Oral, intravaginal, and transdermal estrogen-progestin combinations are used for prevention of conception in women who elect to use one of these preparations as a method of contraception. When taken according to the prescribed regimen, these contraceptives provide almost completely effective contraception.
The pregnancy rate in women using conventional-dosage oral contraceptives (containing 35 mcg or more of ethinyl estradiol or 50 mcg or more of mestranol) is generally reported as less than one pregnancy per 100 woman-years of use. Slightly higher rates (somewhat more than one pregnancy per 100 woman-years) reportedly occur with some oral preparations containing 35 mcg or less of ethinyl estradiol, and rates of about 3 pregnancies per 100 woman-years reportedly occur with oral contraceptives containing progestins only. The pregnancy rate in women using the vaginal contraceptive ring containing ethinyl estradiol and etonogestrel (NuvaRing) is reported as 1-2 pregnancies per 100 women-years of use. The pregnancy rate in women using the transdermal contraceptive system containing ethinyl estradiol and norelgestromin (Ortho Evra) is reported as approximately one pregnancy per 100 women-years of use. Five out of the 15 pregnancies reported in large clinical trials in women using the transdermal contraceptive system Ortho Evra occurred in women with a baseline weight of 90 kg or more; these data suggest that Ortho Evra may be less effective in such women than in those with a lower body weight. Pregnancy rates for other methods of contraception reportedly range from about less than 1-6 pregnancies per 100 woman-years for intrauterine devices (IUDs) to about 14-47 pregnancies per 100 woman-years for the calendar method of periodic abstinence (rhythm). The pregnancy rate when no method of contraception is used is about 60-80 pregnancies per 100 woman-years. Pregnancy rates are derived from various studies conducted by different investigators in different population groups and, therefore, cannot be compared precisely.
Because a positive association between the dose of estrogens in oral contraceptives and the risk of thromboembolism has been shown in at least 2 studies, it is prudent and therapeutically desirable to minimize exposure to estrogens; therefore, the oral contraceptive used in a given patient should be that preparation which contains the least amount of estrogen and is compatible with an acceptable pregnancy rate and patient acceptance. Following a recommendation by the US Food and Drug Administration's (FDA) Fertility and Maternal Health Drugs Advisory Committee, oral contraceptive preparations containing more than 50 mcg of estrogen were discontinued in 1988 since these formulations were considered no more effective than those containing lower dosages of estrogen.
Because the pharmacokinetic profile for the transdermal contraceptive system containing ethinyl estradiol and norelgestromin (Ortho Evra) differs from the profile for oral contraceptive preparations
(see Pharmacokinetics: Absorption), the clinician and patient must weigh the possible risks of higher estrogen exposure with Ortho Evra against the possibility of pregnancy if the oral contraceptive is not taken according to the prescribed regimen. Increased exposure to estrogen may increase the risk of certain adverse effects (e.g., venous thromboembolism). (See Thromboembolic Disorders in Cautions: Cardiovascular Effects.)
The clinician and patient must weigh the possible risks of estrogen-progestin contraception against those of other methods of contraception or no contraception. In addition, potential noncontraceptive benefits associated with use of oral contraceptives can be considered.
(See Pharmacology: Other Effects.)
For information on parenteral use of fixed combinations of medroxyprogesterone acetate and estradiol cypionate (e.g., Lunelle),
A short-course, high-dose regimen of an oral estrogen-progestin combination is used in women for the prevention of conception after unprotected intercourse (postcoital contraception, morning-after pills) as an emergency contraceptive (EC). If taken soon enough after intercourse (i.e., within 72-120 hours), the combination regimen can prevent not terminate pregnancy; therefore, the regimen is contraceptive not abortifacient.
Several regimens employing high-dose combinations of ethinyl estradiol and norgestrel or levonorgestrel have been used safely and effectively for postcoital contraception. One widely studied and used regimen (the Yuzpe regimen) consists of administering 2 tablets containing 50 mcg of ethinyl estradiol and 0.5 mg of norgestrel each (i.e., a dose of 100 mcg and 1 mg, respectively) within 72 hours after unprotected intercourse, repeating this dose 12 hours later. Alternative combination regimens consisting of 100-120 mcg of ethinyl estradiol and 1.2 mg of norgestrel or 0.5-0.6 mg of levonorgestrel administered within 72 hours of intercourse and repeated 12 hours later also have been used. Raw pregnancy (failure) rates in trials employing such regimens have ranged from 0.2-7.4%. However, not all women given emergency postcoital contraception are at genuine risk for pregnancy, since unprotected intercourse that occurs in the early follicular or in the luteal phase is unlikely to result in conception. Therefore, a more accurate indication of efficacy would be based on the timing of unprotected intercourse and the probability that pregnancy would occur without treatment. When efficacy of postcoital contraception with such estrogen-progestin combination regimens is based on the likelihood of pregnancy (computed by matching the cycle day of unprotected intercourse with known conception rates for that cycle day), estimates from various studies of the proportionate reduction in pregnancy risk have ranged from about 55-94%, and pooled analysis of data from studies employing the Yuzpe regimen reveal that such therapy is approximately 74% (confidence interval: 68.2-79.3%) effective in preventing a single pregnancy. Because of study limitations of this pooled analysis, it is likely that true efficacy rates are higher than this estimate, perhaps exceeding 80%. However, postcoital (emergency) contraceptive regimens are not as effective as most other forms of long-term contraception. The efficacy of postcoital regimens employing lower estrogen/progestin doses currently is not known.
An emergency contraceptive regimen employing a progestin alone (levonorgestrel) appears to be more effective and better tolerated than the estrogen-progestin emergency contraceptive (''Yuzpe'') regimen when the regimens are initiated within 72 hours of unprotected intercourse, and therefore, the progestin-alone regimen generally is preferred when readily available.
To prevent pregnancy, oral estrogen-progestin combination therapy ideally should begin within 72 hours following coitus. Studies show that emergency contraception is moderately effective when the first dose is administered up to 120 hours after unprotected intercourse. Postcoital contraceptive efficacy diminishes as the time period between intercourse and administration of the combination increases, with the regimen becoming completely ineffective by day 6 or 7, when implantation usually occurs.
Because of the short time frame for effective postcoital use, women should be informed of the availability of postcoital contraception before such use is warranted and offered advanced provision (e.g., provided a prescription for emergency contraception at the time of a routine gynecology visit), advised of the availability of an over-the-counter (OTC) emergency contraceptive preparation, or advised to contact a clinician immediately if the need arises. By informing women of this emergency option and advising them of steps to take to readily obtain the combinations before or when needed, effective postcoital contraception ultimately could reduce substantially the number of unintended pregnancies and induced abortions. Because of the high incidence of adverse effects (e.g., nausea and vomiting with estrogen-progestin combinations) decreased contraceptive efficacy compared with conventional long-term contraceptive methods, including cyclic use of estrogen-progestin combinations, postcoital contraception with the combinations generally should be limited to emergency situations following unprotected intercourse (e.g., rape, contraceptive failure, missed doses of oral or parenteral contraceptives, lack of planning). Postcoital contraceptive regimens should not be used as a routine method of contraception. Women should be informed that postcoital contraceptives do not protect against human immunodeficiency virus (HIV) infection or other sexually transmitted diseases. Women should be advised about various available routine methods of contraception when given emergency contraception and instructed as to when to begin an effective method of such contraception; the potential value of condoms as a supplement to other methods (e.g., to reduce the risk of sexually transmitted diseases) also should be discussed. Women who request emergency contraceptives repeatedly should be informed about other contraceptive options.
The American College of Obstetricians and Gynecologists (ACOG), other experts, and some states (e.g., Alaska, California, Hawaii, Maine, New Mexico, Washington) have advocated increased access to emergency postcoital contraception (e.g., nonprescription access via pharmacies, advance provision by clinicians) as a means of decreasing unintended pregnancy and abortion rates. There is some evidence that increased access to emergency postcoital contraception may not compromise conventional contraceptive use or sexual behavior, potentially allaying some concerns that have prompted others to advocate for restricted access. The US Food and Drug Administration (FDA) has approved one postcoital contraceptive (Plan B One-Step; levonorgestrel) for nonprescription (OTC) status for women 17 years of age or older; the contraceptive will remain a prescription-only preparation for women younger than 17 years of age.
Use of high-dose oral estrogen-progestin combinations as emergency postcoital contraception may cause menstrual cycle disruption; if menstruation is delayed by a week or more, a sensitive pregnancy test should be performed. If pregnancy has already occurred, there is little, if any, evidence that postcoital regimens will adversely affect the fetus or pregnancy.
(See Cautions: Pregnancy, Fertility, and Lactation.)Because postcoital regimens may not prevent ectopic (tubal or abdominal) pregnancies, women receiving such regimens should be informed that ectopic pregnancy is a medical emergency and to consult their clinician immediately if spotting or cramping occurs (usually beginning shortly after the first missed period with such pregnancy). Women should consult their clinician regarding when they can start or resume cyclic oral contraceptive regimens with a combination; they also should be instructed carefully regarding differences in administration schedule and any differences in formulation (e.g., potency, active versus inert tablets) of the preparations.
For the use of progestin-only therapy as a postcoital contraceptive, .
Contraception and Folate Supplementation
Certain estrogen-progestin combinations (Beyaz [ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg], Safyral[ethinyl estradiol 30 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg]) are used in women choosing oral contraceptives as their method of contraception, for the additional purpose of increasing folate concentrations to reduce the risk of fetal neural tube defects when conception occurs while the woman is receiving the contraceptive or shortly after the contraceptive is discontinued. The US Preventive Services Task Force recommends that women of childbearing age receive supplemental folic acid at a dosage of at least 0.4 mg daily. Other folate supplementation that a woman may be taking should be considered before prescribing ethinyl estradiol in combination with drospirenone and levomefolate calcium (Beyaz, Safyral). Folate supplementation should be maintained if a woman discontinues this contraceptive because of pregnancy.
Certain triphasic or estrophasic oral estrogen-progestin combinations (specifically, Ortho Tri-Cyclen [ethinyl estradiol 35 mcg in fixed combination with norgestimate 0.18, 0.215, or 0.25 mg], or Estrostep [ethinyl estradiol 20, 30, or 35 mcg in fixed combination with norethindrone acetate 1 mg]) can be used for the treatment of moderate acne vulgaris in females 15 years of age or older who have no known contraindications to oral contraceptive therapy, desire contraception, have achieved menarche, and are unresponsive to topical anti-acne medication. The manufacturer of Estrostep states that the drug should be used for the treatment of acne vulgaris only in women who desire oral contraception and plan to take the drug for at least 6 months. Acne is a skin condition with a multifactorial etiology and the combination of ethinyl estradiol and norgestimate may increase sex hormone-binding globulin (SHBG) and decrease free testosterone serum concentrations. This may result in a decrease in the severity of facial acne in otherwise healthy women. In two double-blind, placebo-controlled, 6-month multicenter trials, therapy with the ethinyl estradiol/norgestimate combination resulted in clinically important decreases in inflammatory lesion count and total lesion count as compared with placebo (56.6% versus 36.6% and 49.6% versus 30.3%, respectively). In two 6-month, randomized, double-blind, placebo-controlled, multicenter studies in young women (mean age: 24 years) with acne vulgaris, therapy with the ethinyl estradiol/norethindrone combination or placebo resulted in a 52 or 41% reduction in inflammatory lesion count, respectively, and a 43 or 32% reduction in total lesion count, respectively.
The estrogen-progestin combinations (specifically, Yaz [ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg], Beyaz [ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg]) also are used for the treatment of moderate acne vulgaris in females at least 14 years of age who have no known contraindications to oral contraceptive therapy and who desire oral contraception and have achieved menarche.
Premenstrual Dysphoric Disorder
The estrogen-progestin combinations (Yaz [ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg], Beyaz [ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg]) are used for the treatment of premenstrual dysphoric disorder (formerly known as late luteal phase dysphoric disorder) in women who desire oral contraception. Efficacy of ethinyl estradiol in combination with drospirenone (Yaz) has been evaluated in 2 randomized, placebo-controlled, double-blind studies of 3 months' duration in adult women who met DSM-IV criteria for premenstrual dysphoric disorder. In these studies, ethinyl estradiol in combination with drospirenone was found to be superior to placebo in improving symptoms associated with this disorder. Efficacy of ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg (Yaz) or ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Beyaz) when used for more than 3 menstrual cycles has not been evaluated.
Estrogen-progestin preparations have been used for the treatment of endometriosis or dysfunctional uterine bleeding.