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gynecology

Ovulatory Heavy Menstrual Bleeding

Russ Fothergill, MD; Patricia J. Sulak, MD

New medical therapies are available for heavy menstrual bleeding. These, along with minimally invasive surgical procedures, are effective tools for management of this common condition.

Abnormal uterine bleeding is one of the most common reasons women seek gynecologic care.1,2 There are many etiologies, including hormonal imbalances secondary to hypothalamic/pituitary/ovarian dysfunction, hemostatic issues, and pathologic lesions such as fibroids and polyps. This review will focus on heavy menstrual bleeding (HMB) due to local and systemic hemostatic disorders in ovulatory women.

DEFINITION / ETIOLOGY

Menorrhagia or hypermenorrhea is heavy or prolonged menstrual bleeding in women with ovulatory cycles occurring every 21 to 35 days. This regularly occurring HMB is secondary to loss of hemostatic mechanisms in the endometrium due to local alterations in prostaglandins or systemic hemostatic dysfunction. In order for endometrial hemostasis to properly occur, there must be a balance between vasoconstriction due to prostaglandin F2 alpha and platelet aggregation provided by thromboxane, counterbalanced by vasodilation due to prostaglandin E2 and platelet inhibition provided by prostacyclin. HMB results when there is an increase in the prostaglandin E2 to F2 alpha ratio along with an increase in prostacyclin and decrease in thromboxane. This altered endometrial milieu leads to greater fibrinolysis and hemostatic dysfunction.

HMB in ovulatory women may also be secondary to systemic hemostatic disorders, which may be inherited, acquired, or iatrogenic. The single most common inherited disorder of hemostasis is von Willebrand disease. Inheritance is autosomal dominant with variable penetrance. A prospective study of reproductive-age women with menorrhagia revealed that almost half were found to have hemostatic abnormalities, including platelet dysfunction, von Willebrand disease, and coagulation factor deficiencies.3

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DIAGNOSIS

The diagnosis of ovulatory HMB is primarily subjective. Patients present complaining of heavy and/or prolonged bleeding at regular intervals. The patient’s perception of heavy bleeding often does not correlate with the actual amount of bleeding.4 An exam performed on the patient’s heaviest day of menstrual flow may allow for an objective measure of the amount of bleeding. Prospective data collection of bleeding on a simple menstrual calendar with “S” for spotting, “B” for bleeding, and “H” for heavy flow (having to change a pad/tampon every 1 to 2 hours or less) can also assist with determining degree/number of days of flow. More importantly, the simple menstrual calendar can be used to assess response to treatments.

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EVALUATION

Evaluation of women with HMB should always include assessment of vital signs, pelvic examination, and hemoglobin status. Pregnancy should be ruled out in all patients. Assessment of thyroid function should be considered. Even though hemostatic disorders have been shown to be common in women with HMB, routine extensive coagulation assessment of all patients is not recommended. Evaluation should be considered in patients with a bleeding history during dental procedures or surgery and in those with a family history of bleeding tendencies. In women with risk factors for endometrial neoplasia (eg, obesity, older than 40, nulliparity), endometrial sampling should be performed. While many would consider transvaginal ultrasound (TVUS) as routine in evaluation of HMB, TVUS should be considered if any abnormalities are detected on pelvic examination or if the examination is suboptimal (eg, guarding or obesity). Other indications for endometrial sampling and TVUS include intermenstrual bleeding and/or failure of medical management.

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MEDICAL MANAGEMENT

While anovulatory bleeding can often be simply managed with periodic progestins, treatment of ovulatory HMB can be much more difficult. A variety of medical treatments are available.

NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) given immediately before and during menstruation have been shown to decrease bleeding, but the degree of reduction is not sufficient in the majority of patients with HMB.5 In a randomized study comparing mefenamic acid (500 mg every 8 hours starting on cycle day 1) with the antifibrinolytic tranexamic acid (1 g every 6 hours starting cycle day 1), a statistically significant difference was noted, with a 20% reduction in mean blood loss with mefenamic acid, compared with a 54% reduction with tranexamic acid.6 Other studies have used ibuprofen (400 mg tid), meclofenamate sodium (100 mg tid), and naproxen sodium (275 mg every 6 hours after a loading dose of 550 mg). Finally, Milsom and colleagues demonstrated that the levonorgestrel intrauterine system (LNG-IUS) was most effective in reducing mean blood loss when compared with an NSAID (flurbiprofen 500 mg bid) and with tranexamic acid (1.5 g tid for 3 days, then 1 g bid for 2 days), and it was the only method that reduced mean blood loss below 80 mL.7

Combination OCs

Combination oral contraceptives (OCs) are effective in reducing menstrual blood loss by approximately 50%. In patients with severe HMB, the standard cyclic approach (21/7) may not be adequate. Continuous use of OCs has been shown to be effective in greatly reducing menstrual flow.8,9 Bothersome breakthrough bleeding associated with continuous use of OCs can be effectively managed by taking a 3-day break and resuming active pills.10 Profuse bleeding can be effectively managed in most patients by administering OCs 3 times a day for a week, followed by daily administration.11

Progestins

While 10 to 14 days of low-dose cyclic progestins are effective in the management of anovulatory bleeding, much higher doses and longer intervals are required for management of ovulatory HMB. In one study comparing the LNG-IUS to norethindrone 5 mg tid for 21 days (cycle days 5 to 26), norethindrone reduced blood loss by 87%.12 In another study of patients with HMB, medroxyprogesterone acetate given 20 mg tid for a week followed by 20 mg daily was very effective in halting bleeding.11 While acutely effective, long-term use of oral progestins at these high dosage levels is not practical or well tolerated. Depo-medroxyprogesterone acetate is effective in halting ovarian function and greatly reducing menstrual flow. By 1 year, 60% of patients are amenorrheic, increasing to 80% at 2 years. The main side effect is bothersome breakthrough bleeding.

GNRH Agonists

Gonadotropin-releasing hormone (GNRH) agonists can be beneficial in the management of HMB associated with severe anemia. GNRH agonists such as depot leuprolide 3.75 mg given monthly can be administered along with daily norethindrone 5 mg to inhibit ovarian function and induce amenorrhea. While effective for short-term management in severely anemic patients, long-term use is not practical because of expense.

Antifibrinolytics

The use of antifibrinolytics has been evaluated in the treatment of HMB because of the known importance of fibrinolysis in endometrial hemostasis. In particular, tranexamic acid and its precursors have been found to be effective in reducing menstrual blood loss. In clinical trials, tranexamic acid reduced menstrual blood loss by 45% to 54%.13 Antifibrinolytics are a mainstay for treatment of ovulatory abnormal uterine bleeding in most of the world but not in North America, because of concerns about the possibility of an increased risk for thromboembolic events. One retrospective study in a large cohort of women at enhanced risk for thromboembolic disease failed to show an association between administration of tranexamic acid and thromboembolic events.14 Clinical trials have been completed in the United States, with the FDA giving approval in November 2009 for tranexamic acid as a treatment for HMB.

LNG-IUS

A major addition to the armamentarium of medical management of ovulatory HMB has been the LNG-IUS. While equally effective to sterilization in preventing pregnancy, the LNG-IUS adds the additional benefit of greatly reducing HMB. Numerous studies have shown equality or superiority when compared to other medical management and even to endometrial ablation.12,15 One year after insertion, average blood loss decreased by more than 80%, with 20% of patients achieving amenorrhea. In October 2009, the LNG-IUS was approved by the FDA for treatment of HMB in women needing contraception.

Estrogen

Although single-agent IV conjugated equine estrogens have been shown to effectively treat acute uterine bleeding, they are not practical for long-term management of HMB.16 Most patients will need to be converted to one of the aforementioned regimens, such as a combination OC.

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Surgical Management

Dilation and curettage

Dilation and curettage (D&C) is rarely required for management of acute profuse HMB that has failed medical management. Menstrual cycles that follow a successful D&C are similar to those prior to curettage, thus making it an ineffective sole treatment choice for HMB.17

Endometrial ablation

Endometrial ablation is indicated for the treatment of menorrhagia in the premenopausal patient who has completed childbirth.18 Anemia, failure or intolerance of medical therapy, or a contraindication to medical therapy is an indication for endometrial ablation but should not be considered an absolute prerequisite. While hysteroscopic methods of ablation or resection of the endometrium have proven to be durable and effective, the introduction of global endometrial ablation technology over the past decade has revolutionized the treatment of HMB. These minimally invasive treatment options have fewer risks than traditional procedures, are faster, and have shorter recovery times for patients.19,20 The 5 FDA-approved global devices use a variety of energy sources to achieve endometrial destruction, each designed to ablate down to the basal layer to prevent regeneration and subsequent menstrual flow. A detailed discussion of each device is beyond the scope of this article, but it is worth emphasizing that each technology can be successfully performed in the office setting.21 While endometrial ablation has been shown to have higher success and patient satisfaction rates when compared to oral medical therapy, the long-term satisfaction rates of the LNG-IUS were similar to endometrial ablation after 2 to 3 years.22,23

Hysterectomy

Hysterectomy remains the second most common surgical procedure performed in the United States.24 While rates and route vary by region, the overall rate of hysterectomy has been stable for decades. Roughly one-third of hysterectomies are performed for treatment of leiomyomata, the most common indication.25 Treatment of abnormal uterine bleeding and “menstrual disorders” is the second most common. While hysterectomy has more adverse events when compared to endometrial ablation, as many as one-third of patients who receive ablation may require a return trip to the operating room for a failed procedure.26

The technique used for hysterectomy should be dictated by the indications, patient examination findings and characteristics, and patient and physician preference.27 When feasible, patients should be offered the vaginal route because the morbidity appears to be lower than with any other method.28

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Conclusion

HMB is an important gynecologic concern for many premenopausal women. Etiologies vary, and treatment options should be tailored to specific anatomic, hormonal, or hemostatic abnormalities. Armed with new medical therapies and the advent of minimally invasive surgical procedures, clinicians can be well prepared to manage HMB effectively in their patients.

The authors report no actual or potential conflict of interests in relation to this article.

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Russ Fothergill, MD, is Assistant Professor, Department of Obstetrics and Gynecology, and Vice Chairman and Director, Division of Ambulatory Care Residency Program; Patricia J. Sulak, MD, is Dudley P. Baker Endowed Professor of Research and Education, Medical Director, Division of Research, and Director, Adolescent Sexual Health Program. They are both at Scott and White Hospital, Temple, Texas. Dr Sulak is an Associate Editor of The Female Patient.

References

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