Strategizing treatment for chronic heavy menstrual bleeding

 

Can you stop her flooding? About 30% of women report heavy menstrual bleeding (HMB). For many of them, that flooding is chronic. There are several treatment options for chronic HMB, but how do they compare over the long run? Any treatment needs to account for the age of the patient, the severity of symptoms, the presence of other pelvic pathology, and near-term plans for childbearing. Which are the clear front-runners in the treatment strategy? And what about new therapies coming down the pipeline? Anita Nelson and Lee Shulman describe a framework for choosing the most effective treatments.[1]

Although the differential diagnoses of causes of HMB is extensive, the definition of what constitutes HMB need not be. A key factor in making a diagnosis of HMB is not only the amount of blood being lost, which is difficult to quantify, but how much HMB disrupts one’s life. Only about half of patients will be found to have any identifiable anatomical pathology. Patients with HMB more often have functional problems such as coagulopathy, excessive fibrinolysis, prostaglandin imbalances, vessel instability, or systemic causes.

Table 1. PALM-COEIN classification system for abnormal nongestational uterine bleeding

 

Treatment options

Treatment for chronic HMB can be directed to correct the pathophysiology underlying HMB or it can simply attempt to suppress the endometrium, especially if there are only local causes for the HMB, explain Drs. Nelson and Shulman.

Hormonal Therapies

Hormonal therapies are also available and are more effective than nonhormonal medications in treating HMB.[2] Progestins form the basis of hormonal therapies to effectively control chronic excessive menstrual blood loss.

• The LNG intrauterine contraceptive is the most effective medical therapy for HMB and in many cases it is more effective than procedures such as ablation and hysterectomy (for more detail, see below).[3] The LNG-IUS 20 (Mirena) is approved for the treatment of HMB by the U.S. FDA and by regulatory authorities in over 100 other countries. In clinical trials of women with HMB documented by eluting hemoglobin from sanitary pads, women who randomized to this LNG intrauterine contraceptive had a median reduction in blood loss of 62% by 3 months and a 71% reduction by 6 months.[4] The LNG-IUS is also effective for controlling bleeding from most of the PALM-COEIN causes of HMB[5] (see Table 1) and is effective in women using oral anticoagulant therapy.[6] It is also the most effective medical therapy for endometrial hyperplasia and it reduces HMB and pain due to adenomyosis.[7]
• Cyclic progestin (medroxyprogesterone acetate (MPA) 10 mg or norethindrone acetate (NETA) 5 mg) daily for 10 days a month is most useful for patients with chronic anovulation. Unexpectedly, these luteal phase therapies can increase blood loss in women who ovulate and have monthly cycling.
• Progestin-only pills, progestin injections, and progestin-containing intrauterine contraceptives offer variable control of bleeding as well as contraceptive protection. The progestin-only pill (POP) decreases estrogen-stimulated endometrial proliferation.
• DMPA initially increases unscheduled spotting and bleeding, but over the longer term, it usually results in cessation of spotting and bleeding.[8] DMPA is a first-line treatment for patients with underlying bleeding disorders.
• Oral combined contraceptive. There is one product (Natazia) that is approved by the FDA for treatment of heavy or prolonged menstrual bleeding. In clinical trials of this estradiol valerate (E2V)/dienogest multiphasic pill, the reduction in blood loss reduction was almost as great as that seen in the U.S. clinical trials of Mirena for treatment of HMB.[9] However, other COC formulations are routinely used off-label to reduce cyclic bleeding. Most of the studies demonstrating clinical efficacy of COCs in the treatment of HMB are based on higher dose formulations, but there is one clinical trial of a 20 mcg EE pill that reduced menstrual blood loss by 68%.[10]
• Contraceptive vaginal ring (NuvaRing). Cyclic use has been found to be more effective than COCs in treating HMB because it offered better cycle control.[11]
• Extended-cycle COCs or vaginal rings also reduces total blood loss in patients with HMB by reducing the numbers of episodes of scheduled bleeding as well as the amount of blood lost per episode.[12]^,[13]
• Other agents that are effective for short-term use include GnRH agonists, such as leuprolide acetate (Lupron), nafarelin acetate (Synarel) and goserelin acetate (Zoladex), or buserelin (Suprecur). Pseudomenopause is induced after about two weeks of use and amenorrhea rates approach 90%.[14] Because of concerns about osteoporosis and other hypoestrogenic conditions, the duration of GnRH agonists use is generally limited to 4 to 6 months unless an estrogen-progestin add-back is given.

Nonhormonal therapies

• NSAIDS.     When taken from the onset of menses until the end of the heavy flow days, NSAIDs can reduce total menstrual blood loss by 20% to 45% and offer the additional benefit of analgesia for pain associated with uterine cramping. A Cochrane Systematic Database Review demonstrated that blood loss reduction was not affected by the particular NSAID used, but found that low-dose NSAIDs were far less effective than high-dose regimens.[15] NSAIDs can also be used in conjunction with other therapies (such as hormonal therapies) to boost the efficacy of those treatments. Patients with peptic ulcers and those who have coagulation disorders should avoid NSAIDs or couple the therapy with proton-pump inhibitors (PPIs).
• Antifibrinolytic agents. The antifibrinolytic agent, tranexamic acid, has been used in Europe for treatment of HMB for more than 3 decades and is available over-the-counter in some of those countries. In clinical trials, women who used this tranexamic acid regimen (650 mg 2 tabs orally 3 times a day for up to the first 5 days of menses) experienced a 40% reduction in menstrual blood loss.[16] Reflecting previous theoretical concerns that drugs that block lysis of fibrin clots might create a hypercoagulable state, the FDA labeling for Lysteda advises caution in prescribing this product for women who use hormonal contraceptives (presumably only those with estrogen). These agents can also be helpful in women with von Willebrand disease especially in conjunction with hormonal treatments.[17]

Procedures

• Outpatient endometrial ablation has been popular for the treatment of HMB. At their peak, ablations were almost as common as hysterectomies in the United States. Compared with endometrial ablation, the high-dose LNG IUS has a better record of cost, safety, and reversibility, making it a first-line therapy, and there is no difference in efficacy of endometrial ablation and LNG intrauterine therapy.[18]
• Hysterectomy is the ultimate therapy, but studies have also demonstrated a comparable benefit of the high-dose LNG IUS compared to hysterectomy as first-line therapy for women with HMB who have no other pelvic pathology. One randomized 10-year study comparing LNG IUD use to hysterectomy found that 54% of women who randomized to the LNG IUD avoided surgery.[19] Reserving hysterectomy for use only in women with pelvic pathology and to those who do not respond to LNG IUD therapy would significantly reduce health care costs and risks associated with treatment of HMB.
• Several other procedures are approved for treatment of women with symptomatic fibroids, including myomectomy, uterine artery embolization of leiomyoma, cryotherapy, and ultrasonic destruction of leiomyoma, etc.

 

In the Pipeline

Newer medical therapies to treat HMB related to leiomyoma may become available in the United States. Selective progesterone receptor modulation (SPRMs) exerts partial progesterone antagonistic effects while maintaining estradiol levels, thus avoiding hypoestrogenism seen with many other hormonal therapies.[20] Characteristic histologic changes seen in the endometrium called PAEC (progesterone receptor modulator associated endometrial changes) look like hyperplasia, but these changes apparently do not have the potential for malignancy. In particular, low-dose ulipristal acetate (UPA) has been found to be very effective in establishing amenorrhea in patients with fibroid-induced anemia to increase hemoglobin prior to myomectomy. Long-term use is being investigated.[21]^, [22]

 

 

 

[1] Nelson A, Shulman L.   Menstrual Cycle: Normal Patterns, Menstrual Disorders, and Menstrually-Related Problems. In: Hatcher RA, Nelson AL, Trussell J, Cwiak C, Cason P, Policar MS, Edelman A, Aiken ARA, Marrazzo J, Kowal D, eds. Contraceptive technology. 21st ed. New York, NY: Ayer Company Publishers, Inc., 2018.

[2] Bradley LD, Gueye NA. The medical management of abnormal uterine bleeding in reproductive-aged women. Am J Obstet Gynecol 2016;214:31–44.

[3] Lethaby A, Hussain M, Rishworth JR, Rees MC. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2015;(4):CD002126.pub3.

[4] Kaunitz AM, Bissonnette F, Monteiro I, Lukkari-Lax E, Muysers C, Jensen JT. Levonorgestrel-releasing intrauterine system or medroxyprogesterone for heavy menstrual bleeding: a randomized controlled trial. Obstet Gynecol 2010;116:625–32.

[5] ACOG Committee on Adolescent Health Care; Committee on Gynecologic Practice. Committee Opinion No.580: von Willebrand disease in women. Obstet Gynecol 2013;122:1368–73.

[6] Braga GC, Brito MB, Ferriani RA, et al. Oral anticoagulant therapy does not modify the bleeding pattern associated with the levonorgestrel-releasing intrauterine system in women with thrombophilia and/or a history of thrombosis. Contraception 2014;89:48–53.

[7] Abu Hashim H, Ghayaty E, El Rakhawy M. Levonorgestrel–releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials. Am J Obstet Gynecol 2015;213:469–78.

[8] Maybin JA, Critchley HO. Medical management of heavy menstrual bleeding. Womens Health (Lond) 2016;12:27–34.

[9] Maybin JA, Critchley HO. Medical management of heavy menstrual bleeding. Womens Health (Lond) 2016;12:27–34.

[10] Endrikat J, Shapiro H, Lukkari-Lax E, Kunz M, Schmidt W, Fortier M. A Canadian, multicentre study comparing the efficacy of a levonorgestrel-releasing intrauterine system to an oral contraceptive in women with idiopathic menorrhagia. J Obstet Gynaecol Can 2009;31:340–7.

[11] Dahiya P, Dalal M, Yadav A, Dahiya K, Jain S, Silan V. Efficacy of combined hormonal vaginal ring in comparison to combined hormonal pills in heavy menstrual bleeding. Eur J Obstet Gynecol Reprod Biol 2016;203:147–51.

[12] Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception 2003;68:89–96.

[13] Miller L, Verhoeven CH, Hout J. Extended regimens of the contraceptive vaginal ring: a randomized trial. Obstet Gynecol 2005;106:473–82.

[14] Maybin JA, Critchley HO. Medical management of heavy menstrual bleeding. Womens Health (Lond) 2016;12:27–34.

[15] Lethaby A, Duckitt K, Farquhar C. Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev 2013:CD000400.pub3.

[16] Lukes AS, Moore KA, Muse KN, et al. Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial. Obstet Gynecol 2010;116:865–75.

[17] Leebeek FW, Eikenboom JC. Von Willebrand’s disease. N Engl J Med 2016;375:2067–2080.

[18] Kaunitz AM, Meredith S, Inki P, Kubba A, Sanchez-Ramos L. Levonorgestrel-releasing intrauterine system and endometrial ablation in heavy menstrual bleeding: a systematic review and meta-analysis. Obstet Gynecol 2009;113:1104–16.

[19] Heliövaara-Peippo S, Hurskainen R, Teperi J, et al. Quality of life and costs of levonorgestrel-releasing intrauterine system or hysterectomy in the treatment of menorrhagia: a 10-year randomized controlled trial. Am J Obstet Gynecol 2013;209:535.e1–535.e14.

[20] Donnez J, Donnez O, Matule D, et al. Long-term medical management of uterine fibroids with ulipristal acetate. Fertil Steril 2016;105:165–173.e4.

[21] Safrai M, Chill HH, Reuveni Salzman A, Shushan A. Selective progesterone receptor modulators for the treatment of uterine leiomyomas. Obstet Gynecol. 2017;130:315–318.

[22] Archer DF, Stewart EA, Jain RI, et al. Elagolix for the management of heavy menstrual bleeding associated with uterine fibroids: results from a phase 2a proof-of-concept study. Fertil Steril 2017;108:152–160.e4.