Synthetic Agents Acting Via Estrogen And Progesterone Receptors

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Long-acting semisynthetic estrogens and progestins contain esterified lipophilic substituents. Esterification of steroids prolongs their release from depot injection sites. Medroxyprogesterone acetate (Amen, Cyctin, Provera, Depo-Provera) is a widely used long-acting synthetic progestin.

Synthetic steroid hormones retain the common steroid nucleus, but they may contain novel substituents that affect their pharmacological activity. The two most widely used synthetic steroid estrogens are ethinyl estra-diol (Estinyl) and mestranol, found in oral contraceptives. Synthetic steroids containing an ethinyl substitution are metabolized more slowly. Thus, these synthetic steroid hormones have better oral absorption properties and extended biological half-lives than the natural estrogens.

Approximately 50% of a dose of mestranol is de-methylated to form ethinyl estradiol. Ethinyl estradiol also can be deethinylated. Subsequently, the metabolism of these two synthetic estrogens proceeds by means of the same pathways as the natural steroid hormones. The principal metabolites of mestranol and ethinyl estradiol are hydroxylated derivatives that are conjugated with either glucuronic acid or sulfate. The synthetic steroid estrogens, in contrast to the natural estrogens, are excreted primarily in the feces.

One chemical class of synthetic progestins is derived from testosterone and is referred to as the 19-nortestos-terones.These compounds have progestational activity yet retain some androgenic activity. Norethindrone (Micro-nor, Nor-QD) and norethindrone acetate (Aygestin) are two synthetic progestins derived by the addition of an ethinyl group at the C17 position of 19-nortestosterone. There is little difference between the pharmacological activity of norethindrone and norethindrone acetate because in humans the acetate group is very readily cleaved to yield norethindrone. Norethindrone is metabolized by hydroxylation and conjugation, just as are the natural progestins. The majority of the 19-nortestosterone metabolites are conjugates that are excreted in the urine.

A second chemical class of synthetic progestins contains the pregnane nucleus structure of progesterone along with some additional substitutions. Alkyl chain additions to the C17 position increase the biological half-life of these compounds. Modifications at positions C6 and C7 increase their progestational activity. Examples of these synthetic progestins include me-droxyprogesterone and megestrol acetate (Megace). These compounds are metabolized in the same manner as progesterone and are excreted in the urine.


Selective ER modulators (SERMs) are nonhormonal pharmacological agents that bind to ERs. A characteristic feature of the SERMs is that a given agent will act as an estrogen agonist in one or more tissues and as an estrogen antagonist in one or more other estrogen target organs. Tamoxifen citrate (Nolvadex), clomiphene citrate (Clomid, Serophene) and raloxifene (Evista) are examples of nonsteroidal SERMs. The best studied SERM is tamoxifen citrate, a drug formerly characterized as an antiestrogen.

Tamoxifen is a partial estrogen agonist in breast and thus is used as a treatment and chemopreventative for breast cancer. Tamoxifen is a full agonist in bone and endometrium, and prolonged use of tamoxifen leads to a fourfold to fivefold increase in the incidence of en-dometrial cancer. See Chapter 56 for a detailed discussion of the use of tamoxifen in breast cancer.

Raloxifene (Evista) is a new SERM approved for use in the treatment and prevention of osteoporosis because it has estrogenic activity in bone. Raloxifene is an estrogen antagonist in both breast and endometrial tissues. The estrogenlike properties of raloxifene result in the maintenance of a favorable serum lipid profile (decreased low-density lipoprotein levels with no change in either high-density lipoproteins or triglycerides). Raloxifene is 95% bound to plasma proteins. Absorption of raloxifene is impaired by cholestyramine.

Tamoxifen, clomiphene, and raloxifene are orally active. The primary route of excretion of all three drugs is in the feces. The undesirable effects common to all three of these SERMs are increased frequency of hot flashes and increased risk of thromboembolism. Both effects are attributable to their estrogenic activity.

Faslodex (Fulvestrant) is a SERM with no known agonist activity on the ER. It is administered as a monthly injection. In phase III clinical trials faslodex showed good activity against advanced breast cancer.

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