Estrogen deficiency in the menopause and the role of hormone therapy: integrating the findings of basic science research with clinical trials

Abstract

Menopause, defined by the cessation of menstrual cycles after 12 months of amenorrhea not due to other causes, is associated with significant hormonal changes, primarily a decrease in estrogen, androgen, and progesterone levels. This review delves into the effects of estrogen deficiency during the perimenopausal transition and postmenopause, integrating the findings of basic science with clinical trials. Here, we first outline the variation in endogenous estrogens before and after menopause, exploring both genomic and nongenomic actions of estrogen and its estrogen receptors throughout the body. Next, we detail the spectrum of menopausal symptoms, from acute vasomotor, urogenital, and psychological issues during perimenopause to chronic reproductive, cardiovascular, neurological, skeletal, dermatologic, immune, and digestive changes postmenopause. Finally, we evaluate the role of hormone therapy in alleviating these symptoms, weighing its benefits against known risks. Publicizing these findings and an accurate representation of the risks and benefits of estrogen replacement to our aging patients is fundamental to improving their care, quality, and even quantity of life.

FIG. 1.

Localization of estrogen receptors ERα and ERβ. When both receptors are expressed, the bolded receptor is dominant.

FIG. 2.

Genomic (1–3) and nongenomic (4) regulations of estrogen receptors. (1) Estrogen binds to the estrogen receptor (ER), leading to its dimerization and activation. ER enters the nucleus and binds to estrogen response elements (ERE) leading to transcriptional regulation. (2) Estrogen binds and activates ER leading to ERE-independent transcriptional regulation. (3) Growth factor binds to the growth factor receptor (GFR), activating the protein kinase cascade, phosphorylating ER and resulting in dimerization and activation of phosphorylated ER, which binds to ERE and regulates transcriptional activity. (4) Nongenomic regulations of ER in which estrogen binds membrane ER leading to rapid activation of the protein kinase cascade and downstream signaling.