Finasteride Delayed-Onset Side Effects: What the Evidence Actually Shows

Does finasteride cause side effects months after starting?

In the controlled trials, sexual adverse events were reported during the first year and became less frequent with longer treatment. In the 1 mg hair-loss program the incidence of each fell to 0.3% or less by the fifth year [1]. What those figures do not show is which month within that first year a given symptom began. The label's postmarketing section covers something different: symptoms that continued after the drug was stopped, rather than symptoms that first appeared late in treatment [1].

What the hair-loss trials recorded, and when

Three 12-month trials included 945 men taking finasteride 1 mg and 934 taking placebo, aged 18 to 41 [1]. Drug-related decreased libido was reported by 1.8% versus 1.3%, erectile dysfunction by 1.3% versus 0.7%, and ejaculation disorder by 1.2% versus 0.7% [1]. Combined, 36 of 945 men on finasteride (3.8%) reported one or more of these events versus 20 of 934 on placebo (2.1%), a difference that reached p=0.04 [1]. Discontinuation for drug-related sexual events was 1.2% versus 0.9% [1].

The incidence of each of those events fell to 0.3% or less by the fifth year of treatment [1]. A self-administered sexual function questionnaire at month 12 did detect subtler differences: scores favored placebo in three of four domains (sexual interest, erections, and perception of sexual problems), with no significant difference in overall satisfaction with sex life [1].

What the 5 mg BPH trial recorded

PLESS followed 1,524 men taking finasteride 5 mg and 1,516 taking placebo, aged 45 to 78, for four years [2]. In year one, impotence was reported by 8.1% versus 3.7%, decreased libido by 6.4% versus 3.4%, decreased ejaculate volume by 3.7% versus 0.8%, and ejaculation disorder by 0.8% versus 0.1% [2]. In years two through four there was no significant difference between groups for impotence (5.1% versus 5.1%) or decreased libido (2.6% versus 2.6%) [2]. The Proscar label states that there is no evidence of increased sexual adverse experiences with increased duration of treatment, and that new reports of drug-related sexual adverse experiences decreased with duration of therapy [2].

A pooled analysis of the hair-loss trials

A 2019 meta-analysis of 15 randomized placebo-controlled trials in 4,495 men treated for androgenetic alopecia with finasteride 1 mg or dutasteride 0.5 mg found a relative risk of sexual dysfunction of 1.57 (95% CI 1.19 to 2.08); for finasteride alone the relative risk was 1.66 (95% CI 1.20 to 2.30) [4]. That analysis pools rates across trials; it does not identify a late-onset window.

What the trials cannot tell us about onset

Trial safety reporting has a real weakness. A 2015 meta-analysis of 34 finasteride trials for androgenetic alopecia found that none had adequate safety reporting, 76% evaluated safety for one year or less, and funnel plots were asymmetric in a way that suggested under-detection of sexual adverse effects [8]. The same analysis found that only 31% of 5,704 men prescribed finasteride in real-world practice would have met the entry criteria of the pivotal trials [8].

What the label lists for effects that outlast treatment

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. It also lists male infertility and poor seminal quality, noting that normalization or improvement in seminal quality has been reported after discontinuation [1]. The Proscar label says persistent sexual events were reported rarely in men taking 5 mg for BPH; most of those men were older and taking other medicines, and the drug's independent role is unknown [2]. The Medication Guide for patients describes a decrease in sex drive and problems with ejaculation that continued after stopping the medication [1].

On mood, the labeling history is documented. On May 31, 2022 the FDA sent a Safety Labeling Change order under section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act citing new safety information on the risk of suicidal ideation and behavior, an additional risk of sexual dysfunction, and psychoneurocognitive adverse events. Supplement S-030, approved 08/01/2022, changed the postmarketing wording to depression, suicidal ideation and behavior [3]. 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]. Neither Propecia nor Proscar carries a boxed warning [1][2].

Depression and suicidal ideation: what the cohorts show about timing

Two large cohorts give different pictures, and neither studied young men taking 1 mg for hair loss.

In Ontario, 93,197 men aged 66 or older who started a 5-alpha reductase inhibitor, mostly for prostate enlargement, were compared with matched unexposed men [5]. Depression risk was elevated in the first 18 months (HR 1.94, 95% CI 1.73 to 2.16) and remained slightly elevated afterward (HR 1.22, 95% CI 1.08 to 1.37); self-harm was increased only in the first 18 months (HR 1.88, 95% CI 1.34 to 2.64); suicide was not increased (HR 0.88, 95% CI 0.53 to 1.45). The absolute increases were 237 depression cases and 17 self-harm cases per 100,000 patient-years [5].

In Sweden, 2,236,876 men aged 50 to 90 were followed, of whom 70,645 started finasteride at a median age of 73 [6]. Depression was higher among finasteride users (HR 1.61, 95% CI 1.48 to 1.75), and that hazard was constant over time rather than concentrated in an early window. Suicide was not significantly associated with finasteride (HR 1.22, 95% CI 0.99 to 1.49) [6].

A smaller study interviewed 61 former finasteride users who had persistent sexual side effects and 29 men with hair loss who had never used the drug [9]. Depressive symptoms on the Beck Depression Inventory II (score of 14 or more) were present in 75% (46 of 61) versus 10% (3 of 29), P<0.0001. It was small, self-selected and cross-sectional, so it cannot establish cause [9].

Symptoms that persist after stopping

One series interviewed 71 otherwise healthy men aged 21 to 46 who reported new sexual dysfunction while taking finasteride for hair loss that lasted at least three months after stopping. Mean finasteride use was 28 months and mean persistence was 40 months. Low libido was reported by 94%, erectile dysfunction by 92%, decreased arousal by 92%, and orgasm problems by 69% [7]. Because the men volunteered and reported their own histories, the study cannot show how often this happens or that finasteride caused it [7].

A later internet survey of 131 generally healthy men, mean age 24, reported symptoms at least three months after stopping across sexual, physical, cognitive and psychological domains [10]. The term post-finasteride syndrome is used in this literature for that cluster of reported symptoms; the survey went to men who already reported symptoms, so it cannot show how often they occur [10].

One laboratory study compared three former users who had persistent symptoms with five healthy controls and found lower levels of tetrahydroprogesterone, isopregnanolone and dihydrotestosterone and higher levels of testosterone and estradiol in plasma and cerebrospinal fluid samples [11]. Three patients cannot show how common such changes are.

Mechanistically, finasteride is a competitive inhibitor of type II 5-alpha reductase, roughly 100-fold selective over type I, and a 1 mg tablet suppresses serum dihydrotestosterone by 65% within 24 hours [1]. The enzyme complex turns over slowly, with a half-life of about 30 days, so the hormonal effect outlasts the drug's 5 to 6 hour plasma half-life [1].