January 2014

Heavy and prolonged bleeding on a chronic basis causes significant health problems (resulting from severe anemia) and quality of life issues. With the FDA approval of the Levonorgestrel IUS20, tranexamic acid (antifibrinolytic agent), and the estradiol valerate/dienogestrol oral contraceptive as treatments for women with that problem, clinicians have many important options to offer. The clinical trials for each of these agents have been rigorous and provide excellent data from hundreds of women about the safety and efficacy of these treatment options.^{1, 2, 3, 4, 5, 6} In addition, comparative trials, especially comparing the LNG-IUS with surgical treatments such as endometrial ablation and hysterectomy, have demonstrated even more richly how effective these options are in women with differing underlying pathologies accounting for their excessive bleeding.^{7, 8, 9} There are also off-label uses of NSAIDs, other combined hormonal contraceptives used cyclically or continuously, as well as DMPA to help women reduce their monthly blood loss.^{10, 11}

There are no FDA approved products for treatment of acute excessive bleeding and, amazingly, the clinical evidence supporting any of the medical therapies commonly used to control acute bleeding is embarrassingly scant. Textbooks abound with suggested treatments.^{12, 13} Many hypotheses have been advanced about the effects needed from a therapy to arrest bleeding. However, these are based on only a handful of very small prospective clinical studies in the literature.^{14, 15, 16}

The classic study done by Devore, et al., involved only 17 subjects given high-dose intravenous conjugated equine estrogen and another 17 controls given placebo infusions over a 5-hour study period in an ER setting.¹⁷ At 3 hours, the placebo had a better response than the CEE treatment, but at 5 hours the results reversed. The thought was that the woman’s bleeding was coming from her denuded epithelium. Estrogen was thought to induce endometrial proliferation to cover the denuded patch and also to help cause/stabilize intravascular clotting in the uterine vessels. Progestin was added later to stabilize the remaining un-shed endometrium. Withdrawal of the hormones at a later date would induce a coordinated and limited bleeding episode. The other 2 studies were small scale studies (9 patients each), but reinforced DeVore’s findings.^{18, 19} In this paradigm, administering progestin would only slow the repair process by down-regulating estrogen receptors in the endometrium.

The physiology must be much more complex because high-dose progestins administered to 24 hospitalized adolescents was very effective as a single therapy.²⁰

In 2006 Munro, et al., reported the first randomized, prospective one-month trial of estrogen-containing oral contraceptives and high-dose MPA (see Table 1 for the doses used). Despite a long recruitment time and ample numbers of potential subjects, only 40 women were enrolled into the study because clinicians each had their own favorite treatment and/or were loath to randomize their patients. However, the study showed that both treatments were very effective. None of the subjects required surgery. Most women were satisfied or very satisfied with their therapy (see Table 2 for outcomes). Given that MPA is relatively inexpensive and carries none of the risks of venous thromboembolism associated with high-dose estrogen, it is a very welcome addition to our therapeutic armamentarium and is our first-line treatment today.

One other option that has been studied in a single-arm prospective study involving 48 women (the largest number of subjects yet) used MPA 20 mg orally 3 times a day for 3 days combined with DMPA 150 mg intramuscularly.²¹ In this study, all women stopped bleeding by 5 days. In fact, over 25% stopped in 24 hours and the mean number of pads used in first 24 hours by those who did not completely stop bleeding was 2, down from 8 pads. Long-term follow-up was not done prospectively in this study, but none of the women who were not lost to follow-up required any surgery during the 3-month treatment. We are starting a comparative trial for in patients soon and should be able to report on more detail about bleeding patterns in the weeks and months following the DMPA injection.

The American College of Obstetricians and Gynecologists has recently published Committee Opinion Number 557, which emphasizes the role of estrogen-based therapies, but mentions Munro’s progestin-only regimen.²²

Look below for the current protocol followed by the Women’s Health Care Clinic at Harbor-UCLA Medical Center for the treatment of acute excessive bleeding. Please feel free to adopt or adapt it to your practice. Read Acute and or Chronic Heavy and or Prolonged Menstrual Bleeding for a detailed protocol.

Table 1: Treatment Regimens

Table 2: Outcomes from Munro’s Study Groups      

Munro MG, Mainor N, Basu R, Brisinger M, Barreda L. Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding. Obstet Gynecol 2006;108:924-9

References

1.  Jensen J, Mansour D, Lukkari-Lax E, et al. Bleeding patterns with the levonorgestrel-releasing intrauterine system when used for heavy menstrual bleeding in women without structural pelvic pathology: a pooled analysis of randomized controlled studies. Contraception. 2013;87(1):107-12.
2. Kaunitz AM, Bissonnette F, Monteiro I, et al. Levonorgestrel-releasing intrauterine system or medroxyprogesterone for heavy menstrual bleeding: a randomized controlled trial. Obstet Gynecol. 2010;116(3):625-32.
3. Leminen H, Hurskainen R. Tranexamic acid for the treatment of heavy menstrual bleeding: efficacy and safety. Int J Womens Health. 2012;4:413-21.
4. Freeman EW, Lukes A, VanDrie D, et al. A dose-response study of a novel, oral tranexamic formulation for heavy menstrual bleeding. Am J Obstet Gynecol. 2011;205(4):319.e1-7.
5. Jensen JT, Parke S, Mellinger U, et al. Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: a randomized controlled trial. Obstet Gynecol. 2011;117(4):777-87.
6. Fraser IS, Parke S, Mellinger U, et al. Effective treatment of heavy and/or prolonged menstrual bleeding without organic cause: pooled analysis of two multinational, randomised, double-blind, placebo-controlled trials of oestradiol valerate and dienogest. Eur J Contracept Reprod Health Care. 2011;16(4):258-69.
7. Silva-Filho AL, Pereira Fde A, de Souza SS, et al. Five-year follow-up of levonorgestrel-releasing intrauterine system versus thermal balloon ablation for the treatment of heavy menstrual bleeding: a randomized controlled trial. Contraception. 2013;87(4):409-15.
8. de Souza SS, Camargos AF, de Rezende CP, et al. A randomized prospective trial comparing the levonorgestrel-releasing intrauterine system with thermal balloon ablation for the treatment of heavy menstrual bleeding. Contraception. 2010;81(3):226-31.
9. Middleton LJ, Champaneria R, Daniels JP, et al. Hysterectomy, endometrial destruction, and levonorgestrel releasing intrauterine system (Mirena) for heavy menstrual bleeding: systematic review and meta-analysis of data from individual patients. BMJ. 2010;341:c3929.
10. Lethaby A, Duckitt K, Farquhar C. Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev. 2013;1:CD000400.
11. Farquhar C, Brown J. Oral contraceptive pill for heavy menstrual bleeding. Cochrane Database Syst Rev. 2009;(4):CD000154.
12. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility. 7^th Edition. Philadelphia, PA. Lippincott Williams & Wilkins. 2004.
13. Fritz MA, Speroff L. Clinical Gynecologic Endocrinology and Infertility. 8^th Edition. Philadelphia, PA. Lippincott Williams & Wilkins. 2010.
14. DeVore GR, Owens O, Kase N. Use of intravenous Premarin in the treatment of dysfunctional uterine bleeding–a double-blind randomized control study. Obstet Gynecol. 1982;59(3):285-91.
15. Rao KP. Treatment of menstrual disorders with a combination of norgestrel and ethynyl estradiol. Curr Med Pract. 1971;15(1):586-9.
16. Foss GL. A clinical trial of a new totally synthetic low dose progestagen. J Reprod Fertil. 1969;18(1):59-66.
17. DeVore GR, Owens O, Kase N. Use of intravenous Premarin in the treatment of dysfunctional uterine bleeding–a double-blind randomized control study. Obstet Gynecol. 1982;59(3):285-91.
18. Foss GL. A clinical trial of a new totally synthetic low dose progestagen. J Reprod Fertil. 1969;18(1):59-66.
19. Rao KP. Treatment of menstrual disorders with a combination of norgestrel and ethynyl estradiol. Curr Med Pract. 1971;15(1):586-9.
20. Aksu F, Madazli R, Budak E, Cepni L, Benian A. High-dose medroxyprogesterone acetate for the treatment of dysfunctional uterine bleeding in 24 adolescents. Aust N Z J Obstet Gynaecol. 1997;37(2):228-231.
21. Ammerman SR, Nelson AL. A new progestogen-only medical therapy for outpatient management of acute, abnormal uterine bleeding: a pilot study. Am J Obstet Gynecol. 2013;208(6):499.e1-5.
22. American College of Obstetricians and Gynecologists. ACOG Committee Opinion no. 557: Management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. Obstet Gynecol. 2013;121(4):891-6.

Anita Nelson, MD, professor of obstetrics and gynecology at the David Geffen School of Medicine at UCLA, and medical director of the Women’s Health Care Programs, Harbor-UCLA Medical Center