Advances in hormonal contraception: over time, methods have become safer, more acceptable, easier to use, and more diverse.

Researchers have been altering formulations and delivery systems for hormonal contraceptives--used by more than 100 million women worldwide (1)--to develop new versions that are safer, more acceptable, and easier to use. New products are now entering the market, some only in the developed world but some also in developing countries.

"New methods are coming to the market, and that translates into more choices," says Dr. Miriam Zieman, a family planning expert at Emory University School of Medicine in Atlanta, Georgia, USA, who has extensively studied one of the new delivery systems. "We hope more choices will result in greater method acceptability, client satisfaction, consistent use, continuation, and ultimately fewer unplanned pregnancies."

A major change in hormonal contraception since combined oral contraceptives (COCs) were introduced in the early 1960s has been the development of low-dose hormonal formulations to decrease side effects, says Dr. Malcolm Potts, president emeritus of FHI and professor of population and family planning at the University of California at Berkeley, USA.

High-dose COCs in the 1960s and 1970s contained as much as 50 [micro]g to 150 [micro]g estrogen and 10 mg progestin, and were reported to be associated with risks of serious cardiovascular side effects, including venous thrombosis (a blood clot in a vein), heart attack, and stroke. But, notes Dr. Potts, "these risks were still less than those associated with unplanned pregnancies and much less than other daily risks we all take."

Most countries now distribute mostly low-dose pills containing 35 [micro]g or less estrogen and 400 [micro]g or less progestin (of which there are several types). According to a report by a World Health Organization committee of experts on cardiovascular disease and steroidal hormone contraception, women who use low-dose COCs and do not smoke, do not have high blood pressure, and do not have diabetes are not at increased risk of heart attack or stroke when compared with non-users. (2) Healthy users of low-dose COCs do have a three- to sixfold higher risk of venous thrombosis than healthy women who do not use COCs, but the absolute risk remains minimal. (3) Additional research has shown that certain types of progestins may slightly increase the risk of venous thrombosis and other cardiovascular complications among COC users. (4)

FURTHER REDUCING ESTROGEN

Today, pills with 20 [micro]g or less estrogen are available in several countries, including Chile, India, Malaysia, New Zealand, and the United States and Puerto Rico. Research suggests that these pills are associated with a decrease in most side effects when compared with pills with higher estrogen content. For example, in a U.S. study conducted between 1998 and 1999 among 463 women using pills with 20 [micro]g versus 35 [micro]g estrogen, the common side effects of bloating, breast tenderness, and nausea were approximately half as frequent among users of the 20 [micro]g pills. (5)

One potential disadvantage of lowering estrogen doses is loss of menstrual cycle control. Reports of menstrual disturbances vary greatly; (6) but, overall, COCs containing low doses of estrogen appear to cause more menstrual disturbances. (7) However, for all COCs, spotting and bleeding disturbances are most frequent during the first few cycles of use, after which they often decrease or disappear. (8) If a woman using COCs containing 20 [micro]g estrogen does have persistent spotting or bleeding problems, providers can consider switching to pills that contain 30 [micro]g to 35 [micro]g estrogen. (9) Research also shows that changing the type of progestin and the dosing regimen may improve cycle control. (10)

More data are needed to fully understand the impact of COCs containing 20 [micro]g estrogen, says Dr. David Grimes, vice president of biomedical affairs at FHI. Toward this aim, Maria Gallo, an FHI research associate, Dr. Kavita Nanda, an FHI associate medical director, and colleagues are writing a Cochrane Review comparing the contraceptive efficacy, discontinuation rates, bleeding patterns, and side effects associated with pills containing 20 [micro]g estrogen with those containing more than 20 [micro]g estrogen. Results of the review are expected in 2003.

IMPROVING EASE OF USE

While COC pills are a traditional way to deliver contraceptive hormones, two novel systems for providing the same hormones (estrogen and progestin) were approved by the U.S. Food and Drug Administration in 2001 and are now available in the United States. Both systems--a weekly transdermal contraceptive patch and a three-week vaginal ring--have characteristics that may make them easier for women to use correctly and consistently. This may improve compliance, a problem among many COC users. (See articles, pages 8 and 11.)

The transdermal contraceptive, called Ortho Evra and developed by U.S.-based Ortho-McNeil Pharmaceutical, Inc., is a 20-square-cm patch that can be applied to the abdomen, upper torso, upper outer arm, or buttocks, where it continuously releases low doses of estrogen and progestin through the skin and into the bloodstream. A single patch is worn for one week, discarded, and replaced with a new one. Three weeks of use are followed by a patch-free week to allow for menses (much like the pill-free interval for most COCs).

The vaginal ring, called NuvaRing and developed by U.S.-based Organon, Inc., is a flexible and transparent ring that is slightly smaller than a diaphragm and is inserted into the vagina, where it continuously releases low doses of estrogen and progestin. Each ring is worn for three weeks in a row and then discarded. After a ring-free week for menses, the client inserts a new ring.

"The nice thing about these new methods is they do not require daily attention," says Dr. Ziemen, an author of several recent studies of the Ortho Evra patch. "And, unlike implants or intrauterine devices, the transdermal contraceptive patch and the vaginal ring are user-controlled."

Researchers at FHI are completing a Cochrane Review comparing the Ortho Evra patch and NuvaRing with COCs. Randomized controlled trials from the United States, Canada, Europe, and South Africa have shown that the contraceptive efficacy, cycle control, contraindications, and side effect profiles are generally comparable between the contraceptive patch and low-dose COC pills. However, patch users are more likely to report breast discomfort and have reported the additional adverse events of application site reactions and, rarely, patch detachment. (11)

Of note, Ortho Evra patch users may have higher compliance rates than COC users. Pooled data from the United States and Canada showed that some 800 women using the patch used it perfectly during 89 percent of their cycles, while some 600 COC users used the pill perfectly only 79 percent of the time. (12) The higher compliance rate among contraceptive patch users may result from the convenience of the patch, researchers have noted. Results also suggested that the patch's ease of use was particularly important for young women, who often have the most difficulty remembering to take contraceptive pills consistently. (13)

No randomized controlled trials have been conducted to compare NuvaRing with COCs. Large nonrandomized trials suggest that the efficacy and side effects of NuvaRing are comparable to those of COCs, although NuvaRing users more frequently report vaginitis, vaginal discharge, and vaginal irritation. (14) Like Ortho Evra patch users, NuvaRing users may have higher compliance rates than COC users (92 percent versus 75 percent in one group of comparative studies). (15)

A possible advantage of NuvaRing over other low-dose hormonal methods, including the Ortho Evra patch, is its effect on cycle control. The ring contains only 15 [micro]g estrogen, but studies suggest that this low dose of estrogen is not associated with increased intermenstrual bleeding. About two-thirds of some 100 vaginal ring users, compared with fewer than half of some 100 COC users, reported expected bleeding patterns during all their cycles. (16) Such good cycle control may have been attributable to correct use of the method or, according to the authors, the fact that the ring continuously releases hormones, which prevents the daily fluctuations in hormone levels that occur during COC use.

Novel products such as the Ortho Evra patch and NuvaRing are advances that will appeal to some women. But, Dr. Potts notes, cost may prohibit such products from making a worldwide impact in the near future. (Currently, in the United States, the monthly cost of the patch or NuvaRing may be almost twice that of COCs. (17) "At a world level," he says, "what we need in vast quantities are low-dose, low-cost contraceptive pills that women know how to use consistently and correctly."

WHAT ARE COCHRANE REVIEWS?

Cochrane Reviews are evidence-based systematic reviews published in the Cochrane Library to provide the highest-quality information on specific medical topics to health care providers, clients, administrators, and funders. FHI is a contributor to the international collaborative group producing reviews dealing with fertility regulation. More information on the Cochrane Library and Cochrane Reviews can be found at http://www.update-software. com/Cochrane/default.htm.

REFERENCES

(1.) World Contraceptive Use 2001, wall chart. New York, NY: United Nations Population Division, 2002.

(2.) World Health Organization. Cardiovascular Disease and Steroid Hormone Contraception: Report of a WHO Scientific Group. WHO Technical Report Series 877. Geneva, Switzerland: World Health Organization, 1998.

(3.) World Health Organization; Hannaford PC, Owen-Smith V. Using epidemiological data to guide clinical practice: review of studies on cardiovascular disease and use of combined oral contraceptives. BMJ 1998;316(7136):984-87; Vandenbroucke JP, Rosing J, Bloemenkamp KW, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344(20): 1527-35.

(4.) Vandenbroucke; Kovacs P. The risk of cardiovascular disease with second- and third-generation oral contraceptives. Medscape Women's Health eJournal 2002;7(4). Available: http://www. medscape.com/viewarticle/439354.

(5.) Rosenberg MJ, Meyers A, Roy V. Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: a randomized trial of 20 [micro]g and 35 [micro]g estrogen preparations. Contraception 1999;60(6):321-29.

(6.) Rosenberg MJ, Long SC. Oral contraceptives and cycle control: a critical review of the literature. Adv Contracept 1992;8(Suppl 1): 35-45.

(7.) Saleh WA, Burkman RT, Zacur HA, et al. A randomized trial of three oral contraceptives; comparison of bleeding patterns by contraceptive types and steroid levels. Am J Obstet Gynecol 1993;168(6 Pt 1):1740-45; Endrikat J, Muller U, Dusterberg B. A twelve-month comparative clinical investigation of two low-dose oral contraceptives containing 20 [micro]g ethinylestradiol/75 [micro]g gestodene and 30 [micro]g ethinylestradiol/ 75 [micro]g gestodene, with respect to efficacy, cycle control, and tolerance. Contraception 1997;55(3):131-37; Akerlund M, Rode A, Westergard J. Comparative profiles of reliability, cycle control, and side effects of two oral contraceptive formulations containing 150 micrograms desogestrel and either 30 micrograms or 20 micrograms ethinyl estradiol. Br J Obstet Gynaecol 1993;100(9):832-38.

(8.) Endrikat; Rosenberg, Long.

(9.) Endrikat.

(10.) Rosenberg, Long; van Vliet HA, Grimes DA, Helmerhorst FM, et al. Biphasic versus triphasic oral contraceptives for contraception. Contraception 2002;65(5):321-24.

(11.) Audet MC, Moreau M, Koltun WD, et al. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. JAMA 2001;285(18):2347-54; Dittrich R, Parker L, Rosen JB, et al. Transdermal contraception: evaluation of three transdermal norelgestromin/ethinyl estradiol doses in a randomized, multicenter, dose-response study. Am J 0bstet Gynecol 2002; 186(1): 15-20; Hedon B, Helmerhorst FM, Cronje HS, et al. Comparison of efficacy, cycle control, compliance and safety in users of a contraceptive patch vs an oral contraceptive. Int J Gynaecol Obstet 2000;70 (Suppl 1):78.

(12.) Archer DF, Bigriff A, Smallwood GH. Assessment of compliance with a weekly contraceptive patch (Ortho Evra/Evra) among North American women. Fertil Steril 2002;77(2 Suppl 2): 27-31.

(13.) Rosenberg MJ, Waugh MS, Long S. Unintended pregnancies and use, misuse, and discontinuation of oral contraceptives. J Reprod Med 1995;40(5):355-60; Potter LS. Oral contraceptive compliance and its role in the effectiveness of the method. In Cramer JA, Spilker B, eds. Patient Compliance in Medical Practice and Clinical Trials. New York, NY: Raven Press, 1991.

(14.) Dieben TO, Roumen JME, Apter D. Efficacy, cycle control, and user acceptability of a novel combined contraceptive vaginal ring. Obstet Gynecol 2002;100(3):585-93; Roumen FJ, Apter D, Mulders TM, et al. Efficacy, tolerability, and acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl estradiol. Hum Reprod 2001;16(3):469-75.

(15.) Dieben.

(16.) Bjarnadotfir RI, Tuppurainen M, Killick SR. Comparison of cycle control with a combined contraceptive vaginal ring and oral levonorgestrel/ethinyl estradiol. Am J Obstet Grynecol 2002;186(3):389-95.

(17.) Planned Parenthood Federation of America, Inc. Birth Control: Your Contraceptive Choices. Available: http://www.plannedparenthood. org/bc/cchoices4.html.