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Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management

Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management
Literature review current through: Jan 2024.
This topic last updated: Jan 16, 2024.

INTRODUCTION — Abnormal uterine bleeding (AUB), a term that refers to menstrual bleeding of abnormal quantity, duration, or schedule, is a common gynecologic problem. Heavy or prolonged uterine bleeding can result in anemia, interfere with daily activities, and is the most common presenting symptom in patients with endometrial hyperplasia or carcinoma. It may also be a sign of an underlying bleeding disorder.

Most patients with AUB requiring medical attention can be managed in an outpatient setting. Occasionally, an exacerbation of AUB is severe enough to necessitate emergency medical care.

The management of non-acute AUB in nonpregnant reproductive-age patients will be reviewed here. Other related topics are discussed separately:

Evaluation and diagnosis of AUB (see "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis")

Management of acute AUB (see "Managing an episode of acute uterine bleeding")

Evaluation and management of AUB in adolescents (see "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis" and "Abnormal uterine bleeding in adolescents: Management")

Vaginal bleeding during pregnancy (see "Evaluation and differential diagnosis of vaginal bleeding before 20 weeks of gestation")

Postmenopausal bleeding (see "Approach to the patient with postmenopausal uterine bleeding")

TERMINOLOGY — AUB encompasses a heterogeneous group of conditions with diverse etiologies. The International Federation of Gynecology and Obstetrics (FIGO) classification system includes two systems for AUB: FIGO system 1 for the nomenclature and definitions of normal and abnormal uterine bleeding, and FIGO system 2 for the classification of the causes of AUB [1,2]. The latter is referred to by the acronym PALM-COEIN (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not yet classified). These are summarized in the graphics (table 1 and figure 1) and discussed in detail separately.

MANAGEMENT GOALS — The main goals of AUB management are as follows:

Correct or treat the underlying primary etiology, if present and feasible.

Improve quality of life.

Prevent an episode of acute uterine bleeding.

Prevent, or treat, anemia.

Establish a regular bleeding pattern (or amenorrhea).

Prevent endometrial hyperplasia/carcinoma.

CONSIDERATIONS PRIOR TO INITIATING TREATMENT — To help determine which treatment is best for a particular patient, clinicians should consider several patient factors. These include:

Etiology, if known. The timing of initiating treatment of AUB should be individualized. In patients in whom AUB is not interfering with daily activities, it may be appropriate to delay initiation of treatment until results of diagnostic testing (eg, blood count, imaging, endometrial biopsy) are available. (See 'Patients with a known primary etiology' below and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis", section on 'Endometrial sampling: Choice of modality' and "Overview of the evaluation of the endometrium for malignant or premalignant disease", section on 'Premenopausal patients with abnormal bleeding'.)

By contrast, when AUB is interfering with daily activities and/or marked anemia is present, it is appropriate to immediately initiate treatment, as detailed below, while pursuing diagnostic testing. (See 'Treatment selection' below.)

Severity of bleeding. Most patients with AUB requiring medical attention can be managed in an outpatient setting. By contrast, patients with an episode of acute uterine bleeding may require urgent evaluation in an emergency department. (See "Managing an episode of acute uterine bleeding".)

Associated symptoms and issues. AUB is often associated with other symptoms (eg, pelvic pain/pressure, dysmenorrhea) or issues (eg, infertility); the underlying etiology (eg, adenomyosis, uterine fibroid) should be identified to select the optimal treatment approach. Patients with a bleeding disorder may have a history of other bleeding (eg, nose bleeds, bruising, excessive bleeding after a dental procedure) that they may not report to their gynecologist. (See 'Patients with a known primary etiology' below.)

Contraceptive needs and plans for future pregnancy. Many treatments for AUB also provide contraception. However, for patients trying to conceive, or those desiring pregnancy in the near future, some treatments (eg, levonorgestrel intrauterine device [IUD], depot medroxyprogesterone acetate [DMPA]) should be avoided. (See 'Patients trying to conceive' below.)

Medical comorbidities. Some treatments (eg, estrogen-progestin contraceptives) are contraindicated in patients with comorbidities (eg, elevated risk for venous thromboembolic disease and/or arterial thrombotic events). (See 'Preferred approach for most patients' below.)

Patient preferences regarding, as well as access to, medical versus surgical and short-term versus long-term therapy.

Time to menopause. AUB should resolve when a patient becomes menopausal (which occurs, on average, at the age of 51.5 years), and time to menopause may affect management decisions. (See "Clinical manifestations and diagnosis of menopause", section on 'Menopause'.)

Expectant management may be reasonable for some patients (eg, not anemic, do not desire treatment, approaching menopause). Such patients require close follow-up (eg, ferritin level every 6 to 12 months for patients with heavy menstrual bleeding (HMB), repeat endometrial assessment for patients at risk for hyperplasia/neoplasia).

TREATMENT SELECTION —  (algorithm 1)

Patients with a known primary etiology — Treatment of certain underlying conditions may correct the AUB or make further treatment more effective. These include structural lesions (eg, submucosal fibroids, polyps), endocrine (eg, polycystic ovarian syndrome), infectious (eg, chronic endometritis), or bleeding disorders.

Structural lesions

Submucosal fibroids are a common cause of heavy menstrual bleeding (HMB) and can be treated with medical or surgical therapies. (See "Uterine fibroids (leiomyomas): Treatment overview".)

Endometrial polyps are a common cause of AUB and are typically easily removed with hysteroscopic polypectomy. (See "Endometrial polyps".)

Adenomyosis is a common cause of HMB and dysmenorrhea; while hysterectomy is the definitive treatment, medical or other surgical therapies may also be effective. (See "Uterine adenomyosis".)

Cesarean scar defects (CSD; also referred to as isthmocele or niche) is an increasingly common cause of AUB.

CSD can be surgically resected via operative hysteroscopy, vaginal surgery, laparotomy/laparoscopy, or a combined approach (which allows visualization of the defect from two perspectives). In one meta-analysis including randomized trials and observational studies of surgical treatment for CSD, those undergoing a combined approach with laparoscopy and hysteroscopy compared with vaginal surgery or hysteroscopy alone had a greater reduction in the duration of AUB [3].

Arteriovenous malformations (AVMs) represent a rare cause of AUB. (See "Causes of female genital tract bleeding", section on 'Not otherwise classified (AUB-N)'.)

If bleeding is severe, initial management consists of hemodynamic stabilization with intrauterine tamponade (eg, with a balloon or packing material) followed by uterine artery embolization (UAE (image 1A-E)). While UAE appears to be safe and effective [4-7], and both restoration of normal menstrual cycles and subsequent successful pregnancies have been reported, patients should be counseled that embolization may result in impaired fertility and the safety of pregnancy after embolization is uncertain [8,9]. Laparoscopic bipolar coagulation of the uterine vessels has also been successful in case reports [10]. (See "Managing an episode of acute uterine bleeding", section on 'Role of uterine artery embolization'.)

Hysterectomy is the definitive treatment option in patients in whom childbearing is complete [11].

The management of enhanced myometrial vascularity (EMV), a diagnostic entity distinct from AVM and occurring in the setting of pregnancy and retained products of conception, is discussed in detail separately. (See "Retained products of conception in the first half of pregnancy", section on 'Management' and "Secondary (late) postpartum hemorrhage", section on 'Management'.)

Infection — AUB in patients with suspected or documented chronic endometritis often resolves following a course of antibiotics. (See "Endometritis unrelated to pregnancy".)

Endocrine abnormalities — Endocrine abnormalities (eg, hypothyroidism, hyperprolactinemia) may cause anovulatory bleeding (AUB-O), and treatment often restores regular ovulatory cycles; treatment of other endocrine abnormalities (eg, polycystic ovarian syndrome) can also help decrease the risk of endometrial hyperplasia or carcinoma [12-15]. (See "Treatment of primary hypothyroidism in adults" and "Management of hyperprolactinemia" and "Treatment of polycystic ovary syndrome in adults".)

Bleeding disorders — HMB is a common finding in females with a bleeding disorder. Generally, therapy tailored to the bleeding disorder is preferable to other medical or surgical therapies for AUB [16,17]. (See "Causes of female genital tract bleeding", section on 'Coagulopathy (AUB-C)' and "von Willebrand disease (VWD): Gynecologic and obstetric considerations", section on 'Interventions for HMB'.)

Patients without a known etiology — While many patients with AUB will be diagnosed with a primary etiology (see 'Patients with a known primary etiology' above), patients without a primary etiology also have AUB. Initial management of such patients typically consists of progestin-based treatments including combination oral contraceptives (OCs) or the 52 mg levonorgestrel-releasing intrauterine device (LNG 52 mg IUD, Mirena or Liletta (algorithm 1)). Alternatives for selected patients include progestin-only oral or injectable medications, nonhormonal therapies, minimally invasive surgery, or definitive treatment with hysterectomy; however, surgical options are limited in patients who desire future childbearing.

Preferred approach for most patients — For most patients with AUB and no known primary etiology, we suggest estrogen-progestin contraceptives or the LNG 52 mg as first-line therapy. Both estrogen-progestin contraceptives and the LNG 52 mg are effective treatments for AUB, provide effective contraception, are well tolerated, and have a low risk of adverse effects. (See 'Estrogen-progestin contraceptives' below and 'Levonorgestrel intrauterine device' below.)

How to choose — The choice between the two methods depends on several factors:

Patients with a contraindication to estrogen – For patients with a contraindication to contraceptive doses of estrogen, estrogen-progestin contraceptives are not an option; this includes patients with the following characteristics [18,19]:

Age ≥35 years and smoking ≥15 cigarettes per day.

Multiple risk factors for arterial cardiovascular disease (such as older age, smoking, diabetes, and hypertension). Because age and obesity represent independent risk factors for venous thromboembolism (VTE) [20,21], in our practice, we also avoid estrogen-progestin contraceptives in patients ≥40 years of age with obesity.

Hypertension.

VTE.

Known thrombogenic mutations.

Known ischemic heart disease.

History of stroke.

Complicated valvular heart disease (pulmonary hypertension, risk for atrial fibrillation, history of subacute bacterial endocarditis).

Systemic lupus erythematosus (positive or unknown antiphospholipid antibodies).

Migraine with aura at any age.

The LNG 52 mg is often appropriate for such patients, but medical consultation may be required prior to use. The LNG 52 mg results in a low level of systemic progestin absorption and its use has not been associated with an elevated risk of VTE in average-risk patients [22]. The LNG 52 mg also does not appear to increase the risk of VTE in patients with elevated risk of thrombosis [23]. In a case-control study including reproductive age patients with (21,405) and without (107,025) VTE, current use of LNG 52 mg compared with non-use was associated with similar rates of VTE; results were also similar after controlling for 16 VTE risk factors (including, but not limited to, BMI ≥30 kg/m2, smoking, hypertension, and superficial venous thrombosis) [24]. (See "Contraception: Counseling for women with inherited thrombophilias", section on 'Progestin-only methods'.)

Patient preference – For other patients, the choice is often based on patient preference. Patients may prefer estrogen-progestin contraceptives if they prefer taking a daily oral medication, regular bleeding, or are planning to conceive in the near future. By contrast, patients may prefer the low maintenance of having an IUD or are willing to tolerate the irregular bleeding that initially accompanies placement of a LNG 52 mg given the subsequent light bleeding or amenorrhea that often occurs. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Counseling points' and "Intrauterine contraception: Candidates and device selection", section on 'Reasons to choose an LNG IUD'.)

In systematic reviews and a meta-analysis including randomized trials, the LNG 52 mg reduced menstrual blood loss more than other medical treatments, however, the certainty of this evidence was low [25-29]. In one review including patients with HMB, placement of a LNG 52 mg resulted in a greater reduction in menstrual blood loss (71 to 95 percent reduction) than estrogen-progestin contraceptives (35 to 69 percent reduction) [26].

Estrogen-progestin contraceptives — For many patients with AUB, estrogen-progestin contraceptives are first-line management. The advantages of estrogen-progestin contraceptives are that they typically make bleeding more regular, lighter, and reduce dysmenorrhea, as well as provide contraception. Randomized trials including patients with AUB have shown improvement in bleeding patterns compared with placebo (47 versus 9 percent) [25], and reductions in menstrual blood loss ranging from 35 to 69 percent [26].

The only OC approved by the US Food and Drug Administration (FDA) for treatment of HMB is estradiol-dienogest (Natazia; includes 2 to 3 mg of estradiol valerate [dose varies and is equivalent to 1.5 to 2.25 mg of micronized oral estradiol or <20 mcg of ethinyl estradiol [30]]), which has 26 hormonally active tablets per each 28-day pill pack. In a randomized placebo-controlled trial including 190 patients with AUB (more than three-quarters of whom had documented HMB; the remainder had prolonged or frequent bleeding), estradiol-dienogest compared with placebo reduced menstrual blood loss in more patients (64 versus 8 percent) [31].

In addition to estradiol-dienogest, there are many other formulations of estrogen-progestin contraceptives that vary by the type, dose, route, and schedule (table 2); it appears that most formulations are effective for treating HMB, and for regulating bleeding and providing endometrial protection in patients with AUB-O:

By type – While many other OC types are available, they have not been directly compared with estradiol-dienogest; thus, it is uncertain whether estradiol-dienogest has greater efficacy than other OCs in reducing menstrual blood loss in patients with HMB. OCs with shorter hormone-free intervals are associated with less withdrawal bleeding than formulations with seven hormone-free days per 28-day pill pack [32]. Although further study is needed to determine which OC formulations are more effective in treating HMB, our preference is to use formulations with four or fewer hormone-free days per pill pack.

By route – Other routes of administration include the transdermal contraceptive patch (eg, Xulane, Twirla) and vaginal contraceptive ring (eg, NuvaRing, Annovera). Although these have not been studied extensively for HMB, it is likely that the efficacy of these in treating AUB is similar to OCs, and the choice of delivery system depends on patient preference [33]. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)

By schedule – Estrogen-progestin contraceptives may be prescribed in a cyclic (with a monthly withdrawal bleed), extended (eg, with a withdrawal bleeding every three months), or continuous (no withdrawal bleed) regimen. Although extended or continuous contraceptive use may more effectively suppress menstrual blood loss, unscheduled (breakthrough) bleeding is more common with this approach than with cyclic dosing, limiting this strategy's appeal for some patients. In clinical trials performed in patients with normal menses, extended-cycle OC formulations that replace hormonally inactive tablets with low-dose ethinyl estradiol, a formulation which also modifies the ethinyl estradiol dose during each three-month pill pack, appear to reduce unscheduled bleeding [34,35]. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Hormone components' and "Hormonal contraception for menstrual suppression".)

Estrogen-progestin contraceptives are contraindicated in patients who are at elevated risk for thrombosis. (See 'Preferred approach for most patients' above.)

Levonorgestrel intrauterine device — For patients with HMB who do not desire pregnancy in the near future, or for those with a contraindication to estrogen, the LNG 52 mg is often used as first-line management [36], and is approved by the FDA for this indication [37,38]. Further study is needed to determine the efficacy of other progestin IUDs (eg, 19.5 mg and 13.5 mg LNG devices) in treating HMB [39]. (See "Intrauterine contraception: Background and device types" and "Intrauterine contraception: Candidates and device selection".)

Factors specific to treatment of HMB with the LNG 52 mg include:

Reduction of bleeding – Most patients using the LNG 52 mg develop scant bleeding or amenorrhea, and some studies suggest this treatment, compared with other hormonal or nonhormonal treatments, is associated with an improved quality of life [40-42]. In studies of patients with HMB, within three months of IUD placement, most patients experience spotting [43-45]. At six months, menstrual suppression is substantially greater, with most patients experiencing amenorrhea or infrequent bleeding; median hemoglobin and ferritin levels also increased from baseline (7.5 and 68.8 percent, respectively). In one retrospective study including 89 patients with HMB in whom follow-up data were available, treatment with the LNG 52 resulted in a median decrease in blood loss of 93 and 98 percent at three and six months, respectively [42]. Results were similar for patients with body mass index (BMI) <30 compared with ≥30 kg/m2 and for nulliparous compared with parous patients.

Furthermore, users of the LNG 52 mg require fewer subsequent additional interventions. In one large observational study, increasing use of the LNG 52 mg (a 14-fold increase over 22 years) was accompanied by a decrease in use of oral tranexamic acid, oral progestogen, and hysterectomy [46]. These observations underscore the efficacy of the LNG 52 mg in preventing and/or treating AUB.

Risk of expulsion – Expulsion rates are higher in patients using the LNG 52 mg for treatment of HMB compared with those using the device specifically for contraception (up to 20 versus 10 percent, respectively) [47,48]. For patients with adenomyosis, one study reported a 25 percent expulsion rate with the LNG 52 mg [49]. Package labeling for the LNG 52 mg lists congenital or acquired distortion of the endometrial cavity (eg, by fibroids) as a contraindication to placement of this IUD. Nonetheless, in patients with HMB who wish to avoid surgery or in whom the risk of surgical complications is elevated, use of the LNG 52 mg may be appropriate in well-counseled patients. When placing the LNG 52 mg in patients with a distorted endometrial cavity, some clinicians use abdominal ultrasound guidance to ensure optimal placement.

Frequency of replacing the device – When the LNG 52 mg is used to treat HMB, it is approved by the FDA for five years [37,38]. By contrast, when the LNG 52 mg is used for contraception, it is approved for eight years. Thus, menstrual suppression may attenuate before it needs to be removed for contraception, and patients using the LNG 52 mg for treatment of HMB may benefit from more frequent removal and replacement of the device [36]. The need for more frequent replacement may reflect declining intrauterine progestin concentrations during use of this device. (See "Intrauterine contraception: Background and device types".)

Other patients

Patients who cannot or choose not to use a preferred method — For patients who choose not to, or cannot, use a preferred method, alternatives include other progestin-therapies (eg, oral progestins, depot medroxyprogesterone acetate [DMPA]), noncontraceptive doses of estrogen-progestin, and nonhormonal therapies (eg, tranexamic acid, nonsteroidal antiinflammatory drugs [NSAIDs]). While oral or injectable progestin-only therapies are also reasonable first-line treatment options, they often initially result in irregular menses and are associated with side effects (eg, dysphoria, bloating, increased appetite) that some patients find bothersome. Thus, these medications tend to be used as an alternative to estrogen-progestin contraceptives or LNG 52 mg for selected patients.

Such medical treatments reduce menstrual blood loss less than the LNG 52 mg (see 'Preferred approach for most patients' above). In one systematic review of randomized trials, the percent reduction of menstrual blood loss by treatment method was as follows: LNG 52 mg: 71 to 95 percent reduction; cyclical oral progestins: 87 percent reduction; tranexamic acid: 26 to 54 percent reduction; and NSAIDs: 10 to 52 percent reduction [26]. Similarly, a subsequent systematic review showed the largest reduction of menstrual blood loss with the LNG 52 mg (mean difference [MD] -106 mL/cycle) compared with antifibrinolytic (MD -80 mL/cycle), oral progestin (MD -77 mL/cycle), and NSAID (MD -41 mL/cycle) therapy [29].

Other progestin-only therapies — Other progestin therapies (ie, oral progestins, DMPA) are less well studied for the treatment of AUB.

Oral progestin formulations (eg, norethindrone acetate [NETA], medroxyprogesterone acetate [MPA]) are generally used to treat AUB in patients who have contraindications to, or prefer to avoid, estrogen and who prefer not to use, or do not have access to, the LNG 52 mg, or patients who desire pregnancy in the near future (see 'Patients trying to conceive' below). Package labeling for such oral progestins list a history of VTE as a contraindication to use as they are partially metabolized to ethinyl estradiol [50], which may elevate risk of VTE; thus, medical consultation may be helpful to determine VTE risk. In the case-control study discussed above (see 'Preferred approach for most patients' above), use of NETA or MPA was associated with higher rates of VTE compared with non-use (adjusted odds ratio [aOR] 3, 95% CI 2.17-4.15 and 1.98, 95% CI 1.53-2.58, respectively) [24].

Dose – The dose of such progestins varies and includes NETA 5 mg orally one to three tablets daily and MPA 5 to 30 mg orally daily. In our practice, we typically start with NETA 5 mg once daily; higher doses within these ranges are typically used in patients with obesity. If bleeding does not resolve, the dose is increased (eg, NETA: by 5 mg increments every one to three months to a maximum dose of 15 mg/day; MPA: by 5 to 10 mg increments every one to three months to a maximum dose of 30 mg/day), and the LNG 52 mg should be more strongly considered (see 'Levonorgestrel intrauterine device' above). In patients in whom bleeding resolves, we slowly taper the dose down (eg, NETA: by 2.5 mg increments every month as tolerated; MPA: by 5 mg increments every month as tolerated), to reduce side effects and risk of VTE. Similarly, if cost or side-effect considerations in a specific patient preclude use of one agent, the other agent may be used.

Most data about use of oral progestins for HMB have evaluated NETA, and compared with MPA, it is substantially more potent in promoting endometrial suppression [51]. In one study, the potency of NETA was ten times that of MPA [52].

Schedule – While there are no high-quality data comparing cyclic and continuous progestin therapy for treatment of AUB, we can extrapolate from the LNG 52 mg and DMPA that continuous progestin regimens effectively reduce uterine bleeding. In our experience, we find that continuous rather than cyclical progestin therapy is more effective at reducing blood loss and easier for patients to comply with. Cyclic regimens may be used in select patients (eg, cannot tolerate a continuous regimen, trying to conceive). (See 'Patients trying to conceive' below.)

In a mixed population of older reproductive-age patients with AUB-O or HMB, one study found that oral MPA5 mg tablets administered continuously for two months reduced menstrual blood loss by 33 percent [53]. By contrast, a systematic review including six randomized trials evaluating oral progestins administered cyclically for 7 to 11 days each month did not find this regimen to be effective in ovulatory patients with HMB [54]. However, longer cyclic therapy (eg, 21 days each month) may be effective [33,55] and result in moderate, predictable withdrawal bleeding.

The contraceptive efficacy of these regimens has not been evaluated, and a back-up method (eg, barrier contraceptives) is recommended if needed.

DMPA is typically used for patients with AUB who have contraindications to, or prefer to avoid, estrogen and who prefer not to use, or do not have access to, the LNG 52 mg, or if they prefer this method of contraception. Some data suggest an increased risk of thrombosis with DMPA [24,56,57]. This is discussed in more detail separately. (See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits", section on 'Cardiovascular and thromboembolic risk' and "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration".)

DMPA is not an option for patients who are trying to conceive or interested in conceiving in the next one to two years as the contraceptive effect persists for longer than the three-month dosing interval.

DMPA results in a reduction in bleeding in most patients. In patients with no complaints of AUB at baseline and using DMPA for contraception, approximately one-half become amenorrheic after four injections (one year), and approximately three-quarters of users will become amenorrheic after eight injections (two years). In patients using DMPA for treatment of AUB-O or HMB, one short-term study noted a 49 percent reduction in menstrual blood loss after two months [53].

Neither progestin-only contraceptive pills (eg, norethindrone 0.35 mg, drospirenone) nor the etonogestrel implant are known to be effective in treating HMB.

Role of noncontraceptive estrogen-progestin formulations — For selected patients with AUB who have relative contraindications to contraceptive doses of estrogen (eg, patients over age 35 years with obesity, hypertension, diabetes, or who smoke cigarettes) and who prefer not to use, or do not have access to, the LNG 52 mg or oral progestin therapy, off-label use of ultra-low estrogen dose formulations marketed for treatment of menopausal vasomotor symptoms (eg, ethinyl estradiol 5 mcg with 1 mg of norethindrone acetate [Jinteli 1/5 and other generics]) may be an option [58]. In our experience, use of this formulation in patients with AUB often results in amenorrhea after several months.

Ultra-low estrogen formulations contain 28 days of hormonally active tablets (continuous therapy) with estrogen doses lower than the typical OC dose (20 to 35 mcg ethinyl estradiol). Because this formulation is not proven to provide effective contraception, patients should be counseled to use concomitant back-up (eg, barrier) contraception if needed. Our experience suggests that progestin-related side effects are less common and less severe with this formulation compared with the higher-dose oral progestin regimens. Such use requires careful assessment, patient counseling, and possible medical consultation regarding thrombotic risk. (See 'Preferred approach for most patients' above.)

Nonhormonal therapies — Nonhormonal therapies (eg, tranexamic acid, NSAIDs) are useful for patients with HMB without a primary etiology who have contraindications to, or would prefer to avoid, hormonal agents; these therapies do not provide contraception. There is no known contraindication to concurrent use of tranexamic acid and NSAIDs.

Tranexamic acid

Indications – The optimal patient population for use of tranexamic acid is not well defined. Tranexamic acid is approved by the FDA for the treatment of HMB; in our practice, we sometimes use this medication for patients with HMB in whom hormonal therapy is contraindicated (eg, personal history of breast cancer), however, its role in patients with an increased risk of thrombosis is controversial. As an antifibrinolytic agent, it competitively blocks the conversion of plasminogen to plasmin, thereby reducing fibrinolysis. Tranexamic acid is also commonly used to treat heavy menstrual bleeding in individuals with bleeding disorders, especially von Willebrand disease (VWD). Tranexamic acid has been used in Sweden for treatment of HMB since the 1960s. (See "von Willebrand disease (VWD): Gynecologic and obstetric considerations", section on 'Interventions for HMB'.)

Dose and duration Tranexamic acid is taken only during menses, rather than daily like estrogen-progestin contraceptives. For patients with normal kidney function, the recommended dose is 1300 mg (two 650 mg tablets) three times daily for as long as five days during menstruation. The dose should be adjusted downwards for patients with impaired kidney function.

Evidence for efficacy – In a multicenter randomized trial including almost 200 patients with HMB, participants assigned to tranexamic acid compared with placebo had a greater decrease in menstrual blood loss (40 versus 8 percent reduction) [59]. The most common reported adverse effects were menstrual cramps, headache, back pain, and nausea and the frequency of events was similar in both groups.

Adverse effects Tranexamic acid is generally well tolerated; however, long-term use has been associated with thrombosis [60]. FDA labeling for tranexamic acid lists a history of VTE or elevated risk of thrombosis (including current use of combination hormonal contraceptives) as a contraindication to use. However, studies do not confirm a significantly elevated risk of thrombosis [61,62]. Some experts consider tranexamic acid to be reasonable in patients currently using combined hormonal contraceptives, provided additional thrombosis risk factors (eg, obesity, immobility, coagulopathy) are not present [63].

Representative studies include the following:

-A case-control study from Sweden did not identify an association between use of tranexamic acid and venous thrombosis [61].

-A British case-control study observed that tranexamic acid was associated with an elevated risk of thrombosis that did not reach statistical significance. Additionally, anemia associated with HMB itself was also found to be associated with an elevated risk of thrombosis, likely a result of reactive thrombocytosis [64]; this suggests that anemia associated with HMB represents a prothrombotic condition regardless of medication use [62].

In addition to thrombosis risk, the preference for tranexamic acid may depend on cost, which varies from very expensive in the United States to quite inexpensive and available over-the-counter in Sweden [65]. Generic formulations of tranexamic acid are available, which have resulted in this medication becoming less expensive in the United States.

Nonsteroidal antiinflammatory drugs – NSAIDs used to treat HMB include ibuprofen, naproxen, and mefenamic acid; they reduce the volume of menstrual blood loss by causing a decline in the rate of prostaglandin (PGE2 and PGF2 alpha) synthesis in the endometrium, leading to vasoconstriction and reduced bleeding [66,67]. NSAIDs are not typically used to treat patients with anovulatory AUB (AUB-O). They are generally also avoided in individuals receiving an anticoagulant or with concern for a bleeding disorder, as they may worsening bleeding (as NSAIDs inhibit platelet function). (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Concomitant antiplatelet medications'.)

Advantages of NSAIDs include:

Low risk of adverse effects in otherwise young, healthy, reproductive-age patients. The adverse effects of NSAIDs are discussed in detail separately. (See "Nonselective NSAIDs: Overview of adverse effects".)

Reduction of dysmenorrhea.

Low cost and often available over the counter.

Do not need to be taken daily.

When used for treatment of HMB, NSAIDs are prescribed to start on the first day of bleeding and should be continued for two to three days or until menstruation ceases. Example regimens include:

Ibuprofen 600 mg two [68] to four times daily.

Naproxen 500 mg at onset and three to five hours later, then 250 to 500 mg twice a day [69-71].

Mefenamic acid 500 mg three times per day [72,73] or 500 mg followed by 250 mg every six hours (similar to the dosing used for primary dysmenorrhea) [74].

In systematic reviews of randomized trials including patients with HMB, NSAIDs were more effective than placebo at reducing HMB [27,29]. In this study, the efficacy of naproxen and mefenamic acid in treating HMB were similar.

Other — Other therapeutic options (danazol [27], intravenous estrogen, gonadotropin-releasing hormone analogs) are available for treatment of AUB but either are less effective or have more adverse effects than more preferred treatment options (see 'Preferred approach for most patients' above). These therapies are discussed in detail separately. (See "Managing an episode of acute uterine bleeding", section on 'Alternative: High-dose intravenous estrogen' and "Uterine fibroids (leiomyomas): Treatment overview", section on 'GnRH analogs'.)

Patients trying to conceive — When counseling a patient regarding treatment of AUB, it is important to ask whether the patient is planning on trying to conceive a pregnancy in the near future. Treatment of AUB is challenging for such patients, but experts advise that the best option is oral cyclic progestin therapy (eg, norethindrone or medroxyprogesterone administered on days 5 to 26 of the menstrual cycle) [33,55,75,76] (see 'Other progestin-only therapies' above). By contrast, DMPA does not represent an appropriate option for treating patients with AUB who may wish to conceive in the next one to two years as its contraceptive effect persists for long periods of time. Similarly, placement of a LNG 52 mg may not be desirable or cost-effective for patients who are planning to conceive a pregnancy within the upcoming year.

For patients with HMB, NSAIDs may also be used but should be stopped upon conception, since they are associated with miscarriage and congenital anomalies [77]. There is insufficient evidence about the safety of tranexamic acid in pregnancy and animal studies suggest that tranexamic acid may interfere with ovulation [78,79]. (See 'Nonhormonal therapies' above.)

For patients with infertility, AUB should be treated before proceeding with infertility treatments; treatments to induce ovulation will also often correct symptoms of AUB in patients in whom infertility is the result of anovulation. (See "Overview of ovulation induction".)

Patients on anticoagulant therapy — Approximately two-thirds of patients using oral anticoagulant treatment experience AUB [80]. In such patients, anticoagulant therapy is often not the primary etiology of AUB, but rather exacerbates the underlying issue. The presence of AUB is dose dependent. In our experience, AUB occurs more frequently during warfarin treatment if the International Normalized Ratio (INR) is >3; adjusting the warfarin dose to achieve an INR range of 2 to 3 (if clinically appropriate) often resolves the AUB. AUB also appears to occur more frequently with rivaroxaban than with enoxaparin or vitamin K antagonists [81,82].

Patients who are on anticoagulant medications who have heavy, prolonged, or irregular uterine bleeding should be evaluated for the etiology and treated as appropriate. Structural lesions (eg, endometrial polyps, uterine fibroids) may be removed with appropriate perioperative consultation with the clinician prescribing anticoagulation therapy. (See 'Structural lesions' above and "Perioperative management of patients receiving anticoagulants".)

Our approach to patients on anticoagulant therapy without structural lesions is similar to those with contraindications to estrogen therapy (see 'Preferred approach for most patients' above). Accordingly, we prefer progestin-only therapies, specifically the LNG 52 mg, for treatment of AUB as well as for contraception [80]. However, in anticoagulated patients, neither estrogen-progestin combination contraceptives nor progestin-only methods appears to increase risk of recurrent venous thrombosis [81]. Thus, if an estrogen-progestin contraceptive is used, it is important to discontinue the contraceptive prior to stopping anticoagulation as the procoagulant effects of combination contraceptives may persist for up to six weeks after stopping them [83]. There is limited published evidence addressing medical management of AUB in patients with a history of VTE using low molecular weight heparin or other newer anticoagulants and further study is needed.

Role of surgery — Surgical therapy (eg, endometrial ablation, hysterectomy) may be an option for some patients with AUB; this includes patients who have completed childbearing, those who prefer to avoid medical therapy, or those who desire definitive therapy (hysterectomy). Surgical therapy is also often performed for patients who have failed or have bothersome side effects from medical therapy. In a systematic review of eight randomized trials including patients with HMB, over half of those assigned to medical treatment underwent surgery by two years [84]. At four-month follow-up, endometrial resection was more effective than oral medication in controlling bleeding (odds ratio [OR] 10.6, 95% CI 5.3-21.3) and less likely to cause side effects (OR 0.2, 95% CI 0.1-0.3). Hysterectomy resulted in greater improvements in mental health at six-month follow-up.

For patients considering surgery, the risks and benefits should be compared with the LNG 52 mg, which has many of the advantages of surgery but with a low risk of complications and no recovery time. In the United States, one cost-effective approach is to start with the LNG 52 mg and, if unsuccessful, follow with endometrial ablation and, lastly, hysterectomy. This is based on the comparative efficacy of the LNG 52 mg with the following:

Endometrial ablation – Endometrial ablation is a minimally invasive treatment option for patients who have completed childbearing and have heavy or prolonged uterine bleeding despite medical therapy or do not want to use chronic medical therapy [85]. (See "Overview of endometrial ablation".)

Both endometrial ablation (performed with resectoscopic or nonresectoscopic techniques) and LNG 52 mg are effective in reducing menstrual blood loss [29]. The decision to use endometrial ablation or LNG 52 mg depends on a patient's preferences regarding treatment factors, such as plans for fertility and contraception, convenience, and risks of anesthesia. Advantages of the LNG 52 mg are that it provides reversible contraceptive, is placed in an office setting and requires no or local anesthesia; one disadvantage is the LNG 52 mg needs to be replaced at regular intervals (see 'Levonorgestrel intrauterine device' above). By contrast, pregnancy is contraindicated after endometrial ablation, but the procedure does not prevent pregnancy; thus, patients will need to continue to use contraception following ablation. In addition, while endometrial ablation can be performed in an office, it is often performed in an operating room under general anesthesia; but if successful, is performed once and often does not require repeating.

In a meta-analysis and systematic reviews of randomized trials, the LNG 52 mg and endometrial ablation had similar reductions of menstrual blood loss as well as similar improvements in quality of life [25,28]. However, patients treated with the LNG 52 mg appear to require more reinterventions. In a randomized trial of 270 patients with HMB, patients treated with the LNG 52 mg compared with endometrial ablation underwent more than twice as many surgical reinterventions (27 versus 10 percent, relative risk 2.64, 95% CI 1.49-4.68), which included endometrial ablation and hysterectomy [86].

Hysterectomy – Hysterectomy is the definitive treatment for uterine bleeding. This procedure has a high rate of patient satisfaction because it is curative, is frequently performed after medical management has failed, is not associated with drug-related side effects, and does not require repeated procedures or prolonged follow-up. Hysterectomy also has the advantage of eliminating future risk of uterine and cervical cancer and, in patients who also undergo complete salpingectomy, reduces the risk of developing epithelial ovarian carcinomas. However, hysterectomy has a risk of perioperative complications and, depending on the operative approach, a prolonged recovery. (See "Hysterectomy (benign indications): Selection of surgical route" and "Opportunistic salpingectomy for ovarian, fallopian tube, and peritoneal carcinoma risk reduction", section on 'Ovarian cancer risk reduction'.)

While hysterectomy is curative, treatment with the LNG 52 mg has several potential short- and long-term advantages, in addition to absence of surgical morbidity and reversibility if patients decide they want to try to conceive.

In a 2013 study of 236 patients with HMB that followed patients for 10 years after they were randomized to placement of a LNG 52 mg or hysterectomy, 46 percent of those initially randomized to IUD placement ultimately underwent hysterectomy [87]. Overall, costs were lower among patients initially randomized to the IUD, while health-related quality of life and psychosocial well-being were similar in the two groups. In the same trial, 10-year follow-up reported that patients in the IUD group had lower rates of stress urinary incontinence (34 versus 48 percent) and usage of medications for urinary incontinence (1 versus 12 percent) [88].

As many of the randomized trials comparing treatment modalities for AUB in patients who have completed childbearing are over 10 years old and may have evaluated only open abdominal hysterectomy, further studies are needed to compare laparoscopic hysterectomy with other treatments for AUB.

Use of surgical procedures may also be limited by insurance coverage or medical guidelines; for example, the National Health Service in the United Kingdom advises against routine performance of dilation and curettage and hysterectomy for HMB [89]. Surgical procedures are also costly. In one trial, 63 patients with persistent AUB (median duration four years) who were dissatisfied with cyclic oral progestin therapy were randomized to undergo either hysterectomy or expanded medical therapy (eg, cyclic OCs, NSAIDs, low-dose estrogen-progestin regimens) [90,91]. By 18 months, over 50 percent of those randomized to medical treatment had asked for and received a hysterectomy (median interval to crossing over was six months). At 24 months, mean resource use was higher in the surgical versus medical management arms [92]. Broken down to resource use by treatment received, the costs for medication only, medicine followed by hysterectomy, and hysterectomy only were USD $2595, $6128, and $7024, respectively. However, an undefined cost/benefit is elimination of future risk of endometrial carcinoma in patients undergoing hysterectomy; this should not be overlooked as patients with AUB often have characteristics associated with increased rates of endometrial carcinoma.

SPECIAL CONSIDERATIONS

Patients with iron deficiency — Iron deficiency is common in individuals with heavy menstrual bleeding (HMB). (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Blood loss'.)

Testing for iron deficiency and/or iron deficiency anemia is discussed separately. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)

In addition to treating AUB, patients with iron deficiency (with or without anemia) should have their iron deficiency corrected and undergo appropriate monitoring. This is described in detail elsewhere. (See "Treatment of iron deficiency anemia in adults".)

However, it is important not to attribute all iron deficiency to menstrual bleeding; individuals with new onset iron deficiency or iron deficiency in an adult >50 years (sometimes younger) should prompt evaluation for other causes, which may include upper gastrointestinal disorders (eg, celiac disease, autoimmune gastritis) or colorectal disorders, including cancer. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Search for source of blood and iron loss'.)

Patients with dysmenorrhea or pelvic pain/pressure — Patients with AUB and dysmenorrhea or pelvic pain/pressure often will be diagnosed with a primary etiology (eg, adenomyosis, uterine fibroid). The optimal approach in these patients is to address both issues with one type of treatment. (See "Uterine adenomyosis", section on 'Management of symptomatic patients' and "Uterine fibroids (leiomyomas): Treatment overview".)

WHEN TO REFER — AUB is a common reason for referral to a gynecologist, and 5 percent of female patients between the ages of 30 and 49 years consult a clinician for evaluation of heavy menstrual bleeding (HMB) [93-95]. Referral to a gynecologist is appropriate for patients with heavy bleeding, persistent bleeding despite treatment, if there is suspicion of malignancy, or if surgery is required. Referral is also appropriate if the patient's primary clinician is not comfortable performing endometrial sampling or placing an intrauterine device.

Referral to a bleeding disorders expert is appropriate for patients who report other types of excess bleeding. The likelihood of a bleeding disorder can be assessed using an easy-to-administer (by the clinician or the patient) bleeding assessment tool. (See "Approach to the adult with a suspected bleeding disorder", section on 'Bleeding history' and "Approach to the adult with a suspected bleeding disorder", section on 'Bleeding score'.)

Patients with severe anemia, acute heavy bleeding, or hemodynamic instability should be sent to the emergency department. (See "Approach to the adult with vaginal bleeding in the emergency department" and "Managing an episode of acute uterine bleeding".)

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: von Willebrand disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Abnormal uterine bleeding".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Heavy periods (The Basics)")

Beyond the Basics topics (see "Patient education: Abnormal uterine bleeding (Beyond the Basics)" and "Patient education: Heavy or prolonged menstrual bleeding (menorrhagia) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Clinical significance and causes – Abnormal uterine bleeding (AUB) is a common gynecologic problem that can result in anemia, interfere with daily activities, and is the most common presenting symptom in patients with endometrial hyperplasia or carcinoma. Heavy menstrual bleeding (HMB) is a common presentation of bleeding disorders such as von Willebrand disease. Most patients with AUB requiring medical attention can be managed in an outpatient setting. (See 'Introduction' above.)

Evaluation for the cause is discussed separately. (See "Causes of female genital tract bleeding" and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis".)

Management goals – The goals of initial therapy are to correct the underlying etiology (if present and feasible), improve quality of life, prevent an episode of acute uterine bleeding, prevent (or treat) anemia, establish a regular bleeding pattern, and prevent endometrial hyperplasia/carcinoma. (See 'Management goals' above.)

Considerations prior to treatment

To help determine which therapy is best for a particular patient, clinicians should consider several patient factors including: etiology; severity of bleeding (eg, anemia, interference with daily activities); associated symptoms and issues (eg, dysmenorrhea/pelvic pain, infertility); contraceptive needs and plans for future pregnancy; medical comorbidities (eg, risk of venous or arterial thrombosis); patient preferences regarding (and access to) medical versus surgical and short-term versus long-term therapy; and time to menopause. (See 'Considerations prior to initiating treatment' above.)

Expectant management is reasonable for patients who are not anemic, do not desire treatment, or are approaching menopause. (See 'Considerations prior to initiating treatment' above.)

Patients with a known primary etiology – For patients with AUB and a known primary etiology (eg, structural lesions, endocrine, infectious, or bleeding disorders), treating the underlying condition (if feasible) before initiating other therapy may correct the AUB or make further treatment more effective (algorithm 1). (See 'Patients with a known primary etiology' above.)

Patients without a known etiology (algorithm 1)

For most patients with AUB and no known etiology, we suggest estrogen-progestin contraceptives or the 52 mg levonorgestrel-releasing intrauterine device (LNG 52 mg IUD (Grade 2C)). Both estrogen-progestin contraceptives and the LNG 52 mg are effective treatments for AUB, provide effective contraception, are well tolerated, and have a low risk of adverse effects. While the LNG 52 mg is the most effective medical treatment of heavy menstrual bleeding (HMB), logistical and/or financial issues may make this device unavailable for some patients. (See 'Preferred approach for most patients' above and 'Levonorgestrel intrauterine device' above.)

For patients with AUB who are at an increased risk of venous or arterial thrombosis (eg, history of venous thromboembolism [VTE], known thrombogenic mutations, ≥35 years-old with concomitant smoking ≥15 cigarettes/day, hypertension), therapy with contraceptive doses of estrogen is contraindicated. Thus, for such patients we use the LNG 52 mg. The LNG 52 mg results in a low level of systemic progestin absorption and its use has not been associated with an elevated risk of VTE in average-risk patients. (See 'Preferred approach for most patients' above and 'Levonorgestrel intrauterine device' above.)

For patients who cannot or choose not to use a preferred method (ie, estrogen-progestin contraceptives, LNG 52 mg), reasonable alternatives may include treatment with other progestin-only therapies (eg, depot medroxyprogesterone acetate [DMPA], oral progestins), noncontraceptive estrogen-progestin formulations, nonhormonal therapies (eg, tranexamic acid, nonsteroidal antiinflammatory drugs [NSAIDs]), or surgery. Medical consultation is helpful to determine thrombotic risk with these treatments. (See 'Patients who cannot or choose not to use a preferred method' above.)

For patients with AUB who are trying to conceive or planning a pregnancy in the near future, we suggest oral progestin therapy rather than other medical therapies (Grade 2C). DMPA is not an option for such patients as its contraceptive effect persists for long periods of time; similarly, use of the LNG 52 mg may not be desirable or cost-effective. (See 'Patients trying to conceive' above.)

Surgical therapies (eg, endometrial ablation, hysterectomy) may be an option for some patients with AUB. The risks and benefits should be compared with the LNG 52 mg, which has many of the advantages of surgery but with a low risk of complications and no recovery time. In the United States, one cost-effective approach is to start with the LNG 52 mg and, if unsuccessful, follow with endometrial ablation and, lastly, hysterectomy. (See 'Role of surgery' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Howard Zacur, MD, who contributed to earlier versions of this topic review.

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Topic 5476 Version 67.0

References

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