Do 5α‑reductase inhibitors (e.g., finasteride, dutasteride, saw‑palmetto) affect allopregnanolone synthesis and GABA‑A receptor activity, and therefore require mood monitoring in a patient without prior psychiatric history?

5α-Reductase Inhibitors DO Affect Allopregnanolone and GABA-A Receptor Activity

5α-reductase inhibitors (finasteride, dutasteride, saw palmetto) significantly reduce allopregnanolone synthesis by blocking the conversion of progesterone to its 5α-reduced neurosteroid metabolites, which directly modulate GABA-A receptor activity in the brain. 1, 2, 3

Mechanism of Neurosteroid Disruption

The biochemical pathway is straightforward:

• 5α-reductase converts progesterone → 5α-dihydroprogesterone → allopregnanolone, a potent positive allosteric modulator of GABA-A receptors with anxiolytic, antidepressant, and anticonvulsant properties 1, 2
• Finasteride (1 mg/day) causes gradual decreases in allopregnanolone, isopregnanolone, and pregnenolone during 4 months of treatment 1
• Dutasteride (2.5 mg/day) prevents the normal luteal phase increase in plasma allopregnanolone by blocking 5α-reductase activity 3
• This reduction in GABAergic neuroactive steroids is "probably one of the factors responsible for the increased occurrence of depression" in finasteride-treated patients 1

Clinical Implications: Mood Monitoring is NOT Routinely Required

Despite the documented neurosteroid effects, no major clinical guideline recommends routine psychiatric monitoring for patients on 5α-reductase inhibitors:

• The 2009 ASCO/AUA guideline states sexual side effects are "reversible and uncommon after the first year" with no mention of psychiatric surveillance 4
• The 2003 AUA guideline and 2010 NCCN guideline do not require routine psychiatric monitoring 4
• The 2025 European Urology guideline classifies 5α-reductase inhibitors as drug-induced causes of hypogonadism but does NOT mandate routine psychiatric monitoring 4

Practical Approach to Mood Screening

Before initiating treatment, perform baseline mood symptom screening with a brief questionnaire (e.g., PHQ-2 or GAD-2), but formal psychiatric evaluation is not required 4

This pragmatic approach acknowledges the biochemical reality while recognizing that:

• Overall discontinuation rates are identical (≈15%) between finasteride and placebo groups 4, 5
• Adverse-event-driven discontinuation is 6-7% in both finasteride and placebo arms, indicating most reported side effects may not be drug-related 4, 5
• The data supporting persistent neurological disease after discontinuation are of low quality and remain controversial 4

Important Caveats

The Neurosteroid Effect is Real but Context-Dependent

• In women with PMDD, stabilizing allopregnanolone levels with dutasteride (2.5 mg/day) significantly reduced irritability, sadness, anxiety, food cravings, and bloating 3
• Dutasteride had no effect on mood in asymptomatic control women, suggesting the neurosteroid disruption only manifests clinically in vulnerable populations 3
• Some isolated cases of depression have been reported with finasteride, though causality remains uncertain 1, 2

Saw Palmetto Considerations

Saw palmetto and similar herbal products may contain phytoestrogenic compounds that influence hormone levels, but the composition is poorly characterized and evidence for psychiatric effects is extremely limited 4

Clinical Bottom Line

Screen for baseline mood symptoms before starting any 5α-reductase inhibitor, but do not perform routine psychiatric monitoring during treatment unless new symptoms emerge. 4 The biochemical disruption of allopregnanolone synthesis is well-documented 1, 2, 3, but the clinical significance in patients without pre-existing psychiatric vulnerability appears minimal based on discontinuation rates matching placebo 4, 5.