When released into the circulation, estradiol binds strongly to an α2 globulin (sex hormone–binding globulin [SHBG]) and with lower affinity to albumin. Bound estrogen is relatively unavailable for diffusion into cells, and it is the free fraction that is physiologically active. Estradiol is converted by the liver and other tissues to estrone and estriol (Figure 40–2) and their 2-hydroxylated derivatives and conjugated metabolites (which are too insoluble in lipid to cross the cell membrane readily) and excreted in the bile. Estrone and estriol have low affinity for the estrogen receptor.
Steroidal, natural
Steroidal, synthetic
CCH3CH3COOHOH3CCHC2H5OH3CCCClOCH3OCH3HOCCCH2CH2CH3CH3HONonsteroidal,synthetic
FIGURE 40–3 Compounds with estrogenic activity.
TABLE 40–1 Commonly used estrogens.
Conjugated, esterified, or mixed estrogenic substances: Oral 0.3–1.25 mg/d Injectable 0.2–2 mg/d Transdermal Patch
Quinestrol 0.1–0.2 mg/week
However, the conjugates may be hydrolyzed in the intestine to active, reabsorbable compounds. Estrogens are also excreted in small amounts in the breast milk of nursing mothers.
Because significant amounts of estrogens and their active metabolites are excreted in the bile and reabsorbed from the intestine, the resulting enterohepatic circulation ensures that orally administered estrogens will have a high ratio of hepatic to peripheral effects. As noted below, the hepatic effects are thought to be responsible for some undesirable actions such as synthesis of increased clotting factors and plasma renin substrate. The hepatic effects of estrogen can be minimized by routes that avoid first-pass liver exposure, ie, vaginal, transdermal, or by injection.
A. Mechanism
Estrogens in the blood and interstitial fluid are bound to SHBG, from which they dissociate to cross the cell membrane, enter the nucleus, 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. Unlike glucocorticoid receptors, estrogen receptors are found predominantly in the nucleus, where they are bound to heat shock proteins that stabilize them (see Figure 39–4).
Binding of the hormone to its receptor alters the receptor’s conformation and releases it from the stabilizing proteins (predominantly Hsp90). The receptor-hormone complex forms dimers (usually ERα-ERα, ERβ-ERβ, or ERα-ERβ) that bind to a specific sequence of nucleotides, called estrogen response elements (EREs), in the regulatory regions of various genes and regulate their 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 also involves a number of nuclear proteins, the coregulators, as well as components of the transcription machinery. Complex interactions with various coregulators appear to be responsible for some of the tissue-specific effects that govern the actions of selective estrogen receptor modulators (SERMs, see below). The receptor may also bind to other transcription factors to influence the effects of these factors on their responsive genes. Interestingly, although ERβ has its own separate actions from ERα, it also acts as a dominant negative inhibitor of ERα. Thus, while ERα has many growth-promoting properties, ERβ has anti-growth effects. Many phytoestrogens act via the ERβ protecting cells from the pro-growth effects of ERα.