Newest research eyes shortened pill-free interval
Newest research eyes shortened pill-free interval
Research presented at the latest Clinical Meeting of the American College of Obstetricians and Gynecologists indicates that women using an oral contraceptive (OC) with a 26/2 dosing regimen had less severe hormone withdrawal-associated symptoms than those using a 21/7 pill.1
Investigators looked at women using the estradiol valerate/dienogest OC Natazia (Bayer HealthCare Pharmaceuticals, Wayne, NJ), which has a shortened hormone-free interval. The study was designed to compare the pill to an ethinyl estradiol/norgestimate formulation (Ortho Tri-Cyclen Lo, Janssen Pharmaceuticals, Titusville, NJ) in reducing the severity of hormone withdrawal-associated symptoms.
Natazia was approved as an oral contraceptive by the Food and Drug Administration (FDA) in 2010. It received an additional indication in March 2012 for treatment of heavy menstrual bleeding in women choosing an OC for birth control.
Will the pill manufacturer seek an additional approved indication for reducing the severity of hormone withdrawal-associated symptoms? Bayer spokesperson Rosemarie Yancosek offered no comment about the company' s plans for such action.
Review the results
To conduct the current study, investigators at 59 centers in the United States and Canada enrolled women ages 18-50 who were using an OC in a 21-day regimen and suffering from either of the hormone withdrawal-associated symptoms of headache or pelvic pain. The women were randomized to the estradiol valerate/dienogest OC or the ethinyl estradiol/norgestimate formulation for 13 28-day cycles. The primary efficacy variable was the change in pelvic pain and headache, as assessed by the change in the average of the three highest values on a visual analogue scale during cycle days 22-28 from baseline to treatment cycle six.
In total, 409 women were randomized, and 248 completed the study. By treatment cycle 6, the estradiol valerate/dienogest OC had reduced the symptoms of pelvic pain and headache to a greater extent than the comparator drug. Data also indicates the women who received the study drug used less pain medication than those using the comparator drug.1
Women using oral contraceptives with complaints of headache, pain, or other symptoms associated with their expected withdrawal bleeding might benefit from a reduction in the hormone-free interval (HFI), notes Caryn Dutton, MD, medical director of the gynecology practice in the Department of Obstetrics and Gynecology at Brigham and Women' s Hospital in Boston.
"The study by Mabey et al reports that women with pelvic pain and/or headache during the HFI experienced improvement in the severity of symptoms by treatment cycle 6 when taking a 26/2 regimen compared to a standard 21/7 regimen," Dutton notes. "No studies are yet available to compare the improvements with the 26/2 regimen to other regimens that may also benefit this subset of patients, including a 24/4 regimen, and extended cycle or continuous oral contraceptive use."
Anita Nelson, MD, professor in the Obstetrics and Gynecology Department at the David Geffen School Of Medicine at the University of California in Los Angeles, notes that the estrogen step down regimen creates a steady state of estrogen throughout the cycle, so that women may have less estrogen-withdrawal symptoms, such as headaches. Similarly, the reduction in pelvic pain may result not only from the shortened pill-free interval, but from the strong progestin and the high levels of amenorrhea with this pill, she observes.
Shorter interval better?
Previous research indicates that hormone-related symptoms are worse during the seven-day hormone-free interval than during active treatment.2 Shortening the hormone-free interval might decrease the number of days of symptoms typically associated with hormone withdrawal, data suggests.2-4
During the hormone-free interval, the pituitary gland secretes gonadotropins, stimulating the ovaries. Even as early as day four of a seven-day hormone-free interval, the pituitary secretes follicle-stimulating hormone, and the ovary secretes inhibin-B, followed by luteinizing hormone and estradiol. This process can lead to follicular recruitment and ovulation in some women.5 Despite starting a new pill pack, endogenous estradiol continues to rise then decline in the following two weeks, reaching a nadir in the third week, leading to hormone withdrawal-associated symptoms in that week, which carry over to the pill-free interval.5
If a woman cannot get insurance coverage for a pill with a shortened pill-free interval, Contraceptive Technology advises using conventional pills in this method:
Start the first active pill in the next pack on the first day of the patient' s withdrawal bleed (first day start each cycle.) If she has no withdrawal bleeding by the fifth day of her placebo pills, she should start her next pack.6
"Be aware that this approach results in more frequent bleeding episodes (every 25 days) and will cost the woman the price of at least two extra packs of pills a year, unless the clinician can persuade the insurance company that there is a medical indication of this shortened pill interval," the book advises.6
References
- Mabey RG, Serrani M, Parke S. Hormone Withdrawal-Associated Symptoms: Comparison of E2V/DNG versus EE/NGM. Presented at the 60th Annual Clinical Meeting of the American College of Obstetricians and Gynecologists. San Diego; May 2012.
- Sulak PJ, Scow RD, Preece C, et al. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol2000; 95:261-266.
- Klipping C, Duijkers I, Trummer D, et al. Suppression of ovarian activity with a drospirenone-containing oral contraceptive in a 24/4 regimen. Contraception 2008; 78:16-25.
- Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception 1996; 54:71-77.
- Mayer AP, Files JA, David PS. You can' t fool mother nature: new directions in oral contraception. J Womens Health (Larchmt) 2012; 21(3):366-367.
- Nelson AL, Cwiak C. Combined oral contraceptives. In: Hatcher RA, Trussell J, Nelson AL, et al. Contraceptive Technology: 20th revised edition. New York: Ardent Media; 2011.
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