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

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

Estrogens and Progestins

Estrogens

Combination oral contraceptive pills contain one of two synthetic estrogens: ethinyl estradiol or, less commonly, mestranol. Both of these steroids are created by adding a 17-α ethinyl group to estradiol to increase potency and enhance oral activity by impeding hepatic degradation (Fig. 26-1). Natural estrogens are relatively weak when given by mouth due to their rapid clearance from blood by the liver (i.e., the first-pass effect). As a result of decreased degradation, both of these synthetic estrogens are 10 to 20 times more active than estradiol when given orally, but have similar potency when given intravenously.

Figure 26-1 Synthetic estrogens used in combination oral contraceptives.

The original formulation for oral contraceptive pills contained as much as 150 μg of synthetic estrogen each. When studies found an association between the estrogen content of early oral contraceptives and venous thromboembolism, researchers found that the estrogen component could be significantly reduced with no loss of contraceptive efficacy. As a result, most modern oral contraceptive pills now contain between 25 and 35 μg of ethinyl estradiol, and a few contain as little as 20 μg.⁵ Although reducing the daily estrogen dose to either 30 or 35 μg has been shown to reduce the risk of venous thromboembolism, no study has shown that further decreasing the estrogen dose reduces the risk further.

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.

Figure 26-2 Progestins used in combination and progestin-only oral contraceptives.

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.

Mechanism of Action

Oral contraceptives were originally designed such that progestin would inhibit ovulation by suppressing luteinizing hormone release at the level of the hypothalamus or pituitary. Estrogen was included to stabilize the endometrium to minimize breakthrough bleeding and spotting, although estrogen has been found to help suppress ovulation by inhibiting release of follicle-stimulating hormone.

Other contraceptive mechanisms of action of oral contraceptive pills have since been discovered. Progestins decrease entry of sperm into the uterus by decreasing sperm motility and increasing cervical mucus viscosity. Progestins also inhibit sperm transport by decreasing fallopian tube motility. Finally, progestins alter the endometrium and thus inhibit implantation.

Efficacy

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.^9–12 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 Pelvic Inflammatory Disease

Several studies have shown that oral contraceptive use reduces the risk of pelvic inflammatory disease (PID) by 50% to 80% compared to women who use no method or a barrier method for contraception.^13–15 However, one recent multi-center study failed to show a protective effect of oral contraceptives.¹⁶

Because oral contraceptives do not protect against the acquisition of lower genital tract sexually transmitted diseases (e.g., Chlamydia trachomatis and Neisseria gonorrhoeae), the assumption is that they impede bacterial ascent from the uterine cervix into the upper genital tract. Several possible mechanisms for this have been suggested. Progestins cause cervical mucus to become thick and viscous, and this might substantially inhibit the ascent of bacteria. Alternatively, the reduced menstrual flow resulting from oral contraceptives could decrease retrograde menstrual flow to the fallopian tubes and result in a less favorable environment for promoting bacterial growth. Finally, hormone-related changes in uterine contractility might make ascent of organisms less likely.

Decreased Risk of Malignancies

Decreased Menstrual Flow and Dysmenorrhea

Up to 75% of young women will experience some degree of dysmenorrhea, and 15% to 20% will have severe pain.^29,30 Multiple studies have shown that combination oral contraceptives reduce both menstrual flow and dysmenorrhea.^29–34

Two possible mechanisms have been proposed to explain how oral contraceptives reduce dysmenorrhea. Women taking oral contraceptives have been shown to have reduced prostaglandins in the menstrual fluid. It is hypothesized that by decreasing prostaglandin production by the uterus, oral contraceptives decrease dysmenorrhea by decreasing either endometrial vasoconstriction and ischemia or uterine contractile activity.^35,36

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.

Ovarian Cysts

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.

Increased Bone Density

The majority of studies indicate that oral contraceptives have a positive effect on bone mineral density, and no studies have demonstrated a negative effect.⁴⁵ Oral contraceptives appear to delay or prevent the decline in bone mass that begins between ages 30 and 40. Women who use oral contraceptives for 5 to 10 years or longer are afforded the greatest protection. A population-based, case-control study revealed a 25% reduction in hip fracture risk in these women.⁴⁶

The positive effects of oral contraceptives on bone mineral density are due primarily to estrogen, which has been demonstrated to increase calcium absorption, decrease calcium loss, and directly decrease bone resorption by inhibiting osteoclast activity. Norethindrone also appears to have a positive effect on bone mass, although the mechanism is uncertain.

Improvement in Rheumatoid Arthritis

Oral contraceptives appear to diminish both the severity and symptomatology of rheumatoid arthritis but do not prevent this disease. A large meta-analysis of nine hospital and population-based studies suggested that oral contraceptives prevent the progression of rheumatoid arthritis to more severe varieties.⁴⁷ However, the protective effect was noted in the hospital- based studies only, suggesting the possibility of some unexplained bias.

Insulin Resistance

The effect of combination oral contraceptives on carbohydrate metabolism has been studied for several decades. It is now recognized that both estrogens and progestins affect glucose metabolism by increasing peripheral resistance to insulin. However, studies of women on current low-estrogen (≤35 μg) formulations have shown minimal changes in glucose and insulin levels that are of no clinical significance.⁴⁸ Further, there is no evidence that combination preparations increase the risk of subsequently developing diabetes in women at risk, such as those with prior gestational diabetes.⁴⁹

Women with polycystic ovary syndrome who usually demonstrate some degree of insulin resistance benefit from oral contraceptives. Although oral contraceptives may slightly increase their insulin resistance, they also reduce associated symptoms such as acne and hirsutism, regulate menses, and protect the endometrium against development of endometrial malignancy.⁵⁰

Insulin-dependent diabetic women can use oral contraceptives with little fear of affecting fasting plasma glucose, insulin requirements, or glycosylated hemoglobin levels.⁵¹ However, one should avoid oral contraceptives in diabetics with evidence of vascular disease because of their increased risk of cardiovascular disease.

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.^6,52–54 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.

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.

Nausea

Approximately 50% of women report a feeling of nausea when beginning combination oral contraceptives; however, few experience vomiting. The incidence of these side effects is lower with low-estrogen (≤35μg) pills, but still relatively frequent. Anecdotal reports suggest vitamin B₆ (50 mg orally) taken daily may be of help. Other strategies include taking the pill with meals or at bedtime, decreasing the estrogen dose to 20 or 25μg, and switching to a progestin-only contraceptive. Many gastrointestinal side effects ameliorate over time, so patients should be encouraged to try a several-month trial of oral contraceptives before discontinuing.

Breast Symptoms

Estrogens can stimulate breast tissue, leading to fluid accumulation and discomfort. Combination oral contraceptive pills containing lower doses of ethinyl estradiol (20 or 25μg) may decrease this side effect. If patients are experiencing increased breast tenderness immediately before the pill-free interval, they may actually benefit from a higher dose estrogen combination pill that more effectively inhibits ovulatory cycles. Patients should be reassured that the discomfort is not evidence of growth of a breast cancer and that with time the overall incidence of benign breast disease will decrease.

Headache

Headache is a common complaint among reproductive-age women, including oral contraceptive users. A careful history can differentiate between a tension-like headache and a migraine headache. Tension headaches are often described as a dull, steady ache radiating to the neck and shoulder muscles with no neurologic deficits. Migraine headaches are typically described as recurrent episodes of throbbing pain most often accompanied by nausea and vomiting.

If a migraine headache is suspected, combination oral contraceptives should be used with care. Although there are no conclusive data on differences in stroke risk for migraine with or without aura, oral contraceptive use in the former circumstance should be considered only if other contraceptive methods cannot be used and only after detailed counseling. If migraine occurs without aura in the absence of other risk factors, most women can be given a trial of oral contraceptives. Follow-up should be initiated within the first 2 to 3 months to assess frequency and severity of headaches. If there is an increase in frequency during the trial, a change in formulation might be considered. If headache occurs more frequently in the hormone-free interval, the physician might consider the use of extended-use oral contraceptives without a hormone-free interval. However, if the headaches become significantly more severe or frequent, oral contraceptives should be discontinued.

Irregular Bleeding

Cycle control is one of the most important determinants of both contraceptive acceptability and compliance. Although reducing the daily dose of ethinyl estradiol decreases multiple health risks and symptoms without compromising efficacy, it also compromises cycle control.

As many as 39% of women starting oral contraceptives with previously normal cycles will experience irregular bleeding, midcycle spotting, especially within the first 3 months.¹⁰⁰ Women with a history of irregular menses may be even more likely to experience heavy or irregular bleeding initially. Long-term users sometimes develop amenorrhea. It is important to forewarn patients to expect changes in bleeding and to reassure them that this should resolve within three cycles and is not a sign of cancer.

For women at increased risk of dysfunctional uterine bleeding (e.g., just after puberty or in the perimenopausal period) formulations containing 30 to 35μg ethinyl estradiol may be more likely to control bleeding compared to those 20 to 25μg. No study has demonstrated a relative advantage of either monphasic or multiphasic formulations in terms of either side effects or efficacy.

Persistent abnormal uterine bleeding while using oral contraceptives requires investigation. The initial evaluation should include assessment for cervicitis, sexually transmitted infections, and cervical neoplasia. The evaluation may include sonohysterography or endometrial biopsy, as indicated. If the workup is negative, treatment may include use of a higher-estrogen (50μg) oral contraceptive for one or two cycles or the addition of a small supplemental dose of estrogen to the patient’s current regimen.

Weight Gain

There is no substantive evidence that oral contraceptives cause weight gain. However, estrogens and progestins may act as appetite stimulants or have anabolic steroid effects.

Drug Interactions with Oral Contraceptives

A small number of drugs may interact with oral contraceptives (Table 26-4). There is no substantive evidence that commonly used antibiotics (e.g., tetracyclines, penicillins, or cephalosporins) or analgesics (e.g., aspirin or acetaminophen) decrease the efficacy of oral contraceptives.

Table 26-4 Drugs and Their Potential Interactions with Oral Contraceptives

Missed Pills

Missing pills is a common problem that can decrease efficacy and increase irregular bleeding. The risk of unintended pregnancy is greatest when a pill is missed early in the cycle because follicle recruitment for ovulation may be initiated. If one pill is missed, it should be taken as soon as this is realized. If it is only realized at the time of taking the pill at the regularly scheduled time, two pills should be taken. If two or more pills are missed, the risk of pregnancy is great and alternative contraception should be used for at least 1 week.

Postpartum Contraception

Postpartum women who are not nursing can initiate combination oral contraceptives after the third postpartum week. Earlier initiation increases the risk of venous thromboembolism. Because ovulation is extremely unlikely to occur within 3 weeks of delivery, this delay does not impair contraceptive efficacy.

Breastfeeding

The existing randomized, controlled trials are insufficient to establish an effect of hormonal contraception, if any, on milk quality and quantity.¹⁰¹ Based on the best available data, it appears that hormonal oral contraceptives can be used immediately postpartum. Many clinicians prefer to give progestin-only contraceptives during the first 6 months after delivery because they have no apparent deleterious effect on breastfeeding.¹⁰²

Extended-use Oral Contraceptives

Extended-use oral contraceptives offer an approach whereby active combination oral contraceptive pills are taken daily for 84 days followed by a 7 day hormone-free period, rather than the usual 21 days of active pills followed by a 7-day hormone-free period used for monthly regimens. The purpose is to limit the number of withdrawal menstrual periods to four per year. This is an effective approach for the treatment of any medical condition that causes dysmenorrhea or menorrhagia or is exacerbated by menstruation, including hemorrhagic diathesis, endometriosis, uterine leiomyoma, migraine headaches, and epilepsy.^103–105 It can also be used for women who electively desire to reduce their days of menstrual bleeding.

Originally, standard low-estrogen (≤35 μg) combination oral contraceptive pills were used for this method by having the patient discard the inert pills from four monthly packages and take one of the remaining 84 active pills daily. There is now an FDA-approved prepackaged system commercially available containing 30 μg of ethinyl estradiol and 0.15 mg levonorgestrel in each pill (see Table 26-1).

Progestin-only Contraceptive Pills

The progestin-only oral contraceptive, or “mini-pill,” offers an estrogen-free alternative to combination oral contraceptives. The formulation contains small doses of norethindrone, levonorgestrel, or norgestrel and needs to be taken at the same time every day, starting on the first day of menses.

Emergency Contraception

Emergency contraception is an approach to prevent pregnancy after unprotected intercourse or known failure of a contraceptive method such as a broken or leaking condom.¹⁰⁹ Two oral hormonal methods are currently available.

Formulation

The transdermal contraceptive patch is a three-layer matrix system consisting of an outer polyester protective layer, a middle layer containing an adhesive and the contraceptive steroids, and an inner clear polyester liner that is removed before application to the skin.¹¹⁵ Its size is 20 cm², roughly the size of a matchbook.

The transdermal patch contains a total of 6.0mg of norelgestromin, the active metabolite of norgestimate, and 750μg of ethinyl estradiol. Each patch is designed to deliver 150μg of norelgestromin and 20μg of ethinyl estradiol daily for a 7-day period. As a safety margin, these patches will continue to secrete a contraceptive amount of hormones for 2 additional days to offer continued protection for women who forget to change their patch after 7 days.

After each patch has been worn for 7 days, it is removed and a new one is applied to another skin site. Three consecutive 7-day patches are applied in a typical cycle followed by a 7-day patch-free period to allow withdrawal bleeding. Application sites that have been determined to be therapeutically equivalent in clinical trials include the buttocks, lower abdomen, upper outer arm, and upper torso except for the breasts.¹¹⁶

Mechanism of Action

Ovulation inhibition is the primary contraceptive action of the contraceptive patch, the same mechanism of action as that of combination oral contraceptives. The transdermal contraceptive system maintains relatively steady-state serum concentrations of steroids without the characteristic peaks and troughs of an oral contraceptive.

Efficacy

The pregnancy rate for the transdermal contraceptive patch is less than 1% per 100 women-years.^115,117,118 These rates are comparable to pregnancy rates achieved with current oral contraceptives. There is also data to indicate that it is easier for women to use this method correctly compared to oral contraceptives.¹¹⁹ The rate of perfect compliance for the patch did not vary by age, whereas younger women pill users had lower compliance rates. Among the pregnancies reported, about one-third occurred in women weighing more than 90 kg. However, a Food and Drug Administration (FDA) report has identified a potential increase in the risk of venous thromboembolism.¹²³

Noncontraceptive Benefits

Although the noncontraceptive benefits of the transdermal patch have yet to be demonstrated, it is likely to have benefits similar to oral contraceptives because both methods use the same type of steroid hormones.

Metabolic Changes

The contraceptive patch changes serum lipids and lipoproteins in a manner similar to that seen with oral contraceptives. Contraceptive patch users have some increase in total cholesterol, HDL-C, LDL-C, and triglycerides, but the LDL-C to HDL-C ratio is unaffected.¹²⁰

The transdermal patch, much like combination oral contraceptives, increase conversion of prothrombin to thrombin, which appears to be balanced by increased fibrinolysis.¹²¹ Both the patch and oral contraceptives increase the coagulation activity marker prothombin fragment 1+2, markers for fibrinolysis, fibrin degradation products, and plasma α₂-antiplasmin.

Major Risks

Serious adverse events have been reported that are potentially attributable to the patch, including nonfatal pulmonary embolism, migraine headache, cholecysititis, and carcinoma in situ of the cervix.¹²² Although the rates of serious risks remain unknown, these rates may be similar to those for combination oral contraceptives because the transdermal patch contains the same hormones. However, a Food and Drug Administration (FDA) report has identified a potential increase in risk of venous thromboembolism.¹²³

Side Effects

The most frequently reported side effects of the transdermal patch include irregular bleeding, breast symptoms, headache, nausea, dysmenorrhea, and application site reactions.¹²² There is no evidence that use of the patch influences body weight.

The breakthrough bleeding pattern and spotting with the transdermal contraceptive patch is similar to that seen with oral contraceptives. By about 6 months, the frequency of irregular bleeding declines substantially and remains stable.

Compared to users of oral contraceptives, patch users appear to have more dysmenorrhea and more breast symptoms during the first two cycles. The breast symptoms are described as mild to moderate in 85% of women experiencing them and markedly decline with continued use of the patch.

A unique side effect for patch users is application site reactions, which occur in approximately 20% of women.

Management Issues

Formulation

The contraceptive vaginal ring is flexible, is composed of ethylene vinyl acetate copolymer, and is approximately 5 cm in diameter and 4 mm in thickness. Contact of the ring with the vaginal wall leads to release of ethinyl estradiol at a rate of 15μg daily and etonogestrel (the active metabolite of desogestrel) at 120μg daily.¹²⁴ After vaginal insertion, maximum serum hormone concentrations are reached in about 1 week for progestin, and in 2 or 3 days for estrogen.^123,124 After reaching maximum serum concentrations, these serum levels slowly decline. The vaginal ring results in a relatively steady serum hormone concentration similar to that seen with the contraceptive patch, in contrast to the concentration peaks and troughs seen with oral contraceptives.

Mechanism of Action

The vaginal ring provides contraception by inhibiting ovulation with ovarian suppression similar to that achieved by oral contraceptives. This has been documented by transvaginal ultrasound measurements of follicular activity and measurements of luteinizing hormone and progesterone.¹²⁴

Women are instructed to place the ring as high in their vagina as possible to avoid possible expulsion, but fitting is not required. The ring is worn for 3 weeks out of 4, although there is enough contraceptive steroid content in the ring’s reservoir for a total of 5 weeks.

Efficacy

The reported pregnancy rate for the vaginal ring is 0.65% per 100 women-years.¹²⁵ The ring maintains its efficacy even if removed for up to 3 hours, although it is designed to be left in place continuously, even during intercourse. If removed for longer than 3 hours, a backup method for contraception should be used until the ring has been in place for 7 more days. The ring has not been studied extensively in heavier women, and thus the effect of weight on efficacy is unknown.

Noncontraceptive Benefits

The noncontraceptive benefits of the vaginal ring have yet to be studied. However, because the ring contains the same type of steroids as oral contraceptives, it is likely that the ring has some of the same benefits.

Metabolic Changes

Although studies have not yet been done on metabolic changes associated with the vaginal ring, it is likely that the effects on lipids, coagulation, and carbohydrate metabolism will be similar to oral contraceptives.

Major Risks

As with the transdermal contraceptive patch, there is little published data on the incidence or rates of major side effects. However, because the ring contains steroids similar to those utilized in oral contraceptives, the risks may be similar.

Side Effects

Approximately 10% to 15% of users report vaginal-related symptoms, such as slight discomfort, a sensation of a foreign body, leukorrhea, vaginitis, or coital problems. Systemic side effects are similar to those seen with users of combination oral contraceptives. However, the vaginal ring appears to have a low frequency of irregular bleeding and spotting, which occurs in only 5% of cycles. This compares favorably to the incidence of irregular bleeding seen with oral contraceptives, which occurs in 5% to 39%.^100,125 The irregular bleeding pattern is relatively constant for all cycles, in contrast to the declining incidence seen after several cycles of oral contraceptives.

Specific Management Issues

When starting use, the vaginal ring can be inserted during the first 5 days of a menstrual period. However, backup contraception should be used for the first 7 days of ring use. If the ring is removed for more than 3 hours at any time, backup contraception should be used. Also the vaginal ring has enough hormone content for up to 5 weeks of use. Therefore, failure to remove the ring on time is not a major issue with this method.

Overall acceptance of the ring is high, with 95% of users indicating satisfaction and 97% indicating they would recommend it to others.¹²⁶ Major reasons cited for liking the ring include ease of remembering how to use (45%) and overall ease of use (27%). Approximately 90% of users report using the ring according to the instructions, a rate similar to that seen with the transdermal patch.

Formulation

Depot medroxyprogesterone acetate (DMPA) is an aqueous suspension of 17-acetoxy-6-methyl progesterone. It is the only injectable contraception currently available in the United States.¹²⁷ Although utilized as a contraceptive for at least 40 years, the FDA did not approve its use for contraception until 1992. The usual dose is 150 mg every 3 months, administered intramuscularly into either the gluteus maximus or deltoid muscles. DMPA is also available as a subcutaneous injection of 104 mg every 3 months.

Mechanism of Action

The primary mechanism of action of DMPA is suppression of ovulation by suppressing the surge of gonadotropins.¹²⁸ Despite suppression of gonadotropins, the ovary continues to produce estradiol at levels found in the early follicular phase of the menstrual cycle.¹²⁹ Accordingly, women using DMPA do not exhibit signs or symptoms of estrogen deficiency. Other actions include thickening cervical mucus to impede ascent of sperm and thinning of the endometrium such that implantation of a blastocyst is less likely.

Efficacy

The reported method failure rate for DMPA injections is 0.3% (0.3 pregnancies per 100 women-years), whereas the typical user failure rate is 3%.¹ The contraceptive effectiveness of a DMPA injection persists for at least 16 weeks. This is longer than the manufacturer’s stated effectiveness of only 13 weeks after an injection, allowing for at least a 3-week margin of safety when administration of a subsequent injection is delayed.¹³⁰

Unlike oral contraceptives, there is no evidence of medications that decrease the efficacy of DMPA or that DMPA alters the effectiveness of other medications. Increased weight does not affect DMPA efficacy.

Noncontraceptive Benefits

A number of gynecologic health benefits are associated with use of DMPA.^130–132 The risk of ectopic pregnancy is significantly lower among users compared to women not using contraception. Similar to oral contraceptives, DMPA reduces the risk of endometrial cancer by as much as 80%.¹³³ The risk reduction is long-term and is greater for women who use DMPA for prolonged periods. Although DMPA does not protect against ovarian or breast cancer, neither does it increase risk of these malignancies.

Other benefits of DMPA include reduction in the risk of pelvic inflammatory disease. By producing amenorrhea, DMPA also reduces the symptoms of endometriosis, such as dysmenorrhea. By reducing menorrhagia, DMPA also reduces the risk of iron deficiency anemia.

DMPA has nongynecologic health benefits as well. Sickle cell crises are reduced in frequency by as much as 70%, although the mechanism for this effect remains unknown.¹³⁴ DMPA also appears to reduce the risk of seizure activity among women with epilepsy.

Metabolic Changes

The metabolic changes associated with DMPA are for the most part minor. Although there are small changes in coagulation factors, these are not felt to be clinically significant.¹³⁵ There are no increases in procoagulant factors, probably related to the fact that DMPA does not increase hepatic globulin production.¹³⁶ Relative to lipids and lipoproteins, studies have shown either small declines in HDL-C levels and increases in LDL-C or no changes at all.^135,137,138 As with most progestins, there is evidence that DMPA impairs glucose tolerance in some users, although these changes are not clinically significant.^139,140

Major Risks

Side Effects

Specific Management Issues

The most important determinant of contraceptive efficacy for DMPA users is their return for timely re-injection. Specially designed calendars can aid in scheduling and remembering re-injection appointments. After injection, DMPA users should avoid rubbing the injection site, because that might distribute the drug more rapidly and lead to decreased efficacy near the end of the 3-month cycle. Because menstrual patterns are altered with DMPA, proactive counseling can alleviate future concerns.

CONTRACEPTIVE IMPLANTS

Implanon is the only contraceptive implant approved in the United States.¹⁴⁸ It is a single implant 40mm in length and 2mm in diameter with an ethinylene vinyl acetate core that contains 68mg of etonogestrel, the major metabolite of desogestrel. The progestin is released at rates that vary from 60μg per day initially and slowly decreases to 30μg daily after two years. The device is placed using a preloaded applicator in the superficial subdermal tissue on the inner aspect of the non dominant upper arm and removed after three years.

The mechanism of contraceptive action includes suppression of ovulation and thickening of the cervical mucus. The pregnancy rate per 100 women-years ranges from 0.0 to 0.1. The manufacturer states that there are insufficient data on whether effectiveness decreases in women who are more than 30% above their ideal body weight.

There are no clinically significant metabolic changes reported. There is no evidence of increased cardiovascular or neoplasia risk, and these risks should be similar to other progestin-only contraceptives. Since patients are not hypoestrogenic, osteoporosis is not an issue. Menstrual irregularity is the most common side effect, with 19% experiencing amenorrhea, 27% experiencing infrequent menses, and 14% experiencing more frequent menses. However, 88% of patients with dysmenorrhea reported decreased pain. Weight gain, acne, breast pain and headache have all been reported. Following removal of the device, etonogestrel levels become undetectable within one week, and 94% of users will have return of ovulatory menstrual cycles within three to six weeks. Placement of the device does not require an incision but its removal does. The implant should be palpable; if not, an ultrasound should be ordered. Four percent of patients have implant site complications.