5α-Reductase inhibitors (5-ARIs), also known as dihydrotestosterone (DHT) blockers, are a class of medications with antiandrogenic effects which are used primarily in the treatment of enlarged prostate and scalp hair loss.

[11][12] Epristeride (brand names Aipuliete, Chuanliu) is marketed in China for the treatment of benign prostatic hyperplasia.

[16] Alfatradiol (brand names Ell-Cranell Alpha, Pantostin) is a topical 5-ARI used to treat pattern hair loss in Europe.

[19] As a result, the FDA has notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-ARI class of drugs has been revised to include new safety information about the increased risk of being diagnosed with these rare but more serious forms of prostate cancer.

[29] It has been reported that in a subset of men, these adverse sexual side effects may persist even after discontinuation of finasteride or dutasteride.

[20][30] A 2017 population-based, matched-cohort study of 93,197 men aged 66 years and older with BPH found that finasteride and dutasteride were associated with a significantly increased risk of depression (HRTooltip Hazard ratio, 1.94; 95% CITooltip Confidence interval, 1.73–2.16) and self-harm (HR, 1.88; 95% CI, 1.34–2.64) during the first 18 months of treatment, but were not associated with an increased risk of suicide (HR, 0.88; 95% CI, 0.53–1.45).

[34] There were no differences in the rates of depression, self-harm, and suicide between finasteride and dutasteride, suggesting that the specific 5-ARI used does not influence the risks.

Specific substrates include testosterone, progesterone, androstenedione, epitestosterone, cortisol, aldosterone, and deoxycorticosterone.

[36] The 5α-reductase reaction is a rate-limiting step in the testosterone reduction and involves the binding of NADPH to the enzyme followed by the substrate.

[4][37] Beyond being a catalyst in the rate-limiting step in testosterone reduction, 5α-reductase isoforms I and II reduce progesterone to 5α-dihydroprogesterone (5α-DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC).

In vitro and animal models suggest subsequent 3α-reduction of DHT, 5α-DHP and DHDOC lead to neurosteroid metabolites with effect on cerebral function.

These neurosteroids, which include allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 3α-androstanediol, act as potent positive allosteric modulators of GABAA receptors, and have antidepressant, anxiolytic, prosexual, and anticonvulsant effects.