The naturally-occurring estrogens are estrone , estradiol , and estriol . 16α-hydroxy Estrone (16α-OHE1) is a hydroxylated metabolite of E1 as well as an interconversion product with E2. E1 is 16α-hydroxylated by cytochrome P450 (CYP) isoforms, including CYP1A1, CYP3A5, CYP3A4, and CYP3A7, with CYP3A5 being breast-specific. 16α-OHE1 is sulphatized or glucuronidated before excretion. It is increased in rheumatoid arthritis and decreased by physical activity. Unlike the parent estrogens and other hydroxylated metabolites of E1, 16α-OHE1 binds covalently and persistently activates estrogen receptors. In addition, this metabolite increases cell proliferation and does not suppress TNF-α secretion, whereas other estrogen metabolites are not pro-proliferative and have marked effects on TNF-α secretion. The levels of 16α-OHE1 are increased in some forms of hormone therapy. Because hormone therapy increases breast cancer risk, 16α-OHE1 has been implicated as a risk factor for breast cancer, although supportive data remains elusive.