Abstract
The hormone estrogen is involved in both female and male reproduction, as well as numerous other biological systems including the neuroendocrine, vascular, skeletal, and immune systems. Therefore, it is also implicated in many different diseases and conditions such as infertility, obesity, osteoporosis, endometriosis, and a variety of cancers. Estrogen works through its two distinct nuclear receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Various transcriptional regulation mechanisms have been identified as the mode of action for estrogen, mainly the classical mechanism with direct DNA binding but also a nongenomic mode of action and one using tethered or indirect binding. The expression profiles of ERα and ERβ are unique with the primary sites of ERα expression being the uterus and pituitary gland and the main site of ERβ expression being the granulosa cells of the ovary. Mouse models with knockout or mutation of Esr1 and Esr2 have furthered our understanding of the role of each individual receptor plays in physiology. From these studies, it is known that the primary roles for ERα are in the uterus and neuroendocrine system, as female mice lacking ERα are infertile due to impaired ovarian and uterine function, whereas female mice lacking ERβ are subfertile due to ovarian defects. The development of effective therapies for estrogen-related diseases has relied on an understanding of the physiological roles and mechanistic functionalities of ERα and ERβ in human health and disease.