Researchers explore extended contraception

Extending the traditional 21/7 regimen of several forms of hormonal contraception has captured the attention of research scientists, and results of their investigations may lead to new approved uses of birth control drugs.

For some women, the unpleasant side effects of hormone withdrawal and the withdrawal bleed that accompanies it are inconvenient or problematic. For these women, administration of continuous hormone therapy for longer periods (42 to 96 days) may permit a much improved quality of life and relief from side effects associated with the shorter regimen.1

Since the recent approvals of the NuvaRing contraceptive vaginal ring (Organon, West Orange, NJ) and the Evra transdermal contraceptive (Ortho McNeil Pharmaceuticals, Raritan, NJ), both companies are pursuing studies to determine if the methods can be used beyond their Food and Drug Administration-approved regimens.

"The reason that we are interested in extended use or continuous use is because since NuvaRing provides a very low dose, steady state release of hormones without the usual ups and downs, the peaks and valleys, that you would get from oral contraceptives," says Nancy Alexander, PhD, director of medical affairs for contraception at Organon.

Organon is sponsoring a multicenter study of the ring, which includes 10 research sites. According to one of the investigators, Larry Seidman, DO, MBA, of Philadelphia Women’s Research, the company’s protocol calls for women to be assigned to one of four use categories, allowing Organon to test extended and continuous use of the method. The trial is about midpoint, he estimates. While results are not final, patient acceptability appears high, he notes.

Investigators affiliated with Ortho-McNeil Pharmaceuticals also are conducting research on extended use regimens of the Evra transdermal contraceptive. However, the company is declining to comment on its work at this point, says Mona Terrell, company spokeswoman.

Revamp the OC regimen

Despite many modifications in dose and formulation, the standard oral contraceptive (OC) regimen has changed little in the Pill’s 43-year history.2 While women may consider the withdrawal bleed experienced during the oral contraceptive’s pill-free interval as "natural," it is medically induced and has no proven physiologic or health benefits.3

Researchers now are looking at revamping the conventional OC regimen. In one study, designed to measure acceptance and use of shortening the hormone-free pill interval to reduce the frequency and severity of hormone withdrawal symptoms, the majority of women chose to stay on an extended regimen to relieve associated symptoms.4 Of 267 patients who initiated such a regimen, 57 discontinued OCs, 38 returned to a standard regimen, and 172 were extending use at the last follow-up. Forty-six percent of the women continued extended use for at least five years. All women in the study used a monophasic 30-35 mcg pill.4

In another study, which looked at use of a combined 20 mcg ethinyl estradiol/100 mcg levonorgestrel pill taken with and without a hormone-free interval, findings indicate that continuous use of the drug is associated with less bleeding requiring protection, and more amenorrhea than standard administration.5 Although both groups of women reported a high level of satisfaction with bleeding patterns and side effect profiles, women in the continuous group reported significantly fewer days of bloating and menstrual pain.5

A just-published paper that compares bleeding profiles of a traditional 28-day oral contraceptive pill cycle with continuous administration suggests that extending the pill regimen resulted in significantly fewer bleeding days.6 Amenorrhea or infrequent bleeding was present in 68% of continuous users during cycles 1-3 and increased to 88% during cycles 10-12. Spotting during cycle days 1-21 increased initially with continuous use but reduced over time, and by nine months was less than the spotting reported by cyclic users, investigators found. The study used a 20-mcg ethinyl estradiol/100 mcg levonorgestrel pill.

More research needed

Although it has been 25 years since the first research was published on extending the 21/7 OC regimen, relatively little research has been done to examine the effectiveness, safety, and acceptability of extended regimens. More investigation is needed to determine if extended therapy influences any of the noncontraceptive health benefits of OC therapy, including prevention of osteoporosis and protection from ovarian and endometrial cancers.1

According to Leslie Miller, MD, assistant professor of obstetrics and gynecology at the University of Washington and family planning medical director at Public Health-Seattle and King County, both in Seattle, focus also should be given to a head-to-head comparison of extended and continuous pill regimens.

Miller, who now centers her research on continuous use of low-dose oral contraceptives, also would like to see some form of registry to track the effects of the Pill in long-term use on such areas as bones, breasts, and fertility.

"If you do continuous, will there be protection against breast cancer?" Miller hypothesizes. "It is possible that using these really low doses and having it be continuous so you don’t cycle at all, is that more protective for the breast?"

References

1. Lynch C. Oral contraceptives: Extension of the 28-day regimen. Caring with Confidence: The Influence in Women’s Lives. Accessed at: www.endo-society.org/education/online_cme.cfm.

2. Suppression of menstruation with extended OC regimens. Contraception Report 2002; accessed at: www.contraceptiononline.org/contrareport/article01.cfm?art=223.

3. Schwartz JL, Creinin MD, Pymar HC. The trimonthly combination oral contraceptive regimen: Is it cost-effective? Contraception 1999; 60:263-277.

4. Sulak PJ, Kuehl TJ, Ortiz M, et al. Acceptance of altering the standard 21-day/7-day oral contraceptive regimen to delay menses and reduce hormone withdrawal symptoms. Am J Obstet Gynecol 2002; 186:1,142-1,149.

5. Kwiecien M, Edelman A, Nichols MD, et al. Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low-dose oral contraceptive: A randomized trial. Contraception 2003; 67:9-13.

6. Miller L, Hughes JP. Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: A randomized trial. Obstet Gynecol 2003; 101:653-661.