++
These currently are available in forms that contain both estrogen and progestin or contain only progestin. Progestin-only injectables and pills are considered very effective, yet second-tier agents, due to the need for increased patient compliance. Similarly, products containing both estrogen and progestin, often termed combination hormonal contraception (CHC), are considered in this tier. These may be supplied as pills, transvaginal rings, or transdermal patches.
+++
Combination Hormonal Contraceptives Mechanism of Action
++
Actions of combination hormonal contraceptives are multiple, but the most important effect is suppression of hypothalamic gonadotropin-releasing factors. This in turn blocks pituitary secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and thereby inhibits ovulation. The progestin component of CHCs provides ovulation prevention by suppressing LH; it thickens cervical mucus and thereby retards sperm passage; and it renders the endometrium unfavorable for implantation. Estrogen blocks ovulation by suppressing FSH release. To promote cycle control, estrogen stabilizes the endometrium, which prevents intermenstrual bleeding—also known as breakthrough bleeding. The net effect is an extremely effective yet highly reversible method (Mansour, 2011).
+++
Combination Oral Contraceptive Pills
++
These pills are the most frequently used reversible birth control method in the United States. In a 2006 to 2010 survey, 16 percent of contracepting women in the United States were using these (Daniels, 2015). COCs are marketed in a wide variety of estrogen and progestin combinations. Most are available as generics, and the FDA (2016) confirms the bioequivalence of COC generics. The American College of Obstetricians and Gynecologists (2015a) supports the use of either branded or generic preparations.
++
Pharmacologically, ethinyl estradiol is the most common estrogen present in COC formulations in the United States. Less frequently, mestranol or estradiol valerate is used. Unwanted effects most often attributed to the estrogen component include breast tenderness, weight gain, nausea, and headache.
++
COCs also contain one of several progestins that are structurally related to progesterone, testosterone, or spironolactone. Thus, these progestins bind variably to progesterone, androgen, glucocorticoid, and mineralocorticoid receptors. These affinities explain many pill-related side effects and are often used to compare one progestin with another.
++
Most progestins used in COCs are related to testosterone and may impart androgenic side affects such as acne and adverse HDL and LDL levels. To avoid these effects, antiandrogenic progestins have been introduced and include dienogest and nomegestrol acetate. The latter is used in a COC approved outside the United States. Despite these pharmacological differences, the true advantage of one progestin over another is less apparent clinically (Lawrie, 2011; Moreau, 2007).
++
Another progestin, drospirenone, is structurally similar to spironolactone. The doses in currently marketed COCs have effects similar to 25 mg of this diuretic (Seeger, 2007). Drospirenone displays antiandrogenic activity, provides an antialdosterone action to minimize water retention, and has antimineralocorticoid properties that may, in theory, cause potassium retention and hyperkalemia (Krattenmacher, 2000). Thus, it is avoided in women with renal or adrenal insufficiency or with hepatic dysfunction. Moreover, serum potassium level monitoring is recommended in the first month for patients chronically treated concomitantly with any drug associated with potassium retention. These include NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists, heparin, aldosterone antagonists, and potassium-sparing diuretics (Bayer HealthCare Pharmaceuticals, 2015).
++
Since the development of COCs, their estrogen and progestin content has dropped remarkably to minimize adverse effects. Currently, the lowest acceptable dose is limited by the ability to prevent pregnancy and to avoid unacceptable breakthrough bleeding. Thus, the daily estrogen content varies from 10 to 50 μg of ethinyl estradiol, and most contain 35 μg or less.
++
In a few COCs, inert placebo pills have been replaced by tablets containing iron. These have the suffix Fe added to their name. In addition, Beyaz has a form of folate—levomefolate calcium—within both its active and placebo pills.
++
With COCs termed monophasic pills, the progestin dose remains constant throughout the cycle. In others, the dose frequently is varied, and term biphasic, triphasic, or quadriphasic pill is used depending on the number of dose changes within the cycle. In some formulations, the estrogen dose also varies. In general, phasic pills were developed to reduce the total progestin content per cycle without sacrificing contraceptive efficacy or cycle control. The theoretical advantage of a lower total progesterone dose per cycle, however, has not been borne out clinically (Moreau, 2007). Cycle control also appears to be comparable among mono- through triphasic pills (van Vliet, 2011a,b,c).
++
Hormones are taken daily for a specified time (21 to 81 days) and then replaced by placebo for a specified time (4 to 7 days), which is called the “pill-free interval.” During these pill-free days, withdrawal bleeding is expected.
++
With the trend toward lower estrogen doses to minimize side effects, follicular development and ovulation may occur. To counter this, the active-pill duration in some formulations is extended to 24 days. In comparison, these 24/4 regimens perform similarly to higher-estrogen-dose 21/7 regimens (Anttila, 2011; Marr, 2012).
++
Alternatively, longer durations of active hormone, designed to minimize the number of withdrawal episodes, have similar efficacy and safety profiles as more traditional administration (Edelman, 2014). These extended-cycle products produce a 13-week cycle, that is, 12 weeks of hormone use, followed by a week for withdrawal menses. The product Amethyst provides continuous active hormone pills for 365 days each year. Such extended or continuous regimens may be especially suited for women with significant menstrual symptoms (Mendoza, 2014).
++
For general initiation, women ideally begin COCs on the first day of a menstrual cycle. In such cases, a supplementary contraceptive method is unnecessary. With the more traditional “Sunday start,” women begin pills on the first Sunday that follows menses onset, and an additional method is needed for 1 week to prevent conception. If menses begin on a Sunday, then pills are begun that day and no supplemental method is required. Alternatively, with the “quick start” method, COCs are started on any day, commonly the day prescribed, regardless of cycle timing. An additional method is used during the first week (Westhoff, 2002, 2007b). If the woman is unknowingly already pregnant during quick start initiation, COCs are not teratogenic (Lammer, 1986; Rothman, 1978; Savolainen, 1981). However, a missed menses following COC initiation should prompt pregnancy testing. Similar same-day initiation can be implemented with the contraceptive vaginal ring or patch (Murthy, 2005; Schafer, 2006).
++
For maximum efficiency, pills are best taken at the same time each day. If one dose is missed, the missed pill is taken immediately; the scheduled dose for that day is taken on time; and then daily pills are continued. If two or more doses are missed, the most recent missed pill is taken immediately; the scheduled dose for that day is taken on time; and an effective barrier technique used for 7 days while daily pills are then continued (Curtis, 2016a). If withdrawal bleeding fails to occur during the pill-free interval, a woman should continue her pills but seek attention to exclude pregnancy.
++
With initiation of COCs, spotting or bleeding is common. It does not reflect contraceptive failure and typically resolves within one to three cycles. If unscheduled bleeding persists, those with bleeding during the first part of a pill pack may benefit from an increase in the estrogen dose, whereas those with bleeding during the second part may improve with a higher progestin dose (Nelson, 2011).
+++
Method-Specific Effects
+++
Altered Drug Efficacy
++
Some drugs decrease COC effectiveness, and choosing another contraceptive method is preferable. However, if a COC is selected for concurrent use in these instances, a preparation containing a minimum of 30 μg ethinyl estradiol is ideally chosen. Conversely, some COCs interfere with the actions of certain drugs (see Table 38-2).
++
In obese women, COCs are effective (Lopez, 2016). Some studies point to lowered hormone bioavailability, but overall efficacy remains high (Nakajima, 2016; Westhoff, 2010; Yamazaki, 2015). With the transdermal patch method, however, evidence is more robust that obesity may alter pharmacokinetics and lower efficacy, as discussed in Transdermal Patch.
++
Combination oral contraceptives alter lipid synthesis and in general raise serum levels of triglycerides and of total cholesterol, HDL, and very-low density lipoprotein (VLDL) cholesterol. Estrogen lowers LDL cholesterol concentrations. Oral contraceptives are not atherogenic, and their effect on lipids is clinically inconsequential for most women (Wallach, 2000). In women with dyslipidemias, limited data suggest that COCs increase the risk for myocardial infarction and minimally so for venous thromboembolism or stroke (Dragoman, 2016). For those with multiple additional risk factors for vascular disease, alternative contraceptive methods are recommended.
++
With COCs, protein metabolism is affected, and estrogens boost hepatic production of various globulins. First, fibrinogen and many of the clotting factor levels rise in direct proportion to the estrogen dose and may lead to thrombosis. Angiotensinogen production is also augmented by COCs, and its conversion by renin to angiotensin I may be associated with “pill-induced hypertension,” discussed subsequently. Last, COCs elevate sex hormone-binding globulin (SHBG) levels, which in turn lower concentrations of bioavailable testosterone and lessen androgenic side effects.
++
Regarding carbohydrate metabolism, current low-dose formulations have minimal effects in women who do not have diabetes (Lopez, 2014). And, the risk of developing diabetes is not increased (Kim, 2002). For diabetic women, COCs may be used in nonsmokers with disease duration <20 years and without associated vascular disease, nephropathy, retinopathy, or neuropathy (Curtis, 2016b).
++
Of other metabolic changes, thyroid-binding globulin and thyroid-stimulating hormone (TSH) levels are elevated, but free plasma thyroxine (FT4) levels are unchanged (Raps, 2014). Studies have not supported a connection between COCs and weight gain (Gallo, 2014).
+++
Cardiovascular Effects
++
Despite increased plasma angiotensinogen (renin substrate) levels, women using low-dose COC formulations rarely develop clinically significant hypertension (Chasan-Taber, 1996). However, it is common practice for patients to return 8 to 12 weeks after COC initiation for evaluation of blood pressure and other symptoms.
++
During initial contraception selection, a history of gestational hypertension does not preclude subsequent COC use. Among women with well-controlled hypertension, COC use is linked to greater risks than nonusers for stroke, acute myocardial infarction, and peripheral arterial disease, and in these women, COCs are considered US MEC category 3 (Curtis, 2016b). Severe forms of hypertension, especially those with end-organ involvement, preclude COC use.
++
For nonsmoking women younger than 35, the risk of stroke is extremely low (World Health Organization, 1996). COCs are associated with a small increased risk for ischemic stroke (Chan, 2004; Lidegaard, 2012). Rates increase significantly for women who have hypertension, who smoke, or who have migraine headaches with visual aura or other focal neurological changes and use COCs (MacClellan, 2007; Tepper, 2016c). The evidence for stroke risk in migraineurs without aura is less clear (Etminan, 2005; Schürks, 2009). COC initiation may be considered for women with preexisting migraines without aura if they are otherwise healthy, younger, normotensive nonsmokers. For women with prior stroke, COCs should not be considered due to risks for repeat events.
++
For women with prior myocardial infarction, COCs should not be considered. Also, in women with multiple cardiovascular risk factors, which include smoking, hypertension, older age, and diabetes, the risk for myocardial infarction outweighs the benefits of this method. However, for those without these risks, low-dose oral contraceptives are not associated with an increased risk of myocardial infarction (Margolis, 2007; World Health Organization, 1997).
++
The risks for deep-vein thrombosis and pulmonary embolism are increased in women who use COCs (Stadel, 1981). These clearly are estrogen-dose related, and rates have substantively declined with lower-dose formulations containing 10 to 35 μg of ethinyl estradiol. The general-population risk of venous thromboembolism (VTE) is 4 to 5 events per 100,000 woman-years. The incidence of VTE with COC use increases three- to fivefold compared with nonusers (Shaw, 2013; van Hylckama Vlieg, 2009). Obesity raises the VTE risk, which is compounded by COCs (Horton, 2016; Suchon, 2016). Accordingly, in an obese woman, COCs are considered a US MEC category 2. VTEs are significantly increased in women older than 35 years who smoke, and COCs are not recommended. Those most at risk for VTE include women with thrombophilias (ESHRE Capri Workshop Group, 2013). Moreover, COC use during the month before a major operative procedure appears to double the risk for postoperative VTE (Robinson, 1991). Thus, the American College of Obstetricians and Gynecologists (2016d) recommends balancing the risks of VTE and the degree of postoperative immobility with the risk of unintended pregnancy during the 4 to 6 weeks required to reverse the thrombogenic effects of COCs before surgery. In the early puerperium, VTE risks are also increased, and COCs are not recommended for women within the first 4 weeks after delivery.
++
Certain progestins within COC are linked with greater rates of thromboembolism. A slightly higher VTE risk with drospirenone-containing COCs has been shown in two studies. In response, an assessment of benefits and VTE risks in users of these pills has been emphasized (Food and Drug Administration, 2012; Jick, 2011; Parkin, 2011). Desogestrel and gestodene are also implicated and carry similarly elevated risks (Stegeman, 2013; Vinogradova, 2015).
++
Most studies indicate that COCs overall are not associated with an increased risk of cancer (Cibula, 2010). In fact, a protective effect against ovarian and endometrial cancer has been shown (Collaborative Group on Epidemiological Studies of Ovarian Cancer, 2008; Tsilidis, 2011). As an exception, the relative risk of cervical dysplasia and cervical cancer is higher 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). It is unclear whether COCs contribute to breast cancer development. Major studies show no risk or a small risk among current users, which drops with time following cessation (Collaborative Group on Hormonal Factors in Breast Cancer, 1996; Hannaford, 2007; Marchbanks, 2002).
++
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, 1998). Moreover, no evidence supports concern for greater risk of hepatocellular cancer (Maheshwari, 2007). For women with known tumors, COCs may be used in those with focal nodular hyperplasia, but avoided in those with benign hepatic adenoma and hepatocellular carcinoma (Kapp, 2009b). Rates of colorectal cancer appear to be reduced in ever users (Bosetti, 2009; Luan, 2015).
++
Cholestasis and cholestatic jaundice are uncommon, but they resolve when COCs are discontinued. In women who have active hepatitis, COCs should not be initiated, but these may be continued in women who experience a flare of their liver disease while already taking COCs. Use of progestin-only contraception in these women is not restricted. Moreover, there is no reason to withhold COCs from women who have recovered. Mild compensated cirrhosis does not limit the use of COCs or progestin-only methods. But in those with severe decompensated disease, all hormonal methods are avoided (Kapp, 2009a).
++
Chloasma, which is hyperpigmentation of the face and forehead, is more likely in women who demonstrated such a change during pregnancy (Chap. 4, Breasts). This is less common with low-dose estrogen formulations. Although previously used for treating functional ovarian cysts, low-dose COC formulations have been shown to have no effects related to cyst resolution or prevention (European Society of Human Reproduction and Embryology, 2001; Grimes, 2014).
++
Many noncontraceptive benefits are associated with COC use (American College of Obstetricians and Gynecologists, 2016c). And indeed, COCs may be used for these effects, even in those without contraceptive needs. Dysmenorrhea and heavy menstrual bleeding lessen with COC use. Another action is to improve androgenic conditions such as acne and hirsutism. For women with premenstrual dysphoric disorder (PMDD), several studies have shown symptom improvement in those who use the drospirenone-containing COC Yaz (Lopez, 2012b; Pearlstein, 2005; Yonkers, 2005).
++
The Ortho Evra patch contains ethinyl estradiol and the progestin norelgestromin. It has an inner layer containing an adhesive and hormone matrix, and a water-resistant outer layer. Thus, 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. 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.
++
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. This affords a 2-day window for patch-change delays (Abrams, 2001).
++
In general, the transdermal patch and vaginal ring produce metabolic changes, side effects, and efficacy rates comparable to those with COC pills. However, the patch has been associated with a higher thromboembolism risk in some but not all studies (Cole, 2007; Jick, 2010; Lidegaard, 2011). In response, the Food and Drug Administration (2015b) approved labeling for the patch to state that the risk for VTE may be increased compared with other COCs, and relative risk estimates range from 1.2 to 2.2. Obesity—90 kg or greater—may be associated with a higher risk for patch contraceptive failure (Janssen Pharmaceuticals, 2015; Zieman, 2002). Finally, application-site reaction and breast tenderness are more frequent during initial cycles in patch wearers (Urdl, 2005).
++
The NuvaRing is yet another form of combination hormonal contraception and is a flexible intravaginal ring. The ring is constructed of ethinyl vinyl acetate, and it measures 54 mm in diameter and 4 mm in cross section (Fig. 38-5). During insertion, the ring is compressed and threaded into the vagina, but no specific final orientation within the vagina is required. Its core releases ethinyl estradiol and the progestin etonogestrel, which are absorbed across the vaginal epithelium. Before being dispensed, 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 (Merck, 2016b).
++
++
Patient satisfaction is high with this method, although vaginitis, ring-related events, and leukorrhea are more common (Lopez, 2013b; Oddsson, 2005). Despite this, no deleterious affect on lower reproductive tract or endometrial epithelia has been found (Lete, 2013; Veres, 2004). A ring may be used concurrently with vaginal medications or with a tampon (Haring, 2003; Verhoeven, 2004a,b). Approximately 70 percent of partners feel the ring during intercourse (Dieben, 2002). If this is bothersome, the ring may be removed for intercourse but should be replaced within 3 hours to maintain efficacy.
+++
Injectable Progestin Contraceptives
++
Both intramuscular depot medroxyprogesterone acetate—Depo-Provera (DMPA)—150 mg every 3 months, and norethisterone enanthate, 200 mg every 2 months, are injectable progestin contraceptives used worldwide. Of the two, DMPA is available in the United States. DMPA is injected into the deltoid or gluteus muscle, but massage is avoided to ensure that the drug is released slowly. Alternatively, a subcutaneous version, depo-subQ provera 104, is also available and is injected into the subcutaneous tissue of the anterior thigh or abdomen every 3 months.
++
DMPA is effective, and as with other progestin-only methods, contraception is provided by ovulation inhibition, greater cervical mucus viscosity, and creation of an endometrium unfavorable for ovum implantation. Initial injection is given within the first 5 days following menses onset. Serum levels sufficient for contraception are observed by 24 hours. Thus, no additional contraceptive method is required for initiation within this window. Alternatively, limited data support a “quick wtart,” or initiation of DMPA regardless of cycle day. If so implemented, investigators recommend an initial negative pregnancy test result before injection, a supplemental contraceptive method during the 7 days following injection, and a second pregnancy test after 3 to 6 weeks to identify an early pregnancy (Rickert, 2007; Sneed, 2005). Pregnancies conceived during DMPA use are not associated with a higher risk of fetal malformation (Katz, 1985). For women who present for intramuscular DMPA reinjection more than 13 weeks or for subcutaneous DMPA reinjection more than 14 weeks after the prior dose, the manufacturer recommends exclusion of pregnancy before reinjection (Pfizer, 2015a,b).
+++
Actions and Side Effects
++
Injected progestins offer the convenience of a 3-month dosing schedule, contraceptive efficacy comparable with or better than COCs, and minimal to no lactation impairment. Iron-deficiency anemia is less likely in long-term users because of amenorrhea, which develops in up to 50 percent after 1 year and in 80 percent after 5 years.
++
Similar to other progestin-only contraceptive, irregular menstrual bleeding is common, and a fourth of women discontinued DMPA in the first year because of this (Cromer, 1994). Unique to DMPA, prolonged anovulation can follow discontinuation, which results in delayed fertility resumption. After injections are stopped, a fourth of patients do not resume regular menses for up to 1 year (Gardner, 1970). Accordingly, DMPA may not be ideal for women who plan to use birth control only briefly before attempting conception.
++
As with other progestins, DMPA has not been associated with cardiovascular events or stroke in otherwise healthy women. However, in those with severe hypertension, a higher risk of stroke has been found in DMPA users (World Health Organization, 1998). Moreover, the US MEC authors express concerns regarding hypoestrogenic effects and reduced HDL levels from DMPA in women with vascular disease or multiple risks for cardiovascular disease.
++
Weight gain is generally attributed to DMPA, and these increases are comparable between the two depot forms (Bahamondes, 2001; Vickery, 2013; Westhoff, 2007c). In long-term users, loss of bone mineral density is also a potential problem (Petitti, 2000; Scholes, 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. That said, World Health Organization (1998) and American College of Obstetricians and Gynecologists (2016b) believe that DMPA should not be restricted in those high-risk groups. And, it seems prudent to reevaluate overall risks and benefits during extended use. It is somewhat reassuring that bone loss appears to be reversible after discontinuation of therapy, although reversal is still not complete after 18 to 24 months (Clark, 2006; Scholes, 2002).
++
So-called mini-pills are progestin-only contraceptives that are taken daily. These contraceptives have not achieved widespread popularity and are used by only 0.4 percent of reproductive-aged American women (Hall, 2012). Unlike COCs, they do not reliably inhibit ovulation. Rather, their effectiveness depends more on cervical mucus thickening and endometrial atrophy. 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. If a progestin-only pill is taken even 4 hours late, a supplemental form of contraception must be used for the next 48 hours. Progestin-only pills are contraindicated in women with known breast cancer or pregnancy. Other cautions are listed in Table 38-2.