Wednesday, January 10, 2007

The Demise of the Placebo Week

Instructive editorial by Dr. Sulak in support of altering the current 21/7-day (placebo week) Pill regimen:

Oral contraceptives are the most common method of reversible contraception, with the majority of women using them sometime during their reproductive life. Modifications have primarily involved lowering hormone content and utilizing new progestin components.

The 21/7-day OC regimen (21 days active/7 days hormone-free) was arbitrarily created to mimic the average spontaneous menstrual cycle of 28 days. After more than 40 years of use, the traditional 21/7-day OC regimen is undergoing necessary, overdue changes in design. Numerous studies over the last decade have documented that lowering the doses of hormones in OCs without altering the standard 7-day hormone-free interval (HFI) compromises suppression effects and can induce hormone withdrawal symptoms.

Although today's low-dose OCs are very effective in preventing pregnancy, studies have confirmed incomplete inhibition of pituitary-ovarian function with follicular growth and resultant endogenous hormone production and potential for follicular cysts and ovulation. With a standard 7-day HFI, follicle-stimulating hormone begins to increase on day 3–4 of the HFI, allowing follicular recruitment and estradiol production. While uncommon, pregnancy can occur because of this escape ovulation, even in perfect users. Low-dose OCs have also been shown to provide little to no protection from the development of functional ovarian cysts because of the 7-day HFI. Unfortunately, most of our patients do not take their pills perfectly, increasing the chance of ovarian cysts and pregnancy.

Today's standard low-dose 21/7-day OCs have also been responsible for the occurrence of nuisance side effects in many patients. Published data document an increased incidence of menstruation-related symptoms during the 7-day HFI in patients on standard 21/7-day low-dose OCs, with increases reported in headache, pelvic pain, bloating/swelling, breast tenderness, and use of pain medication during this placebo interval. Menstruation-related symptoms including headache, mood swings, abdominal cramping, bloating, and breast tenderness are long-recognized side effects associated with OCs and often lead to untimely discontinuation and resultant unintended pregnancy.

The question is not "Should the current 21/7-day OC be altered?" but instead "How is the 21/7-day OC to be altered?" Modifications are necessary to address the issues of increased symptomatology and follicular development. We need to set women up for success rather than failure.

Currently, several approaches alter the typical 21/7-day OC regimen. Shortening the 7-day hormone-free interval of today's low-dose OCs can provide greater pituitary-ovarian inhibition, reducing the risk of ovulation, ovarian cyst formation, and common hormone withdrawal symptoms. Two OC products that utilize 24 days of active hormones and a 4-day HFI (24/4) have been approved by the FDA in 2006: ethinyl estradiol 20 mcg/drospirenone 3 mg (Yaz, Berlex) and ethinyl estradiol 20 mcg/norethindrone acetate 1 mg (Loestrin 24 Fe, Warner Chilcott).

Extending the number of active pills beyond the standard 3 weeks to 6, 9, 12, or more weeks is also common practice. A recent survey of health care providers in the United States revealed that the majority thought extended regimens should be offered to women who desired elimination of monthly withdrawal bleeding and associated symptoms.

The first approved extended regimen became available in the United States in 2003 (Seasonale, Barr Laboratories), and consists of 84 days of 150 mcg of levonorgestrel and 30 mcg of ethinyl estradiol followed by a 7-day HFI. But, a 7-day HFI with an extended regimen can lead to the same problems seen with a 21/7-day regimen.

A new OC approved in May 2006 both extends combination active therapy to 84 days and adds low-dose estrogen to the usual 7-day HFI (ethinyl estradiol 30 mcg/levonorgestrel 150 mcg for 84 days plus ethinyl estradiol 10 mcg for 7 days; Seasonique, Barr Laboratories). By doing so, it becomes the first approved OC to completely eliminate the HFI. Addition of low-dose ethinyl estradiol during the HFI provides greater pituitary-ovarian suppression, preventing an increase in follicle-stimulating hormone, follicular development, and endogenous estradiol production.

Continuous OC regimens that entirely eliminate the HFI are being extensively studied. While these extended, continuous regimens decrease scheduled bleeding, they can cause irregular, nuisance bleeding or spotting. Breakthrough bleeding with continuous OCs has been shown to be effectively managed by institution of an abbreviated 3-day HFI.

As more modifications of the 21/7 regimen are approved, it is important to ascertain from each patient her desired menstrual frequency. As in the movie, we must find out “What Do Women Want?” Whether she wants to bleed once a month, once every 3 months, or never will determine what regimen we should recommend. Today, we can give women what they want and decrease side effects, increase compliance, and decrease unintended pregnancy. No matter what the menstrual frequency, the 7-day HFI needs to be eliminated.

Today's low-dose 21/7-day contraceptive regimens have documented design flaws that can result in discontinuation and unintended pregnancy. Modifications of the standard 21/7-day design seen in today's vaginal contraceptive ring, transdermal patch, and OCs can greatly improve the side effect profile and continuation rates. Shortening the HFI, adding estrogen to the standard HFI, and extending the active component are all effective improvements that provide greater ovarian suppression, and will eventually lead to the demise of low-dose 21/7-day regimens. The sooner, the better.

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