The 21/7 Combined OCP: Is It Time to Abandon This Formulation?
By Rebecca H. Allen, MD, MPH
Assistant Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports no financial relationships relevant to this field of study.
The original combined oral contraceptive (coc) pill approved by the FDA in 1957 contained as much as 10 mg of norethynodrel and 150 mcg of mestranol. Although the doses of progestin and estrogen in the pill have decreased in the past 50 years, it is only recently that the original formulation of 21 active pills and 7 hormone-free days has been challenged. This original formulation was designed to allow women to have a withdrawal bleed every month, similar to menstruation. The pill inventors felt this would allow combined oral contraception to seem more "natural" and also reassure women that they were not pregnant in an era when home urine pregnancy tests were unavailable. However, this was an arbitrary decision, as the original regimen designed by John Rock was a daily dose of active hormone for 3-4 months continuously.
While gynecologists had always used COCs continuously to treat endometriosis and other disorders, marketing COCs this way for contraception did not occur until the 2000s. Seasonale, a pill with 84 active pills and 7 placebo pills, was approved by the FDA in 2003 and reduced the number of withdrawal bleeds from 13 to 4.1 The release of Seasonale and publication of the book, Is Menstruation Obsolete? by Dr. Coutinho, launched a debate regarding the necessity of monthly menstruation, whether it was from natural ovulation or artificially induced from COCs. Of note, scientists report that the average number of menstrual periods modern women have in their lifetime is 450 compared to 160 among women in hunter-gatherer times, mainly due to earlier menarche, lower parity, shorter periods of breastfeeding, and later menopause.2 In addition, international surveys showed that many women desired to reduce the number of monthly withdrawal bleeds they experienced whether for personal or occupational reasons. One survey of 1470 U.S. women revealed that 59% would be interested in not having a period every month, and one-third would choose to never have a period.3 Therefore, the idea of not having a monthly withdrawal bleed was becoming more acceptable to U.S. women. Since that time, multiple formulations of extended COCs have been introduced into the U.S. market including Lybrel (levonorgestrel [LNG] 90 mcg/ethinyl estradiol [EE] 20 mcg), a 365-day pill.
Another new formulation change is the 24/4 COC formulation or 24 active pills followed by a 4-day hormone-free interval rather than 21/7. In 2006, the first 24/4 COC, LoEstrin 24 Fe, was released onto the market in the United States. Several other products, such as Yaz, Lo Loestrin 24, and Generess Fe, have followed suit. This formulation was created to decrease the common problem of breakthrough bleeding with lower-dose estrogen pills (≤ 20 mcg), and, as discussed below, to reduce hormone withdrawal symptoms in the hormone-free interval (HFI) and potentially increase efficacy.4
The benefits of shortening or eliminating the HFI when using COCs may be twofold. One, there is evidence that some women experience hormone withdrawal symptoms during the placebo week of the pill. Sulak and her colleagues measured hormone-related symptoms in 262 women using cyclic COCs and found that current users had patterns of symptoms that were more frequent during HFIs than during the three active-pill weeks.5 These included pelvic pain (70% vs 21%; P < 0.001), headaches (70% vs 53%; P < 0.001), use of pain medication (69% vs 43%; P < 0.001), bloating or swelling (58% vs 19%; P < 0.001), and breast tenderness (38% vs 16%; P < 0.001). The group then published a small study in 50 women showing that extending the number of active pills could alleviate these symptoms.6 This has since been confirmed by a Cochrane meta-analysis comparing cyclic to extended COCs. This same review also showed a lower incidence of headaches, bloating, and menstrual pain in the continuous group.7
Shorter hormone-free intervals (4 days) and continuous COC use have also been shown to have superior ovarian suppression compared to 7 days. Several trials have documented that FSH, LH, estradiol, and inhibin-B levels increase during the 7-day HFI to a greater extent than the 4-day HFI. If ethinyl estradiol is added to the 7-day HFI, similar results were found.8-10 This residual ovarian activity with a 7-day HFI may lead to ovarian follicular development and escape ovulation. Given that typical use failure rates with COCs approaches 9% in the first year of use and COCs are still the most popular method of contraception in the United States, any intervention that could potentially make COCs more forgiving of user error and therefore more effective would be welcome.
While it has been shown that 24/4 formulations have greater ovarian suppression than 21/7 formulations, it is only recently that this had been linked to actual greater clinical efficacy in preventing unintended pregnancies. Dinger and colleagues evaluated effectiveness data from the International Active Surveillance of Women Taking Oral Contraceptives study, a large prospective cohort study of 52,218 U.S. women using both 24-day and 21-day regimens.11 The authors found that 24-day regimens had lower rates of contraceptive failure compared to 21-day regimens even controlling for age, body mass index (BMI), education level, parity, and smoking status. While this has not been confirmed in a head-to-head trial, the data are strong and very suggestive that 24-day regimens are superior to 21-day regimens in terms of effectiveness. This may be even more pronounced in women with morbid obesity (BMI ≥ 35 kg/m2).11 Pharmacokinetic studies suggest that obese women take longer to reach a therapeutic steady state on COCs, and therefore 24/4 or continuous regimens may be preferable for these women.12 Now that two 24/4 (20 mcg EE/1000 mcg NET and 20/3 mg drospirenone) and the 84/7 30 EE/150 LNG formulations are available as generics, they will likely be more accessible to U.S. women.
- Kaunitz AM. Menstruation: Choosing whether and when. Contraception 2000;62:277-284.
- Eaton SB, et al. Women's reproductive cancers in evolutionary context. Q Rev Biol 1994;69:353-367.
- Andrist LC, et al. Women's and providers' attitudes toward menstrual suppression with extended use of oral contraceptives. Contraception 2004;70:359-363.
- Nakajima ST, et al. Efficacy and safety of a new 24-day oral contraceptive regimen of norethindrone acetate 1 mg/ethinyl estradiol 20 micro g (Loestrin 24 Fe). Contraception 2007;75:16-22.
- Sulak PJ, et al. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol 2000;95:261-266.
- Sulak PJ, et al. Extending the duration of active oral contraceptive pills to manage hormone withdrawal symptoms. Obstet Gynecol 1997;89:179-183.
- Edelman AB, et al. Continuous or extended cycle vs cyclic use of combined oral contraceptives for contraception. Cochrane Database Syst Rev 2005;(3):CD004695.
- Vandever MA, et al. Evaluation of pituitary-ovarian axis suppression with three oral contraceptive regimens. Contraception 2008;77:162-170.
- Baerwald AR, et al. Ovarian follicular development is initiated during the hormone-free interval of oral contraceptive use. Contraception 2004;70:371-377.
- Spona J, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception 1996;54:71-77.
- Dinger J, et al. Effectiveness of oral contraceptive pills in a large U.S. cohort comparing progestogen and regimen. Obstet Gynecol 2011;117:33-40.
- Society of Family Planning, Higginbotham S. Contraceptive considerations in obese women: Release date 1 September 2009, SFP Guideline 20091. Contraception 2009;80:583-590.