Natural Inhibitors of 5-Alpha Reductase: Mechanisms, Therapeutic Potential, and Emerging Perspectives in Androgen-Dependent Prostate Disorders

Androgen signaling plays a central role in the development and progression of androgen-dependent prostate disorders, particularly benign prostatic hyperplasia (BPH) and prostate cancer (PCa). The conversion of testosterone (T) to dihydrotestosterone (DHT) by steroid 5α-reductase (5αR) is a key step in this pathway. Although finasteride and dutasteride effectively suppress DHT synthesis, their use may be associated with adverse effects and does not fully address the complex inflammatory, oxidative, and proliferative mechanisms involved in prostate disease. This review evaluates naturally occurring compounds as potential modulators of 5αR and androgen receptor (AR) signaling. A narrative review of experimental and clinical evidence concerning natural compounds affecting 5αR activity and AR signaling was conducted. Phytosterols, terpenoids, flavonoids, catechins, isoflavones, phenolic compounds, and fatty acids were considered, with particular emphasis on their molecular mechanisms, inhibitory potency, and therapeutic relevance. Multiple natural compounds have demonstrated inhibitory effects on 5αR and/or modulation of AR signaling primarily in experimental models. Several compounds additionally exhibit antioxidant, anti-inflammatory, antiproliferative, and pro-apoptotic properties, suggesting potential multitarget effects. Fatty acids also demonstrate structure-dependent 5αR inhibitory activity influenced by chain length, degree of unsaturation, and lipophilicity. Natural products represent a promising source of multitarget modulators of androgen signaling and may offer complementary approaches to conventional 5αR inhibition. However, their clinical efficacy and safety remain insufficiently established. Standardized preparations, pharmacokinetic studies, clinically relevant dosing, and well-designed clinical trials are required to determine whether the experimental effects observed with individual compounds translate into clinically meaningful benefits in androgen-dependent prostate disorders. Available clinical evidence should be considered separately from findings derived primarily from laboratory and animal studies.