CHAPTER 3 – Regulation of the Hypothalamic–Pituitary–Gonadal Axis: Role of Gonadal Steroids and Implications for the Menopause

Menopause is characterized by a marked decrease in estrogen production from the ovaries. The estrogen decrease that occurs not only results in a loss of reproductive function, but is also associated with a number of conditions that reduce the quality of life of this population of women. It has become clear over the past 10-15 years that the ubiquitous presence of the estrogen receptor (ER) in body tissues and organ systems provides the substrate for estrogenic regulation or modulation of multiple body functions. That knowledge has run in parallel with ever increasing evidence of the beneficial effects of estrogen replacement therapy after the menopause. What started originally as an approach to treat vasomotor symptoms and vaginal dryness has evolved into a comprehensive therapeutic approach that can span several decades after the menopause and is intended to prevent and/ or treat osteoporosis, cardiovascular disease, cognitive dysfunction, and possibly other neurodegenerative disorders such as Alzheimer disease. Central to this expansive approach to hormone replacement therapy is not only a more refined understanding of the mechanisms that lead to estrogen's beneficial effects on many tissues and functions, but also to an understanding of the undesired side effects that result from estrogenic activity at sites that are not the intended therapeutic targets (i.e., uterus and breast). The concept of tissue selectivity in estrogen action has emerged in recent years and provides the cellular and molecular basis to understand the diversity of estrogen activity and the distinct mode of action of full versus partial estrogen agonists.