Women have specific health care needs throughout their reproductive and postreproductive life cycle. A woman’s reproductive life cycle begins with menarche, the start of spontaneous menstruation, and continues through menopause, the permanent cessation of menstruation. Successful contraception is essential to the health and well-being of sexually active women of reproductive age. During the reproductive years, many disorders can occur in women’s health. These gynecologic conditions interfere with a woman’s overall health and well-being and may impede her ability to become pregnant.
Successful adaptation to menopause, control of menopausal symptoms, and continued sexual health is essential to the well-being of older women. This chapter reviews pharmacologic products that may be used throughout the reproductive and menopausal life cycle of women as well as typical drug regimens used for disorders in women’s health. Drugs for female infertility are also addressed with an emphasis on drugs that stimulate ovulation.
Under the Affordable Care Act, contraception is classified as a preventive health service. All plans in the Health Insurance Marketplace must cover contraceptive methods approved by the U.S. Food and Drug Administration (FDA) (e.g., barrier methods, hormonal methods, implanted devices, emergency contraception and sterilization) and related counseling for women. These services are provided without copay or coinsurance, thus reducing the cost of contraception and improving access to health care.
Combined Hormonal Contraceptives
All combined hormonal contraceptives (CHCs) contain a synthetic version of estrogen and a compound known as progestin. Ethinyl estradiol (EE) is the most commonly used synthetic estrogen found in CHCs; however, a new CHC contains estradiol valerate. Progestins are natural or synthetic hormones that have progesterone-like effects. Progesterone is the naturally occurring sex hormone produced in the ovaries of women; progestogen refers to any synthetically produced progesterone compound. Almost all progestins are derivatives of testosterone, a steroid hormone classified under the androgen group that binds to and activates the progesterone receptors. The term progestin will be used to describe the compound used in CHC products. Not only do progestins have contraceptive properties, they serve to balance out the effects of estrogen.
One of eight different types of progestins is used in CHC products. Norethindrone, norethindrone acetate, and ethynodiol diacetate are first-generation progestin compounds (estrane family) and were the earliest progestin formulations to be used in oral contraceptives (OCs). Second-generation progestins (gonane family) include norgestrel and levonorgestrel (LNG). Third-generation progestins include desogestrel, and norgestimate. The new-generation progestins have a higher efficacy rating and fewer effects on lipid and carbohydrate metabolism compared with their earlier counterparts. They also have fewer androgenic side effects, which are described later in this chapter.
Drospirenone (DRSP) is a fourth-generation progestin. It is an analogue of spironolactone. As with spironolactone, a potassium-sparing diuretic, DRSP can increase serum potassium levels in women taking DRSP-containing OCs, altering water and electrolyte balance.
One of the newer progestins, dienogest, is considered a hybrid progestin, as it is derived from the estrane family and is an analog of spironolactone. Like DRSP, dienogest can alter fluid and electrolyte balance.
The amount of estrogen and type of progestin determine bioactivity and possible side effects of CHC products. The combination of estrogen and progestin causes the products to have estrogen-like, or estrogenic, activity; progesterone-like, or progestational, activity; and androgen-like, or androgenic, activity. The combination of estrogen and the selected progestin also has an effect on the uterine endometrium, therefore the lowest effective dose that successfully prevents conception should be used.
Mechanism of Action
The estrogen component of CHC products inhibits ovulation by preventing the formation of a dominant follicle. When a dominant follicle does not mature, estrogen remains at a consistent level and is unable to reach the peak level needed to stimulate the luteinizing hormone (LH) surge. The progestin component also suppresses the LH surge. When the LH surge is suppressed, ovulation is prevented, and pregnancy does not occur. Any cycle in which ovulation does not occur, whether induced by drugs or naturally occurring, is called an anovulatory cycle. CHCs produce drug-induced anovulatory cycles. The estrogen component of CHC products also stabilizes the uterine endometrium, inhibiting proliferation and secretory changes and decreasing the occurrence of irregular or heavy bleeding. The progestational effects of progestin change the endometrium to make it less favorable for implantation of a fertilized ovum. In addition, progestins have an effect on the quantity and viscosity of the cervical mucus, making it thick and hostile to sperm penetration. Progestins alter the motility of both the muscles of the fallopian tube and the cilia within the tube, impeding the movement of the ovum through the tube.
Route of Delivery
There are several routes of administration for CHC products. Most women are familiar with oral contraception, in which a pill is ingested daily that is absorbed by the gastrointestinal (GI) tract and metabolized by the liver. However, CHC products can also be administered through transvaginal and transdermal routes. The advantage of these alternative sites is avoiding GI absorption and the initial metabolism by the liver, or the first-pass effect. Theoretically, side effects such as nausea and vomiting, heart and circulatory risks, and nonadherence with a daily dosage regimen can be avoided. Intramuscular (IM) and subcutaneous (subcut) routes of administration for CHCs are not available in the United States.
Combined Hormonal Contraceptives
Combined hormonal contraceptives are one of the most commonly used methods of reversible contraception in the world because of their ease of use, high degree of effectiveness, and relative safety. The theoretic effective rate (absolute correct use) for CHCs is 99.3%, whereas the typical use effective rate (accounting for patient error) is around 92%. This means that CHCs are 92% to 99.3% effective for contraception. When the pill was approved for use by the FDA in 1960, little was known about the best combination of estrogen and progestin or their optimum effective doses. In the 1970s, research provided evidence that the adverse side effects, particularly heart and circulatory effects, were directly related to the dose of estrogen in OCs. The higher dose of estrogen increased risk for venous thromboembolism (VTE), myocardial infarction (MI), and stroke. Subsequently, low-dose OCs and, more recently, ultra-low-dose OCs have been introduced. Low-dose CHCs greatly reduce the risk for dangerous side effects. A low-dose CHC contains 35 mcg or less of ethinyl estradiol and a progestin, whereas ultra-low-dose CHC pills contain 20 mcg or less of EE and a progestin. Research continues to focus on actual and potential short- and long-term benefits and risks associated with use of low-dose oral contraceptives, particularly in the areas of heart and circulatory risks as well as carcinogenesis. Clinical studies also continue to investigate the venous circulatory effects of new-generation progestins.
CHC formulations are differentiated based on the strength of the estrogen component, the type of progestin used, and whether estrogen or progesterone (and androgen) activity predominates. Increased estrogenic activity may include side effects such as cyclic breast changes, dysmenorrhea (painful periods), menorrhagia (heavy periods), chloasma (hyperpigmentation of the skin), and VTE, whereas decreased estrogenic activity can cause amenorrhea (absence of periods) or spotting at certain points in the cycle. Increased progestational activity can cause weight gain, depression, fatigue, and decreased libido, and a lack of progestational activity may cause breakthrough bleeding (BTB) and headaches. BTB is an episode of bleeding that occurs during the active pill cycle of CHCs. It is more common at the start of CHC use, when a woman changes the type of pill she is taking, and with progestin-only preparations of contraception. There is no evidence that an episode of BTB is associated with a decrease in the CHC’s effectiveness as long as the patient continues to take the pill on a daily basis as prescribed. Increased androgenic activity may cause acne, hirsutism, edema, and cholestatic jaundice. The estrogens and progestins in OC pills also have an effect on the uterine endometrium, which may cause changes in the patient’s periods that can include irregular bleeding, heavy or light periods, or spotting between periods. The undesirable side effects of hormonal contraception products are discussed later in this chapter.
Most women on CHC products experience shorter, lighter periods. Other advantages with CHCs are decreased blood loss and uterine cramps, elimination of mittelschmerz (mid-cycle pain usually associated with ovulation), reduction of symptoms in many forms of benign breast disorders, and prevention of physiologic ovarian cysts. CHC products also reduce the incidence of pelvic inflammatory disease (PID), ectopic pregnancy, endometrial and ovarian cancer risk, and deaths from colorectal cancer. CHC products do not reduce the incidence of sexually transmitted infections (STIs; see Chapter 54 for further discussion of STIs.)
The goal of therapy is to identify the product that offers the best contraceptive protection while producing the fewest unwanted side effects as a result of either the estrogen or the progestin component. It is important to note that the effectiveness of oral contraceptives can also be compromised by concurrent use of some drugs (e.g., antibiotics) or herbal products (Complementary and Alternative Therapies 52.1).
|Drug||Route and Dosage||Uses and Considerations|
|Combination products containing norethindrone and ethinyl estradiol|
Oral: 1 tablet PO daily from the 21-tablet package: 1 tablet daily for 21 consecutive days followed by 7 days off. A new course begins on the eighth day after a tablet is taken.
28-tablet package: 1 tablet daily without interruption taken at the same time each day
Estrogen and progestin combination used for contraception and for treatment of moderate acne vulgaris in females 15 years and older who have achieved menarche, are unresponsive to topical treatments, have no contraindications to CHC use, and plan to stay on therapy for 6 months or longer.
Contraindications: History of or current thrombophlebitis, DVT, PE, CVA, CAD, valve disease, hypertension, diabetes mellitus with vascular involvement, migraines in women >35 y, cancers, neoplasms, and tumors. Cardiovascular side effects are increased in women who smoke, especially those >35 y and in those who use CHCs.
Pregnancy category: X∗ PB: >95%; t½: 19-24 h
|Combination products containing levonorgestrel (LNG) and ethinyl estradiol (EE)||Same as above|
Estrogen and progestin combination used for contraception. Contraindications and black-box warnings are same as above; use with caution in patients with depression, and monitor patients on thyroid replacement therapy, who may require higher doses of thyroid hormone while receiving estrogens.
Pregnancy category: X∗; PB: 95%-99%; t½: EE, 12-23 h; LNG, 22-49 h
|Combination products containing norgestrel and EE||Same||Same|
|Combination products containing ethynodiol diacetate and EE||Same||Same|
|Combination products containing norethindrone and mestranol||Same||Same|
|Combination products containing desogestrel and EE||Same||Same|
|Combination products containing DRSP and EE||Same|
Estrogen and progestin combination used for contraception, for acne treatment in adults, and for PMDD
Same contraindications and black-box warnings as above
Pregnancy category: X∗; PB: 97%-98%; t½: 24-30 h
|Combination products containing norgestimate and EE||Same|
Estrogen and progestin combination used for contraception and for acne treatment in adults
Same contraindications and black-box warnings as above
Pregnancy category: X∗; PB: 97%-99%; t½: 16-38 h
|Combination with folate in the form of EE–DRSP–levomefolate calcium||Same|
Estrogen and progestin combination used for contraception, acne, and PMDD
Same contraindications and black-box warnings as above
Pregnancy category: X∗; PB: 97%-99%; t½: DRSP, 31 h; EE, 24 h (approx.); levomefolate calcium, 4-5 h (approx.)
Types of Combined Hormonal Contraceptives
Combination pills are classified as either monophasic or multiphasic (biphasic, triphasic, or four-phasic). The monophasics provide a fixed ratio of estrogen to progestin throughout the menstrual cycle. In biphasics, the amount of estrogen is fixed throughout the cycle, but the amount of progestin varies; it is reduced in the first half to provide for some proliferation of the endometrium and is increased in the second half to promote secretory development of the endometrium. This simulates the normal physiologic process of menstruation while still inhibiting ovulation. The triphasics deliver low doses of both hormones with minimal side effects, including BTB. With triphasics, the amount of either estrogen or progesterone varies throughout the cycle in different ratios during the phases (Table 52.1). The newest CHC is a four-phasic drug where each phase has varying doses of estradiol valerate (1, 2, or 3 mg) and dienogest (0, 2, or 3 mg). Each pill pack contains 26 pills with hormones and 2 without.
One monophasic combination pill contains 30 mcg of ethinyl estradiol and 3 mg of DRSP. Whereas the progestin found in other CHCs is structurally similar to androgens, DRSP is an analog of spironolactone, which is structurally similar to progesterone. As noted, use of DRSP may increase serum potassium, which can alter water and electrolyte balances in women using this product. Consequently, this drug is contraindicated in women with kidney, liver, or adrenal insufficiency and in women who require daily long-term treatment with drugs such as nonsteroidal antiinflammatory drugs (NSAIDs; e.g., ibuprofen) taken long-term daily for arthritis or other diseases or conditions, potassium-sparing diuretics (e.g., spironolactone), potassium supplementation, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II–receptor antagonists, and heparin.
Most of the monophasic, biphasic, and triphasic CHC products are packaged in both 21- and 28-day tablet packs. In the 21-day tablet packs, 21 days of active pills that contain estrogen and progestin are followed by a 7-day “pill-free” period. A new pack of pills is started after the 7-day pill-free period. In the 28-day tablet pack, 21 days of active pills are followed by 7 days of inert pills, called counters. The patient takes one pill daily and begins a new pack the day after the last counter is taken. During the hormone-free period (counters) or the 7-day pill-free period, the level of estrogen and progestin decreases to allow for a breakdown of the endometrial lining. This causes a pseudomenstruation known as withdrawal bleeding or withdrawal menses. The withdrawal bleeding is not a true menstrual period, and the bleeding experienced by a woman can vary in amount and duration.
There are CHCs that provide ferrous fumarate, an iron compound, or folic acid, a B vitamin, during the hormone-free period. Ferrous fumarate provides supplementation during the phase of withdrawal bleeding, promoting healthy iron stores in women and protecting against menstrual-associated iron-deficiency anemia. Folic acid reduces the risk of neural tube defect should the woman become pregnant on OCs or shortly after OCs are discontinued.
Withdrawal bleeding periods are scheduled monthly to mimic a normal 28-day menstrual cycle; however, researchers have established that a monthly episode of withdrawal bleeding is not necessary to maintain a healthy uterus. CHCs are available that (1) decrease the number of withdrawal menses per year by having 81 to 84 continuous days of active pills and 7 days of less-active pills, resulting in four withdrawal menses per year; or (2) eliminate withdrawal bleeding altogether by continuous oral administration of active pills.
Extended-Use Combined Hormonal Contraceptives
A continuous-dosing CHC pill that contains EE and LNG is a 91-day regimen of pills. This regimen includes 84 days of active pills and 7 days of inert pills. This drug causes withdrawal bleeding to occur just four times per year. The active hormone pills contain 30 mcg of EE and 0.15 mg of LNG.
Another combination is still a 91-day regimen, but it contains 30 mcg of EE and 0.15 mg of LNG and is followed with 7 days of tablets that contain 10 mcg EE, instead of 7 days of inactive pills. During the 7 days of low-dose estrogen pills, women usually experience withdrawal menses. However, by adding very low levels of estrogen in the 7-day “break” period, instead of inert pills, this combination provides additional benefits such as a reduction in breakthrough bleeding. Users of extended-use birth control pills are more likely to experience bleeding or spotting between periods. The continued progestin dose causes extreme atrophy of the endometrial lining; the atrophic endometrium subsequently breaks down, and the patient experiences uterine bleeding in an irregular pattern.
Continuous-Use Combined Hormonal Contraceptives
The first continuous-dose CHC to be FDA approved comes in a 28-day pack and contains 20 mcg of EE and 90 mcg of LNG. This drug is taken daily and continuously without interruption for withdrawal menses.
Although these products are more commonly known for their contraceptive value, women with menstrual disorders such as menorrhagia (heavy periods), metrorrhagia (irregular bleeding between periods, usually heavy), endometriosis, dysmenorrhea, premenstrual syndrome (PMS), and physiologic ovarian cyst formation may benefit from continuous-cycle CHC products because of their ability to suppress ovarian function and limit uterine bleeding.
Ethinyl Estradiol and Norelgestromin Transdermal Patch
This is a weekly form of CHC patch that delivers either 20 mcg EE and 150 mcg norelgestromin every 24 hours or 35 mcg EE and 150 mcg norelgestromin every 24 hours through a transdermal system. The system is a thin plastic patch placed on the skin of the buttocks, stomach, upper outer arm, or upper torso. The patch is placed once a week for 3 weeks in a row. The fourth week is patch-free to allow for withdrawal bleeding. The patch should be placed on clean, dry skin; placement on or near the breasts should be avoided because of the estrogen component, and the site of the patch placement should be rotated to avoid skin irritation. If the patch partially or completely detaches from the skin, a new patch should be placed. When used correctly, the patch protects against pregnancy on a monthly basis. The theoretic and typical use effective rate for the patch is 99.3% and 92%, respectively, making it 92% to 99.3% effective at preventing pregnancy.
The patch works in a similar manner to CHC pills by inhibiting ovulation, thickening cervical mucus to prevent sperm penetration, and preventing a fertilized egg from implanting in the uterus. The patch avoids the first-pass effect (through the liver). Advantages include not having to remember to take a pill daily. As with CHC products, the ability to become pregnant returns quickly when the pill is discontinued. Menstrual flow, cramping, acne, iron-deficiency anemia, excess body hair, premenstrual symptoms, and vaginal dryness are all lessened with the patch. As with CHC pills, the patch reduces the risk for ovarian and endometrial cancers, PID, breast and ovarian cysts, and osteoporosis (loss of bone mass) that predisposes women to fractures. With the patch, occurrences of ectopic pregnancy are also reduced.
Disadvantages of the patch include skin reaction at the site of application, menstrual cramps, and a change in vision or the inability to wear contact lenses; it is not as effective for women who weigh more than 198 lb. The EE and norelgestromin transdermal patch carries a boxed warning stating that it exposes women to higher levels of estrogen, thereby increasing the risk for VTE. With OCs, peak serum estrogen levels are reached rapidly after ingestion and then steadily decline. With the patch, peak serum estrogen levels are 25% less than in women taking the pill; however, these peak levels remain fairly constant throughout the week the patch is in place and then decline, exposing women to 60% more estrogen than with OCs. Ongoing research is necessary to demonstrate the exact risk for VTE, as well as other cardiovascular complications (particularly heart attack and stroke), in women using the transdermal patch. Women being prescribed the transdermal route of CHCs should be notified of potential risks, and the patch should be used with extreme caution in any patient with increased risk for VTE. Women who are older than 35 years and smoke should not use the transdermal patch. Other side effects include temporary irregular bleeding, weight gain or loss, breast tenderness, and nausea.
Ethinyl Estradiol and Etonogestrel Transvaginal Contraception
The ethinyl estradiol and etonogestrel transvaginal ring is a 2-inch flexible indwelling ring that is inserted into the vagina. It is nonbiodegradable, transparent, and colorless. This ring releases 15 mcg of EE and 120 mcg of the progestin etonogestrel daily, similar to the quantities of estrogen and progestin found in lower-dose CHC products. Etonogestrel is a biologically active metabolite of desogestrel and is a third-generation progestin, which may be associated with an increased risk for VTE. The transvaginal ring remains in place for 3 weeks. As with the transdermal patch, this may expose the patient to higher levels of estrogen. Studies have been inconclusive, therefore the FDA has placed no additional warnings on the transvaginal ring.
Theoretic effectiveness and typical effectiveness rates are 98% and 92%, respectively, which reflects a rate similar to that of other leading CHCs. The patient inserts the ring during the first 5 days of the menstrual cycle and removes the ring after 3 weeks, remains “ring-free” for 1 week (for withdrawal menses), and then inserts a new ring. Backup contraception is recommended during the first 7 days after the first ring is placed. During this time, the hormones reach an appropriate protective level. After this, contraceptive effects are expected to be continuous provided the ring is correctly inserted. Correct insertion involves placing the ring into the middle or upper third of the vagina. Unlike the diaphragm, it does not need to be placed near or over the cervix. It is the close proximity of the ring to the vaginal mucosa that causes absorption of steroid hormones to occur. The ring remains in place during intercourse, tampon use, or administration of intravaginal drugs. If the ring slips out, it can be rinsed with lukewarm water and reinserted into the vagina. It should be reinserted within 3 hours after becoming dislodged; if the ring remains out for more than 3 hours, additional contraception is required until the ring has been in place for 7 days. Possible side effects include vaginal discharge, irritation, or infection. Other associated risks are the same as for low-dose CHCs and are increased in patients who smoke.
Progestin contraceptives do not contain estrogen. The estrogen component of contraceptives increases the risk of circulatory disorders, therefore these products allow contraception to be available for women who cannot take CHCs. Advantages of progestin contraceptive include relative safety, ease of use, spontaneity of sexual intercourse, and reversibility. However, because the estrogen component is missing, these products have a higher incidence of irregular bleeding and spotting as well as the possibility of depression, mood changes, decreased libido, fatigue, and weight gain. Progestin contraceptives do not protect women against STIs. Women who cannot take estrogen but may be candidates for progestin contraceptives include patients with a personal or strong family history of VTE or heart disease, breastfeeding patients, smokers older than 35 years of age, and women with uncontrolled hypertension. Women who have an untoward response to estrogenic effects such as chloasma, migraine headaches, or changes in lipid profiles may also be candidates for progestin contraceptives. Progestin contraceptives are available in oral, IM, subcut, and implantable routes of delivery.
Progestin-Only Oral Contraceptive Pills
The progestin-only oral contraceptive pill (POP), called the minipill, has four mechanisms of action: (1) it alters cervical mucus, making it thick and viscous, which blocks sperm penetration; (2) it interferes with the endometrial lining, which makes implantation difficult; (3) it decreases peristalsis in the fallopian tubes, slowing the transport of ovum; and (4) in approximately 50% of cycles, it interferes with the LH surge and thereby inhibits ovulation.
POPs contain 0.35 mg of norethindrone. The minipill is taken continuously, without a break for withdrawal bleeding. Patients should be instructed to take the minipill daily within a 3-hour window.
The theoretic and typical use effective rates for the first year of use are similar to those of CHC products even though patient adherence to the dosage schedule with POPs is more specific. It takes 4 to 6 hours for the progestin to thicken the cervical mucus to prevent sperm penetration, and the duration of the effect of the progestin on cervical mucus lasts just over 24 hours. Risk for pregnancy will increase if a patient misses a pill because POPs do not suppress the release of follicle-stimulating hormone (FSH) and LH to the same degree as CHC products. If the minipill is taken more than 3 hours late, a back-up contraceptive method should be used for 48 hours. There are no placebo pills in a pack of progestin-only pills. All 28 pills contain active hormones, so the patient continuously takes one active pill daily. Because the endometrial lining is altered, an increase in the amount of irregular bleeding is noted.
Depot Medroxyprogesterone Acetate
Depot medroxyprogesterone acetate (DMPA) is a highly effective, long-acting injectable progestin with theoretic and typical use efficacy rates of 99% and 97%, respectively. This makes DMPA one of the most effective hormonal methods of contraception. It appeals to women because it is discreet and has a convenient dosing schedule; DMPA is popular with adolescents for these same reasons. Injectable progestin is administered in a flexible dosing schedule every 11 to 13 weeks. The mechanism of action of DMPA relies on the progestational activities: thickening of the cervical mucus, thinning of the uterine endometrium, and a decrease in fallopian tube motility. Because the progestin in DMPA reaches a higher circulating level than with POPs, DMPA inhibits both FSH and LH secretion from the anterior pituitary gland. This results in both anovulation (lack of ovulation) and amenorrhea. Because FSH and LH secretion is inhibited, formation of a dominant follicle is inhibited, and the production of estrogen in the body is greatly decreased. However, the patient experiences a hypoestrogen state, which can affect bone mineral density (BMD).
The DMPA vial or prefilled syringe should be vigorously shaken just prior to administration to ensure a uniform drug suspension. DMPA 150 mg/1 mL is given by deep IM injection into the ventral gluteus or deltoid muscle. The site should not be massaged after injection, and the injection site must be documented so that sites can be rotated. The patient is given a personalized calendar for subsequent doses and should return for another injection within 13 weeks. If the patient is late for her injection (e.g., 13 weeks and 1 day), pregnancy should be ruled out before she receives another injection.
As with oral contraceptives, DMPA does not protect against STIs. Due to the hypoestrogenic state produced by DMPA, bone resorption exceeds bone formation. This results in a reduction of BMD, greatest during the first 1 to 2 years of DMPA use. Following discontinuation of DMPA, BMD substantially improves (more so at the spine than hips), but may not be completely reversible. Based on this data, the FDA issued a boxed warning recommending DMPA be discontinued after 2 years of continuous use, unless other methods of contraception are inadequate. Many professional provider organizations agree that the concerns of the 2-consecutive-year limit given by the FDA and the BMD effects of DMPA should not prevent the practitioner from considering the benefit-risk ratio for each individual patient. The American Congress of Obstetricians and Gynecologists (ACOG) states in a committee opinion that “the possible adverse effects of DMPA must be carefully balanced against the significant personal and public health impact of unintended pregnancy.” The benefits, risks, and alternatives and the prevention of BMD loss while taking DMPA must be discussed with the patient before administration of the product.
Women taking DMPA should be instructed to increase calcium and vitamin D intake to the daily recommended allowance for their age and to participate in regular weight-bearing exercises. DMPA is safe to receive immediately postpartum, and women can breastfeed while using this contraceptive without affecting milk supply. The most common side effects include initially irregular uterine bleeding or spotting. Menstruation may cease about 1 year after starting. In addition, DMPA has been shown to cause progressive weight gain in some women. Other side effects include breast tenderness and an increase in depression. The drug is contraindicated in cases of undiagnosed vaginal bleeding and known or suspected pregnancy. Caution should be used in giving DMPA postpartum in women who are at risk for or have a history of postpartum depression.
Depot medroxyprogesterone acetate formulated for subcutaneous injection is available as an injectable suspension of 104 mg/0.65 mL. It is administered to women every 11 to 13 weeks. This drug has the same mechanism of action, benefits, and risks as DMPA for intramuscular injection, and women should be counseled about the potential loss of BMD. Women taking DMPA have a slower return to fertility than those using other hormonal methods of contraception.
A progestin implant is a single-rod device that contains 68 mg of etonogestrel; it is implanted in the inner side of the upper nondominant arm. It needs to be removed no later than 3 years after the date of insertion; it may be replaced with a new implant at the time of removal. The progestin implant contains barium, a radiopaque substance that can help locate the device on two-dimensional radiography, ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT) scanning if necessary. Also, the device comes in a preloaded application system that reduces insertion errors. The progestin implant may not be as effective in women who have a body mass index (BMI) greater than 30 (obese) or who are on drugs that induce liver enzymes. Theoretic and typical effectiveness rates for implantable progestins are the same, at 99.6%.
Pharmacokinetics: Combined Hormonal Contraceptives
Ethinyl estradiol is rapidly absorbed orally and reaches peak serum concentration in 1 to 2 hours. It undergoes significant first-pass metabolism resulting in 40% bioavailability. Ethinyl estradiol is 98.5% protein bound. It is excreted as metabolites, via feces and urine. It undergoes some enterohepatic circulation.
The steroid hormones in the transvaginal ring are rapidly absorbed through the vaginal mucosa. Etonogestrel in the transvaginal ring has a bioavailability of 100%; bioavailability of EE is 55%. The transdermal patch also bypasses the hepatic portal system. Avoiding first-pass metabolism through the liver has the potential to decrease adverse drug interactions. The norelgestromin in the patch binds to albumin. Levels of serum steroid hormones in the patch reach constant levels of contraceptive efficacy within 48 hours. Serum hormone levels are rapidly reached, and blood levels do not fluctuate as much as is seen with oral contraceptive products.
Pharmacokinetics: Progestin Contraceptives
Progestin contraceptives are well absorbed from the GI tract. Peak plasma levels occur 1 to 2 hours after ingestion, depending on the particular compound. Norethynodrel and ethynodiol diacetate are converted to norethindrone. LNG is 100% bioavailable and does not undergo first-pass liver metabolism; norethindrone undergoes first-pass metabolism and is 65% available. The progestins are bound to plasma proteins and to sex-hormone–binding globulin. The half-life of norethindrone varies from 5 to 14 hours; the half-life of LNG is 11 to 45 hours.
DMPA provides higher peak levels of progestin than POPs and implantable progestins. Once injected, the levels of DMPA increase for 3 weeks, remain stable for a few days, then begin to decline. DMPA is undetectable in the blood between 120 and 200 days after injection. The formulation for subcutaneous administration of DMPA provides a slower and more sustained absorption than IM, permitting a lower dose. DMPA is 90% protein bound, metabolized in the liver, and excreted primarily in the urine.
A progestin implant is a sustained-release system that releases progestin at a level of 60 to 70 mcg/day during the first 6 weeks after insertion, declining to 35 to 45 mcg/day during the first year. This decreases to 30 to 40 mcg/day after 2 years of implantation and 25 to 30 mcg/day by the end of the third year. Bioavailability remains constant at 95%. Once the rod is inserted, effective contraceptive levels are reached within 8 hours.
Start Date and Dosing Schedule
There are three ways to implement the start of hormonal contraception products unless otherwise indicated by the manufacturer. With the first-day start method, the contraception product is initiated on the first day a women experiences bleeding; the first day of bleeding is day 1 of the menstrual cycle. Days are then counted 2, 3, 4, 5, 6, and so on until the first-day bleeding begins again, usually around day 28. Most methods of contraception can be safely started on day 1 through day 5 of the menstrual cycle, when it is less likely that the patient has an early undiagnosed pregnancy. No back-up method of contraception is needed when the product is started on the first through fifth day of menstruation. (A back-up method is a second method of contraception that is used until the primary method reaches its peak level of contraceptive effectiveness; usually this is a barrier method, such as a condom or diaphragm.)
Many products require a Sunday start, meaning the patient starts the tablets or patch on the Sunday after the first day of menstruation. If menstruation actually starts on Sunday, the patient starts her tablet or patch on that day. The Sunday start aids a woman in remembering the first day of her contraception cycle. If a patient starts the contraception later than day 5 of her menstrual cycle, a back-up form of contraception should be used for 7 days.
The quick-start method of initiating contraception starts on the day the patient receives the prescription regardless of where she might be in her menstrual cycle. This method increases patient adherence and resolves the risk for becoming pregnant while waiting for a menstrual period to begin to start the contraceptive. Pregnancy should be ruled out prior to the quick-start method, but there is a risk that the patient could have an early pregnancy undetectable by screening. A back-up method of contraception must be used for 7 days if the quick-start method is used after the first 5 days of the menstrual cycle. Both estrogen-progestin and progestin-only contraception methods are contraindicated in pregnancy (formerly category X). Nonetheless, there is no evidence of fetal risks associated with these drugs when inadvertently used in pregnancy. If withdrawal menses does not occur when planned, a pregnancy test is administered.
DMPA and the transvaginal ring should be started within the first 5 days of the menstrual cycle. (Sunday start and quick-start methods are off label.) The continuous-dosing CHC products use a Sunday start only. If the patient is on a 21-day CHC regimen, the next pack should be started following the 7-day break whether bleeding has stopped or not. With 28-day packs, a pill is taken daily without stopping regardless of the bleeding pattern. Usually, withdrawal menses occur in a cyclic fashion. In multiphasic preparations, the day 1 pill is clearly marked, and the tablets are taken in the order noted. A difference in the color of the tablets delineates the change in the dose of estrogen or progestin through the phases. With the POP, a pill is taken daily without a break. To increase effectiveness, all OCs should be taken at the same time daily. With the POP, women should strictly adhere to this instruction.
Box 52.1 provides guidelines for patients on how to handle missing a dose of their OC.
Not every patient is a candidate for use of CHCs. Box 52.2 lists contraindications to CHC use.
The effectiveness of some drugs is impaired by CHC products; other drugs impair the effectiveness of CHCs and progestin contraceptives. Box 52.3 shows drugs that may have interactive effects with CHCs. Patients receiving low-dose formulations of oral contraceptives need to be particularly cautious about potential interactions. If a patient is taking a drug that affects estrogen absorption or metabolism, a CHC with a higher dose of EE may be prescribed.
Potential Side Effects and Adverse Reactions
It is accepted by health care providers that the risks associated with hormonal contraception are much less than the risks associated with pregnancy. This is especially true if the patient does not have any of the contraindications listed in Box 52.2. In most cases, the benefits of any contraceptive method usually outweigh the risks when using a benefit-risk ratio to determine patient eligibility.
Benefit-risk ratio is partially determined by the risk related to the particular contraceptive method compared with the risk pregnancy poses for the patient. Also included in the benefit-risk ratio is consideration of age, smoking status, allergies and drugs, health histories and physical assessments, and patient lifestyle patterns and changes. These considerations determine patient selection or nonselection for the method as well as continuing or discontinuing a method of contraception.
Most of the untoward side effects are related to differences in the estrogen-progestin ratio of the products and the patient’s response to these differences. Side effects primarily caused by an excess of estrogen include nausea, vomiting, dizziness, fluid retention, edema, bloating, breast enlargement, breast tenderness, chloasma (slightly more in dark-skinned patients on higher-dose tablets who are exposed to sunlight), leg cramps, decreased tearing, corneal curvature alteration, visual changes, vascular headache, and hypertension (in about 1% to 5% of previously normotensive patients within the first few months).
Side effects primarily caused by estrogen deficiency include vaginal bleeding (BTB, especially in the first few cycles after starting therapy) that lasts several days, usually during days 1 to 14; oligomenorrhea (very scant periods), especially after long-term use; nervousness; and dyspareunia (painful sexual intercourse) secondary to atrophic vaginitis.
Side effects primarily caused by an excess of progestin include increased appetite, weight gain, oily skin and scalp, acne, depression, vulvovaginal candidiasis (vaginitis from the yeast microbe Candida), excess hair growth, decreased breast size, and amenorrhea after cessation of use (1% to 2% of patients).
Side effects primarily caused by progestin deficiency include dysmenorrhea, bleeding late in the cycle (days 15 to 21), heavy menstrual flow with clots, or amenorrhea. There may also be changes in laboratory values, including thyroid and liver function, blood glucose, and triglycerides.
CHCs may increase the vascularity of the cervical epithelium, extend the area of cervical ectopy, and alter certain immune parameters. Advise pill users to use male or female latex or polyurethane condoms unless they are confident that both partners are free of human immunodeficiency virus (HIV) and other STIs.
Adverse reactions of a more severe nature include cardiovascular and carcinogenetic risks.
There is an increased risk for hypertension (usually seen within 3 months after initiating CHCs in women with preexisting risk) and arterial blood clot complications such as MI, pulmonary embolus, and cerebrovascular accident (CVA) in women using CHCs compared with women who are not using CHCs. However, in terms of absolute risk for adolescents and women, the rate of dangerous complications from hormonal methods of contraception is extremely low because women younger than 50 years rarely experience heart attack or stroke. The risk for hypertension in women younger than 35 years is also low. Hormonal methods of contraception that contain DRSP or etonogestrel may double a woman’s risk for venous thromboembolic events. Cardiovascular risks are increased in women older than 35 years who smoke, women older than 45 years, and women with hypertension that is undiagnosed or uncontrolled by drugs.
Long-term use of CHCs may increase the risk for breast cancer in younger women, but the risk is minimal. Breast cancer risk returns to normal 10 years or more after discontinuing CHCs. There is also an increased risk for benign liver tumors. Risk for cervical cancer is slightly increased, which is thought to be because CHCs change cervical epithelium, making it more susceptible to the high-risk pathogenic strains of human papillomavirus (HPV) and because condoms may be used less frequently in prevention of STIs. Women who use hormonal methods of contraception have a greatly reduced risk for ovarian and endometrial cancers, and the protective effect is directly related to the duration of time the method is used.