In the treatment of women with abnormal uterine bleeding, once a thorough history, physical examination, and indicated imaging studies are performed and all significant structural causes are excluded, medical management is the first-line approach. Determining the acuity of the bleeding, the patient’s medical history, assessing risk factors, and establishing a diagnosis will individualize their medical regimen. In acute abnormal uterine bleeding with a normal uterus, parenteral estrogen, a multidose combined oral contraceptive regimen, a multidose progestin-only regimen, and tranexamic acid are all viable options, given the appropriate clinical scenario. Heavy menstrual bleeding can be treated with a levonorgestrel-releasing intrauterine system, combined oral contraceptives, continuous oral progestins, and tranexamic acid with high efficacy. Nonsteroidal antiinflammatory drugs may be utilized with hormonal methods and tranexamic acid to decrease menstrual bleeding. Gonadotropin-releasing hormone agonists are indicated in patients with leiomyoma and abnormal uterine bleeding in preparation for surgical interventions. In women with inherited bleeding disorders all hormonal methods as well as tranexamic acid can be used to treat abnormal uterine bleeding. Women on anticoagulation therapy should consider using progestin-only methods as well as a gonadotropin-releasing hormone agonist to treat their heavy menstrual bleeding. Given these myriad options for medical treatment of abnormal uterine bleeding, many patients may avoid surgical intervention.
Abnormal uterine bleeding (AUB) is a common clinical problem, affecting up to 14% of women during their reproductive years and impairing their quality of life by creating significant physical, emotional, sexual, social, and financial burdens.
AUB is the preferred term to describe a spectrum of symptoms, such as heavy menstrual bleeding (HMB), intermenstrual bleeding, and a combination of both heavy and prolonged menstrual bleeding. This terminology was established by the International Federation of Gynecology and Obstetrics (FIGO) Menstrual Disorders Working Group in 2011 and has since been adopted worldwide.
The goal of this review was to provide an updated reference of the medical therapeutic options available for treatment of patients with AUB, with a view toward reducing the need for major surgical intervention. Treatment of AUB in selected clinical scenarios is described in Table 1 .
| Clinical scenarios | Medical treatment options |
|---|---|
| Acute AUB a (normal uterus without underlying systemic cause) |
|
| HMB (normal uterus without underlying systemic cause) |
|
| Symptomatic leiomyomas |
|
| Inherited bleeding disorder |
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| Anticoagulation therapy |
|
a American College of Obstetricians and Gynecologists. Management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. ACOG Committee opinion no. 557. Obstet Gynecol 2013;121:891-6
b Bedaiwy MA, Mousa NA, Casper RF. Aromatase inhibitors prevent the estrogen rise associated with the flare effect of gonadotropins in patients treated with GnRH agonists. Fertil Steril 2009;91(Suppl 4):1574-7.
The normal menstrual cycle
A solid understanding of the normal menstrual cycle is essential to effectively evaluate and treat women with irregularities. The normal menstrual cycle occurs over a span of 4.5–8 days every 24–38 days, with cycle-to-cycle variation over 12 months of ±2 to 20 days. Cycle length varies most during the years immediately succeeding menarche (age <20 years) and during the perimenopausal transition (age >40 years) because these age ranges have the highest prevalence of anovulatory cycles.
The normal menstrual cycle is a manifestation of coordinated interplay within the hypothalamic-pituitary-ovarian axis. During the follicular phase of the menstrual cycle, follicle-stimulating hormone (FSH) causes the ovarian follicles to produce estrogen from granulosa cells. A dominant follicle emerges on days 5–7, leading to another rise in the estrogen level and further growth of the endometrium.
The rise in estrogen triggers negative feedback to FSH at the same time that it stimulates a surge in luteinizing hormone (LH), triggering ovulation. The remaining corpus luteum produces progesterone, stimulating a secretory endometrium. If fertilization does not occur, progesterone and estrogen levels fall rapidly, leading to synchronous shedding of the endometrial lining approximately 14 ± 1 day after ovulation has occurred.
Fifty percent of the endometrial lining is shed during the first 24 hours of menstrual flow. Vasoconstriction of the denuded spiral arterioles in the basal layer of the endometrium (and, potentially, the radial arteries in the surface of the myometrium) brings about the end of menses. Endothelins and prostaglandins are highly concentrated in the endometrium and are responsible for the intense vasoconstriction of the spiral arterioles that leads to the cessation of bleeding. The duration of the follicular phase is highly variable, ranging from 10.3 to 16.3 days, whereas the luteal phase remains fairly constant at a mean of 14.13 days (±1.41 days).
A synchronous rise and fall in estrogen and progesterone levels throughout the cycle is the most important determinant of normal menses. This synchronization leads to the organized growth of the endometrial epithelium, stroma, and microvasculature as well as subsequent controlled endometrial shedding.
In women who have chronic anovulatory AUB, the cyclic stimulation and withdrawal of estrogen and progesterone are lost because of the persistent follicular and proliferative state. After a prolonged period of undisturbed estrogen-primed endometrial proliferation, without the influence of progesterone on its stability and organization, unpredictable sloughing of the endometrial lining occurs.
Women with ovulatory AUB without any anatomical causes have regular menses that occur every 24–35 days, accompanied by either of the following:
- •
large volumes of blood loss (ie, > 80 mL), 90% of which is lost within the first the first 3 days of menstruation or
- •
menses lasting longer than 7 days.
The hypothalamic-pituitary-ovarian axis and steroid hormone production are normal in ovulatory women with AUB. The cause of AUB in these women is the dysregulation of the hemostatic and vasoconstrictive capabilities of the endometrial lining. There is a rise in the total prostaglandin (PG) production, with a significant increase in PGE 2 (promoting vasodilation) as well as a rise in PGE 2 (a potent vasodilator) and PG I2 (an inhibitor of platelet aggregation) receptors. This disproportionate rise in PG production is well documented to disrupt the body’s ability to control the quantity of menstrual blood loss in women with ovulatory AUB.
Evaluation of AUB
The first step in evaluating a patient with AUB is to determine whether the bleeding is acute or chronic. This goal can be achieved through a directed history, physical examination, and laboratory testing. The history should elicit the nature of the bleeding and the associated symptoms as described in Table 2 as well as a detailed sexual and reproductive history. It is important to determine whether the patient has any signs or symptoms of anemia, including pallor, headache, shortness of breath, dizziness, fatigue, and pica.
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It is also important to elicit any personal or family history of chronic medical illnesses that are associated with or can lead to AUB (ie, inherited bleeding disorders such as coagulopathy, blood dyscrasias, platelet functional disorders, etc; hypothyroidism; hyperprolactinemia; hypothalamic or adrenal disorder; systemic lupus erythematosus or other connective tissue diseases; liver disease; or renal disease).
A detailed personal and family history should also elucidate possible coagulation or thromboembolic disorders, hormone-sensitive cancers, and heart disease and should also be obtained to help tailor potential treatment options.
In addition, women who are obese are at risk for menstrual aberrations and have a higher incidence of polycystic ovarian syndrome (PCOS). Thirty-five to 60% of women with chronic anovulation and PCOS are obese. Obese women suffer from ovulatory dysfunction because they have persistently elevated estrogen levels through increased peripheral androgen aromatization; they have elevated free circulating estradiol and testosterone as a result of a reduction in sex hormone-binding globulin; and their insulin levels are elevated as a result of insulin resistance, which stimulates androgen production in the ovarian stroma and disrupts normal follicular development.
Weight loss in these women is imperative, and counseling must be a component in addressing treatment of their menstrual dysfunction. It can lead to the restoration of normal menses by reducing their levels of free insulin and androgen concentrations.
The targeted physical examination and laboratory assessments are detailed in Table 2 . It is in our opinion to reserve transvaginal sonography (TVS), saline infusion sonography, or office hysteroscopy for patients with a normal pelvic examination and laboratory evaluation who do not respond to routine medical management. TVS is more widely available and often utilized first in the search for an anatomic cause of AUB. However, it is important to remember that 1 of 6 intracavitary lesions can be missed on TVS in women with AUB. Therefore, we believe that when it is possible, it is preferable to perform saline infusion sonohysterography (SIS) instead of TVS, given its higher sensitivity in detecting submucosal myomas and endometrial polyps in premenopausal women. If SIS is not available, we believe that a diagnostic hysteroscopy should be considered if available.
Also recommended is endometrial sampling in all women with unrelenting AUB who are older than 45 years as well as in younger women in whom medical therapy has failed or who have risk factors for endometrial cancer. These risk factors include anovulation with long-term exposure to unopposed estrogen (ie, PCOS or obesity), nulliparity, diabetes, and hereditary nonpolyposis colorectal cancer. Endometrial biopsies can be limiting based on the size and location of endometrial pathology, size of the endometrial cavity, presence of congenital malformations, focal or global endometrial process, and sample size obtained with office endometrial sample devices.
Acute AUB is defined as a discrete episode of bleeding that, in the clinician’s judgment, requires immediate medical attention to prevent subsequent bleeding, given an abnormal volume, duration, and/or frequency. In such cases, the priorities are determining the patient’s volume status and hemodynamic stability and proceeding with appropriate volume resuscitation. Transvaginal imaging also should be used to evaluate pelvic pathology. When available, SIS should be performed to evaluate for endometrial pathology. Once the patient is stabilized, the clinician must swiftly identify the cause of the AUB.
Patients with chronic AUB have abnormal volume, duration, and/or frequency of uterine bleeding for at least 6 months and can safely be evaluated on an outpatient basis. Women with intermenstrual bleeding have regular menstrual cycles with random or predictable uterine bleeding between each cycle, commonly owing to a structural abnormality.
Evaluation of AUB
The first step in evaluating a patient with AUB is to determine whether the bleeding is acute or chronic. This goal can be achieved through a directed history, physical examination, and laboratory testing. The history should elicit the nature of the bleeding and the associated symptoms as described in Table 2 as well as a detailed sexual and reproductive history. It is important to determine whether the patient has any signs or symptoms of anemia, including pallor, headache, shortness of breath, dizziness, fatigue, and pica.
|
|
|
It is also important to elicit any personal or family history of chronic medical illnesses that are associated with or can lead to AUB (ie, inherited bleeding disorders such as coagulopathy, blood dyscrasias, platelet functional disorders, etc; hypothyroidism; hyperprolactinemia; hypothalamic or adrenal disorder; systemic lupus erythematosus or other connective tissue diseases; liver disease; or renal disease).
A detailed personal and family history should also elucidate possible coagulation or thromboembolic disorders, hormone-sensitive cancers, and heart disease and should also be obtained to help tailor potential treatment options.
In addition, women who are obese are at risk for menstrual aberrations and have a higher incidence of polycystic ovarian syndrome (PCOS). Thirty-five to 60% of women with chronic anovulation and PCOS are obese. Obese women suffer from ovulatory dysfunction because they have persistently elevated estrogen levels through increased peripheral androgen aromatization; they have elevated free circulating estradiol and testosterone as a result of a reduction in sex hormone-binding globulin; and their insulin levels are elevated as a result of insulin resistance, which stimulates androgen production in the ovarian stroma and disrupts normal follicular development.
Weight loss in these women is imperative, and counseling must be a component in addressing treatment of their menstrual dysfunction. It can lead to the restoration of normal menses by reducing their levels of free insulin and androgen concentrations.
The targeted physical examination and laboratory assessments are detailed in Table 2 . It is in our opinion to reserve transvaginal sonography (TVS), saline infusion sonography, or office hysteroscopy for patients with a normal pelvic examination and laboratory evaluation who do not respond to routine medical management. TVS is more widely available and often utilized first in the search for an anatomic cause of AUB. However, it is important to remember that 1 of 6 intracavitary lesions can be missed on TVS in women with AUB. Therefore, we believe that when it is possible, it is preferable to perform saline infusion sonohysterography (SIS) instead of TVS, given its higher sensitivity in detecting submucosal myomas and endometrial polyps in premenopausal women. If SIS is not available, we believe that a diagnostic hysteroscopy should be considered if available.
Also recommended is endometrial sampling in all women with unrelenting AUB who are older than 45 years as well as in younger women in whom medical therapy has failed or who have risk factors for endometrial cancer. These risk factors include anovulation with long-term exposure to unopposed estrogen (ie, PCOS or obesity), nulliparity, diabetes, and hereditary nonpolyposis colorectal cancer. Endometrial biopsies can be limiting based on the size and location of endometrial pathology, size of the endometrial cavity, presence of congenital malformations, focal or global endometrial process, and sample size obtained with office endometrial sample devices.
Acute AUB is defined as a discrete episode of bleeding that, in the clinician’s judgment, requires immediate medical attention to prevent subsequent bleeding, given an abnormal volume, duration, and/or frequency. In such cases, the priorities are determining the patient’s volume status and hemodynamic stability and proceeding with appropriate volume resuscitation. Transvaginal imaging also should be used to evaluate pelvic pathology. When available, SIS should be performed to evaluate for endometrial pathology. Once the patient is stabilized, the clinician must swiftly identify the cause of the AUB.
Patients with chronic AUB have abnormal volume, duration, and/or frequency of uterine bleeding for at least 6 months and can safely be evaluated on an outpatient basis. Women with intermenstrual bleeding have regular menstrual cycles with random or predictable uterine bleeding between each cycle, commonly owing to a structural abnormality.
Classification of AUB
A classification system developed by the FIGO Menstrual Disorders Working Group and supported by the American College of Obstetricians and Gynecologists facilitates investigation into the etiology of AUB. Under the FIGO system, AUB can be described as either heavy menstrual bleeding (AUB/HMB) or intermenstrual bleeding (AUB/IMB).
The causes of AUB are divided into 2 groups: those related to uterine structural abnormalities and those unrelated to such abnormalities. The first group consists of polyps, adenomyosis, leiomyoma, malignancy and hyperplasia and the second consists of coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and not otherwise classified ( Figure ). The goals of this new classification system are to provide a uniform and clear communication modality for physicians, scientists, and patients and to facilitate optimal patient care by fostering a common language for research.
A recent study showed 38% of women < 40 years of age have unsupported pathology at the time of hysterectomy performed for AUB, uterine fibroids, endometriosis, or pelvic pain. In addition, overall, up to 38% of the women who underwent a hysterectomy were never offered an alternative treatment option. Therefore, it is crucial to review the medical options available and to reduce the reliance on major surgical interventions, when possible. Among women in whom medical therapies have failed, who do not desire future fertility, and who do not desire a hysterectomy, endometrial ablation can be considered.
Medications used in the treatment of AUB, as well as their dosages, contraindications, and side effects, are listed in Table 3 . The specific treatment of AUB due to ovulatory dysfunction based on age groups is outlined in Table 4 .
| Medication | Regimen | Efficacy | Contraindications (select list) | Side effects (select list) | Contraception |
|---|---|---|---|---|---|
| Hormonal | |||||
| Combined contraceptives | Acute: monophasic pill 35 μg estradiol 3 times daily for 1 week, then daily dosing for 3 wks HMB: cyclic monophasic or triphasic oral contraceptive pills, extended or continuous monophasic oral contraceptive pill, transdermal patch or vaginal ring | High | Pregnant, smoking (aged ≥ 35 years and ≥ 15 cigarettes/d), history of malabsorptive bariatric surgery, multiple risk factors for arterial cardiovascular disease (ie, older age, smoking, diabetes, and hypertension), hypertension (systolic ≥ 160 mm Hg or diastolic ≥ 100 mm Hg), active or previous venous or arterial thromboembolic disease, known thrombogenic mutations, current or past ischemic heart disease, stroke, complicated valvular heart disease, SLE with vascular disease, nephritis, or antiphospholipid antibodies, headaches with aura, current or past history of breast cancer, diabetic nephropathy, retinopathy, neuropathy, or diabetes for > 20 y, liver cirrhosis, or tumor a | Spotting, nausea, headache, breast tenderness, breakthrough bleeding, VTE, stroke, MI | Yes |
| Conjugated equine estrogen | Acute: 25 mg IV every 4–6 h for 24 h | High | Pregnant, active or previous venous or arterial thromboembolic disease, breast cancer Use with caution in obese women | Spotting, nausea, headache, breast tenderness, breakthrough bleeding, VTE, stroke, MI | No |
| Oral progestins | Acute: MPA 20 mg 3 times a day for 7 days HMB: oral MPA (2.5–10 mg), norethindrone (2.5–5 mg), megestrol acetate (40–320 mg), or micronized progesterone (200–400 mg) Without ovulatory dysfunction, take 1 tablet daily starting day 5 for 21 d With ovulatory dysfunction, take 1 tablet daily for 2 wks every 4 wks | High | Pregnant, history of malabsorptive bariatric surgery, liver disease or tumor, breast cancer, current or past ischemic heart disease a | Irregular bleeding | No |
| LNG-IUS | HMB: intrauterine placement every 5 y, releases 20 μg/d | High | Pregnant, unexplained abnormal vaginal bleeding, untreated cervical or uterine cancer, large or distorted cavity should sound to a depth of 6–10 cm, b breast cancer, cervix or uterus abnormalities, pelvic inflammatory disease within 3 mo, STI such as chlamydia or gonorrhea within 3 mo, liver disease or tumor | Irregular bleeding and spotting, cramping, breast tenderness, mood changes, acne, nausea, decreased libido | Yes |
| DMPA | HMB: 150 mg IM injection every 12 wks | Low | Pregnant, multiple risk factors for arterial cardiovascular disease (ie, older age, smoking, diabetes, and hypertension), current or past ischemic heart disease, stroke, hypertension with vascular disease, CAD, CVD, current or previous history of breast cancer, liver disease or tumor a | Decreased bone mineral density, irregular (reversible) bleeding, weight gain, amenorrhea, bloating, breast tenderness, and fluid retention | Yes |
| Leuprolide acetate | HMB: 3.75 mg IM monthly or 11.25 mg IM every 3 mo | High | Pregnant | Hot flashes, sweating, and vaginal dryness (effects minimized with add-back therapy with estrogen and progestins), trabecular bone loss with use for longer than 6 mo (reversible) | No |
| Danazol | HMB: 100–400 mg orally daily (in divided doses) | Low | Pregnant, unexplained vaginal bleeding, impaired hepatic, renal, or cardiac function | Weight gain, acne, androgenic effects | No |
| Nonhormonal | |||||
| NSAIDs | HMB: Meclomen: 100 mg 3 times daily Ibuprofen 600-800 mg every 6-8 h, respectively (best if used in combination with other medication) | Moderate | Pregnant, gastrointestinal bleeding, inflammatory bowel disease, severe asthma, use after CABG procedure, renal disease, CVD, CHF | Gastrointestinal adverse effects (bleeding, ulceration, and perforation), worsening of asthma, effect on platelet function | No |
| Tranexamic acid | Acute: 1.3 g orally every 8 h for 5 d (indicated in ovulatory women with excessive menstrual bleeding) | High | Current or past thromboembolic disease, acquired impaired color vision (cannot be used with combined oral contraceptives) c | Headaches, nausea, vomiting, diarrhea, muscle pain, dysmenorrhea | No |
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