Estrogen, or oestrogen, is the primary female sex hormone. It is responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens in females that have estrogenic hormonal activity: estrone, estradiol, and estriol. The estrane steroid estradiol is the most potent and prevalent of these. Estrogens are synthesized in all vertebrates as well as some insects. Their presence in both vertebrates and insects suggests that estrogenic sex hormones have an ancient evolutionary history. The three major naturally occurring forms of estrogen in women are estrone (E1), estradiol (E2), and estriol (E3). Quantitatively, estrogens circulate at lower levels than androgens in both men and women. While estrogen levels are significantly lower in males compared to females, estrogens nevertheless also have important physiological roles in males. Like all steroid hormones, estrogens readily diffuse across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors (ERs) which in turn modulate the expression of many genes. Additionally, estrogens bind to and activate rapid-signaling membrane estrogen receptors (mERs), such as GPER (GPR30). In addition to their role as natural hormones, estrogens are used as medications, for instance in menopausal hormone therapy and hormonal birth control.