A proprietary lipidosterolic extract of Serenoa repens promotes hair growth through mechanisms that extend beyond 5‐alpha reductase inhibition: Insights from human hair follicle organ culture

While androgenetic alopecia (AGA) is primarily driven by excessive 5-α reductase (5-αR) activity, further mechanisms also contribute to the development of AGA and other hair loss disorders. Here, we explored the properties of the proprietary lipidosterolic extracts of the plant Serenoa repens (LSESr), also known as Saw Palmetto, focusing on USPlus® DERM Bioactive Fatty Acids (USPlus® DERM). USPlus® DERM contains concentrated levels of bioactive free fatty acids (FFAs) that are integral lipids found in the hair shaft and modulate pathways relevant to hair follicle (HF) function. Therefore, USPlus® DERM promises to have both 5-αR-dependent and also -independent hair growth-promoting effects. Here, we initially confirmed the 5-αR inhibitor activity of USPlus® DERM in primary human hair follicle dermal papilla cells. USPlus® DERM exhibited a more potent 5-αR inhibition than a standard, commercially available saw palmetto extract and a standardized LSESr meeting the US Pharmacopoeia monograph, with IC₅₀ values of 0.39, 29.1 and 9.1 μg/mL respectively. To explore potential 5-αR-independent responses, USPlus® DERM was administered at two different concentrations, 0.4 and 10 μg/mL, to androgen-independent, 'clinically healthy' full-length HFs ex vivo obtained from the occipital scalp of male donors, in the absence of testosterone. Interestingly, USPlus® DERM at 0.4 μg/mL significantly reduced the number of melanin clumps, regarded as signs of organ culture mediated stress conditions. Despite inter-donor variations, USPlus® DERM prolonged anagen ex vivo, particularly at the low concentration, evidenced by a significant reduction in the hair cycle score and the tendency to boost hair matrix keratinocyte proliferation (Ki-67⁺cells). USPlus® DERM did not affect dermal papilla inductivity, as measured by versican expression and alkaline phosphatase activity. While the percentage of K15⁺ epithelial HF stem cells (eHFSC) remained unaffected, 0.4 μg/mL USPlus® DERM tendentially enhanced K15 expression and reduced the number of Ki-67⁺K15⁺ cells, indicating reinforcement of the eHFSCs niche. These preliminary findings suggest that USPlus® DERM has the potential to promote hair growth and to enhance HFSC stemness in the 'clinically predictive' HF organ culture model, independently from 5-αR inhibition. Thus, USPlus® DERM deserves to be further investigated as an anti-hair loss strategy, for not only AGA management but also other hair loss disorders.