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F O R P H Y S I C I A N S – resources
Selective Estrogen Receptor Modulators
The Estrogen Receptor; Clomiphene
The estrogen receptor (ER) was first isolated in the 1960s (8). In 1996, a second ER, ERb, was cloned from rat prostate, which had a significant amount of homology to the original ER, now termed ERa (9). Even though conserved regions of ERa and ERb are homologous, there are various nonconserved regions, which may account for differences in action between the two receptors. It is hypothesized that individual SERMs may induce specific and unique changes in receptor conformations, accounting for their particular pharmacological properties (10). Alternatively, it has been proposed that ligand binding by a SERM or an estrogen will act differently at gene transcription-activating regions (11). As the molecular pathways of function are identified there will be a better understanding of how SERM action and tissue selectivity is accomplished.
The mechanism of action of clomiphene to bind to and interact with estrogen receptors acting as an agonist in some tissue and an antagonist in others is a prototype of SERM compounds. Clomiphene has been used widely to initiate or augment ovulation by antagonizing estrogen's action at the hypothalamus and pituitary, thereby accentuating the release of gonadotropins during the follicular phase. In addition to acting on the hypothalamus and pituitary, clomiphene may act directly on the ovary (12). Within the endometrium, cervical mucous-producing glands and in mammary tissue, clomiphene exerts an antiestrogenic effect.
Clomiphene is typically begun at a dose of 50 mg per day for 5 days. It is given in the follicular phase on days 3-7 or days 5-9 of a spontaneous menstrual cycle or induced withdrawal bleed. Follicular ultrasound measurements or urinary LH kits may be used to time intercourse or insemination. If ovulation does not occur with the 50-mg dose, the dose is then increased in increments of 50 mg. If ovulation does not occur with doses of 200 to 250 mg it is often necessary to move to other alternative treatments.
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