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Letter From the Editor

Endometrial cancer is the fourth most common cancer among women in the United States.

Health Benefits of Oral Contraceptives: Update on Endometrial Cancer Protection

Oral contraceptives (OCs) provide women with many well-documented health benefits, including protection against both ovarian and endometrial cancers. The most well-known data concerning endometrial cancer come from studies of high estrogen dose pills (≥50 µg ethinyl estradiol [EE] or ≥80 µg mestranol [ME]), which also contained relatively high doses of progestin. How lowering the dose of both estrogen and progestin has impacted this health benefit has not been elucidated. Recent data, however, suggest modern low-dose OCs also provide protection against endometrial cancer.

Combined Contraceptive Vaginal Ring Awaiting US Approval

The US Food and Drug Administration is considering approval of a combined contraceptive vaginal ring. The device releases etonogestrel 120 µg and ethinyl estradiol 15 µg daily.

Once-a-Month Injectable Contraception

In the fall of 2000, the US Food and Drug Administration (FDA) approved a new monthly birth control injection. This birth control shot contains two female hormones: estrogen and progestin.

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FDA Approves Combined Monthly Injectable Contraceptive

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Last fall, the FDA approved a once-a-month combined injectable contraceptive. The product contains medroxyprogesterone acetate (MPA) 25 mg plus estradiol cypionate (E2C) 5 mg.


Last fall, the FDA approved a once-a-month combined injectable contraceptive. The product contains medroxyprogesterone acetate (MPA) 25 mg plus estradiol cypionate (E2C) 5 mg. MPA/E2C is highly effective; its first-year failure rate is below 0.2%. The most prominent side effects are menstrual irregularities during the first 3 to 6 months of use. In US trials, weight gain was the most common side effect leading to discontinuation.


On October 5, 2000, the FDA approved the first combined estrogen- progestin injectable contraceptive to become available in this country.1 Marketed as Lunelle™ Monthly Contraceptive Injection* in the US, the product has been available in many countries for more than 2 decades. To date, more than 17,000 women worldwide have participated in controlled trials of the method.2

The new monthly injectable contains medroxyprogesterone acetate 25 mg and estradiol cypionate 5 mg in a 0.5 ml aqueous suspension. The progestin is the same one used in the progestin-only injectable depot medroxyprogesterone acetate (DMPA). MPA/E2C is administered by intramuscular injection into the deltoid, gluteus maximus, or anterior thigh. Because the route of administration bypasses hepatic first-pass metabolism, oral medications (other than aminoglutethimide) will not impair efficacy.

The first injection is administered within 5 days of either the onset of a normal menstrual period or a first-trimester abortion. These administration guidelines help ensure the contraceptive is not administered to a patient who is pregnant. For women who have recently given birth, approved guidelines stipulate that the first injection be administered no earlier than 4 weeks postpartum if not breastfeeding or 6 weeks postpartum if breastfeeding.

Ideal administration is once every 28 to 30 days, although efficacy has been demonstrated within a 10-day reinjection window (23 to 33 days following the previous injection).3 If a patient presents for a follow-up injection more than 33 days after the previous injection, pregnancy should be ruled out before the drug is readministered.


MPA/E2C is highly effective. First-year failure rates in international clinical trials have ranged from 0% to 0.2%.2 Large multicenter studies by the World Health Organization have confirmed the method's efficacy in routine use: among 12,000 women in nine countries comprising more than 100,000 woman-months of experience, a total of five pregnancies were reported (<0.1%).4,5 In a recent US trial, no pregnancies were reported among 782 women using the method for 8,920 woman-months.3

When administered monthly, MPA/E2C inhibits the secretion of gonadotropins, preventing follicular maturation and ovulation. Although ovulation inhibition is the primary mechanism of action, other possible mechanisms include thickening and a reduction in volume of cervical mucus and thinning of the endometrium. Mean serum concentrations of MPA peak during the first week after administration and remain above the level needed to suppress ovulation for approximately 45 days.6 Estradiol cypionate serum concentrations peak about 2 days after injection and decline substantially around day 14.

Return of Ovulation

The contraceptive effects reverse relatively rapidly following discontinuation. MPA is cleared from the body within 60 to 90 days, and ovulation has been observed as early as 63 days after the final injection.7 Injection site and body weight affect MPA pharmacokinetics and may have an impact on ovulation return. Return of ovulation may be delayed in lighter women (body mass index <28) receiving injections in the arm.8

Cumulative conception rates following discontinuation are similar to those observed with oral contraceptives (Figure 1).9 Fertility returns considerably faster than with the 3-month, progestin-only injectable DMPA. Five months after the last injection, nearly twice as many MPA/E2C users are able to conceive compared with DMPA users. At 12 months, 82% of former MPA/E2C users who desire pregnancy have achieved conception&mdashsimilar to 12-month pregnancy rates among former users of other methods and those who have never used a contraceptive.2

Side Effects

Data from international trials indicate this combined injectable is well tolerated. No serious adverse events or laboratory abnormalities have been attributed to the method. Hematologic tests show no significant changes in median hemoglobin.

The effect of MPA/E2C use on bone mineral density has not been formally studied. Small, cross-sectional studies of bone density loss among DMPA users have yielded conflicting results, with some suggesting a decrease in spinal bone density among subgroups of long-term users. The 3-month MPA dose in the combined injectable is one-half that in DMPA (75 mg vs 150 mg, respectively), however, and estrogen levels remain physiologic with MPA/E2C.

The most commonly reported side effects are menstrual disturbances, including irregular, frequent, and/or prolonged bleeding.2,3 Irregular bleeding may be more frequent during the first year among MPA/E2C users compared with OC users. Bleeding pattern disturbances occur less frequently after the first 3 months of use and continue to decrease over time (Figure 2). Indeed, long-term use tends to produce regular, predictable monthly cycles, similar to the cycle control observed with oral contraceptives.10

Combined injectable users are less likely to experience bleeding pattern changes than users of progestin-only injectables (Figure 3).2 During the first 90 days of use, fewer than 1% of MPA/E2C users report infrequent bleeding or absence of bleeding compared with 11% to 16% of DMPA users. Users of the monthly combination injectable also are half as likely to report prolonged bleeding, a common cause of DMPA discontinuation. Overall, 57% of MPA/E2C users report variations in bleeding patterns during the first 90 days of use, compared with 91% of DMPA users. By the end of the first year, only 30% of MPA/E2C users show bleeding variations, while the corresponding proportion of DMPA users remains virtually unchanged (92%). Absence of bleeding occurs in about 2% of combination injectable users after 1 year of use.2

Discontinuation and Satisfaction

Other side effects include weight change, breast tenderness, emotional lability, acne, and nausea. In most cases, these side effects were less likely to be reported over time and were not major causes of treatment discontinuation. In a US trial, the 12-month method-related discontinuation rate for MPA/E2C was under 30%, comparable to the 32% rate observed with oral contraceptives and substantially lower than the 44% who stop using progestin-only injectables during the first year of use.11

Hormone-related side effects were the most common cause of method-related discontinuation (Figure 4). Excessive bleeding was cited by about 3% of those stopping the method; breast pain, by 2%; menorrhagia, by 2%; and dysmenorrhea, by 1%.3 Discontinuation rates associated with hormone-related side effects were similar in US and international trials.2,3 Patient counseling regarding potential menstrual changes and management of bleeding irregularities may help reduce the number of discontinuations related to these events.

In US trials, weight gain was the most common individual reason for discontinuation. Nearly 6% of women stopped using the method because of weight gain.3 Weight change during 12 months of use varied widely—from 48 pounds lost to 49 pounds gained. Mean body weight change was a gain of 4 pounds after 13 injections and 5 pounds after 15 injections, comparable to the average annual weight gain of 4 to 5 pounds in DMPA users. An increasing percentage of users experienced weight change in excess of 10 and 20 pounds with continued treatment.3

Discontinuation due to weight gain appears to be unique to US users of the monthly combination injectable. The phenomenon was not observed in international trials, where mean weight change after 12 months was <2 pounds.2 Importantly, the US trial included a substantial proportion of obese women.3 Many international trials were performed in developing countries where nutritional levels and perceptions of ideal body image differ substantially from those in the US. Patient counseling regarding possible weight gain and the importance of proper nutrition and exercise may help reduce the rate of discontinuation associated with this side effect.

Despite lingering issues related to weight change, most US users of MPA/E2C were satisfied with the method. Most women (84%) reported having a somewhat or very favorable overall impression of the method and would recommend the monthly combination injection to others.12

Future Issues

The cost of a 1-month dose is comparable to the retail price of a pack of oral contraceptives (about $30 per month). Relative cost and convenience may improve as new programs are developed to facilitate administration. Options under consideration would allow injections to be administered by nonclinicians, such as pharmacists. A self-administration system is currently under development.


Take Home Messages

  • MPA/E2C is highly effective (first-year failure rate <0.2%)
  • The suspension contains medroxyprogesterone acetate 25 mg and estradiol cypionate 5 mg
  • Intramuscular administration (deltoid, gluteus maximus, or anterior thigh) is ideally given every 28 to 30 days
  • Bleeding irregularities diminish over time; monthly cycles become regular
  • Weight gain was the leading cause of method-related discontinuation in US trials
  • Fertility returns rapidly after method is stopped

*Brand names are used for identification purposes only and do not imply endorsement.

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1National Women's Health Information Center Web site. FDA approves once-a-month birth control injection. Available at: Accessed March 23, 2001.
2Hall PE. New once-a-month injectable contraceptives, with particular reference to Cyclofem/Cyclo-Provera. Int J Gynaecol Obstet 1998;62:S43-S56.
3Kaunitz AM, Garceau RJ, Cromie MA. Comparative safety, efficacy, and cycle control of Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension) and Ortho-Novum 7/7/7 oral contraceptive (norethindrone/ethinyl estradiol triphasic). Contraception 1999;60:179-187.
4Hall PE. The introduction of Cyclofem into national family planning programmes: experience from studies in Indonesia, Jamaica, Mexico, Thailand and Tunisia. Contraception 1994;49:489-507.
5Hall PE, Bahamondes L, Diaz J, et al. Introductory study of the once-a-month, injectable contraceptive Cyclofem in Brazil, Chile, Colombia, and Peru. Contraception 1997;56:353-359.
6Rahimy MH, Ryan KK, Hopkins NK. Lunelle monthly contraceptive injection (medroxy-progesterone acetate and estradiol cypionate injectable suspension): steady-state pharmacokinetics of MPA and E2 in surgically sterile women. Contraception 1999;60:209-214.
7Rahimy MH, Ryan KK. Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): assessment of return of ovulation after three monthly injections in surgically sterile women. Contraception 1999;60:189-200.
8Rahimy MH, Cromie MA, Hopkins NK, et al. Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): effects of body weight and injection sites on pharmacokinetics. Contraception 1999;60:201-208.
9Kaunitz AM. Injectable contraception. New and existing options. Obstet Gynecol Clin North Am 2000;27:741-780.
10Garceau RJ, Wajszczuk CJ, Kaunitz AM. Bleeding patterns of women using Lunelle monthly contraceptive injections (medroxy- progesterone acetate and estradiol cypionate injectable suspension) compared with those of women using Ortho-Novum 7/7/7 (nore-thindrone/ethinyl estradiol triphasic) or other oral contraceptives. Contraception 2000;62:289-295.
11Trussell J, Vaughan B. Contraceptive failure, method-related discontinuation and resumption of use: results from the 1995 National Survey of Family Growth. Fam Plann Perspect 1999;31:64-72,93.
12Shulman LP, Oleen-Burkey M, Willke RJ. Patient acceptability and satisfaction with Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension). Contraception 1999;60:215-222.



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