Mechanisms Of Action

Estrogens and progestins exert their effects in target tissues by a combination of cellular mechanisms. High-affinity estrogen and progestin receptors are found in target tissues. There are two forms of the estrogen receptor, ER-a and ER-p, and two forms of the progesterone receptor, PR-a and PR-p. Receptor binding by estrogens and progestins can activate a classic pathway of steroid hormone gene transcription. Gene activation is mediated by the ability of steroid hormone receptor complexes to recruit nuclear coactivator proteins to the transcription complex. Gene repression occurs in a ligand-dependent fashion by the recruitment of nuclear corepressor proteins to the transcription complex. This latter effect is an important mechanism of action of estrogen antagonism. Activation of steroid hormone receptors by their cognate ligands proceeds through receptor phosphorylation events. It is well established that estrogen and progesterone receptor activation also takes place in a ligand-independent fashion. As a result of cross-talk among cell signaling pathways, ER and PR are activated by phos-phorylation events triggered by such diverse stimuli as epidermal growth factor, insulinlike growth factor, protein kinase A, and protein kinase C.

An additional mode of estrogen and progesterone action is classified as nongenomic effects. Nongenomic mechanisms for steroid hormone action are attributed to responses to estrogens and progestins that occur in a very short time (seconds to several minutes) such that they are difficult to explain by transcriptional activa tion. The role of the ER and PR receptors in these responses is incompletely understood. One important example of a nongenomic estrogen action that is mediated by ER-a is the rapid stimulation of endothelial nitric oxide synthase (eNOS).This enzyme produces nitric oxide. Nitric oxide has vasodilatory activity, and activation of eNOS may be an important mediator of the cardio-protective effects of estrogens.

Estradiol can augment target tissue responses to progesterone by inducing an increase in the concentration of progesterone receptors. Progesterone, on the other hand, appears to limit tissue responses to estrogen by decreasing the concentration of ERs.

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