Plasma estrogens in the blood and interstitial fluid are bound to SHBG, from which they dissociate to enter the cell and bind to their receptor. Two genes code for two estrogen receptor isoforms, α and β, which are members of the superfamily of steroid, sterol, retinoic acid, and thyroid receptors. The estrogen receptors are found predominantly in the nucleus bound to heat shock proteins that stabilize them (see Figure 39–4).
Binding of the hormone to its receptor alters its conformation and releases it from the stabilizing proteins (predominantly Hsp90). The receptor-hormone complex forms homodimers that bind to a specific sequence of nucleotides called estrogen responseelements (EREs) in the promoters of various genes and regulatetheir transcription. The ERE is composed of two half-sites arranged as a palindrome separated by a small group of nucleotides called the spacer. The interaction of a receptor dimer with the ERE alsoinvolves a number of nuclear proteins, the coregulators, as well as components of the transcription machinery. The receptor may also bind to other transcription factors to influence the effects of these factors on their responsive genes.
The relative concentrations and types of receptors, receptor coregulators, and transcription factors confer the cell specificity of the hormone’s actions. The genomic effects of estrogens are mainly due to proteins synthesized by translation of RNA tran-scribed from a responsive gene. Some of the effects of estrogens are indirect, mediated by the autocrine and paracrine actions of auta-coids such as growth factors, lipids, glycolipids, and cytokinesproduced by the target cells in response to estrogen.
Rapid estrogen-induced effects such as granulosa cell Ca2+ uptake and increased uterine blood flow do not require gene acti-vation. These appear to be mediated by nongenomic effects of the classic estrogen receptor-estrogen complex, influencing several intracellular signaling pathways.
Recently, all steroid receptors except the mineralocorticoid receptors were shown to have palmitoylation motifs that allow enzymatic addition of palmitate and increased localization of the receptors in the vicinity of plasma membranes. Such receptors are available for direct interactions with, and effects on, various membrane-associated or cytoplasmic proteins without the need for entry into the nucleus and induction of transcriptional actions.
Estrogens are required for the normal sexual maturation and growth of the female. They stimulate the development of the vagina, uterus, and uterine tubes as well as the secondary sex char-acteristics. They stimulate stromal development and ductal growth in the breast and are responsible for the accelerated growth phase and the closing of the epiphyses of the long bones that occur at puberty. They contribute to the growth of axillary and pubic hair and alter the distribution of body fat to produce typical female body contours. Larger quantities also stimulate development of pigmentation in the skin, most prominent in the region of the nipples and areolae and in the genital region.
In addition to its growth effects on uterine muscle, estrogen plays an important role in the development of the endometrial lining. When estrogen production is properly coordinated with the pro-duction of progesterone during the normal human menstrual cycle, regular periodic bleeding and shedding of the endometrial lining occur. Continuous exposure to estrogens for prolonged periods leads to hyperplasia of the endometrium that is usually associated with abnormal bleeding patterns.
Estrogens have a number of important metabolic and cardiovascu-lar effects. They seem to be partially responsible for maintenance of the normal structure and function of the skin and blood vessels in women. Estrogens also decrease the rate of resorption of bone by promoting the apoptosis of osteoclasts and by antagonizing the osteoclastogenic and pro-osteoclastic effects of parathyroid hor-mone and interleukin-6. Estrogens also stimulate adipose tissue production of leptin and are in part responsible for the higher levels of this hormone in women than in men.
In addition to stimulating the synthesis of enzymes and growth factors leading to uterine and breast growth and differentiation, estrogens alter the production and activity of many other proteins in the body. Metabolic alterations in the liver are especially impor-tant, so that there is a higher circulating level of proteins such as transcortin (corticosteroid-binding globulin, CBG), thyroxine-binding globulin (TBG), SHBG, transferrin, renin substrate, and fibrinogen. This leads to increased circulating levels of thyroxine, estrogen, testosterone, iron, copper, and other substances.
Alterations in the composition of the plasma lipids caused by estrogens are characterized by an increase in the high-density lipo-proteins (HDL), a slight reduction in the low-density lipoproteins (LDL), and a reduction in total plasma cholesterol levels. Plasma triglyceride levels are increased. Estrogens decrease hepatic oxida-tion of adipose tissue lipid to ketones and increase synthesis of triglycerides.
Estrogens enhance the coagulability of blood. Many changes in factors influencing coagulation have been reported, including increased circulating levels of factors II, VII, IX, and X and decreased antithrombin III, partially as a result of the hepatic effects mentioned above. Increased plasminogen levels and decreased platelet adhesiveness have also been found (see Hormonal Contraception, below).
Estrogens induce the synthesis of progesterone receptors. They are responsible for estrous behavior in animals and may influence behavior and libido in humans. Administration of estrogens stimulates central components of the stress system, including the production of corticotropin-releasing hormone and the activity of the sympathetic system, and promotes a sense of well-being when given to women who are estrogen-deficient. They also facilitate the loss of intravascular fluid into the extracellular space, produc-ing edema. The resulting decrease in plasma volume causes a compensatory retention of sodium and water by the kidney. Estrogens also modulate sympathetic nervous system control of smooth muscle function.