [3].

How complete is the trial safety data?

A 2015 JAMA Dermatology meta-analysis of 34 finasteride trials for androgenetic alopecia found that none had adequate safety reporting and 76% evaluated safety for 1 year or less [4]. Funnel plots suggested under-detection of sexual adverse effects, and only 31% of 5,704 finasteride-treated men in a real-world cohort would have met the eligibility criteria of the pivotal trials [4].

Postmarketing reports: what the labels list

The clinical trial tables do not cover everything. The current Propecia label's postmarketing section lists sexual dysfunction that continued after discontinuation of treatment, including erectile dysfunction, libido disorders, ejaculation disorders and orgasm disorders; male infertility and poor seminal quality, with normalization or improvement reported after discontinuation; depression; suicidal ideation and behavior; hypersensitivity reactions including rash, itching, hives and angioedema; testicular pain; hematospermia; breast tenderness and enlargement; and male breast cancer, with the relationship to long-term use unknown [1]. The Proscar label lists depression, suicidal ideation and male breast cancer in the same section [2]. The labels state that these reports are voluntary, come from a population of uncertain size, and that a causal relationship cannot reliably be established [1][2].

The wording has a documented history. The June 2021 Propecia label listed postmarketing depression; on May 31, 2022 the FDA sent a Safety Labeling Change order citing new safety information on suicidal ideation and behavior and additional risk of sexual dysfunction and psychoneurocognitive adverse events, and supplement S-030, approved 08/01/2022, changed the wording to depression, suicidal ideation and behavior [5]. There is no boxed warning on either product, and depression is not a numbered Warnings and Precautions subsection [1][2].

One group of 71 otherwise healthy men aged 21 to 46, interviewed after reporting new sexual dysfunction on finasteride for hair loss that lasted at least 3 months after stopping, had a mean 28 months of use and a mean 40 months of persistence; 94% reported low libido, 92% erectile dysfunction, 92% decreased arousal and 69% problems with orgasm [6]. The group was self-selected and recall-based, so it cannot give a frequency or a cause [6].

Depression and self-harm in large cohorts

In 93,197 Ontario men aged 66 or older starting a 5-alpha reductase inhibitor, mostly for BPH, matched to unexposed men, suicide risk was not increased (HR 0.88, 95% CI 0.53 to 1.45) [7]. Self-harm was higher in the first 18 months (HR 1.88, 1.34 to 2.64) and not afterward, and depression was higher in the first 18 months (HR 1.94, 1.73 to 2.16) and after (HR 1.22, 1.08 to 1.37), with absolute increases of 17 self-harm and 237 depression cases per 100,000 patient-years [7]. In a Swedish register cohort of 2,236,876 men aged 50 to 90, of whom 70,645 started finasteride (median age at initiation 73), depression risk was higher on finasteride (HR 1.61, 1.48 to 1.75) with no clear suicide association (HR 1.22, 0.99 to 1.49) [8]. Both cohorts studied mainly older men treated for prostate symptoms, not young men using 1 mg for hair loss.

Prostate cancer and PSA: two numbers from the 5 mg trials

The Prostate Cancer Prevention Trial randomized 18,882 men aged 55 or older to finasteride 5 mg or placebo for 7 years; prostate cancer was found in 18.4% (803 of 4,368) versus 24.4% (1,147 of 4,692), a 24.8% reduction (95% CI 18.6 to 30.6) [9]. Gleason 7 to 10 tumors were more common on finasteride — 280 of 757 tumors (37.0%), or 6.4% of the 4,368 men, versus 5.1% — and Gleason 8 to 10 cancer occurred in 1.8% versus 1.1% [9][2]. The Proscar label states the drug is not approved for the prevention of prostate cancer and that whether prostate volume reduction or study-related factors affected these results has not been established [2].

Finasteride also moves PSA. Proscar lowers serum PSA by approximately 50% within six months, and the Proscar label instructs clinicians to double an isolated PSA value after six months or more of treatment when comparing it with ranges for untreated men; any confirmed rise from the lowest value on treatment should be evaluated [2]. In men 18 to 41 taking 1 mg, mean PSA fell from 0.7 ng/mL to 0.5 ng/mL at month 12 [1].

The nocebo effect inside the numbers

One randomized trial of 120 men with BPH gave finasteride 5 mg concealed as an unnamed BPH compound, with or without counseling about sexual side effects; 107 completed [10]. One or more sexual side effects were reported by 43.6% of the counseled group (55 men) versus 15.3% of the uncounseled group (52 men), p=0.03 [10].