17?-Estradiol is the major pre-menopausal bioactive estrogen and an active metabolite of testosterone.{68406,68407,68408} It is produced primarily by the ovary, and to a lesser extent, by the adrenals, testes, and adipose tissue, as well as by the placenta during pregnancy.{68406} 17?-Estradiol binds to estrogen receptors localized to the nucleus, cytoplasm, and plasma membrane and induces gene transcription or non-genomic intracellular signaling in a location-dependent manner.{68407} It regulates reproductive development in females and spermatogenesis in males, as well as various non-reproductive processes including lipid and glucose homeostasis, bone mass maintenance, cognition, energy balance, and dilation of blood vessels.{68407,68408} 17?-Estradiol deficiency due to hypogonadism or 17?-hydroxylase/17,20-lyase deficiency is associated with fatigue, incontinence, osteoporosis, depression, emotional instability, and hot flashes. Formulations containing 17?-estradiol have been used in the treatment of menopause symptoms and the prevention of osteoporosis.