17b-Estradiol is Abundant in Skin and Regulates the Hair Follicle Cycle and Mirex Tumor Promotion

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Skin is a complex, hormone responsive tissue that functions as a barrier against water loss and infection. Estrogens have been shown to influence dermal thickness, vasodilatation and hair growth in skin. Remarkably, cutaneous E2 levels and capacity for E2 synthesis have not been fully assessed. We have determined that cutaneous17b-estradiol (E2) levels average nine times greater than serum E2 levels in female mice and that skin E2 is independent of serum E2. Additionally, we determined that estrogens are a major metabolite of testosterone in mouse skin explants, indicating that skin is a major site of extraglandular estrogen biosynthesis. Earlier studies have shown that castration accelerates hair growth in mice, and we have determined that castration induces a greatly diminished telogen phase, of the hair cycle. Previously our laboratory has shown that E2 blocks telogen to anagen transition of the hair cycle. We observed that only twice weekly 1 nmol E2 treatment reversed the effects of castration while daily treatment with 100 nmol testosterone or 25 nmol DHT was required, indicating that E2 is up to 100 times more potent than androgens. Previous studies have shown that mirex, a non-phorbol ester skin tumor promoter, promotes three times more tumors in female mice than OVX mice. E2 implants were able to restore 80% of the intact female mirex promotion response to OVX mice, indicating that E2 is the primary ovarian hormone that regulates mirex promotion. Since mirex promotes three times more tumors in female mice than in male mice, we conducted a tumor promotion study on intact and castrate mice given empty or E2 containing implants, and found that intact mice develop three times more tumors than castrated mice and that E2 implants fully restore intact male response to castrate mice, indicating that E2 also regulates mirex tumor promotion sensitivity in male mice. Collectively, these data indicate that skin is an important extraglandular source of E2 and skin E2 influences the hair cycle and chemical carcinogenesis.