Monday, January 23, 2012

Hormonal contraception

Author : Dr Philip Darney Department of Obstetrics, Gynecology and Reproductive Sciences University of California San Francisco

2008-06-26
Family Planning with Hormonal Contraception : A number of new methods for family planning have been introduced in recent years expanding women’s choices. Health care providers, including obstetrician–gynecologists, primary care physicians, and nurse practitioners can help women determine the method that is best for them, given their health histories, future reproductive plans, and lifestyles.
A number of new methods for family planning have been introduced in recent years expanding women’s choices. Health care providers, including obstetrician–gynecologists, primary care physicians, and nurse practitioners can help women determine the method that is best for them, given their health histories, future reproductive plans, and lifestyles.
All hormonal contraceptives contain progestin alone or estrogen plus a progestin. These hormones are synthetic modifications of the hormones naturally secreted by the ovaries.   They are modified so that they remain active when taken by mouth, so that they are potent enough to serve as contraceptives, and so that they have less severe unwanted effects. I will discuss the various methods in four parts: ‘progestin only’ methods, combined hormonal methods and then intrauterine contraception (IUC) and emergency contraception. I have separated these last two methods out because they feature combinations of various types of methods.  

Hormonal Contraceptives Using Progestin Alone

 
Changes in bleeding are the single most frequent, concerning, and obvious side effect of hormonal contraceptives because irregular bleeding is sometimes perceived as a sign of a health problem and because it interferes with daily activities.  Knowing about the possibility, frequency, and duration of menstrual disturbances can decrease concern about and dissatisfaction with contraception, and decrease the rate of early discontinuation.   Up to 40% of women starting a new method of hormonal contraception experience some bleeding at a time when it is unexpected and, if uninformed about bleeding changes, up to half of these may discontinue their method, risking pregnancy if another contraceptive is not substituted. Progestin-only contraceptive pills, injectable depot-medroxyprogesterone acetate (DMPA), subdermal (beneath the skin) implants, and the levonorgestrel intrauterine system (IUS) (see “Intrauterine Contraception”) cause more changes in bleeding than do methods containing both estrogen and progestin.

Who Should Consider Using Progestin-only Contraceptives?

Progestin-only methods should be considered for women in whom estrogen is contraindicated, including: women with a history of thromboembolic disease, sickle cell anemia, or congenital heart disease; those who are older than 35 years and smoke, and; those with hypertension, migraines with aura, or other risk factors, but some women without these conditions prefer progestin only methods because intrauterine, implant and injectable contraceptives are longer-acting than the methods that contain both hormones. These methods are also highly effective, discreet, and reversible, and for these reasons those at high risk for unplanned pregnancy – such as adolescents – have used them more successfully than oral contraceptive pills.
 

Benefits          

The non-contraceptive benefits of progestin-only methods include decreases in menstrual blood loss, anemia, menstrual cramping, ovulatory pain, and pain with endometriosis (abnormal growth of the tissue that lines the uterus), as well as decreased risks of endometrial and ovarian cancer (1). Progestin-only methods may be safely used while breastfeeding.
 

Disadvantages and Side Effects

Hormonal methods do not protect against sexually transmitted diseases (STDs) and human immunodeficiency virus (HIV), although they may provide some protection against pelvic inflammatory disease (PID) by thickening cervical mucus, which is also an important factor in their contraceptive action (2). Menstrual disturbances are the main reason why women discontinue progestin-only contraception, but women may also experience systemic side effects, such as breast tenderness, acne, and mood changes, including depression. Some of the less common systemic side effects of implants and injections, such as acne and unwanted hair growth or loss, are associated with the decrease in levels of sex hormone-binding globulin caused by decreased ovarian production of estradiol (1).
Weight gain is a common reason for discontinuing hormonal contraceptives, but only the injectable DMPA (DepoProvera) has been clearly associated with increasing weight, and then only in young women who were already overweight when they initiated use.
Absolute contraindications (unacceptable risks) to progestin-only methods are limited to pregnancy and current breast cancer. Use of a progestin-only method is generally NOT recommended for women who have had breast cancer treated without recurrence for less than five years, active hepatitis, severe cirrhosis, benign or malignant liver tumors, current deep vein thrombosis (blood clots), or pulmonary embolism (blood clot in the lung). Discontinuing progestin-only methods should be considered by who anyone who develops migraines with focal neurologic symptoms, ischemic heart disease, or stroke (3). Case–control studies by the World Health Organization showed no increased risk of thrombosis for depot medroxyprogesterone (injectable DMPA) or implant users (4); however, the absolute safety of progestin-only methods with regard to the risk of thrombosis has not been studied prospectively.  Large epidemiologic studies have not identified an increased risk of stroke, myocardial infarction, or venous thromboembolism with use of progestin-only oral contraceptives (OC), thus progestin-only OCs represent a reasonable contraceptive choice for women at high risk of, or who have coronary artery disease, cerebrovascular disease, venous thromboembolic disease, hypertension, or other conditions in which use of contraceptive doses of estrogen are contraindicated (5).
 

Methods

 

Progestin-Only Pills (Minipills)

 
Mechanism of Action and Efficacy
Progestin-only pills contain one of the synthetic progestins (levonorgestrel, norethindrone, norgestrel, lynestrenol, desogestrel, or ethynodiol diacetate) in small amounts to prevent conception through a combination of mechanisms: ovulation suppression in some cycles, thickening of cervical mucus to prevent sperm penetration, atrophy of the endometrium (shrinking of the lining of the uterus), and altered tubal function. The amount of progestin in progestin-only pills is about 25% of that in combined (estrogen and progestin) oral contraceptive pills.
Progestin-only pills must be taken at the same time each day to be effective. The hormone is eliminated within 24 hours, at which time the cervical mucus regains its normal permeability to sperm. As a result, progestin-only pills typically have higher failure rates than combined oral contraceptives. With perfect use, the first-year probability of pregnancy is 0.5%. With typical use, the failure rate is 8%, varying according to age, with younger women having more unintended pregnancies – an association seen with all contraceptives (1, 6).
 
Advantages and Disadvantages
The Progestin-only pill is the only oral birth control method that does not contain estrogen. This can be beneficial for women who cannot take estrogen for a variety of previously listed contraindications.
When progestin-only pills are discontinued, fertility returns immediately because ovulation is not usually suppressed and cervical mucous returns quickly to an estrogen-dominated state. Because ovulation is not reliably inhibited, the minipills are less effective than other methods of hormonal contraception unless they are taken with absolute regularity. If a minipill user becomes pregnant, there is a higher risk of pregnancy outside the uterus (ectopic pregnancy) than in women using no or other methods of contraception. Women taking medications that stimulate liver function (such as antiepileptics or a few antibiotics) should not rely on progestin-only pills (3) as their sole method of pregnancy prevention because these pills provide such a low dose of the hormone that any increase in its metabolic break down could lead to decreased contraceptive efficacy do to lowered blood concentrations of the hormone.
 

Injectable Depot medroxyprogesterone (DepoProvera)

 
Mechanism of Action and Efficacy
Depot medroxyprogesterone acetate is given as a 1 milliliter (150 mg of microcrystals), deep intramuscular injection every 12 weeks. Because DMPA is not a sustained-release system, its action relies on obtaining high levels of progestin which decline over three months, but can remain above a contraceptive concentration for many additional weeks. This high concentration of DMPA  not only thickens the cervical mucus and alters the endometrium, as do other progestins, but it also suppresses levels of follicle-stimulating hormone and luteinizing hormone and blocks the luteinizing hormone surge, thereby preventing ovulation. The failure rate of DMPA in the first year of use in the United States is 0.3% with perfect use and three percent in the first year with typical use because some women do not return for their injections from a nurse or physician every three months as required for maximum efficacy.  The newer, lower dose, subcutaneously administered version of DMPA can be injected by the user herself, which may decrease failure rates since an office visit is not needed in order to continue the method. (1,7). A contraceptive level is maintained for at least 14 weeks, providing a two week period for re-injection to maintain maximum efficacy.
 
Advantages and Noncontraceptive Benefits
Injectable DMPA is highly effective, discreet, reversible, coitus independent (is not reliant on a couple implementing birth control at the time of intercourse), and easy to use. Although most women experience irregular bleeding and spotting during the first year of use, 70% of users experience amenorrhea (the absence of menstrual bleeding) after two years and 80% after 5 years (1).  This change is acceptable for many women and desired by some. Injectable DMPA decreases the risk of ectopic pregnancy, decreases the frequency of sickle cell crises in African-Americans with sickle cell disease, and decreases the frequency of seizures in women with epilepsy (1). Adolescents using DMPA have higher continuation rates and fewer unplanned pregnancies than do those taking oral contraceptive pills (1).
Because serum concentrations of DMPA are high in women receiving tri-monthly DMPA injections, the efficacy of this method is not influenced by weight or by the use of medications that induce liver enzymes, like anti epileptics. (1). DMPA can be used by breast-feeding mothers because negligible concentrations are found in breast milk immediately after delivery  and DMPA increases the quantity of breast milk produced and can help lengthen the duration of breast feeding. (1).
 
Disadvantages and Side Effects
The most common side effect of DMPA is irregular bleeding and spotting, which decreases after the first 12 months, and eventual amenorrhea (lack of menstruation)((1). Up to 25% of patients discontinue DMPA in the first year because of irregular bleeding (1). Users also may experience breast tenderness, weight gain, headaches, and depression (6). Because some women have a delay in ovulation and fertility of up to 10 months after the last injection (1), this method is not recommended for women hoping to conceive within a year.
Lower measurements of bone density in current DMPA users have led to concerns that DMPA-induced bone loss might increase the long-term risk of fractures years after discontinuation of the drug, particularly in young women who have not yet attained their peak bone mass and among perimenopausal women who upon discontinuation may have reached menopause with no opportunity to regain bone mass and who may be starting to lose bone (8,9). However, studies do not show that DMPA use reduces peak bone mass or increases the risk of osteoporotic fractures in later life (10,11,12). Despite the lack of a proven increase in fracture rate, the Food and Drug Administration (FDA) issued in 2004,a “black box” warning on DMPA package labeling so that women would be informed about the changes detected by bone scans even though they are not associated with fractures.  Subcutaneous administration of 104 DMPA, rather than 150 mg in muscle, has somewhat less effect on bone density.
 

SINGLE ROD ETONORGESTREL IMPLANT (Implanon- TM)

 
A contraceptive implant containing 68 mg of the progestin etonogestrel (ENG), in a single rod made of ethylene vinyl acetate (EVA) was approved for use in the United States in July, 2006, and is the only implantable contraceptive currently available in the USA since sales of Norplant ended in 2002. ( PROVIDE DIAGRAM AND/OR A VIDEO OF INSERTION AND REMOVAL.) ENG is initially absorbed by the body at a rate of 60 micrograms (mcg) per day which slowly declines to 30 mcg per day after two years of use. The ENG implant can be removed at any time at the woman’s discretion, but will remain effective for at least three years compared to the seven years efficacy of Norplant.
 
Implanon Insertion

                                    

Mechanism of Action and Efficacy
Progestin-containing implants have two primary mechanisms of action: inhibition of ovulation and restriction of sperm penetration through cervical mucus (13).  The ENG implant (Implanon) suppresses ovulation by controlling hormones in the pituitary and hypothalamus glands which is required to support the production, growth, and maturation of eggs in the ovary (14).  Progestins affect the cervical mucus, making it viscous and scanty so that sperm cannot enter the uterus and reach the egg to fertilize it.  These ovarian and cervical mechanisms of action provide high contraceptive efficacy and occur prior to fertilization. No signs of embryonic development have been found among implant users, indicating that progestin implants prevent fertilization even when ovulation occurs. (15).
Advantages
In clinical trials, the ENG implant demonstrated 100% contraceptive effectiveness. Neither intrauterine nor ectopic pregnancies were observed. Among subjects who were overweight, blood concentrations of the ENG remained at levels adequate to prevent pregnancy, but not enough overweight subjects participated to demonstrate efficacy in this group.  Administration of a low dose of progestin and maintenance of stable blood levels provide high efficacy, a long duration of action, a short fertility recovery time, and no serious cardiovascular effects. (17)
Because Implanon is a progestin-only method, it can be used by women who have contraindications to estrogen-containing contraceptives.  The sustained release of low doses of progestin avoids the high initial dose delivered by injectables and the daily hormone surges associated with oral contraceptives.  Implants are an excellent choice for a breastfeeding woman and can be inserted immediately after birth of a baby (1).  There are no effects on breast milk quality or quantity, and infants grow normally (13, 18). Another advantage of the implant method is that it allows women to plan their pregnancies precisely because return of fertility after removal is prompt, in contrast to the six- to 18-month delay in ovulation that can follow depot-medroxyprogesterone acetate (DMPA) injections (14,19).
One of the major advantages of the implant and other low-dose, sustained-release methods is high contraceptive efficacy without changes in body functions like carbohydrate and lipid metabolism, coagulation, liver or kidney function, or immunoglobulin levels (1) as do some sex steroids in higher doses than those from subdermal or intrauterine delivery.
Disadvantages and Side Effects
Implants (Implanon) require a minor surgical procedure by trained clinicians for insertion and removal. Cost-effectiveness of the method depends upon long-term (two to three years) use; early discontinuation makes implants more expensive than other hormonal methods. (16) Side effects associated with the implant include menstrual irregularities including infrequent bleeding, amenorrhea, prolonged bleeding, frequent bleeding, weight gain, acne, breast pain, and headache. These symptoms rarely provoke discontinuation. (20); bleeding irregularities are the most common reason for discontinuation of the ENG implant.
Despite side effects and dependence on clinicians to insert implants, most women using implantable contraception are satisfied with the method; they cite its long duration of use, convenience, and high efficacy (21,22).
           

Combined Hormonal Contraceptives

Combined hormonal contraceptives include both estrogen and progestin.  Oral contraceptive pills, the contraceptive vaginal ring, and the contraceptive skin patch are all “combined” hormonal contraceptives. These hormonal delivery methods have similar mechanisms of action, serum levels of estrogen and progestin, physiologic effects, noncontraceptive benefits, and prescribing precautions so these are described together.  What is different is the route of administration of the hormones (through the stomach for the pill, the vaginal lining for the ring, and the skin for the patch).  Because the pill has been in use for much longer than the other two, more is known about its side effects.  In fact, the birth control pill is the most thoroughly studied of any drug, and it seems safe to assume that we can apply this knowledge to the ring and the patch.
For guidelines of the use of hormonal contraception in women with co-existing medical conditions, see Table 1.
Mechanism of Action
Combined hormonal contraceptives contain an estrogen to control bleeding and a progestin to inhibit ovulation. The progestational agent inhibits ovulation and causes cervical mucus thickening and shrinkage of the lining of the uterus (endometrial glandular atrophy). In addition to preventing breakthrough bleeding by stabilizing the endometrium (tissue lining the uterus), the estrogenic agent suppresses the hormone (FSH) that stimulates the growth of an ovarian follicle into an egg and enhances the action of the progestin (1).
Advantages and Noncontraceptive Benefits

Combined hormonal contraceptives have excellent contraceptive efficacy, numerous noncontraceptive benefits, and high user satisfaction. They are safe for most women, can be used throughout the reproductive years, are rapidly reversible, can be discontinued without a medical visit, are coitus independent, and are for the most part well tolerated. These products decrease menstrual blood loss and pain, menstrual irregularities, and iron-deficiency anemia. They are useful in the management of excess androgens (male hormones) because they create a regular bleeding pattern and protect the endometrium against the effects of unopposed estrogen.  In addition, combined hormonal contraceptives offer a noncontraceptive benefit for perimenopausal symptoms like hot flushes. Although they do not protect against sexually-transmitted infections or the AIDS virus (HIV), these contraceptives, like progestin-only methods, provide protection against infertility caused by infection of the upper reproductive tract (uterus, tubes, and ovaries) by thickening cervical mucus. They decrease the risk of ovarian, endometrial, and possibly colon cancers.  They also reduce acne and unwanted hair growth; decrease pain with endometriosis (a condition where the tissue similar to the lining of the uterus is found elsewhere in the body); and decrease the risk of pregnancies outside the uterus (ectopic pregnancies) (1, 6).

Side Effects
Side effects of combined hormonal contraceptives can be caused by the estrogen or the progestin component. Estrogenic side effects include nausea, bloating, increased breast size and tenderness, hypertension, rise in the “good” cholesterol (HDL) concentrations, arterial and venous clotting, and stimulation of preexisting breast cancer (6), but estrogen-related side effects are a rare source of complaints about current lower dose OCs - pills containing less than 50 mg of the estrogen ethinyl estradiol (EE).
The progestin in combined oral contraceptives suppresses production of testosterone and, in combination with the estrogen in pills, can decrease acne, oily skin, unwanted hair growth (hirsutism), and libido. However, progestin in combined hormonal contraceptives can also sometimes produce androgenic effects including headache, emotional lability, including depression, weight gain, breast tenderness, and increased low density and decreased high density cholesterol levels (6). Carbohydrate metabolism is not affected by current low-dose formulations (6). Three more progestin receptor-selective, less androgenic progestins are in use in the USA and others are available elsewhere.  These include norgestimate and desogestrel (nortestosterone derivatives), and drospirenone (a spironolactone derivative). Drospirenone has diuretic like effects and should not be used in women with kidney or adrenal insufficiency or liver disease and requires additional monitoring of potassium for women using certain medications (8). The use of combination oral contraceptives formulated with the progestin desogestrel is associated in some epidemiologic studies with a deep venous thromboembolism (DVT) risk 1.7–1.9 times higher than that associated with levonorgestrel oral contraceptives, but the rate of DVT is much lower than in pregnancy with all lower estrogen dose contraceptives, no matter which progestin they use, ranging from 1 to 3 cases per 10,000 women per year of use (5).

Methods

Combined Oral Contraceptive Pills

Traditionally the use of combined oral contraceptive pills entails taking one active, hormonal pill daily for 21 days, which is followed by a pill-free or placebo interval of one week to allow a scheduled withdrawal bleed. Most combined oral contraceptives currently in use contain an estrogen dose equivalent to 35 mcg or less of ethinyl estradiol as well as 0.15–1 mg of a progestin, depending on its potency.
Failures of combined oral contraceptives are usually attributable to missed pills or early discontinuation. First-year failure rates among women using combined oral contraceptives are 0.1% with perfect use and 7.6% with typical use (6). Up to 60% of women using combined oral contraceptives discontinue their use in the first year because of poor menstrual cycle control (unexpected bleeding and spotting) and other side effects; of these women, most discontinue use in the first month. Breakthrough bleeding occurs in 35–62% of women at sometime in their first four cycles of combined oral contraceptive use and in 15-40% in the first cycle, depending primarily on the estrogen content; usually the less estrogen, the more bleeding (6). There is no physiologic advantage to phased preparations with different progestin and/or estrogen doses during specific days of each cycle, although some women have improved bleeding patterns at lower doses using these pills. Addition of either estrogen (as in Mircette and Seasonique) or progestin (as in Yaz) pills following the usual three weeks of pill-taking can also result in better bleeding control at a lower estrogen dose   Extended use of OCs can avoid menses altogether, but some irregular bleeding usually occurs.  Any OC can be taken continuously and some (Lybrel, Seasonale and Seasonique) are specially packaged for continuous use.

Combined Contraceptive Vaginal Ring

The combined contraceptive vaginal ring is a flexible, transparent ring 54 mm in diameter, made of ethylene vinyl acetate (EVA) copolymer plastic. The user places and removes the ring herself; there is no “wrong” way to insert it as long as it touches the vaginal lining. Each ring is designed for one cycle of use, which is three weeks of continuous ring use followed by one week without the ring to provoke a scheduled withdrawal bleed. The ring releases 120 mcg of etonogestrel (the active metabolite of desogestrel) and 15 mcg of ethinyl estradiol per day. The ring is approved for three weeks of continuous use, but contraceptive levels of steroid are maintained in the blood for 5 weeks, and like OCs the ring can be used continuously.  A single ring with enough hormones for a year is under study. It can be left in place all the time or removed every three weeks to permit withdrawal bleeding. 
In addition to having the advantages of all combined hormonal contraceptives, the ring is convenient and discreet and provides good cycle control with sustained delivery of low-dose hormones (the total amount of hormones released –area under the curve or “AUC” is less with the ring than with OCs or the patch) . With perfect use, 0.3% of women will become pregnant in the first year of ring use (23). The pregnancy rate with typical use is unknown because the ring is too new to allow researchers to collect adequate data. The ring has been demonstrated to have high acceptability, high compliance, and high continuation rates (24). In a large study at several offices and clinics, the 4% of women who discontinued the ring did so because of foreign body sensations, coital problems, expulsion, and vaginal discomfort. Unlike other combined methods, the ring rarely causes irregular bleeding in the initial months of use. In a clinical trial (24), adverse events associated with the ring were rare and included headache and vaginal discharge.

Transdermal Contraceptive System (THE PATCH)
The transdermal contraceptive system is a 4.5-cm square patch that provides continuous circulatory levels of norelgestromin (the active metabolite of norgestimate) and ethinyl estradiol equivalent to 150 mcg of norelgestromin and 20 mcg of ethinyl estradiol per day. It is usually placed on the hip or abdomen and should not be applied to the breasts. The total amount (measured by AUC) of the hormonal concentrations achieved by the patch is greater than with typical OCs. One patch is applied weekly for three consecutive weeks, followed by one week without its use to allow for a scheduled withdrawal bleed. The first-year pregnancy rate for perfect use is 0.3% (23); the rate for typical use is not yet determined. Patch users have higher rates of compliance and more perfect use than do users of combined oral contraceptives (25, 26).  Patches maintain adhesiveness for a week regardless of heat, moisture, activity levels, or site of application with detachment occurring in less than 2% of patients (26, 27). Advantages of the patch, in addition to those of all combined hormonal contraceptives, include convenience, ease of use, and continuous delivery of low-doses of estrogen and progestin. Application site reactions, breast discomfort, and dysmenorrheal (pain during menstruation) are seen more commonly in initial cycles of the patch use (26).
Risks and Disadvantages
Most medical concerns about combined hormonal contraceptives focus on the estrogen component and the associated risk of venous thromboembolism (VTE) and arterial vascular disease. Many of the original precautions were based on risks observed with pills containing 50–100 mcg of estrogen. These risks are greatly reduced with current lower-dose pills, which have fewer metabolic and blood clotting effects (28). The increased risk of VTE remains the greatest concern with combined hormonal contraceptives; this risk is increased three to four times with even the lowest-dose combined oral contraceptive but remains low, at three per 10,000 woman-years (28, 29). The risk of deep vein thrombosis may be approximately two times higher with combined oral contraceptives containing the newer progestins (such as desogestrel and gestodene) when compared with those containing levonorgestrel (29). Overall, there is a decreased risk of VTE with lower-dose formulations. The risk of arterial cardiovascular disease is increased in women using combined hormonal contraceptives who have other risk factors, particularly smoking, hypertension, diabetes, and obesity; age over 35 amplifies the effects of these conditions, but women who are healthy can continue OCs into the menopause.
The average overall ethinyl estradiol concentration ("area under the curve" or AUC) in patch users is 60 percent higher than in women who use a 35 mcg ethinyl estradiol pill; however, peak ethinyl estradiol concentrations are 25 percent lower than in pill users (30,31). It is unclear whether this finding will be associated with a higher frequency of adverse events, such as thrombosis in deep veins (VTE) leading to embolism. Two studies, both based on medical insurance claims, demonstrated conflicting reports in terms of the increased risk of venous thromboembolism and contraceptive patch use (32,33). Although these are observational studies with a relatively small number of events, limitations in design, and conflicting results, there is a possibility of increased VTE risk in patch users. This potential risk should be balanced against the benefits of this method for preventing pregnancy by women who may not be able to use other methods successfully. (34)

Breast Cancer Risk and Hormonal Methods
Users of combined oral contraceptives are slightly more likely than the general population to have a breast cancer diagnosis. This increased risk may be due to earlier detection or to the promotion of a cancer that is already present. Current or past users of combined oral contraceptives are more likely than non–hormone users to have localized disease and less malignant tumors explaining why they are less likely to die of breast cancer even if it is more often diagnosed during use. Women who have used combined oral contraceptives in the past are at no increased risk of being diagnosed with breast cancer 10 years after discontinuing combined oral contraceptives or at age 55 years and are less likely to die of breast cancer, perhaps due to earlier diagnosis or a protective effect of the hormones. Women with a strong family history of breast cancer do not increase their risk by taking combined oral contraceptives (35, 36).

Obesity and Contraceptive Efficacy
Use of most hormonal contraceptives is associated with little or no effect on body weight.  Weight fluctuations in women, particularly weight gain, tends to be due to increasing age and changes in lifestyle, irrespective of contraceptive use. (37)
Whether elevated body weight reduces the effectiveness of combined hormonal contraceptives is controversial.  While several studies have shown an association between increasing body weight and/or BMI and pregnancy rate while on combined oral contraception (38,39), most trials do not include enough overweight women to draw meaningful conclusions.  In addition, when adjustment is made for age, parity, education, income and race/ethnicity, the differences in pregnancy rates are often not significant (40).
 The impact of body weight on the efficacy of the ring is unknown; however clinical trials of the ring did not show excess pregnancies in obese women (41). Pooled data from three clinical trials of the transdermal combination hormonal contraceptive patch demonstrate one-third of the on-treatment pregnancies occurring in the heaviest one-tenth of women (more than198 pounds) (39, 42-43). The efficacy of copper or levonorgestrel intrauterine contraceptives (IUC) or injectable DMPA is not decreased by obesity, making these methods good choices for heavy women.
Despite a few studies that have demonstrated slightly reduced contraceptive efficacy with excessive body weight, heavier women should not be restricted from using combined hormonal contraception if these methods are the best available options: the risk of pregnancy is still significantly lower with these methods than with a barrier method or no method at all.

CONTINUOUS SUPPRESSION

Combined hormonal contraception can be prescribed for continuous use to achieve a number of different goals (44, 45):
  •  decrease the number of hormone-free days per cycle for women who have symptoms  without hormones (usually “estrogen withdrawal” effects)
  • reduce the number of placebo weeks or withdrawal weeks per year for women who would prefer to have fewer periods
  • eliminate withdrawal weeks entirely for those who want no vaginal bleeding
  • reduce the incidence of unscheduled vaginal bleeding
Combined oral contraceptives are also marketed in packaging specifically designed to facilitate continuous pill-taking, providing for four pill-free intervals per year or for an entire year of pill-taking. With the elimination of placebo pills, other monophasic combined oral contraceptives can be used in the same way to decrease the frequency of withdrawal bleeding (8). The combined contraceptive patch and ring also can be used continuously without a monthly withdrawal bleed. The primary disadvantage of continuous use is unpredictable, light bleeding, although some women may prefer this to menstrual-like symptoms.

table one:    Precautions for use of hormonal contraceptives

Use of COMBINED hormonal contraception in women with coexisting medical conditions (5)
Medical Condition
 Recommendation regarding combined hormonal contraception use *
Older than age 35 years
 Safe in healthy, nonsmoking women
Cigarette smokers
 Use with caution, if at all, in women older than 35 years who smoke
Chronic hypertension
 Safe in women with well-controlled and monitored hypertension who are aged 35 years or younger, healthy, show no evidence of end-organ vascular disease, and do not smoke cigarettes
Cholesterol disorders
 In women with controlled cholesterol disorders, monitor fasting serum lipid levels each month until stabilization of cholesterol has been observed
Diabetes
 Safe in nonsmoking, otherwise healthy women who are younger than 35 years and show no evidence of hypertension, kidney, eye, or other vascular disease;
combination hormonal contraceptive use does not cause diabetes.
Migraine headaches
 Safe in women under 35 and without focal neurologic symptoms, and nonsmoking.
Avoid combined hormonal contraception in women age older than 35 with migraines or women with migraines with focal neurologic symptoms irrespective of age
Fibrocystic breast changes, fibroadenoma, or family history of breast cancer BRCA1 or BRCA2
 Not regarded as contraindications to combined contraceptive use.
Uterine leiomyomata
 No contraindications
Breastfeeding postpartum
 Defer use until 4 weeks postpartum in nonbreastfeeding women; Use of combination hormonal contraceptives can be considered once milk flow is well established as use by well-nourished breastfeeding women does not result in infant development problems
Concomitant medications
 See Table 2,3,4
Efficacy of selective serotonin reuptake inhibitors (SSRIs) for treatment of depression not affected by combined hormonal contraception and SSRI use does not increase pregnancy rate.
St John’s Wort can increase likelihood of ovulation and breakthrough bleeding with concomitant combined hormonal contraception use.
Scheduled for surgery
 Benefits associated with stopping combination contraceptives 1 month or more before major surgery should be balanced against the risks of an unintended pregnancy. If oral contraceptives are continued before major surgical procedures, heparin prophylaxis should be considered.
History of venous thromboembolism
 Women with a documented history of unexplained venous thromboembolism or venous thromboembolism associated with pregnancy or exogenous estrogen use should not use combination hormonal contraceptives unless they are currently taking anticoagulants. An individual who had a single episode of venous thromboembolism years earlier associated with a nonrecurring risk factor (e.g., venous thromboembolism occurring after immobilization following a motor vehicle accident) may not be at increased risk for venous thromboembolism.
Blood clotting abnormalities
 Women with familial thrombophilic (coagulation) syndromes, including factor V Leiden mutation, prothrombin G2010 A mutation, and protein C, protein S, or antithrombin deficiency have an increased risk of venous thromboembolism during combined hormonal contraceptive use and also develop venous thromboembolism earlier during use than lower risk users
Anticoagulation therapy
 Combination hormonal contraceptives can reduce menstrual blood loss and do not increase the risk of recurrent thrombosis in well anti-coagulated women
Obesity
 See section on Obesity and Contraceptive Efficacy
Systemic lupus erythematosus (SLE)
 Combination hormonal contraceptives are safe for women with mild SLE who do not have antiphospholipid antibodies
Combined hormonal contraceptive use should be avoided in women with SLE and a history of vascular disease, nephritis, or antiphospholipid antibodies
Sickle cell disease
 Pregnancy carries a greater risk than does combination hormonal contraceptive use, but DMPA, IUC, or Implanon are even less risky than combined hormonal methods.
Depression
 Data on use of hormonal contraceptives in women with depression are limited, but generally show no effect. Women with depressive disorders do not appear to experience worsening of symptoms with use of hormonal methods of contraception.
Human immunodeficiency virus (HIV) (acquisition, transmission, and progression)
 Conflicting data on the effect of hormonal contraception on the risk of HIV acquisition. Data on transmission are too limited to draw firm conclusions.
 
*Where studies have been done with combined oral contraception, data is extrapolated to include combined transdermal and vaginal contraception.
 
Table 2
Interaction of Anticonvulsants and Combination Oral Contraceptives (5)
Anticonvulsants that decrease steroid hormone levels in women taking combination oral contraceptives
Barbiturates (including phenobarbital and primidone)
Carbamazepine and oxcarbazepine
Felbamate
Phenytoin
Topiramate
Vigabatrin
Anticonvulsants that do not decrease steroid levels in women taking combination oral contraceptives
Ethosuximide*
Gabapentin†
Lamotrigine†
Levetiracetam
Tiagabine†
Valproic acid
Zonisamide
*No pharmacokinetic data are available.
†Pharmacokinetic study used anticonvulsant dose lower than that used in clinical practice.



Table 3
Interaction of Antiinfective Agents and Combination Oral Contraceptives (5)
Antiinfective agent that decreases steroid hormone levels in women taking combination oral contraceptives
Rifampin
Antiinfective agents that do not decrease steroid levels in women taking combination oral contraceptives
Ampicillin
Doxycycline
Fluconazole
Metronidazole
Miconazole*
Quinolone antibiotics
Tetracycline
*Vaginal administration does not lower steroid levels in women using the contraceptive vaginal ring.






















 
Table 4. Pharmacokinetic Combination Oral Contraceptive–Antiretroviral Drug Interactions (3,5)
Antiretroviral
Levels
 Contraceptive
Steroid Levels
 Antiretroviral
Protease inhibitors
Nelfinavir

No data
Ritonavir

No data
Lopinavir/ritonavir

No data
Atazanavir

No data
Amprenavir


Indinavir

No data
Saquinavir
 No data
 No change
Nonnucleoside reverse transcriptase inhibitors
Nevirapine

No change
Efavirenz

No change

Intrauterine Contraception (IUC)

Two types of modern intrauterine contraceptives are available in the USA, one non-hormonal and one with progestin. Several others are widely used in other countries, where IUC is much more popular than in the USA.  In China and Finland, for example, more than half of women who want to avoid pregnancy use IUC. IUC use is low in the USA because several myths persist. More women would be interested in using IUC if they knew that IUC does NOT cause pelvic infection or make it worse, does NOT increase ectopic pregnancies, does NOT cause abortion, is NOT limited to women over 25 who have had children, and CAN be provided immediately after pregnancy termination. Modern IUC is at least as effective as sterilization operations in preventing pregnancy, and is safer, more convenient and cheaper.  Hormone-releasing IUCs reduce symptoms from uterine fibroids, adenomyosis, and endometriosis while reducing uterine bleeding and the risk of pelvic infection.
 

COPPER INTRAUTERINE CONTRACEPTION (Paragard)



The copper device is approved for 10 years of use but has been shown to be effective for at least 12 years (49). After prolonged continuous use, the cumulative pregnancy rate is 1.6 percent at seven years, and 2.2 percent at 8 and 12 years (49). Overall, the failure rate is substantially less than one per 100 women per year, except in women under age 25 who experience a slightly higher failure rate, most likely because they are more fertile than older women (47,50).  Over a ten year period, failure is less common with copper intrauterine contraception than after typical sterilization operations.
Mechanism of Action and Efficacy
The contraceptive action of all IUDs is mainly in the uterine cavity. Nonhormonal IUDs depend for contraception on the general reaction of the uterus to a foreign body. It is believed that his reaction produces a sterile inflammatory response that creates a spermicidal environment. In other words sperm cannot reach the ova and thus fertilization cannot occur. The copper IUD releases free copper and copper salts that have both a biochemical and morphologic impact on the uterine lining (endometrium) and produce alterations in cervical mucus and secretions which also have spermicidal effects.
Advantages and Noncontraceptive Benefits
Women who cannot use hormonal methods can use copper IUCs. After five years of continued use, the TCu-380A IUC is the most cost-effective method of contraception available (47). IUCs protect against ectopic pregnancy: copper IUD users are 90% less likely to have an ectopic pregnancy occur than women using no method (because they are more well protected again pregnancy in general), although a larger proportion of pregnancies with either IUC are ectopic (51,52). There are no systemic side effects with the copper IUC. Long-term use is associated with a high degree of safety. There is rapid return to fertility and no increased risk of infertility after IUC removal even in nulliparous (women who have never given birth to a viable infant) users (53). The copper device is associated with a decreased risk of endometrial cancer, and no increased risk, and possibly a decreased risk, of cervical cancer (54).
Disadvantages and Side Effects
The copper IUC may increase menstrual blood loss, cramping, intermenstrual spotting, and vaginal discharge. Heavy menses and dysmenorrhea (severe, frequent menstrual cramps and pain) are the most frequent reasons for copper IUC removal in the first year (1,6).

Levonorgestrel Intrauterine System (Mirena tm)


 
The U.S. Food and Drug Administration (FDA) approved the hormone-releasing levonorgestrel IUD in 2000. The levonorgestrel IUD is composed of a T-shaped polyethylene plastic frame with a collar attached to the vertical stem containing 52 mg of levonorgestrel dispersed in polydimethylsiloxane plastic. It releases 15 mcg of levonorgestrel daily into the uterus. The levonorgestrel system is approved for up to five years of use in the United States but has been shown to be effective up to seven years (55).

Mechanism of Action and Efficacy
In addition to the foreign-body reaction seen with IUCs, the progestin released by hormonal IUCs shrinks the glandula structures in the uterine lining and thickens cervical mucus so that sperm cannot penetrate it (1, 48). The levonorgestrel system also produces serum concentrations of progestin that lead to partial inhibition of ovarian egg development and ovulation, although most women have some ovulatory cycles (56). It results in the lowest serum concentrations of progestin of any hormonal contraceptive but does not decrease normal production of estrogen.  Levonorgestrel concentrations in the uterus are much higher than in the blood which means that there are few effects other than those directly on the uterus (1).
The levonorgestrel IUC (Mirena) is the most effective form of reversible contraception available (1,6, 50), followed closely by the copper TCu-380A (Paragard). With perfect use of the levonorgestrel system, the first-year probability of pregnancy is 0.1%; with typical use, the probability is 0.1–0.2% (6, 50, 57). With seven years of continuous use, the cumulative pregnancy rate is 1.1% (50). By comparison, the cumulative risk of pregnancy 10 years after tubal ligation is 1.9% (58).
 
Advantages and Noncontraceptive Benefits
Similar to the copper device, the levonorgestrel system is highly effective, discreet, coitus independent, easy to use, and cost-effective if used for longer than two years. It does not interfere with breast feeding, protects against ectopic pregnancy, and is rarely associated with side effects other than those on the uterus where it decreases menstrual blood loss, increases hemoglobin levels, and decreases menstrual pain (47, 55, 59). It is as effective as intrauterine surgery for the treatment of heavy menses (60,61, 62), and more effective than oral progestins (63). In women who sometimes fail to ovulate and in perimenopausal and postmenopausal women taking estrogen, the levonorgestrel IUC can be used to protect the uterine lining from the effects of estrogen by preventing the overgrowth that can lead to cancer of the uterus (64, 65). It is associated with a lower incidence of STD-related pelvic infections than the copper IUD and may afford some protection against tubal infections that lead to infertility (66, 67).
Disadvantages and Side Effects
Intrauterine levonorgestrel may cause irregular bleeding and spotting in the first several months of use. The main reason for its discontinuation is absence of menstrual periods (amenorrhea) that is caused by shrinkage of the uterine lining. This side effect is experienced by 30% of women after two years of use (66, 68). Complaints of menstrual problems, including amenorrhea, missing periods, and spotting decline after one year and are less common among patients older than 30 (55, 69). Hormonal side effects (including headache and skin and hair changes) are the most common reasons for wanting removal of the levonorgestrel IUC in the first 36 months of use, although removals for these complaints are rare (55).

Contraindications and Precautions
There are few absolute contraindications to the use of intrauterine levonorgestrel. Recommendations against use of progestin-only contraceptive methods apply to the levonorgestrel IUC as well.  A study of breast cancer rates among Finnish women using the levonorgestrel IUC showed no increase in risk compared to non users, suggesting that this method of hormonal contraception can be safely used in women at increased risk and those who have been treated for breast cancer.

Emergency Contraception

Postcoital contraception (used after intercourse has occurred), also called emergency contraception, is used to prevent pregnancy after unprotected intercourse. The several methods of postcoital contraception currently available include oral levonorgestrel, combined oral contraceptives (including the Yuzpe regimen), mifepristone, and insertion of a copper IUC (Table 5); oral levonorgestrel (Plan B) is by far the most commonly used. Postcoital contraception is indicated when: another method of contraception fails (such as when a condom breaks or a diaphragm dislodges); when there is lapsed use of another method, such as when a woman forgets two or more oral contraceptive pills, to replace her ring or patch, or to return for a DMPA injection; when no contraception was used; for example, when sex was forced.
Although there is no harm associated with the repeated use of postcoital contraception, its routine use is not recommended because its efficacy is lower than that of routine methods of contraception. In addition, the methods used for postcoital contraception afford no protection against STDs. Many women, however, would choose to use emergency contraception rather than to take the risk of an unintended pregnancy.
  Emergency contraception has the potential to reduce the incidence of unintended pregnancy and induced abortion (1), but it is underutilized. In 1997, only 1% of U.S. women reported ever having used emergency contraception (1). The advanced provision of emergency contraception, in the form of a prescription or a packet of pills, has been shown to increase its use, and giving the patient the pill package was most likely to result in use (70).  However, this US study and another in Scotland failed to show a decrease in unintended pregnancies associated with use of emergency contraception, perhaps because it was not used frequently enough (71, 72).   

Postcoital Oral Levonorgestrel (Plan B)

In 1999, the U.S. Food and Drug Administration approved levonorgestrel in 0.75-mg tablets for use as emergency contraception, and in 2006 approved over-the-counter availability of emergency contraception for individuals (men or women) age 18 and older. Proof of age is required (government issued photo or nonphoto identification) (73). Studies show that adolescents use emergency contraception appropriately and tolerate the drug about as well as adults (70,74).
Mechanism of Action and Efficacy
Although the exact mechanism of pregnancy prevention is unknown, levonorgestrel is believed to inhibit ovulation, prevent fertilization, or interfere with abdominal pain, headache, dizziness, breast tenderness, and heavier or lighter bleeding with subsequent menses (75). Postcoital levonorgestrel has not been shown to affect fetal development. There is a slightly increased risk of ectopic pregnancy if postcoital levonorgestrel fails (1).
Postcoital levonorgestrel (Plan B in the USA and Postinor elsewhere) can be taken up to five days after unprotected intercourse. The efficacy of levonorgestrel decreases with time from intercourse and is greatest when taken within 24 hours of unprotected intercourse. Two dosing schedules have been  studied and have similar efficacy and safety: 1) a 0.75-mg levonorgestrel tablet taken as soon as possible after exposure, followed by a second tablet 12 hours later, and 2) a single 1.5-mg dose of levonorgestrel (76-78).  Postcoital levonorgestrel reduces the risk of pregnancy from 8% to 1% for a single act of unprotected intercourse in the second or third week of the menstrual cycle, which is equivalent to an 88% reduction in risk (75).

Advantages, Disadvantages and Side Effects
There are almost no contraindications to postcoital levonorgestrel other than allergy to ingredients in the tablets, unexplained vaginal bleeding, and pregnancy, although the hormone will not harm the fetus if it is mistakenly taken when the woman is already pregnant. Side effects are fewer with levonorgestrel than with the use of postcoital estrogen plus progestin (combined oral contraceptive pills) and include nausea, vomiting and headache. For specific regimens and pill combinations, please see www.not-2-late.com.
           

Yuzpe Regimen

In 1982, A. A. Yuzpe developed a postcoital method with standard combined oral contraceptives in higher doses than those used for long-term contraception. The mechanism of action of the regimen is presumed to be similar to that of postcoital levonorgestrel. The Yuzpe regimen has a failure rate of 2–3%. It reduces the risk of pregnancy by about 75% for a single act of unprotected intercourse in the second or third week of the menstrual cycle (1). The absolute contraindications to the use of oral contraceptives, however, are also considered to be contraindications to the use of the Yuzpe regimen. The Yuzpe regimen is associated with more side effects, particularly nausea and vomiting, than is postcoital levonorgestrel. The regimen should be taken within 72 hours of unprotected intercourse but has proven efficacy through five days after exposure (78). Like levonorgestrel-only Plan B, the efficacy of the Yuzpe regimen decreases the longer its use is delayed after unprotected intercourse.
           

Postcoital Copper IUC Insertion

A copper device can be inserted up to the time of implantation, approximately five days after ovulation, for the prevention of pregnancy after unprotected intercourse. Most providers choose to provide the IUD up to five days from unprotected intercourse because it is usually difficult to determine the precise time of ovulation (81). This method should be considered for women who desire long-term contraception with IUC. The intrauterine presence of a foreign body and the copper ions are thought to prevent implantation. The levonorgestrel system (Mirena), along with other long-acting hormonal methods, has not been studied for postcoital contraception and is not recommended for this use. With a failure rate of less than 0.1%, postcoital copper IUC insertion has the highest efficacy of any emergency contraception method available (6). Side effects are similar to those associated with routine insertion and include cramping, spotting, and increased menstrual bleeding. Women who want to continue intrauterine contraception are the best candidates.
 

Table 5. Postcoital Contraception

 
Method
 Recommended
Time from
Unprotected
Intercourse
Failure
Rate per
 100 Women*
    Contraindications
None
8
Levonorgestrel
 5 days
 1
 Pregnancy
Yuzpe regimen
 5 days
 2–3
 Pregnancy, absolute
contraindications to
oral contraceptives
Mifepristone
 5 days
 <1
 Unknown
Copper IUD
 5 days
 <0.1
 Pregnancy, risk of
sexually transmitted
diseases
 
*For a single act of unprotected intercourse in the second or third week of the menstrual cycle.
 

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