Estrogen Plus Progestin Contraceptives
Combination oral contraceptives (COCs) are the most frequently used method of hormonal contraception, and an almost bewildering variety that are marketed are listed in Table 32-3. Most are also available as generics, and the U.S. Food and Drug Administration (FDA) (2008) confirms the bioequivalence of COC generics. Moreover, the American College of Obstetricians and Gynecologists (2007a) supports the use of either branded or generic COCs.
Table 32-3. Combination Oral Contraceptives Available in the United States |Favorite Table|Download (.pdf)
Table 32-3. Combination Oral Contraceptives Available in the United States
20 μg estrogen
Alesse, Aviane, Lutera; Levlite, Lessina, Sronyx
Loestrin 1/20, Junel 1/20, Microgestin 1/20
Loestrin 24 Fe
30–35 μg estrogen
Desogen, Ortho-Cept, Apri, Reclipsen, Solia
Demulen 1/35, Kelnor, Zovia 1/35
Levlen, Nordette, Levora, Portia
Lo/Ovral, Cryselle, Low-Ogestrel
Ovcon-35, Balziva, Zenchent
Brevicon; Modicon, Necon 0.5/35, Nortrel 0.5/35; Nelova 0.5/35E
Ortho-Novum 1/35, Necon 1/35, Nortrel 1/35, Nelova 1/35E; Norinyl 1+35
Loestrin 1.5/30, Junel 1.5/30, Microgestin 1.5/30
Ortho-Cyclen, Sprintec, Mononessa
50 μg estrogen
Demulen 1/50, Zovia 1/50
Norinyl 1+50; Ortho-Novum 1/50, Necon 1/50
20 μg estrogen
25 μg estrogen
Ortho Tri-Cyclen Lo
30–35 μg estrogen
Ortho Tri-Cyclen, Tri-Sprintec, Trinessa, Tri-Previfem
Tri-Levlen, Triphasil, Trivora, Enpresse
Estrostep Fe, Tri-Legest Fe, Tilia Fe
Ortho-Novum 10/11, Necon 10/11,
Ortho-Novum 7/7/7, Necon 7/7/7, Nortrel 7/7/7
Tri-Norinyl, Aranelle, Leena
Micronor, Errin; Nor-QD, Camila, Nor-BE, Jolivette
Seasonalec, Quasensec, Jolessac
The contraceptive actions of COCs are multiple, but the most important effect is to prevent ovulation by suppression of hypothalamic gonadotropin-releasing factors. This in turn prevents pituitary secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Progestins prevent ovulation by suppressing LH and also thicken cervical mucus, thereby retarding sperm passage. In addition, they render the endometrium unfavorable for implantation. Estrogen prevents ovulation by suppressing FSH release. It also stabilizes the endometrium, which prevents intermenstrual bleeding—also known as breakthrough bleeding.
The net effect is extremely effective ovulation suppression, inhibition of sperm migration through cervical mucus, and creation of an unfavorable endometrium for implantation. Thus, they provide virtually absolute protection against conception if taken as directed.
In the United States, the estrogens used for contraception are ethinyl estradiol and much less commonly, its 3-methyl ether, mestranol. Almost all currently available progestins are 19-nortestosterone derivatives, but one is an aldosterone derivative. Although individual progestins are initially chosen because of their progestational potencies, they are often compared and prescribed based on their presumed progestational, estrogenic, and especially their androgenic effects. A scientific basis for such selective prescribing, however, is lacking (Wallach and Grimes, 2000).
Over time, the estrogen and progestin contents of COCs have been reduced remarkably to minimize hormone-related adverse effects. Currently, the lowest acceptable dose is limited by their ability to prevent pregnancy and unacceptable breakthrough bleeding. Although daily estrogen content varies from 20 to 50 μg of ethinyl estradiol, most contain 35 μg or less (see Table 32-3). The amount of progestin varies in two ways. In some formulations, the progestin dose remains constant during the cycle—monophasic. In others, the progestin and in some, the estrogen dose varies during the cycle—biphasic and triphasic.
Phasic pills were developed to reduce the amount of total progestin per cycle without sacrificing contraceptive efficacy or cycle control. The reduction is achieved by beginning with a low dose of progestin and increasing it later in the contraceptive cycle. Despite the theoretic advantage of lower total progesterone dose per cycle, this has not been borne out clinically (Moreau and colleagues, 2007; van Vliet and associates, 2006).
With the exception of one preparation, COCs are taken daily for a specified time (21 to 81 days) and then omitted for a specified time (4 to 7 days) called the “pill-free interval.” During these pill-free days, withdrawal bleeding is expected. One trend of pills with lower estrogen doses is to shorten the pill-free interval, which seems to reduce the occurrence of intermenstrual bleeding (Nakajima and colleagues, 2007). For example, Loestrin 24 Fe and Yaz provide hormones for 24 days followed by 4 pill-free days. Alternatively, longer durations of active hormone, designed to minimize the number of withdrawal episodes, have been implemented (Edelman and co-workers, 2006). These extended-cycle products, such as Seasonale and Seasonique, produce a 13-week cycle, that is, 12 weeks of hormone use, followed by a week for withdrawal menses. More recently, in 2007, the FDA approved the first continuous COC, Lybrel, which is taken 365 days of each year.
Ideally, women should begin COCs on the first day of a menstrual cycle, in which case a back-up contraceptive method is unnecessary. With the more traditional “Sunday start,” women begin pills on the first Sunday that follows menses onset, and a back-up method is needed for 1 week to prevent conception. With the “Quick Start” method, COCs are started on any day, commonly the day prescribed, regardless of cycle timing. A back-up method is used during the first week. This latter approach improves short-term compliance (Westhoff and co-workers, 2002, 2007b). If the woman is already pregnant during Quick Start initiation, COCs are not teratogenic (see Chap. 14, Estrogens) (Lammer and Cordero, 1986). Similarly, same-day initiation can be implemented with the contraceptive vaginal ring or patch (Murthy and co-workers, 2005; Schafer and associates, 2006).
For maximum efficiency, pills should be taken at the same time each day. If one dose is missed, contraception is likely not diminished with higher-dose monophasic COCs. Doubling the next dose will minimize breakthrough bleeding and maintain the pill schedule. If several doses are missed or lower-dose pills are used, the pill may be stopped, and an effective barrier technique used until menses. The pill may then be restarted after this withdrawal bleeding. Alternatively, a new pack can be started immediately following identification of missed pills, and a barrier method used as a back-up method for 1 week. If there is no withdrawal bleeding, the woman should continue her pills but seek attention to exclude pregnancy.
Combination oral contraceptives interfere with the actions of some drugs (Table 32-4). Conversely, some drugs decrease the effectiveness of COCs (Table 32-5).
Table 32-4. Drugs Whose Effectiveness Is Influenced by Combination Oral Contraceptives |Favorite Table|Download (.pdf)
Table 32-4. Drugs Whose Effectiveness Is Influenced by Combination Oral Contraceptives
Larger doses of analgesic may be required
Larger doses of analgesic may be required
Smaller doses of analgesic may be required
Larger doses of analgesic may be required
Decrease dosage about a third
May need to increase dose
Observe for increased effect
Watch for potentiation of effects, decrease dose accordingly
Reduce starting dose by a third
May need to lower dose
Suspected liver damage
May use smaller dose
See the manufacturer or othera
Table 32-5. Drugs that May Reduce Combined Hormonal Contraceptive Efficacy |Favorite Table|Download (.pdf)
Table 32-5. Drugs that May Reduce Combined Hormonal Contraceptive Efficacy
Established—reduced efficacy <50 μg EE
Anticonvulsants and Sedatives
Phenytoin, mephenytoin, phenobarbital, primidone, carbamazepine, ethosuximide
Strongly suspected—reduced efficacy <50-μg EE, trials lacking
Two small studies find no association
No association documented
No effect on efficacy of 30-μg EE + desogestrel
No effect on efficacy of a 30-μg EE + levonorgestrel
Variable effects—see the manufacturer or othera
When used reliably, COCs offer effective rapidly reversible methods of pregnancy prevention. In addition, there are a number of noncontraceptive benefits (European Society of Human Reproduction and Embryology, 2005). Some are listed in Table 32-6.
Table 32-6. Some Benefits of Combined Estrogen Plus Progestin Oral Contraceptives |Favorite Table|Download (.pdf)
Table 32-6. Some Benefits of Combined Estrogen Plus Progestin Oral Contraceptives
Increased bone density
Reduced menstrual blood loss and anemia
Decreased risk of ectopic pregnancy
Improved dysmenorrhea from endometriosis
Fewer premenstrual complaints
Decreased risk of endometrial and ovarian cancer
Reduction in various benign breast diseases
Inhibition of hirsutism progression
Improvement of acne
Prevention of atherogenesis
Decreased incidence and severity of acute salpingitis
Decreased activity of rheumatoid arthritis
A number of metabolic changes, often qualitatively similar to those of pregnancy, have been identified in women taking oral contraceptives. For example, total plasma thyroxine (T4) and thyroid-binding proteins are elevated. Plasma cortisol concentration increases with a nearly comparable increase in transcortin. Therefore, these pregnancy-like effects should be considered when evaluating laboratory tests in women using COCs.
In general, COCs increase serum levels of triglycerides and total cholesterol. Estrogen decreases the concentration of low-density lipoprotein (LDL) cholesterol and increases high-density lipoprotein (HDL) cholesterol. Some progestins cause the reverse. Despite this, the clinical consequences of these perturbations have almost certainly been overstated. Oral contraceptives are not atherogenic, and their impact on lipids is inconsequential for most women (Wallach and Grimes, 2000). But in women with dyslipidemias, the American College of Obstetricians and Gynecologists (2006b) recommends assessment of lipid levels following initiation of COCs. In women with LDL cholesterol levels >160 mg/dL, or if there are multiple additional risk factors for cardiovascular disease, alternative contraceptive methods are recommended.
There are limited effects on carbohydrate metabolism with current low-dose formulations in women who do not have diabetes. In addition, the risk of developing diabetes is not increased (Lopez and colleagues, 2007; Kim and associates, 2002). Moreover, COCs may be used in nonsmoking, diabetic women younger than 35 years who have no associated vascular disease (American College of Obstetricians and Gynecologists, 2006b).
Estrogens increase hepatic production of a variety of globulins. One is sex-hormone binding globulin (SHBG), which leads to decreased bioavailable testosterone concentrations and its consequent effects. Angiotensinogen production is also augmented by COCs, and its conversion by renin to angiotensin I may be associated with “pill-induced hypertension” discussed subsequently. Fibrinogen, and likely factors II, VII, IX, X, XII, and XIII, are all increased in direct proportion to estrogen dose (Comp, 1996; Kaunitz, 1999). Associated risks for venous and arterial thrombosis are also discussed subsequently.
Cholestasis and cholestatic jaundice are uncommon, but they resolve when COCs are discontinued. There are conflicting reports regarding the risk for cholelithiasis and cholecystectomy with COC use. If the risk exists, it appears small (Stuart and colleagues, 2007). Although active hepatitis is a contraindication to COC use, there is no reason to withhold oral contraceptives from women who have recovered.
A stimulatory effect on some cancers is always a concern with female sex steroids. Fortunately, most studies indicate that overall, COCs are not associated with an increased risk of cancer (Hannaford and associates, 2007). In fact, a protective effect against ovarian and endometrial cancer has been shown (Collaborative Group on Epidemiological Studies of Ovarian Cancer, 2008; Cancer and Steroid Hormone Study, 1987). Protection from these cancers decreases, however, as time from pill use increases (Tworoger and co-workers, 2007). Rates of colorectal cancer appear to be reduced in ever users (Kabat and co-workers, 2008).
Although COC use in the past was linked to development of hepatic focal nodular hyperplasia and benign hepatic adenoma, large studies do not support this (Heinemann and colleagues, 1998). There is also no evidence for increased risk of hepatocellular cancer (Maheshwari and colleagues, 2007).
Because a third of cases of malignant melanoma in women develop during childbearing years, an association with hormonal and reproductive factors has been sought. To date, however, no association between COCs and melanoma has been identified (Lens and associates, 2008).
The relative risk of cervical dysplasia and cervical cancer is increased in current COC users, but this declines after use is discontinued. Following 10 or more years, risk returns to that of never users (International Collaboration of Epidemiological Studies of Cervical Cancer, 2007). Furthermore, after cervical dysplasia treatment, rates of recurrence are not increased by COC use (Frega and colleagues, 2008).
It is unclear whether COCs contribute to the development of breast cancer. The Collaborative Group on Hormonal Factors in Breast Cancer (1996) analyzed data from 54 studies that included more than 53,000 women with and more than 100,000 without breast cancer. There was a small but significantly increased relative risk for breast cancer of 1.24 for current users, 1.16 for those 1 to 4 years after stopping, and 1.07 for those 5 to 9 years after stopping. In this study, tumors associated with COC use tended to be less aggressive and to be detected at an earlier stage—a finding consistent with the possibility that the increased risk of breast cancer was due to greater surveillance among users. In women who are carriers of the BRCA1 or BRCA2 mutation, risks for breast cancer are not increased by COC use (Brohet and associates, 2007). With regard to benign breast disease, COCs appear to lower rates (Vessey and Yeates, 2007).
Aberrations in the levels of several nutrients, similar to changes induced by normal pregnancy, have been described for women who use oral contraceptives. Lower plasma levels have been described for ascorbic acid, folic acid, vitamin B6 (pyridoxine), vitamin B12, niacin, riboflavin, and zinc. An adequate diet, however, is sufficient for any detrimental deficiency (Mooij and co-workers, 1991). Although it is widely held that COCs lead to weight gain, studies have not verified this (Gallo and associates, 2008).
A number of infrequent but significant cardiovascular risks are associated with COC use. These include thromboembolic disease, myocardial infarction, and stroke. For women with prior history of these events, COCs should not be considered (Table 32-7). And because these complications are increased in women older than 35 years and who smoke, COCs are not recommended for this population.
Table 32-7. Typical Package Insert Listing Contraindications and a Warning About the Use of Combination Oral Contraceptives |Favorite Table|Download (.pdf)
Table 32-7. Typical Package Insert Listing Contraindications and a Warning About the Use of Combination Oral Contraceptives
CONTRAINDICATIONS: Combination contraceptives should not be used in women with:
- Thrombophlebitis or thromboembolic disorders
- History of deep-vein thrombophlebitis or thrombotic disorders
- Cerebrovascular or coronary-artery disease
- Thrombogenic cardiac valvulopathies
- Thrombogenic heart arrhythmias
- Diabetes with vascular involvement
- Severe hypertension
- Known or suspected breast carcinoma
- Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
- Undiagnosed abnormal genital bleeding
- Cholestatic jaundice of pregnancy or jaundice with pill use
- Hepatic adenomas or carcinomas, or active liver disease with abnormal liver function
- Known or suspected pregnancy
- Major surgery with prolonged immobilization
Cigarette smoking increases the risk of serious cardiovascular side effects from oral-contraceptive use. This risk increases with age and with the extent of smoking (in epidemiological studies, 15 or more cigarettes per day was associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
It has long been known that the risk of deep-venous thrombosisandpulmonary embolism is increased in women who use COCs (Stadel, 1981). These clearly are estrogen-dose related, and rates have been substantively decreased with lower-dose formulations containing 20 to 35 μg of ethinyl estradiol (Westhoff, 1998). Even with increased risk, the incidence with COCs use is only 3 to 4 per 10,000 woman-years (Mishell, 2000). Moreover, the risk is lower than the incidence of 5 to 6 per 10,000 woman-years estimated for pregnancy (see Chap. 47, Thromboembolic Disorders: Introduction). The enhanced risk of thromboembolism appears to decrease rapidly once COCs are stopped.
Those most at risk for venous thrombosis and embolism include women with protein C or S deficiencies (Comp, 1996). Other clinical factors that increase the risk of venous thrombosis and embolism with COC use are hypertension, obesity, diabetes, smoking, and a sedentary lifestyle (Pomp and co-workers, 2007, 2008). Contraceptive use during the month before a major operative procedure appears to double the risk for postoperative thromboembolism (Robinson and co-workers, 1991). The American College of Obstetricians and Gynecologists (2007c) recommends balancing the risks of thromboembolism with those of unintended pregnancy during the 4 to 6 weeks required to reverse the thrombogenic effects of COCs prior to surgery.
According to the World Health Organization Collaborative Study (1998), the increase of ischemic and hemorrhagic strokes in nonsmoking women younger than 35 years is about 10 and 25 events per 1 million woman years, respectively. Several studies have concluded that the use of COCs by healthy, nonsmoking women is not associated with an increased risk of either type strokes (World Health Organization Collaborative Study, 1996). Conversely, women who have hypertension, smoke, or have migraine headaches with visual aura and use oral contraceptives have an increased risk of strokes (MacClellan and associates, 2007). Because the absolute risk of stroke is low, however, the American College of Obstetricians and Gynecologists (2006b) has concluded that COCs may be considered for women with migraines that lack focal neurological signs if they are otherwise healthy, normotensive nonsmokers younger than 35 years.
Oral contraceptives containing low-dose estrogen and low-androgenic progestins are not associated with an increased risk of myocardial infarction in nonsmokers (Margolis and associates, 2007; World Health Organization Collaborative Study, 1997). Smoking is an independent risk factor for myocardial infarction, and oral contraceptives act synergistically to increase this risk, especially after age 35 (Craft and Hannaford, 1989).
The estrogen component of COCs increases plasma angiotensinogen (renin substrate) to levels near those found in normal pregnancy. And although most women demonstrate these changes, low-dose COCs formulations rarely, if ever, cause clinically significant hypertension (Chasan-Taber and colleagues, 1996). A history of gestational hypertension does not preclude subsequent COC use. Because the absolute risk of stroke is low in hypertensive women using COCs, those with well-controlled uncomplicated hypertension who are nonsmokers, otherwise healthy, and younger than 35 may be considered for their use (American College of Obstetricians and Gynecologists, 2006b).
At least 90 percent of women who previously ovulated regularly begin to do so within 3 months after discontinuance of oral contraceptives. There is no evidence that COCs are teratogenic (Rothman and Louik, 1978; Savolainen and associates, 1981).
Very small quantities of the hormones are excreted in breast milk, but no adverse effects on infants have been reported (World Health Organization, 1988). There is concern that these agents reduce the volume of breast milk, although data are limited (Truitt and colleagues, 2003). Alternatively, progestin-only oral contraceptives have little effect on lactation, provide excellent contraception, and thus may be preferred in women who are exclusively breast feeding their infants as subsequently discussed (see Lactation).
Low-dose estrogen formulations are not associated with depression or premenstrual mood changes, and indeed, may improve the latter (Joffe and associates, 2007). This is especially true with the drospirenone-containing COCs, Yaz and Yasmin (Bayer HealthCare, Wayne, NJ). Several studies have shown improvement in symptoms for women with premenstrual dysphoric disorder (PMDD) who use these (Lopez, 2009; Pearlstein, 2005; Yonkers, 2005, and all their associates, 2005). In fact, the FDA has approved indications to include treatment of premenstrual syndrome and moderate acne vulgaris for women requesting oral contraception.
Drospirenone is an analog of the aldosterone antagonist, spironolactone, and the dose of drospirenone in COCs currently marketed has properties similar to 25 mg of this diuretic (Seeger and co-workers, 2007). It displays antiandrogenic activity, and its antimineralocorticoid properties may, in theory, cause potassium retention, leading to hyperkalemia (Krattenmacher, 2000). Thus, drospirenone should not be prescribed for those with renal or adrenal insufficiency or with hepatic dysfunction. Moreover, monitoring of serum potassium levels is recommended in the first month for patients chronically treated concomitantly with any drug associated with potassium retention. These include nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists, heparin, aldosterone antagonists, and potassium-sparing diuretics (Bayer HealthCare Pharmaceuticals, 2007b). All of this is recommended in the face of evidence that oral drospirenone in doses used in current COCs has no significant effect on serum potassium levels in patients with mild or moderate renal insufficiency (Schürmann and co-workers, 2006).
There are conflicting data concerning a role for COCs and episodic vulvovaginal candidiasis, although lower rates of bacterial vaginosis have been reported (Geiger and Foxman, 1996; Riggs and colleagues, 2007). Most but not all studies show increased rates of Chlamydia trachomatis infection in COC users, but not of Neisseria gonorrhoeae (Baeten and co-workers, 2001; Stuart and colleagues, 2003). Ness and co-workers (2001) found that COCs did not decrease the incidence of pelvic inflammatory disease but did modify its clinical severity. Some but not all studies suggest that COCs increase susceptibility to human immunodeficiency virus (HIV) infection and its progression (Baeten and associates, 2007a, b; Morrison and co-workers, 2007).
The progestin component of COCs reduces serum free testosterone levels and inhibits 5α-reductase to limit conversion of testosterone to its active metabolite, dihydrotestosterone. The estrogen component increases sex-hormone binding globulin (SHBG) production and also lowers circulating androgen levels. The expected results of these actions are to improve androgen-related conditions such as acne and hirsutism.
Hyperpigmentation of the face and forehead—chloasma—is more likely in women who demonstrated such a change during pregnancy. This is seen less commonly with the low-dose estrogen formulations. Cervical mucorrhea, likely due to cervical ectopy, is common in response to the estrogen component of COCs (Critchlow and colleagues, 1995). COCs may decrease formation of uterine leiomyomas in some women (Parazzini and co-workers, 1992). Although previously used for treating functional ovarian cysts, low-dose COCs have no effects (Grimes and colleagues, 2006b).
The Ortho Evra patch (Ortho-McNeil Pharmaceutical, Raritan, NJ) has an inner layer containing an adhesive and hormone matrix, and a water-resistant outer layer. As a result, women can wear the patch in bathtubs, showers, swimming pools, saunas, and whirlpools without decreased efficacy. The patch may be applied to buttocks, upper outer arm, lower abdomen, or upper torso, but the breasts are avoided (Fig. 32-2). Because the hormones are combined with the adhesive, improper skin adherence will lower hormone absorption and efficacy. Therefore, if a patch is so poorly adhered that it requires reinforcement with tape, it should be replaced.
OrthoEvra transdermal contraceptive patch. (Courtesy of Ortho-McNeil Pharmaceuticals.)
Initiation of the patch is the same as for COCs, and a new patch is applied weekly for 3 weeks, followed by a patch-free week to allow withdrawal bleeding. Although a patch is ideally worn no longer than 7 days, hormone levels remain in an effective range for up to 9 days, and this affords a 2-day window for patch change delays (Abrams and co-workers, 2001).
Audet and co-workers (2001) found that the patch was slightly more effective than a low-dose oral contraceptive, with respective pregnancy rates 1.2 versus 2.2 pregnancies per 100 woman-years. Moreover, compliance appears to be improved compared with oral regimens (Dittrich and associates, 2002). In general, the patch shows a comparable side effect profile with COC pills. However, application-site reaction and breast tenderness are more frequent during initial cycles in patch wearers (Urdl and co-workers, 2005).
Obesity—90 kg or greater—may be associated with an increased risk for patch contraceptive failure (Zieman and associates, 2002). There is conflicting data that the patch has higher rates of venous thromboembolism (VTE) than COCs, and the package insert reflects these concerns. Specifically, studies by Jick and co-workers (2006a, b, 2007) have shown no increased rates of thromboembolism, ischemic stroke, or myocardial infarction. Conversely, Cole and associates (2007) reported a twofold increased rate of these three.
For women who prefer weekly application rather than daily dosing, the patch provides an effective alternative hormonal contraceptive method. Candidates should weigh less than 90 kg and have no risk factors for cardiovascular disease and thromboembolism. Its other metabolic and physiological effects are substantively the same as for low-dose oral contraceptives, although the accumulated experience with the patch is small compared with that of COCs.
The NuvaRing (Organon USA, Roseland, NJ) is a flexible intravaginal hormonal contraceptive ring. Constructed of ethinyl vinyl acetate, the ring measures 54 mm in diameter and 4 mm in cross-section (Fig. 32-3). Its core contains ethinyl estradiol and the progestin, etonogestrel. These are released at rates of 15 μg and 120 μg per day, respectively and absorbed across the vaginal epithelium. Although this release results in systemic hormone levels lower than that from low-dose oral and patch contraceptive formulations, ovulation inhibition is complete (van den Heuvel and associates, 2005).
NuvaRing: estrogen-progestin-releasing vaginal contraceptive ring. (Courtesy of Organon, USA.)
Before dispensing, the rings are refrigerated, and once dispensed, their shelf life is 4 months. The ring is placed within 5 days of menses onset and after 3 weeks of use, is removed for 1 week to allow withdrawal bleeding. Contraception will still be afforded if a ring is left in place for a fourth week. For rings left in place longer than 4 weeks, however, pregnancy should be excluded, a new ring placed, and alternative method used for 7 days (Organon USA, 2005).
Both usage compliance and contraceptive efficacy are comparable with that of COCs (Ahrendt and co-workers, 2006). Breakthrough bleeding is uncommon and appears less frequently than with pill use (Bjarnadóttir and colleagues, 2002). Patient satisfaction is high with this method, although vaginitis, ring-related events, and leukorrhea are more common (Oddsson and associates, 2005). Despite this, no deleterious affect on vaginal flora or on lower reproductive-tract or endometrial epithelia have been found (Bulten, 2005; Fraser, 2000; Veres, 2004, and their co-workers). Approximately 70 percent of partners report being able to feel the ring during intercourse (Dieben and colleagues, 2002). If this is bothersome, the ring may be removed for intercourse but should be replaced within 3 hours.
Lunelle is a contraceptive injection containing 25 mg of medroxyprogesterone acetate and 5 mg of estradiol cypionate. In 2002, prefilled Lunelle syringes were recalled by the manufacturer due to lack of assurance of full contraceptive potency. Although still FDA-approved, this method is no longer available in the United States.
So-called mini-pills are progestin-only contraceptives that are taken daily. Unlike COCs, they do not reliably inhibit ovulation. Rather, their effectiveness depends more on alterations in cervical mucus and effects on the endometrium. Because mucus changes are not sustained longer than 24 hours, mini-pills should be taken at the same time every day to be maximally effective. These contraceptives have not achieved widespread popularity because of a much higher incidence of irregular bleeding and a somewhat higher pregnancy rate than COCs.
Progestin-only pills have minimal if any effect on carbohydrate metabolism or coagulation, and they do not cause or exacerbate hypertension. They may be ideal for some women who are at increased risk of cardiovascular complications. Moreover, the mini-pill is often an excellent choice for lactating women. In combination with breast feeding, it is virtually 100-percent effective for up to 6 months and does not impair milk production.
These contraceptives must be taken at about the same or nearly the same time each day. If a progestin-only pill is taken even 4 hours late, a back-up form of contraception must be used for the next 48 hours. And their effectiveness is decreased by the medications shown in Table 32-5. As with other hormonal contraceptive failures and pregnancy, there is a relative increase in the proportion of ectopic pregnancies (Sivin, 1991). Functional ovarian cysts develop with a greater frequency in women using these agents, although they do not usually necessitate intervention. Irregular uterine bleeding is another distinct disadvantage and may manifest as amenorrhea, metrorrhagia, or menorrhagia.
Progestin-only pills are contraindicated in women with unexplained uterine bleeding, known breast cancer, benign or malignant liver tumors, pregnancy, or acute liver disease (Ortho-McNeil Pharmaceutical, 2007).
Injectable Progestin Contraceptives
Both intramuscular depot medroxyprogesterone acetate (Depo-Provera), 150 mg every 3 months, and norethisterone enanthate (Norigest), 200 mg every 2 months, are injectable progestin contraceptives that have been effectively used worldwide for years. Depot medroxyprogesterone (DMPA) is injected into the deltoid or gluteus muscle without massage to ensure that the drug is released slowly. Alternatively, a subcutaneous version, depo-SubQ provera 104, is available and is injected into the subcutaneous tissue of the anterior thigh or abdomen every 3 months. This subcutaneous preparation contains 104 mg of DMPA, which is absorbed more slowly than the intramuscular formulation. Thus, even with a third less medication per dose, it maintains serum progestin levels sufficient to suppress ovulation for 3 months (Jain and associates, 2004). Currently, DMPA contraceptions are used in the United States by about 5 percent of women aged 18 to 44 who use contraception, and this method is particularly popular with adolescents (Mosher and co-workers, 2004).
The mechanisms of action are multiple and include ovulation inhibition, increased cervical mucus viscosity, and creation of an endometrium unfavorable for ovum implantation. Initial injection should begin within the first 5 days following menses onset. Therapeutic serum MPA levels sufficient to exert a consistent contraceptive effect are observed by 24 hours. Thus, no back-up contraceptive method is required if initiated within 5 days of menses onset (Haider and Darney, 2007). DMPA is an effective method with perfect-use pregnancy rates of 0.3 percent (Said and co-workers, 1986). Typical-use failure rates, however, approximate 7 percent at 12 months (Kost and associates, 2008).
Injected progestins offer the convenience of a 3-month dosing schedule, contraceptive effectiveness comparable with or better than COCs, and minimal to no lactation impairment (American College of Obstetricians and Gynecologists, 2000). Iron-deficiency anemia is less likely in long-term users because of amenorrhea, which develops after 5 years in 80 percent of women (Gardner and Mishell, 1970).
The principal disadvantages of depot progestins include irregular menstrual bleeding and prolonged anovulation after discontinuation, which results in delayed fertility resumption. Cromer and associates (1994) reported that a fourth of women discontinued its use in the first year because of irregular bleeding. After injections are stopped, a fourth do not resume regular menses for up to 1 year (Gardner and Mishell, 1970).
Although DMPA use does not affect overall breast cancer risk, there is a small increased risk in recent or current users (Skegg and co-workers, 1995). Cervical and hepatic malignancy do not appear to be increased, and the risk of ovarian and endometrial cancers is decreased (Kaunitz, 1996; World Health Organization, 1991).
Weight gain is generally attributed to DMPA, although not all studies have found this effect (Bahamondes and co-workers, 2001; Moore and associates, 1995). Weight gain is comparable between the two depot forms (Westhoff and co-workers, 2007c). Breast tenderness is reported by some users, as is depression, although a causal link for the latter has not been demonstrated.
In long-term users, loss of bone mineral density (BMD) is a potential problem (Scholes and colleagues, 1999). In 2004, the FDA added a black box warning to DMPA labeling which notes that this concern is probably most relevant for adolescents, who are building bone mass, and perimenopausal women, who will soon have increased bone loss during menopause. It is the opinion of the World Health Organization (1998) and American College of Obstetricians and Gynecologists (2008) that DMPA should not be restricted in those high-risk groups. However, the overall risks and benefits for continuing use should be reevaluated over time (d'Arcangues, 2006). It is somewhat reassuring that bone loss appears to be reversible after discontinuation of therapy but is still not complete after 18 to 24 months (Clark and colleagues, 2006; Scholes and co-workers, 2002).
DMPA use has not been shown to increase the risk for thromboembolism, stroke, or cardiovascular disease. Still, prior thromboembolism is considered a contraindication to its use. Other contraindications to DMPA include pregnancy, undiagnosed vaginal bleeding, breast cancer, cerebrovascular disease, or significant liver disease (Pfizer, 2006, 2007).
The Norplant System (Wyeth-Ayerst) provides levonorgestrel in six silastic rods that are implanted subdermally. Despite the effectiveness, safety, and patient satisfaction with this contraceptive, its use waned dramatically in the United States after a flurry of litigation. The manufacturer stopped distributing the system in July 2002.
Jadelle (Bayer Schering Pharma Oy, Turku, Finland), originally named Norplant-2, is a two-rod system similar to Norplant. It provides similar contraception for 3 years, but its two rods significantly shorten implant removal time (Sivin and co-workers, 2001). Jadelle has been approved for use, although it has not been marketed or distributed in the United States (Population Council, 2008).
Approved by the FDA in 2006, Implanon (Organon, Roseland, NJ) is a single-rod subdermal implant with 68 mg of the progestin etonogestrel (ENG), and an ethylene vinyl acetate copolymer cover (Fig. 32-4). The implant is placed in the medial surface of the upper arm 6 to 8 cm from the elbow in the biceps groove within 5 days of onset of menses. It may be used as contraception for 3 years and then replaced at the same site or opposite arm.
Implanon insert. (Courtesy of Organon, USA.)
Progestin is released continuously to suppress ovulation as the primary contraceptive action, although cervical mucus thickening and an atrophic endometrium add to its efficacy. Return of ovulation after implant removal is rapid. It is a highly effective method, and Croxatto and Mäkäräinen (1998) reported no pregnancies with its use during 53,530 cycles.
Implanon is not radiopaque, and a misplaced implant may be identified with sonography using a 10- to 15-MHz linear array transducer (Shulman and Gabriel, 2006). In some cases, magnetic resonance imaging may be required (Merki-Feld and associates, 2001).
Weight gain is neither a prominent side effect nor a common reason for implant discontinuation (Funk and co-workers, 2005). The ENG implant does not significantly affect bone mineral density, lipid profile, or liver enzymes (Beerthuizen and associates, 2000; Biswas and co-workers, 2003, 2004). The most frequently reported adverse event leading to removal was prolonged and frequent bleeding (Bitzer and colleagues, 2004). Contraindications for ENG implant use are those for DMPA.