Topical administration of testosterone ameliorates atopic dermatitis of KFRS4 rats

Atopic dermatitis (AD) is a chronic inflammatory skin disorder influenced by genetic, environmental, and immunological factors, and its prevalence shows notable sex‑associated differences. KFRS4 rats spontaneously develop AD‑like dermatitis with higher severity in females, suggesting a role for sex hormones in disease modulation. This study investigated the contribution of gonadal hormones to dermatitis development in KFRS4 rats by examining the effects of gonadectomy and topical testosterone treatment. Ovariectomy did not alter dermatitis onset or severity in female rats, whereas orchiectomy markedly exacerbated dermatitis in males. Orchiectomized males developed severe lesions characterized by crusting and erosion, and exhibited significantly higher total skin lesion severity scores (TSLSS) compared with sham controls, indicating a protective role of testicular factors. To further evaluate testosterone's contribution, we applied testosterone ointment to ovariectomized females and orchiectomized males. Testosterone treatment significantly reduced TSLSS in both sexes and prevented lesion formation in the treated dorsal neck region. Histological analysis revealed increased sebaceous gland number and epidermal thickening in testosterone‑treated skin, accompanied by robust induction of androgen receptor (AR)‑positive cells within sebaceous glands and across epidermal layers. In contrast, dermatitis‑affected skin lacked AR‑positive cells, likely due to architectural disruption. In addition, testosterone treatment significantly increased the expression of filaggrin and decreased the expression of Th2 (Il4 and Il5) and Th17 (Il17a) cytokine genes. Together, these findings suggest that testosterone ameliorates dermatitis by enhancing skin barrier function and modulating type 2 and Th17 immune responses. These findings identify testosterone as a key regulator of dermatitis in KFRS4 rats and highlight androgen-mediated barrier enhancement as a potential therapeutic strategy for AD.