Hormonal Contraceptives

Oral contraceptives are widely used worldwide and have had a revolutionary impact by providing a convenient, affordable, and reliable means of contraception. Myriad agents with substantially different components, doses, and side effects provide real therapeutic options. In addition to contraceptive actions, these agents have substantial health benefits.

Types of Hormonal Contraceptives combination oral contraceptives The most frequently used agents in the U.S. are combination oral contraceptives containing both an estrogen and a progestin. Their theoretical efficacy is considered to be 99.9%. Ethinyl estradiol and mestranol are the two estrogens used (with ethinyl estradiol being much more frequently used). The progestins are 19-nor compounds in the estrane or gonane series that have varying degrees of androgenic, estrogenic, and antiestrogenic activities that may be responsible for some side effects. Compounds such as deso-gestrel and norgestimate have less androgenic activity than other 19-nor compounds. Combination oral contraceptives are generally provided in 21-day packs with an additional 7 pills containing no active hormone. For monophasic agents, fixed amounts of the estrogen and progestin are present in each pill, which is taken daily for 21 days, followed by a 7-day "drug-free" period. The biphasic and triphasic preparations provide two or three different pills containing varying amounts of active ingredients, for different days in the 21-day cycle. This reduces the total amount of steroids administered and more closely approximates the estrogen-to-progestin ratios that occur during the menstrual cycle. Predictable menstrual bleeding generally occurs during the 7-day "off' period each month. The FDA recently approved a levonorgestrel-ethinyl estradiol combination (lybrel) that is taken continuously for the full 90 days, eliminating any menstrual periods. Additional options include a once-monthly medroxyprogesterone-estradiol cypionate injectable (lunelle), an ethinyl estradiol- norelgestromin (the active metabolite of norgestimate) patch (ortho evra) applied weekly, and an ethinyl estradiol-etonogestrel (the active metabolite of desogestrel) flexible vaginal ring (nuvaring) used for 3 weeks (followed by a removal for 1 week that leads to menstrual bleeding).

The estrogen content ranges from 20 to 50 pg; most contain 30—35 pg. Preparations containing <35 pg of an estrogen are termed "low-dose" pills. The progestin dose is more variable because of different potencies of the compounds. Monophasic pills available in the U.S. contain 0.4—1 mg of norethindrone, 0.1-0.15 mg of levonorgestrel, 0.3-0.5 mg of norgestrel, 1 mg of ethynodiol diacetate, 0.25 mg of norgestimate, and 0.15 mg of desogestrel, with slightly different dose ranges in biphasic and triphasic preparations.

progestin-only contraceptives Progestin-only contraceptives are only slightly less efficacious than combination oral contraceptives, with theoretical efficacy of 99%. Specific preparations include the "minipill"; low doses of progestins (e.g., 350 pg of norethindrone [nor-qd, micronor] or 75 pg of norgestrel [ovrette]) taken daily without interruption; subdermal implants of 216 mg of norgestrel (norplant ii, jadelle) for slow release and resultant long-term contraceptive action (e.g., up to 5 years); and crystalline suspensions of MPA (depo-provera) for intramuscular injection of 150 mg of drug, which provides effective contraception for 3 months.

An intrauterine device (progestasert) that releases low amounts of progesterone locally is available for insertion on a yearly basis. Its effectiveness is considered to be 97-98%; contraceptive action probably is due to local effects on the endometrium. Another intrauterine device (MIRENA) releases levonorgestrel for up to 5 years. It again is thought to act primarily by local effects.

postcoital or emergency contraceptives The FDA has approved two preparations for postcoital contraception. plan-b is two doses of the "minipill" (0.75 mg levonorgestrel per pill) separated by 12 hours; plan-b will soon be available without a prescription for women 18 years old and older. preven is two 2-pill doses of a high-dose oral contraceptive (0.25 mg of levonorgestrel and 0.05 mg of ethinyl estradiol per pill) separated by 12 hours. The FDA also has declared other products with the same or very similar composition safe and effective for use as emergency contraceptive pills.

The first dose of such preparations should be taken within 72 hours after intercourse, and this should be followed 12 hours later by a second dose. These treatments reduce the risk of pregnancy following unprotected intercourse by approximately 60-80%. With either preparation, effectiveness appears to increase the sooner after intercourse the pills are taken.

Mechanism of Action combination oral contraceptives Combination oral contraceptives act by preventing ovulation. Plasma LH and FSH levels are suppressed, the midcycle surge of LH is absent, endogenous steroid levels are diminished, and ovulation does not occur. While either component alone can exert these effects, the combination synergistically decreases plasma gonadotropin levels and suppresses ovulation more consistently than either alone.

Oral contraceptives exert hypothalamic and pituitary effects. Progesterone diminishes the frequency of GnRH pulses, and oral contraceptives also decrease pituitary responsiveness to GnRH. Estrogens also suppress FSH release from the pituitary during the follicular phase of the menstrual cycle, which likely contributes to the lack of follicular development in oral contraceptive users. The progestin may also inhibit the estrogen-induced LH surge at midcycle. Other effects may contribute to a minor extent to the efficacy of oral contraceptives, including impaired oocyte transport in the fallopian tubes. Progestin also leads to a thick, viscous mucus that reduces sperm penetration and induces an endometrium that is not receptive to implantation.

progestin-only contraceptives Progestin-only pills and levonorgestrel implants are highly efficacious for contraception. The pills block ovulation in only 60-80% of cycles; effectiveness is thought to be due largely to local effects in the cervix and uterus; such effects also account for the efficacy of intrauterine devices that release progestins. Depot injections of MPA yield plasma levels of drug high enough to prevent ovulation in virtually all patients, presumably by decreasing the frequency of GnRH pulses.

Untoward Effects combination oral contraceptives The consensus is that low-dose oral contraceptives pose minimal health risks in women who have no predisposing risk factors and also provide many beneficial health effects.

Cardiovascular Effects

There is no significant increase in the risk of myocardial infarction or stroke in nonsmokers without other risk factors such as hypertension or diabetes. There is a 28% increase in relative risk for venous thromboembolism, but the estimated absolute increase is very small because these events are rare in women without other predisposing factors. Nevertheless, the risk is significantly increased in women who smoke or have other factors that predispose to thrombosis. The incidence of hypertension is much lower with low-dose preparations, and most reported changes in blood pressure are not significant. The cardiovascular risk associated with oral contraceptive use apparently does not persist after drug cessation. Studies of low-dose oral contraceptives have not found significant changes in total serum cholesterol or lipoprotein profiles.

Cancer

There is not a widespread association between oral contraceptives and cancer. Combined oral contraceptives may increase the risk of cervical cancer by about twofold, but only in long-term users with human papilloma virus infection. There are reported increases in the incidence of hepatic adenoma and hepatocellular carcinoma in oral contraceptive users (perhaps a doubling in the risk of liver cancer after 4-8 years of use) but these are rare cancers and the absolute increases are small.

The risk of breast cancer in women of childbearing age is very low, and current oral contraceptive users in this group have only a very small increased relative risk of 1.1-1.2 that is not substantially affected by duration of use, dose or type of component, age at first use, or parity. Importantly, 10 years after discontinuation of oral contraceptives, breast cancer incidence is comparable in past users and never users. In addition, breast cancers diagnosed in women who have used oral contraceptives are more likely to be localized to the breast and thus easier to treat. Thus, overall there is no significant difference in the cumulative risk of breast cancer between those who have ever used oral contraceptives and those who have never used them.

Combination oral contraceptives actually cause a 50% decrease in the incidence of endometrial cancer that lasts 15 years after the pills are stopped. This is thought to be due to the inclusion of a progestin, which opposes estrogen-induced proliferation, throughout the entire 21 days. These agents also decrease the incidence of ovarian cancer and may decrease the risk of col-orectal cancer.

Metabolic and Endocrine Effects

Current low-dose combination contraceptives do not impair and may even improve insulin sensitivity and lipid profiles. In women who smoke, the ethinyl estradiol in oral contraceptives appears to cause a dose-dependent increase in several serum factors that may shift the hemostatic profile toward a hypercoagulable condition.

The estrogenic component of oral contraceptives may increase hepatic synthesis of a number of serum proteins, including CBG, TBG, and SHBG. While physiological feedback mechanisms generally adjust hormone synthesis to maintain normal "free" hormone levels, these changes can affect endocrine function tests that measure total plasma hormone levels and may necessitate dose adjustment in patients receiving thyroid-hormone replacement.

Miscellaneous Effects

Nausea, edema, and mild headache occur in some individuals; migraine headaches may be precipitated by oral contraceptives in a smaller fraction of women. Some patients may experience breakthrough bleeding during the 21-day cycle when the active pills are being taken. Withdrawal bleeding may fail to occur in a small fraction of women during the 7-day "off" period, thus causing confusion about a possible pregnancy. Acne and hirsutism are thought to be mediated by the androgenic activity of the 19-nor progestins.

progestin-only contraceptives Episodes of irregular, unpredictable spotting and breakthrough bleeding are the most frequent untoward effect and the major reason women discontinue use of progestin-only contraceptives. With time, the incidence of these bleeding episodes decreases; amenorrhea becomes common after a year or more of use.

Progestin-only minipill preparations do not increase thromboembolic events or blood pressure or cause nausea and breast tenderness. Acne may result from the androgenic activity of norethin-drone-containing preparations. These preparations may be attractive for nursing mothers because they do not decrease lactation as do products containing estrogens.

Aside from bleeding irregularities, headache is the most commonly reported untoward effect of depot MPA. Mood changes and weight gain also have been reported. Of more concern, many studies have found decreases in HDL levels and increases in LDL levels and decreased bone density. The labeling information for depot MPA for contraceptive injection contains a "black box" warning about increased risk of osteoporosis. There are no increases in breast, endometrial, cervical, or ovarian cancer in women receiving MPA.

Norethindrone implants may be associated with infection, local irritation, pain at the insertion site, and rarely, expulsion of the inserts. Headache, weight gain, mood changes, and acne occur in some patients.

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