Contraceptives agents

The most notable achievement in chemical contraception came in the late 19.30s and early 1960s with the development of oral contraceptive agents— the pill. Since then, a vari- 

The modem homional contraceptives fall into. several major categories (Table 23-3). each with its own mechanism of cnniraccpiivc action. Individual compounds arc discussed W ith the estrogens and progestins in the section above. 

TABLE 23-3 Comparison of Steroid Contraceptive Regimens 1. Combination—Monophask 

Products arc available in 21- or 28-day dispensers and tetllls. They arc taken on the same sdtcdntc of 21 days plus 7 day.s of no (or incite lahlcts cs die nionopluisics above, except Mircelle. Doses of aciivc tablets are shown. 

11 days Noielhindrone, I mg, and cltiinyl csinidtol., 35 pg todays Niireihiiidnme. 0.5 mg. and ethinyl csir.idiol. 25 pg 

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The application of the Birch reduction to ethers of estradiol by A. J. Birch opened up the area of 19-norsteroids to intensive research. The major Birch reduction product is an enol ether which affords either a 3-keto-A -or a 3-keto-A -19-norsteroid depending upon the hydrolysis conditions. Various 19-norsteroids have been found to have useful clinical activity compounds (30), (31), and (32) are oral contraceptive agents and compound (33) has been used as an oral anabolic agent. Several of these compounds were prepared on an industrial scale for a number of years by the Birch reduction of estradiol derivatives. 

The oral contraceptive agent Mestranol is synthesized using a carbonyl addition reaction like that shown in Problem 8.42. Draw the structure of the ketone needed. 

Heller, J., Penhale, D. W. H., Fritzinger, B. K., and Ng, S. Y., Controlled release of contraceptive agents from poly(ortho ester), in Long Acting Contraceptive Delivery Systems (G. I. Zatuchni, A. Goldsmith, J. D. Shelton, and J. Sciarra, eds.), Harper and Row, Philadelphia, 1984, pp. 113-128. 

Whole microbial cells as well as microbially derived enzymes have played a significant role in the production of novel antibiotics. The potential of microorganisms as chemical catalysts, however, was first fully realized in the synthesis of industrially important steroids. These reactions have assumed increasing importance following the discovery that certain steroids such as hydrocortisone have anti-inflammatory activity, whilst derivatives of the steroidal sex hormones are nsefiil as oral contraceptive agents. More recently, chiral inversion of non-steroidal anti-inflammatory dmgs (NS AIDs) has been demonstrated. 

As discussed later in this chapter, contraindications exist for various forms of contraception. Patients must be evaluated completely by a health care professional to rule out any medical contraindications to certain contraceptives. The physical examination also will allow health care professionals to determine if there are other medical concerns, such as hypertension, diabetes, or liver disease, that need to be considered when determining the appropriate contraceptive agent. Clinicians also should review family history for potential risks with certain forms of birth control. 

RC, a 22-year-old woman, presents to your clinic requesting information on contraception. You begin to take a history and determine that the patient is currently sexually active and is not using any method of birth control. Her past medical history is significant only for acne, and she takes no medications except occasional ibuprofen for menstrual cramps. On further questioning, you discover that she has a positive family history for hypertension and coronary artery disease. As you begin to discuss various contraceptive options with the patient, it is clear that she has a preference for an oral contraceptive agent. 

Based on the information provided by the patient, what oral contraceptive agent would you recommend for the patient and why ... 

Oral contraceptives containing both an estrogen and progestin are used as an alternate treatment for moderate acne in women. Contraceptive agents currently FDA approved for this indication include norgestimate with ethinyl estradiol and norethindrone acetate with ethinyl estradiol. 

Affairs of the American Medical Association recommends that women be informed about the small risk of interactions with antibiotics, and, if desired, appropriate additional nonhormonal contraceptive agents should be considered. Women who develop breakthrough bleeding during concomitant use of antibiotics and CHCs should be told to use an alternate method of contraception during the period of concomitant use. 

A wealth of epidemiological, clinical, and experimental studies link estrogens with cardiovascular disease (CVD). This evidence has promoted CVD as a key area within the extragenital effects of estrogens. The question is of interest because it directly affects the wide clinical use of estrogens as contraceptive agents or as principal constituents of hormonal therapy (HT) formulations in postmenopausal women. The significance of the subject is further reinforced by the relevance of CVD as a cause of mortality and morbidity in both women and men. 

Drugs That Interfere with Hormonal Contraceptives Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John s wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two other effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide... 

Table 40-3 Some Oral and Implantable Contraceptive Agents in Use.1 ...

Important alterations in hepatic drug excretion and metabolism also occur. Estrogens in the amounts seen during pregnancy or used in oral contraceptive agents delay the clearance of sulfobromophthalein and reduce the flow of bile. The proportion of cholic acid in bile acids is increased while the proportion of chenodeoxycholic acid is decreased. These changes may be responsible for the observed increase in cholelithiasis associated with the use of these agents. 

Another example of concern is the effect of antibiotic therapy on the efficiency of the synthetic and semisynthetic steroids used by more than 50 million women as contraceptive agents. Since 1973, many antibiotics such as ampicillin, amoxycillin, chloramphenicol, and sulfonamides have been shown to cause failures of oral contraceptives due to perturbation of intestinal microflora (56, 57). 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone applies a tandem Claisen rearrangement and intramolecular ene-reaction. Most 19-nonsteroid contraceptive agents are produced by total synthesis from nonsteroidal starting materials. 

Removable cation-stabilizing auxiliaries have been investigated for polyene cyclizations. For example, a silyl-assisted carbocation cyclization has been used in an efficient total synthesis of lanosterol. Other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol Besides the aforementioned A-ring aromatic steroids and contraceptive agents, partial synthesis from steroid raw materials has also accounted for the vast majority of industrial-scale steroid synthesis. 

Fasting growth hormone concentrations are higher in women using a contraceptive agent than in controls (162). 

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