Testosterone perturbs epidermal permeability barrier homeostasis

Although there are no known gender-related differences in permeability barr ier function in adults, estrogens accelerate whereas testosterone retards b arrier development in fetal skin, and male fetuses demonstrate slower barri er development than female littermates. Moreover, prenatal administration o f the androgen receptor antagonist, flutamide, equalizes developmental rate s in male and female fetuses. Therefore, we evaluated the effects of change s in testosterone on barrier homeostasis in adult murine and human skin. Hy pogonadal mice (whether by castration or by treatment with systemic flutami de) displayed significantly faster barrier recovery at 3, 6, and 12 h than did controls, and testosterone replacement slowed barrier recovery in castr ated mice. Moreover, testosterone directly effects the skin, as topical flu tamide also accelerated barrier recovery in normal male mice. These finding s appear to be of physiologic significance, since prepubertal male mice (ag e 5 wk) displayed accelerated barrier recovery in comparison with adult pos tpubertal (11 wk) males. These studies also appear to be relevant for human s, as a hypopituitary human subject demonstrated repeated changes in barrie r recovery in parallel with peaks and nadirs in serum testosterone levels d uring intermittent testosterone replacement. Mechanistic studies showed tha t differences in epidermal lipid synthesis do not account for the testoster one-induced functional alterations. Instead, epidermal lamellar body (LB) f ormation and secretion both decrease, resulting in decreased extracellular lamellar bilayers in testosterone-replete animals. These studies demonstrat e that fluctuations in testosterone modulate barrier function, and that tes tosterone repletion can have negative consequences for permeability barrier homeostasis.