Hormonal Contraception

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Chapter 26 Hormonal Contraception


The history of the development of “the pill” is fascinating. At the turn of the 20th century, an Austrian professor of physiology, Ludwig Haberlandt, demonstrated that pregnancy could be prevented in mice by giving them oral extracts from mice ovaries.3 In the 1940s, Dr. Carl Djerassi, working for the pharmaceutical company Syntex, discovered that the removal of the 19 carbon from yam-derived progesterone increased its progestational activity. This discovery led to the synthesis of norethindrone, an orally active progestin, in 1951.3,4

Dr. Pincus

Dr. Gregory Pincus is commonly referred to as the father of the pill. After making national headlines in 1934 by achieving in vitro fertilization of rabbit oocytes, he found that the world was not ready for this technology. He thus shifted his attention from mammalian fertilization to oral contraception for women and received a grant from the Planned Parenthood Federation in 1951 to find a progestin that could be used as an oral contraceptive agent.

After evaluating hundreds of substances, Pincus found two steroid compounds derived from the roots of the wild Mexican yam that could inhibit ovulation in laboratory animals. Pharmaceutical companies refined and advanced these discoveries to extract progestins and estrogens from plant material. Of interest, Pincus and his colleagues devoted a great deal of time and energy to purify the progestin norethynodrel from its estrogen contaminant mestranol. However, they subsequently discovered that mestranol could reduce breakthrough bleeding and acted synergistically with progestins to enhance contraceptive efficacy.

In 1956, Pincus, working in conjunction with the G.D. Searle Pharmaceutical Company and Dr. John Rock, conducted field tests of a hormonal contraceptive pill with hundreds of women in Massachusetts, Puerto Rico, and Haiti. They demonstrated that oral steroid hormones could be effective contraception, with side effects limited primarily to nausea. The U.S. Food and Drug Administration (FDA) authorized the production of contraceptive pills for limited use in 1957. Three years later, the FDA licensed G.D. Searle to produce the first commercially available oral contraceptive, Enovid, which contained 150 μg of mestranol and 9.85mg norethynodrel. Soon after the introduction of Enovid, other manufacturers introduced additional oral contraceptive formulations.

Modern Hormonal Contraceptives

Since the introduction of oral contraceptives more than 40 years ago, the hormone dosage used has been reduced by as much as eightfold. More recently, multiple new estrogens and progestins and several different delivery systems have been utilized in an effort to increase effectiveness, compliance, and continuation rates.

A broad range of contraceptive hormones and delivery systems are presently available in the United States today (Table 26-1). Several of the newer hormonal delivery systems are parenteral, and some of the preparations no longer need to be taken daily. The most frequently used and best studied are the combination oral contraceptives that contain a synthetic estrogen and one of several progestins. Three progestin-only oral contraceptives are currently available. In addition, a vaginal patch, a vaginal ring, a single rod implant, and an injectable medroxyprogesterone are commercially available.

Table 26-1 Formulations of Some Modern Hormonal Contraceptives

Delivery System Estrogens Progestins*
Oral contraceptives Ethinyl estradiol (dose: 20–50 μg) Estranes:
Combination (constant dose) Mestranol (dose: 50 μg)

Combination (sequential*) Ethinyl estradiol (20–40 μg)

Progestin only   Transdermal patch Ethinyl estradiol Norelgestromin Vaginal ring Ethinyl estradiol Etonogestrel Injectable   Medroxyprogesterone acetate (depot form) Subdermal implant   Etonorgestrel

* Sequential oral contraceptives have changing doses of estrogens, progestins, or both throughout the cycle.


Patient Selection

Oral contraceptives are an excellent contraceptive choice for many patients who are willing and able to consistently take a daily pill. In some cases, oral contraceptives may be recommended to patients because of their noncontraceptive benefits, such as treatment of dysmenorrhea or acne. The vast majority of healthy women can take oral contraceptives with an extremely low risk of serious side effects or risks. However, there are several standard contraindications to use of hormonal contraceptive methods that contain estrogen (Table 26-2). Many of these women are good candidates for progestin-only contraceptives. The remainder should be counseled to use an alternative nonhormonal method.

Table 26-2 Contraindications to Use of Combination Oral Contraceptives

Contraindication (current or past history) Combination (estrogen-containing) Progestin-only
Absolute Contraindications
Suspected pregnancy X X
Undiagnosed uterine bleeding X X
Liver disease X X
Symptomatic gall bladder disease X X
Breast cancer X X
Estrogen-induced liver tumor X  
Thromboembolism X  
Cerebral vascular disease X  
Coronary heart disease X  
Estrogen-dependent tumors X  
Seriously impaired liver function X  
Relative Contraindications
Age > 35 years with any cardiovascular risk factors: X  
Cigarette smoking
Abnormal lipid profile
Diabetes mellitus
Known cardiovascular disease X  
Severe headaches: vascular or migraine X
Hypertension X
Diabetes X
Gallstones X X
Within 3 weeks of childbirth X
Breastfeeding (especially first 6 weeks) X
History of cholestasis of pregnancy X
Systemic lupus erythematosus X
Abdominal or lower extremity surgery contemplated within 4–6 weeks X
Lower leg cast X
Hypertriglyceridemia X
Use of drugs that interact with oral contraceptives (e.g., rifampin) X

Estrogens and Progestins


The prototype progestin used in modern oral contraceptive pills is norethindrone (an estrane), which is created from progesterone by adding both a 19-carbon methyl group and a 17-α ethinyl group similar to ethinyl estradiol (Fig. 26-2). Norgestrel (a gonane) is the 18-carbon-ethyl derivative of norethindrone and is a racemic mixture of dextronorgestrel and levonorgestrel. Levonorgestrel is the biologically active component of norgestrel.

Norethynodrel and ethynodiol diacetate are related progestin analogues with longer durations of action. These progestins have a more potent effect on the endometrium than norethindrone, allowing the daily progestin dose to be reduced to between 0.15 and 1 mg.

In the 1980s, a number of new progestins were developed such as desogestrel and norgestimate. Desogestrel is a “prodrug” and must be metabolized to its active metabolic component, etonogestrel. Norgestimate, although active, is primarily metabolized to norelgestromin and small amounts of levonorgestrel. These progestins maintain desired effects on the endometrium, but had reduced androgenic effects, such as acne, weight gain, and undesired effects on lipids and lipoproteins. Today, the most commonly used progestins in oral contraceptives are norgestimate, norethindrone, and norgestrel. Progestin-only pills with no estrogen component are also discussed in this chapter.

Recently, drospirenone, a somewhat unique progestin, has been introduced in the United States.6 This anti-androgenic analogue of spironolactone has a high binding affinity for progesterone and mineralocorticoid receptors, but a low binding affinity for the androgen receptors. Oral contraceptives containing this progestin are associated with less fluid retention but have a slight theoretical risk of hyperkalemia.7 Women with renal insufficiency, hepatic dysfunction, or adrenal insufficiency should not use oral contraceptives containing drospirenone.


The majority of oral contraceptive pills on the market today contain both an estrogen and progestin in tablets that are taken daily for 21 days out of each 28-day cycle (see Table 26-1). During the remaining 7 days, women are instructed to take either inert pills (to assist the patient in maintaining the daily habit of taking a contraceptive pill) or no pills at all. At least one modern contraceptive pill gives women a lower dose of estrogen alone during 5 of these remaining 7 days. Extended-use oral contraceptives refers to an approach where active combination oral contraceptive pills are taken daily for 84 days followed by a 7-day hormone-free period.


Approximately 7% of women using combination oral contraceptives will have an unintended pregnancy during the first 12 months of use.8 Rates reported in different clinical trials can be highly variable because of factors, including methodology, demographics, various types of bias, and methods of calculating rates.912 Two of the most common methods are the Pearl index and life table analysis.

The Pearl index is a common method used to compare contraception efficacy. The Pearl index indicates the number of unintentional pregnancies related to 100 women-years of use. To calculate this index, the number of pregnancies that occur during a year are divided by cumulative months of exposure, and the quotient multiplied by 1200. If three pregnancies occur during a year in 100 women, the Pearl index will be 3.0 (i.e., 1200 months × 3 pregnancies/1200). This method is not ideal for comparing rates if studies are of different durations, because pregnancy rates can change over time.

Life table analysis is more effective for comparing failure rates than the Pearl index because a separate failure rate is determined for each month of use.12 Life table analysis also allows separate evaluation of both method and user failure rates. Method failure rates refer to pregnancy rates that occur when the method has been used correctly, in a consistent manner, and according to the instructions in the package insert. User failure rates (i.e., typical failure rates) refer to pregnancies that occur when the method is not used correctly. The reported method failure rates for oral contraceptive pills are between 1% and 3% and user failure rates are approximately 7%.11 Both method and user failure rates are similar for women over age 30 who are in higher socioeconomic groups. In contrast, the user failure rate is much higher for teenagers and unmarried women, sometimes surpassing 30%.


Decreased Risk of Ectopic Pregnancies

Combination oral contraceptives reduce the risk of ectopic pregnancy by 90%.13 The likely mechanism is through suppression of ovulation, an effect that obviously prevents all types of pregnancy. In contrast, some studies have indicated that women using progestin-only oral contraceptives are at higher risk for an ectopic pregnancy than the general population.

Decreased Risk of Malignancies

Endometrial Cancer

Multiple case-control and cohort studies have shown that oral contraceptives protect against endometrial cancer.1719 The overall reduction in risk is up to 50% and begins 1 year after initiation of use. This protection increases with the duration of use and persists for up to 20 years after oral contraceptives are discontinued. The strength of the protective effect varies according to the existence of other risk factors, such as obesity and nulliparity. The purported protective mechanism of action is a reduction in the mitotic activity of endometrial cells by the action of the progestin component of oral contraceptives.

Colorectal Cancer

Multiple studies have demonstrated up to a 40% reduction in colon and rectal cancer among women who have used oral contraceptives.2426 However, one study did not find a protective effect of oral contraceptives.27 Theoretical protective mechanisms include a reduction in bile acid production and concentration, and effects on colonic mucosa or flora.28

Decreased Benign Breast Disease

Several studies have shown a 30% to 50% decrease in the incidence of benign fibrocystic breast changes in women using oral contraceptives.37,38 One of the clearest effects is a decrease in the occurrence of fibroadenomas among current and recent long-term users of oral contraceptives under age 45. The most likely mechanism is through suppression of ovulation and therefore inhibition of the breast cell proliferation that normally occurs in the first half of an ovulatory menstrual cycle.

Improved Acne

Randomized, placebo-controlled clinical trials have demonstrated that some combination oral contraceptives will reduce acne lesions by as much as 50%.44 Several combination oral contraceptives containing new-generation progestins (e.g., norgestimate, desogestrel) or progestational anti-androgens (e.g., drospirenone in the United States, cyproterone acetate overseas) have been shown to be able to effectively reduce acne. Although it is likely that many other pill formulations will reduce acne, most formulations have not been studied for this outcome.

The mechanisms by which oral contraceptives improve acne include elevation of sex hormone-binding globulin, which binds and decreases available testosterone; suppression of the enzyme that converts testosterone to dihydrotestosterone; and suppression of gonadotropins, resulting in decreased levels of ovarian androgens. Pills containing drospirenone also block the action of androgens by acting as an antagonist at the androgen receptors.


Changes in Lipids

The estrogen component of combination oral contraceptives causes elevations in serum triglycerides but has a favorable change on the other two major lipids by elevating high-density lipoprotein cholesterol (HDL-C) while lowering low-density lipoprotein cholesterol (LDL-C) levels.52 Contraceptive formulations containing progestins with low or no androgenicity (e.g,. desogestrel, drospirenone, or norgestimate) lower LDL-C and elevate HDL-C and triglycerides. In contrast, contraceptive formulations containing more androgenic progestins may change lipids in an unfavorable direction by lowering HDL-C levels and elevating LDL-C levels.6,5254 It is important to be aware of these differences when prescribing oral contraceptives to women with risk factors for cardiovascular disease or to those who have strong family histories of ischemic heart disease or substantial lipid abnormalities.

Coagulation Changes

Low-estrogen (≤35 μg) oral contraception formulations are associated with clinically insignificant changes in both procoagulant and anticoagulant factors.55,56 However, women with risk factors for venous thromboembolism, such as factor V Leiden mutations, should avoid combination oral contraceptives.


The major risks associated with oral contraceptive use can be grouped into disorders of the cardiovascular system and neoplasms.

Cardiovascular Risk

The significant areas of concern with oral contraceptives are venous thromboembolism, stroke, and myocardial infarction. However, all of these cardiovascular risks have been dramatically decreased by the significant reduction in estrogen and progestin dosages in modern formulations.

Venous Thromboembolism

Multiple studies have established that women taking combination oral contraceptives containing 50 to 100 μg of ethinyl estradiol are at a small but increased risk of venous thromboembolism.57,58 It soon became clear that the risk correlates with the estrogen dose. When compared to women taking low-estrogen (≤35 μg) pills with an age-adjusted relative risk of venous thromboembolism of 1, women taking intermediate-estrogen (50 μg) pills are found to have a relative risk of 1.5, and women taking high-estrogen (>50 μg) pills have a risk of 1.7.59 However, even in the highest risk group, the absolute risk of venous thromboembolism was extremely low, at only 10 events per 10,000 women-years of use.

There is some evidence that two of the newer generation progestins might also increase the risk of venous thromboembolism. Two studies published a decade ago suggested gestodene and desogestrel had a greater risk for venous thromboembolism than previously used progestins, such as levonorgestrel.6063 Subsequent analyses and reviews have failed to reach consensus about whether these finding are real or somehow spurious.6471

The relative incidence of venous thromboembolism in young women taking low-estrogen (≤35μg) pills with different progestins is given in Table 26-3. At worst, the attributable risk of using oral contraceptives containing gestodene or desogestrel is only about 18 additional cases annually per 100,000 users compared to nonusers. Other risk factors for venous thromboembolism include age, obesity, pregnancy, trauma, smoking, immobilization, recent surgery, medical conditions such as cancer or collagen vascular disorders, and inherited coagulation disorders. Surprisingly, there is no evidence that cigarette smoking or varicose veins appreciably increases oral contraceptive users’ relative risk of venous thromboembolism.72

The mortality due to venous thromboembolism is low in reproductive-age women using oral contraceptives. Age significantly increases this risk of mortality, such that women age 44 have twice the mortality as women age 35.

Because major surgery increases the risk of venous thromboembolism, it is reasonable to discontinue oral contraceptives 3 to 4 weeks in advance. This is especially important before surgery involving extensive dissection in a lower extremity or the pelvic veins, or those that will require prolonged immobility postoperatively. For ambulatory surgery, such as tubal ligation or ovarian cystectomy, it is not recommended that oral contraceptives be discontinued before surgery because the risk of pregnancy associated with discontinuing oral contraceptives far outweighs the subsequent risk of venous thromboembolism.

Factor V Leiden Mutation

The most common genetic cause of primary and recurrent venous thromboembolism in women is factor V Leiden mutation. The identification of the factor V Leiden mutation in 1993 has led to new insights into the relationship between oral contraceptive use and venous thromboembolism.73 White women have approximately 5% prevalence of a homozygous mutation; African-American and Asian women have a much lower prevalence. Women with this mutation not using oral contraceptives have a risk of venous thromboembolism of approximately 5.7 events per 10,000 women-years. In contrast, women with this mutation using oral contraceptives have an increased risk of venous thromboembolism of 28.5 events per 10,000 women-years.

Screening women who desire oral contraceptives for factor Leiden V mutation would not be a cost-effective strategy in light of the low absolute risk of venous thromboembolism in women with this mutation. It has been calculated that screening 1 million potential oral contraceptive users for all known coagulation factor deficiencies or mutations would identify approximately 50 women at risk but also would result in approximately 62,000 false-positive results.69 However, screening women with a strong family history of thromboembolic events for factor V Leiden mutation remains appropriate. Certainly, a known homozygous or heterozygous factor V Leiden mutation is a relative contraindication to estrogen-containing hormonal contraceptives, although the absolute risk of thromboembolism in these patients is still relatively low.