Medical Education Library

Extended Regimen Oral Contraceptives—Practical Management

Publish date: January 1, 2007

References

1. The Mircette™ Study Group. An open-label, multicenter, noncomparative safety and efficacy study of Mircette™, a low-dose estrogen-progestin oral contraceptive. Am J Obstet Gynecol. 1998;179:S2-S8.

2. Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception. 2003;68:89-96.

3. Bachmann G, Sulak PJ, Sampson-Landers C, Benda N, Marr J. Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 micrograms ethinylestradiol and 3 mg drospirenone. Contraception. 2004;70:191-198.

4. Archer DF, Ellman H, for the Loestrin-24 Study Group. Bleeding profile of a new 24-day oral contraceptive regimen of norethindrone acetate 1 mg/ethinyl estradiol 20 mcg compared with a 21-day regimen. Paper presented at: Annual Meeting of the American Society for Reproductive Medicine; October 15-19, 2005; Montreal, Canada.

5. Archer DF, Ellman H, for the Loestrin-24 Study Group. Efficacy and safety of a 24-day oral contraceptive regimen of norethindrone acetate 1 mg/ethinyl estradiol 20 mcg. Paper presented at: Annual Meeting of the American Society of Reproductive Medicine; October 15-19, 2005; Montreal, Canada.

6. Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

7. Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

8. Trussell J. Contraceptive failure in the United States. Contraception. 2004;70:89-96.

9. Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

10. Vercellini P, Frontino G, De Giorgi O, Pietropaolo G, Pasin R, Crosignani PG. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not response to a cyclic pill regimen. Fertil Steril. 2003;80:560-563.

11. Coffee AL, Kuehl TJ, Willis S, Sulak PJ. Oral contraceptives and premenstrual symptoms: comparison of a 21/7 and extended regimen. Am J Obstet Gynecol. 2006;195:1311-1319.

12. Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

14 Sulak PH, Willis S, Kuehl T, Coffee A, Clark J. Headaches and oral contraceptives: impact of eliminating the standard 7-day placebo interval. Headache. 2007;47:27-37.

15. Rosenberg MJ, Meyers A, Roy V. Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: a randomized trial of 20 μg and 35 μg estrogen preparations. Contraception. 1999;60:321-329.

16. Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

17. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

18. van den Heuvel MW, van Bragt AJ, Alnabawy AK, Kaptein M. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception. 2005;72:168-174.

13. Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

19. Canto De Cetina TE, Canto P, Ordonez Luna M. Effect of counseling to improve compliance in Mexican women receiving depo-medroxyprogesterone acetate. Contraception. 2001;63:143-146.

20. Lei ZW, Wu SC, Garceau RJ, et al. Effect of pretreatment counseling on discontinuation rates in Chinese women given depo-medroxyprogesterone acetate for contraception. Contraception. 1996;53:357-361.

Disclosures (prior 12 months)

Dr Sulak has received research grants from Barr Pharmaceuticals, Inc., Berlex Laboratories, and Organon Inc; is a consultant to Barr Pharmaceuticals, Inc., Berlex Laboratories, and Wyeth; and is a speaker for Barr Pharmaceuticals, Inc., Berlex Laboratories, Merck, and Wyeth.

Dr Kaunitz has received support for clinical trials (funding to University of Florida Research Foundation) from Berlex, Duramed Pharmaceuticals, Johnson and Johnson, and Warner Chilcott. He serves as a speaker for and/or a consultant to the American College of Obstetricians and Gynecologists, Berlex, Duramed Pharmaceuticals, Johnson and Johnson, Merck, Organon, and Pfizer. He holds stock in Barr, Noven, Procter and Gamble, Roche, and sanofi-aventis.

Dr London is a speaker for and/or consultant to Berlex, Duramed, Eli Lilly and Co, Merck, Solvay Pharmaceuticals, and Wyeth.

Ms Moore is a speaker for and/or consultant to Berlex, Duramed, Organon, Ortho, and Wyeth.

Dr Nelson has served as a speaker for Barr, Berlex, FEI Women’s Health, Merck, Organon, Ortho McNeil, Pfizer, Ther-Rx, and Wyeth. She has served as an advisor for Ascend Therapeutics, Barr, Berlex, Church and Dwight, Organon, and Wyeth. She also has received research support from Berlex, Organon, Pfizer, and Wyeth.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

Polycystic ovarian syndrome	Anorexia nervosa
Premenarchal status	Athletic amenorrhea
Uterine adhesions	Cervical stenosis
Pregnancy	Ovarian failure
Perimenopause	Ovarian tumor
Emotional stress	Brain tumor
Endocrine disorders (thyroid, pituitary, adrenal)

TABLE 2

Health Risks

Recurrent Ovulation/Bleeding
Bleeding/anemia	Endometriosis with associated pain and infertility
Ovarian cancer	Ovarian cysts
Premenstrual syndrome	Premenstrual dysphoric disorder
Amenorrhea
Osteoporosis	Atrophic vaginitis
Cardiac arrhythmia
Oligomenorrhea
Endometrial hyperplasia	Endometrial cancer
Infertility

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Product Content	Brand	Regimen	Duration of HFI	No. Withdrawal Bleeding Episodes/Year
30 mcg EE/150 mcg LNG and 10 mcg EE	Seasonique	91 days: 84 days active + 7 days low-dose EE	No HFI	4
20 mcg EE/1 mg NETA	Loestrin 24 Fe	28 days: 24 days active + 4 days placebo	4 days	13
20 mcg EE/3 mg DRSP	Yaz	28 days: 24 days active + 4 days placebo	4 days	13
20 mcg EE/150 mcg DSG and 10 mcg EE	Mircette	28 days: 21 days active + 2 days placebo + 5 days low-dose EE	2 days	13
30 mcg EE/150 mcg LNG	Seasonale*	91 days: 84 days active + 7 days placebo	7 days	4
DRSP=drosperinone, DSG=desogestrel, EE=ethinyl estradiol, HFI=hormone-free interval, LNG=levonorgestrel, NETA=norethindrone acetate, OC=oral contraceptive.
*Seasonale is the only extended regimen OC for which there is a generic substitute.