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Chapter: Modern Pharmacology with Clinical Applications: Estrogens, Progestins, and Specific Estrogen Receptor Modulators (SERMs)

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Synthetic Agents Acting Via Estrogen and Progesterone Receptors

Long-acting semisynthetic estrogens and progestins contain esterified lipophilic substituents.

SYNTHETIC AGENTS ACTING VIA ESTROGEN AND PROGESTERONE RECEPTORS

 

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 contracep-tives. Synthetic steroids containing an ethinyl substitution are metabolized more slowly. Thus, these synthetic steroid hormones have better oral absorption properties and ex-tended 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 metabo-lism 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 conju-gated with either glucuronic acid or sulfate. The syn-thetic steroid estrogens, in contrast to the natural estro-gens, 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 ac-tivity of norethindrone and norethindrone acetate be-cause 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 me-tabolites are conjugates that are excreted in the urine.

 

A second chemical class of synthetic progestins con-tains 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.

 

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