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Update


CONTRACEPTION

A number of refinements in access to, or use of, hormonal contraception deserve our attention

August 2007 · Vol. 19, No. 08

IN THIS ARTICLE

A year ago, the US Food and Drug Administration (FDA) granted over-the-counter (OTC) status for Plan B, the levonorgestrel-only emergency contraceptive. In the past few years, we have accumulated data on the general impact of improved access to emergency contraception (EC), as well as evidence of its overall efficacy. We also have another year of experience with the levonorgestrel-releasing intrauterine system (Mirena) and its multiple benefits beyond contraception, and with extended hormonal contraceptive regimens. This article highlights what we know about these three forms of contraception.

Greater access to Plan B leads to increased—and faster—use

Now that Plan B is available OTC to both men and women 18 years and older,1 several questions are in order:

  • What are the effects of this change?
  • Does OTC access or provision of the drug in advance reduce condom or oral contraceptive use?
  • Does it increase the number of sexual partners or rate of sexually transmitted disease (STD)?
  • Does it reduce unintended pregnancy?

To acquire the drug OTC, an adult must ask the pharmacist for it and show proof of age. Even before the FDA approved OTC status, many clinicians gave patients an advance prescription or actual medication so an appointment would be unnecessary in a time of need.

Several randomized trials have found that advance provision of EC not only increases its utilization, but causes it to be used sooner.2-7 Most of the trials conducted so far have compared advance provision of EC with counseling about EC or a prescription for it. Only one trial has included a pharmacy-access arm, and it was conducted before FDA approval of OTC status.3 It found that pharmacy access did not increase use of EC, compared with standard access (ie, returning to the clinic when EC was needed). It is too early to tell what effect OTC availability will have on the usage rate, but data so far support the practice of giving the patient a supply of EC rather than just a prescription.

Increased access to EC does not affect regular contraceptive behavior

Multiple studies have shown that advance provision of EC has no significant effect on the use of regular contraception. Studies have examined the impact of EC on both baseline oral contraceptive usage and condom usage and found no significant change in either among women who used EC during the study.3-6

… nor does it cause promiscuity or increase the rate of STD

Multiple studies have demonstrated that advance provision of EC does not increase the number of sexual partners or rate of STD.3-6 The largest of these studies compared both pharmacy access without a prescription and advance provision of EC to standard access. That study included 2,117 sexually active young women and found no difference in the rate of STD or number of sex partners among the three study groups.3 Smaller studies comparing advance pro-vision of EC with standard access also found no significant difference in these variables.8,9

No evidence of fewer unintended pregnancies—yet

We know that progestin-only EC can reduce unintended pregnancy by almost 90%.10 However, studies have not yet demonstrated such a decrease in the general population. One reason may be that the two studies that considered unintended pregnancy as a primary outcome3,9 were too small to detect a difference in pregnancy rates, or it may be that EC was underutilized by women in the studies.

Levonorgestrel pills can be taken both at once and as long as 5 days after intercourse

Prescribing information for levonorgestrel emergency contraception (EC) recommends ingestion of the first 0.75-mg tablet within 72 hours (3 days) of a single act of unprotected intercourse, with the second tablet taken 12 hours after the first.11 However, data show that levonorgestrel EC can prevent pregnancy up to 5 days after intercourse. In a World Health Organization multicenter randomized trial of various EC regimens, levonorgestrel EC prevented 79% to 84% of expected pregnancies when taken within 1 to 3 days, and 60% to 63% when taken 4 to 5 days after intercourse.12 Randomized trials have also found that taking both 0.75-mg levonorgestrel pills simultaneously prevents pregnancy as effectively as taking them 12 hours apart.

Levonorgestrel EC prevents or delays ovulation by inhibiting the luteinizing hormone surge during the follicular phase.13 Secondary mechanisms of contraceptive action include thickening of the cervical mucus; decreased pH level, which immobilizes sperm; and decreased recovery of sperm from the uterus.14

Levonorgestrel intrauterine system has benefits beyond contraception

The levonorgestrel intrauterine system (LNG-IUS) has been shown to significantly decrease blood loss and increase hemoglobin and serum ferritin levels in women with idiopathic menorrhagia.15 The LNGIUS reduces blood loss to a greater degree (as much as 96% after 1 year) than do placebo, nonsteroidal anti-inflammatory drugs, antifibrinolytic medication, and oral contraceptives.16 In one study,16 the LNG-IUS was the only treatment that reduced menstrual bleeding to less than 80 mL/day—the upper limit of normal.

LNG-IUS compares favorably to endometrial ablation

The LNG-IUS provides nonoperative, local, and minimally invasive treatment of menorrhagia, producing clinical results similar to those of different endometrial ablation methods for dysfunctional uterine bleeding or menorrhagia. The LNG-IUS is comparable to endometrial resection in its reduction of blood loss, patient satisfaction, rate of amenorrhea, and recurrent menorrhagia.17 It also is equivalent to thermal balloon ablation in its reduction of bleeding and increased quality of life and hemoglobin level.18,19 And it produces a higher amenorrhea rate than expectant management after endometrial resection in women with adenomyosis, and averts the need for further procedures, such as hysterectomy and repeat resection.20

In many women, LNG-IUS renders hysterectomy unnecessary

In a controlled trial involving 56 women on a waiting list for hysterectomy, 64% of those who received the LNG-IUS and 14% of those in a control group removed themselves from the list at the end of 6 months because they were satisfied with symptom control (P<.001).21 In a trial involving 236 women with menorrhagia randomized to LNG-IUS or hysterectomy, the groups had similar quality-of-life scores at 1 and 5 years of follow-up—and costs associated with the LNG-IUS were significantly lower than those associated with hysterectomy, even after 50 women randomized to the LNG-IUS opted for and underwent hysterectomy.41

Consider the LNG-IUS a first-line therapy for symptomatic fibroids

The LNG-IUS continuously decreases fibroid and uterine volume and blood loss and increases ferritin levels over time among women with symptomatic fibroids.22 It should therefore be routinely considered a first-line therapy for women with fibroids who wish to preserve their childbearing potential.

Endometrial hyperplasia is reduced

The LNG-IUS can prevent and induce regression of endometrial hyperplasia.23,24 In addition, it reduces bleeding and spotting among women using hormone replacement therapy.25,26 Studies also suggest it may be beneficial in the treatment of stage I endometrial cancer, although further research into this effect is needed.27

Endometriosis-related pain is eased

In a randomized trial comparing the LNG-IUS with a gonadotropin-releasing hormone (GnRH) analogue among women with chronic pelvic pain due to endometriosis, both treatments reduced pain and improved psychological well-being to the same degree—but the LNG-IUS caused no systemic hypoestrogenic symptoms, unlike the GnRH analogue.28 In a randomized trial comparing the LNGIUS with expectant management among women who had undergone laparoscopic resection of endometriosis, women in the LNG-IUS arm had significantly decreased recurrent dysmenorrhea.29

In addition, the LNG-IUS is effective for as long as 5 years, can be used in conjunction with systemic estrogen, and is an effective contraceptive.

Continuous oral contraceptive regimens: 4 effective options

Oral contraceptives (OCs) can be prescribed for continuous use to achieve a number of different goals30:

  • decrease the number of placebo days per cycle
  • reduce the number of placebo weeks or withdrawal weeks per year
  • eliminate withdrawal weeks from the cycle entirely
  • reduce the incidence of breakthrough bleeding

The first two options are highly effective and produce shorter and fewer bleeds, and the last option is especially appropriate for women troubled by un-scheduled bleeding during continuous OC use. All four options decrease menstrual symptoms.

Reduce the number of placebo days

Compared with the standard 28-day regimen (21 days of active pills followed by 7 days of placebo), extended regimens significantly reduce ovarian activity and produce smaller follicles and a lower estrogen level.31,32 Extended regimens may involve fewer days of placebo pills per cycle, or very small amounts of estrogen throughout the withdrawal week of the regimen. These modifications may translate into increased efficacy. In two randomized trials comparing extended regimens with a standard regimen, the extended regimens were highly effective, with a Pearl index of up to 1.29 (1.29 pregnancies for every 100 woman-years of use), and produced shorter withdrawal bleeds.33,34

Decrease the number of placebo or withdrawal weeks

The FDA approved the first OC to be packaged for extended use (Seasonale) in 2003. Each pack contains 84 active tablets of ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg), followed by seven placebo pills. This highly effective regimen has a failure rate of 0.60 per 100 woman-years.35 Another extended-use OC (Seasonique) contains 7 days of ethinyl estradiol (10 μg) instead of placebo pills and may, therefore, suppress follicular development to an even greater degree during the withdrawal week.36

Extended cycles can be achieved with any monophasic OC in an off-label manner. Simply instruct the patient to take one active tablet for 42 consecutive days (known as “bicycling”) or for 63 consecutive days (“tricycling”), followed by 4 to 7 pill-free days.

Unscheduled bleeding with the 63-day regimen appears to be similar to the rate associated with the 21-day regimen.35 An extended-cycle regimen can be modified according to how often the user wants withdrawal bleeding.

Eliminate the withdrawal week

Perhaps the most radical extended-cycle regimen is continuous use of active pills with no placebo or withdrawal interval. This option is safe and acceptable to women, according to two small randomized trials and two prospective trials, but larger studies are needed to confirm these results.37-40 Continuous use for 1 year is associated with less bleeding, higher rates of amenorrhea, and similar side effects, compared with conventional regimens.37,38 Patient acceptance and satisfaction also are high,39 with most women choosing to keep taking the pill continuously. Lybrel, an OC designed for this purpose, contains 20 μg of ethinyl estradiol and 90 μg of levonorgestrel and is intended to eliminate menses through 1 year of continuous use.

Reduce breakthrough bleeding

For women who experience unscheduled bleeding while taking an OC continuously, one option is to stop taking pills when breakthrough bleeding occurs and initiate a hormone-free interval. This approach was studied in a randomized trial in which women were scheduled to take an OC continuously for 168 days.40 Women who had persistent unscheduled bleeding for longer than 7 days were randomized to a 3-day hormone-free interval or continuation of the active pills. Those who continued taking active pills had more bleeding over the long term, and a large percentage found it necessary to institute a delayed hormone-free interval.

This option may be particularly useful for women who experience persistent breakthrough bleeding on a continuous regimen.40

References

1. U.S. Food and Drug Administration. FDA approves over-the-counter access for Plan B for women 18 and older; prescription remains required for those 17 and under [August 24, 2006]. Available at: http://www.fda.gov/bbs/topics/NEWS/2006/NEW01436.html. Accessed July 11, 2007.

2. Harper CC, Cheong M, Rocca CH, Darney PD, Raine TR. The effect of increased access to emergency contraception among young adolescents. Obstet Gynecol. 2005;106:483-491.

3. Raine TR, Harper CC, Rocca CH, et al. Direct access to emergency contraception through pharmacies and effect on unintended pregnancy and STIs: a randomized controlled trial. JAMA. 2005;293:54-62.

4. Raymond EG, Trussell J, Polis CB. Population effect of increased access to emergency contraceptive pills: a systematic review. Obstet Gynecol. 2007;109:181-188.

5. Walsh TL, Frezieres RG. Patterns of emergency contraception use by age and ethnicity from a randomized trial comparing advance provision and information only. Contraception. 2006;74:110-117.

6. Jackson RA, Schwarz EB, Freedman L, Darney PD. Advance supply of emergency contraception. Effect on use and usual contraception—a randomized trial. Obstet Gynecol. 2003;102:8-16.

7. Hu X, Cheng L, Hua X, Glasier A. Advanced provision of emergency contraception to postnatal women in China makes no difference in abortion rates: a randomized controlled trial. Contraception. 2005;72:111-116.

8. Gold MA, Wolford JE, Smith KA, Parker AM. The effects of advance provision of emergency contraception on adolescent women’s sexual and contraceptive behaviors. J Pediatr Adolesc Gynecol. 2004;17:87-96.

9. Raymond EG, Stewart F, Weaver M, Monteith C, Van Der Pol B. Impact of increased access to emergency contraceptive pills: a randomized controlled trial. Obstet Gynecol. 2006;108:1098-1106.

10. Trussell J, Ellertson C, Stewart F. The effectiveness of the Yuzpe regimen of emergency contraception. Fam Plann Perspect. 1996;28:58-64, 87.

11. Plan B. [package insert] Pomona, NY: Duramed Pharmaceuticals Inc; 2006.

12. von Hertzen H, Piaggio G, Ding J, et al. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. Lancet. 2002;360:1803-1810.

13. Durand M, del Carmen Cravioto M, Raymond EG, et al. On the mechanisms of action of short-term levonorgestrel administration in emergency contraception. Contraception. 2001;64:227-234.

14. Croxatto HB, Devoto L, Durand M, et al. Mechanism of action of hormonal preparations used for emergency contraception: a review of the literature. Contraception. 2001;63:111-121.

15. Xiao B, Wu SC, Chong J, et al. Therapeutic effects of the levonorgestrel-releasing intrauterine system in treatment of idiopathic menorrhagia. Fertil Steril. 2003;79:963-969.

16. Milsom I, Andersson K, Andersch B, Rybo G. A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia. Am J Obstet Gynecol. 1991;164:879-883.

17. Crosignani PG, Vercellini P, Mosconi P, et al. Levonorgestrel-releasing intrauterine device versus hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding. Obstet Gynecol. 1997;90:257-263.

18. Soysal M, Soysal S, Ozer S. A randomized controlled trial of levonorgestrel releasing IUD and thermal balloon ablation in the treatment of menorrhagia. Zentralbl Gynakol. 2002;124:213-219.

19. Barrington JW, Arunkalaivanan AS, Abdel-Fattah M. Comparison between the levonorgestrel intrauterine system (LNG-IUS) and thermal balloon ablation in the treatment of menorrhagia. Eur J Obstet Gynecol Reprod Biol. 2003;108:72-74.

20. Maia H, Jr, Maltez A, Coelho G, et al. Insertion of Mirena after endometrial resection in patients with adenomyosis. J Am Assoc Gynecol Laparosc. 2003;10:512-516.

21. Lahteenmaki P, Haukkamaa M, Puolakka J, et al. Open randomised study of use of levonorgestrel releasing intrauterine system as alternative to hysterectomy. BMJ. 1998;316:1122-1126.

22. Grigorieva V, Chen-Mok M, Tarasova M, Mikhailov A. Use of a levonorgestrel-releasing intrauterine system to treat bleeding related to uterine leiomyomas. Fertil Steril. 2003;79:1194-1198.

23. Scarselli G, Tantini C, Colafranceschi M, et al. Levonorgestrel-nova-T and precancerous lesions of the endometrium. Eur J Gynaecol Oncol. 1988;9:284-286.

24. Perino A, Quartararo P, Catinella E, et al. Treatment of endometrial hyperplasia with levonorgestrel releasing intrauterine devices. Acta Eur Fertil. 1987;18:137-140.

25. Ettinger B, Pressman A, Silver P. Effect of age on reasons for initiation and discontinuation of hormone replacement therapy. Menopause. 1999;6:282-289.

26. Andersson K, Mattson LA, Rybo G, Stadberg E. Intrauterine release of levonorgestrel—a new way of adding progestogen in hormone replacement therapy. Obstet Gynecol. 1992;79:963-967.

27. Montz FJ, Bristow RE, Bovicelli A, et al. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol. 2002;186:651-657.

28. Petta CA, Ferriani RA, Abrao MS, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod. 2005;20:1993-1998.

29. Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, Crosignani PG. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril. 2003;80:305-309.

30. Steinauer J, Autry AM. Extended cycle combined hormonal contraception. Obstet Gynecol Clin North Am. 2007;34:43-55, viii.

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

32. Sullivan H, Furniss H, Spona J, Elstein M. Effect of 21-day and 24-day oral contraceptive regimens containing gestodene (60 microg) and ethinyl estradiol (15 microg) on ovarian activity. Fertil Steril. 1999;72:115-120.

33. 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.

34. Endrikat J, Cronin M, Gerlinger C, Ruebig A, Schmidt W, Düsterburg B. Open, multicenter comparison of efficacy, cycle control, and tolerability of a 23-day oral contraceptive regimen with 20 microg ethinyl estradiol and 75 microg gestodene and a 21-day regimen with 20 microg ethinyl estradiol and 150 microg desogestrel. Contraception. 2001;64:201-207.

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

36. 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.

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

38. 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.

39. Foidart JM, Sulak PJ, Schellschmidt I, Zimmermann D. Yasmin Extended Regimen Study Group. The use of an oral contraceptive containing ethinylestradiol and drospirenone in an extended regimen over 126 days. Contraception. 2006;73:34-40.

40. 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.

41. Hurskainen R, et al. Quality of life and cost-effectiveness of levonorgestrel-releasing intrauterine system versus hysterectomy for treatment of menorrhagia: a randomised trial. Lancet. 2001;357:273-277.

Dr. Newmann reports no financial relationship relevant to this article. Dr. Darney receives support from Organon, is a consultant to Organon and Bayer, and is a speaker for Organon and Bayer.

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