The oral contraceptives in general use are synthetic steroids similar to the natural female sex hormones - the estrogens and progestins. These steroids are used in doses and in combinations that provide contraception by inhibiting ovulation.

When first developed, the 2 principal regimens of oral contraception were combined and sequential. In the combined method, pills containing estrogen and progestin are taken each day for 20-21 days. The sequential method, in which an estrogen pill is taken each day for 15-16 days followed by an estrogen-progestin pill each day for 5 days, has been abandoned in the U.S. because several studies showed a higher than normal incidence of endometrial cancer in women using this method of contraception.

The combined regimen is begun either with the onset of the menstrual cycle or on the Sunday closest to the start of menses. Since most oral contraceptive preparations are packaged in 28-day regimens (the pills taken the last 7 days being placebos), the Sunday start approach may be easier to follow for most women. However, a good practice is to recommend use of an additional form of contraception during the first cycle to maximize efficacy. Withdrawal bleeding can be expected within 3-5 days after completion of the 20- or 21-day regimen.

The serum levels of FSH and LH throughout the normal menstrual cycle are shown in Figure 33-2A. During a typical cycle under the combined oral contraceptive regimen (Fig 33-2B), there is no rise during the first half of the cycle; thus, follicle growth is either not initiated or, if initiated, recruitment does not occur, ovulation does not occur, and consequently there is no FSH and LH surge. During the sequential oral contraceptive regimen (Fig 33-2C), the estrogen stimulates LH secretion in an irregular manner. There is no concomitant early rise in FSH when progestin is added, and another LH surge usually is produced. When a progestin-only regimen (

Fig 33-2D) is followed (eg, with the minipill; see Minipill section), there are multiple LH surges but no significant changes in FSH levels. For the reasons given, these oral contraceptive regimens significantly alter the physiologic hormonal balance. The minipill regimen causes the least derangement, but its efficacy as a contraceptive is less than that of combined oral contraception. Moreover, occasional amenorrhea may occur.

Advantages
Major noncontraceptive advantages derived from use of oral contraceptives in the U.S. alone include approximately 50,000 hospitalizations averted annually for conditions that include benign breast disease, retention cysts of the ovaries, iron deficiency anemia, and pelvic inflammatory disease. Studies in the U.S. and Great Britain showed that users of oral contraceptives have almost complete protection against ectopic pregnancies. Oral contraceptive use is estimated to prevent about 10,000 hospitalizations for this life-threatening complications annually in the U.S. alone.

Oral contraceptives provide a reduction in risk of developing ovarian and endometrial cancer. The data with ovarian cancer are significant enough to recommend oral contraceptive usage to women considered at high risk by family history or BRCA gene status. In one population-based, case-control study to evaluate the impact of dose of oral contraceptives on ovarian cancer risk, the adjusted risk of ovarian cancer was reduced by 40% for oral contraceptive users overall, with longer duration of use affording greater protection.

Other well-established benefits include a reduction in menorrhagia and dysmenorrhea, iron-deficiency anemia, and acne, as well as improvements in hirsutism and symptomatic endometriosis.

Disadvantages & Side Effects
Much attention has been paid to a possible relationship between the use of oral contraceptives and the incidence of thromboembolic disease, including Pulmonary embolism and cerebral thrombosis. Between 1967 and 1969, reports of retrospective studies in Great Britain and the U.S. provided statistically valid data indicating that deep vein thrombosis, Pulmonary embolism, and cerebral thrombosis occur 3-6 times more frequently in users of oral contraceptives than in nonusers. However, since those earlier reports were published, the dosages of steroids contained in oral contraceptives have been reduced 3 to 4 times. In particular, ethinyl estradiol, the most widely used estrogen, is now provided in doses of about 20-35 ug in most preparations. More recent publications studying these disorders in association with oral contraceptive use suggest that a significant reduction in risk has occurred in conjunction with dosage reduction. A recent case-control study revealed that current users of low estrogen dose (< 35 ug ethinyl estradiol) combined oral contraceptives containing desogestrel or gestodene appear to be at higher risk of developing venous thromboembolism than users of combined oral contraceptives containing levonorgestrel, but this remains controversial. Another British study in 1995 concluded that there was a significant association between idiopathic venous thromboembolism and current smoking, body mass index over 35, and asthma. Current users of low estrogen dose oral contraceptives have a small increased risk of ischemic stroke, although most of the risk occurs in women with other risk factors such as smoking, hypertension, and history of migraines.

Some users of oral contraceptives may have a greater risk of developing coronary thrombosis than nonusers. The increased risk, if present, appears to be confined to older users who smoke one or more packs of cigarettes per day. Furthermore, following oral contraceptive use, the Nurses Health Study has shown that past oral contraceptive use, regardless of duration, does not increase the risk of subsequent cardiovascular disease, including myocardial infarction. Although the progestins contained in oral contraceptives may change the lipid/ lipoprotein profile in an adverse direction, the advent of new progestins and dosage reductions have led to a reduction in the magnitude of such changes. In addition, estrogen affects such profiles in a favorable direction. Thus, the interaction of the two steroids combined with recent dosage and formulation changes has led to preparations that are essentially neutral relative to their effects on the cardiovascular system.

Although epithelial abnormalities of the uterine cervix among users of oral contraceptives were at one time a matter of concern, the preponderance of evidence cannot demonstrate that the use of oral contraceptives either causes or predisposes to the development of cancer of the cervix. A major problem with studies attempting to examine this relationship is the confounding factors such as multiple sexual partners, age at first intercourse, and frequency of sexual activity.

The association between oral contraceptive use and breast cancer has been extensively studied during the past decade. At this time, it is unclear whether any positive association exists. The data in some studies suggest that long-term oral contraceptive use before childbearing may increase the risk of premenopausal breast cancer. However some data also suggest that use may also offer modest protection against the more common postmenopausal form of this cancer. As with cervical neoplasia, studies attempting to explore this relationship are subject to a number of potential biases such as varying practices of breast disease screening. Other infrequent problems occasionally noted with oral contraceptive use include hypertension, cholelithiasis, and benign liver tumors. However, none of these problems occurs frequently enough to be of significant concern to most users.

Since the current formulations are associated with significant reductions in risk of serious sequelae, side effect control will be of greater importance to most users in the future. Furthermore, studies have also shown that compliance is affected by occurrence of side effects and that such “minor” problems account for about 40% of the discontinuations. Factors affecting compliance are of significance particularly when one studies efficacy. For example, the theoretical failure rate with combination oral contraceptives after 1 year’s use is less than 1%. However, the use-effectiveness failure rate in some studies is as high as 4-6%. Intermenstrual bleeding including breakthrough bleeding and spotting may be experienced by about 10-20% of users in the first few months of use. With today’s formulations, at about 6 months of use such problems stabilize and are seen in only about 5% of users. Missed menstrual periods or amenorrhea are relatively infrequent and of little clinical significance except that these problems can raise concern as to whether a contraceptive failure has occurred. Nausea may be seen in up to 10% of users; as with intermenstrual bleeding, this is a duration effect that declines rapidly after several months of use. With current formulations, acne tends to improve or show little change. Furthermore, significant headaches and weight gain are far less frequent than reported with higher-dose preparations.

Since compliance and a clear understanding of how to take oral contraceptives are important to their successful use, health care providers should take the time at the initial visit to explain the packaging of the brand being prescribed, discuss the side effects, review how to start the first cycle, and discuss what to do when pills are missed. It should be emphasized that the patient package insert provides useful information on these topics. In addition, users should be encouraged to contact their provider or someone in the office or clinic who is familiar with oral contraceptive health care if problems occur. Finally, users should be advised to use alternate forms of contraception if oral contraceptive use is interrupted because of forgotten pills or the occurrence of side effects.

Table 33-1 lists the currently available oral contraceptives and their contents.