Menorrhagia

Practice Essentials

Menorrhagia (heavy vaginal bleeding or heavy uterine bleeding) is defined as menstruation at regular cycle intervals but with excessive flow (greater than 80 cc of blood loss per cycle or requiring more frequent than 2 hour changes of hygiene products) and/or duration (longer than 7 days), or perceived as heavy bleeding by the patient. It is one of the most common gynecologic complaints in contemporary gynecology. As the most common cause of irregular bleeding in women of reproductive age is pregnancy, this diagnosis should be excluded before any further testing or drug therapy.

Signs and symptoms

Symptoms related by a patient with menorrhagia often can be more revealing than laboratory tests. A detailed patient history is imperative and should include inquiries about the following:

• A detailed menstrual history (eg, last menstrual period, number of days of bleeding, the severity of bleeding, the presence of intermenstrual bleeding, time between menses)
• Presence of pelvic pain related to menstrual cycle or bleeding pattern
• Menses pattern from menarche including change in symptoms over time
• Contraceptive use
• Presence of hirsutism
• Systemic illnesses (eg, hepatic, renal failure, and diabetes)
• Symptoms of thyroid dysfunction
• Excessive bruising or known bleeding disorders
• Current medications (eg, hormones and anticoagulants)
• Previous diagnoses or surgical procedures

The physical examination should be tailored to the differential diagnoses suggested by the history (Table 1). Initial inspection should include evaluation for the following:

Table 1. Differential diagnosis of abnormal uterine bleeding and associated clinical features.

View Table

See Table

According to an international expert panel, an underlying coagulopathy or bleeding disorder should be considered when a patient has any of the following^[1] :

• Menorrhagia since menarche
• Family history of bleeding disorders
• Personal history of 1 or more of the following: (1) Notable bruising without known injury, (2) bleeding of the oral cavity or gastrointestinal tract without an obvious lesion, or (3) epistaxis of more than 10 minutes’ duration (possibly necessitating packing or cautery)

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies that may be useful include the following:

• Complete blood cell count
• Iron studies (eg, total iron-binding capacity [TIBC] and total iron)
• Thyroid function tests and prolactin level
• Liver function tests (LFTs) and renal function tests (eg, blood urea nitrogen [BUN] and creatinine)
• Hormone assays (eg, luteinizing hormone [LH], follicle-stimulating hormone [FSH], and androgen) for suspected polycystic ovary syndrome (PCOS); adrenal function tests for suspected adrenal tumors
• Coagulation factor studies (expensive and to be used sparingly)

Imaging studies and other diagnostic measures that may be helpful include the following:

• Pelvic ultrasonography
• Sonohysterography (saline-infusion sonography)
• Cervical specimens (eg, Pap smear, sexually transmitted infection [STI] testing)
• Endometrial biopsy (EMB)
• Hysteroscopy

See Workup for more detail.

Management

Medical therapy should be tailored to treat the underlying cause of abnormal bleeding, characteristics of the patient (eg, age, coexisting medical diseases, family history, and desire for fertility). Agents used to alleviate heavy uterine bleeding unrelated to underlying systemic disease include the following:

• Nonsteroidal anti-inflammatory drugs (NSAIDs): Continuous dosing beginning on the first day of bleeding for 3-4 days or until bleeding ceases.
• Combined hormonal contraceptives: Oral contraceptive pills (OCPs) are a popular first-line therapy for women who desire contraception in addition to management of abnormal uterine bleeding. Dienogest−estradiol valerate has been approved by the US Food and Drug Administration (FDA) for heavy menstrual bleeding; however, other pills on the market have also proven effective to control heavy menstruation. The estrogen-containing transvaginal ring or transdermal patch can also be used.
• Progesterone-only containing contraceptives: Progestin is one of the most frequently prescribed medicines for menorrhagia. Depo-medroxyprogesterone acetate injection can also be used. Rarely, an etonogestrel implant may be used.
• Levonorgestrel intrauterine device: Approved by the FDA for treatment of menorrhagia in women who use intrauterine contraception.
• Tranexamic acid

Clinically less commonly used agents may also include:

• Gonadotropin-releasing hormone (GnRH) agonists and antagonists
• Danazol
• Conjugated estrogens

Surgical management has been the standard of treatment in menorrhagia when the cause is structural, when medical therapy fails to alleviate symptoms, or for ablation, uterine artery embolization, and hysterectomy, if the patient strongly desires definitive management and no longer desires childbearing. Options for surgical intervention include the following:

Nondefinitive therapy

• Dilation and curettage: Used for diagnosis (and in the case of acute, life-threatening bleeding used for treatment) typically in combination with hysteroscopy.
• Myomectomy

Definitive therapy

• Resectoscopic endometrial ablation (first-generation): Includes transcervical resection of the endometrium (TCRE; criterion standard),^[2] roller-ball endometrial ablation,^[3] and endometrial laser ablation; these techniques have largely been replaced by the nonresectoscopic procedures.
• Nonresectoscopic endometrial ablation (second-generation): Includes thermal balloon therapy,^{[4, 5]} heated free fluid,^[6] cryoablation,^[7] microwave endometrial ablation,^[8] and radiofrequency ablation.^[7]
• Uterine artery embolization
• Hysterectomy

See Treatment for more detail.

• References

Background

A normal menstrual cycle is 21-35 days in duration, with bleeding lasting an average of 7 days and flow measuring 25-80 mL.^[9]

Menorrhagia (more contemporarily addressed as heavy menstrual bleeding) is defined as menstruation at regular cycle intervals but with excessive flow and/or duration and is one of the most common gynecologic complaints in contemporary gynecology. Clinically, menorrhagia is defined as total blood loss exceeding 80 mL per cycle,^[10]  menses lasting longer than 7 days, or bleeding that is considered bothersome in quantity to the patient.^[11] The World Health Organization reports that 18 million women aged 30-55 years perceive their menstrual bleeding to be excessive.^[12] Reports show that only 10% of these women experience blood loss severe enough to cause anemia or be clinically defined as menorrhagia; however, in cases where menstrual bleeding is bothersome, treatment is warranted.^{[11, 13, 14]} In practice, measuring menstrual blood loss is difficult. Thus, the diagnosis is usually based upon the patient's history.

Table 2. Terminology for normal and abnormal menses.^[15]

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See Table

Menorrhagia must be distinguished clinically from other common gynecologic diagnoses. Many terms for abnormal uterine bleeding (AUB) are poorly defined and have largely been replaced by instead using descriptive terms (eg, menstrual volume, duration, frequency, and regularity) (Table 2). Polymenorrhea is bleeding that occurs more frequently than every 21 days, and oligomenorrhea is bleeding that occurs less frequently than every 35 days. Metrorrhagia (more contemporarily addressed as intermenstrual bleeding) is bleeding between menses.^[16]  AUB is often paired with descriptive terms to characterize bleeding patterns, then further characterized by etiology. Dysfunctional uterine bleeding has often been used interchangeably with AUB when no known etiology is identified, though this terminology is falling out of favor.

Nearly 30% of all hysterectomies performed in the United States are performed to alleviate heavy menstrual bleeding.^[17] Historically, definitive surgical correction has been the mainstay of treatment for menorrhagia. Modern gynecology has trended toward conservative therapy to decrease risk to patients, control of costs, and the desire of many women to preserve their uterus.

Heavy menstrual bleeding is a subjective finding, making the exact problem definition difficult. Treatment success is usually evaluated subjectively by each patient, making positive outcome measurement difficult.

• References

Pathophysiology

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Phases of the menstrual cycle.

Knowledge of normal menstrual function is imperative in understanding the etiologies of menorrhagia. Four phases constitute the menstrual cycle: follicular, luteal, implantation (in the case of pregnancy), and menstrual (in the case of unfertilized ovum and no pregnancy) (Figure 1).^[15]

In response to pulsatile gonadotropin-releasing hormone (GnRH) from the hypothalamus, the pituitary gland synthesizes follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which induce the ovaries to produce estrogen and progesterone.

During the follicular phase, estrogen stimulation results in hypertrophy of endometrial tissue causing an increase in endometrial thickness in preparation for implantation. This also is known as the proliferative phase.

The luteal phase is intricately involved in the process of ovulation. During this phase, also known as the secretory phase, progesterone causes endometrial maturation. An LH surge is the harbinger of ovulation and release of an ovum from the ovary.

If fertilization occurs, beta-HCG will stimulate the corpus luteum to continue to make progesterone and ultimately maintain the implantation phase and continued decidualization of the endometrium. Without fertilization, estrogen and progesterone withdrawal results in menstruation.

The endometrium consists of two discrete zones, the basalis layer and the functionalis layer. The basalis layer allows for regeneration of the functionalis layer following menses and is positioned between the myometrium and functionalis layer. The functionalis layer is the most superficial layer, covering the entire uterine cavity and sloughs off with menstruation. Blood supply to the uterus is primarily through the uterine and ovarian arteries. These arteries anastomose and branch into arcuate arteries that supply the myometrium, which branch further into radial arteries to supply the two layers of the endometrium. The fall in progesterone at the end of the menstrual cycle leads to enzymatic breakdown of the functionalis layer, ultimately leading to sloughing of the endometrium and blood loss, also known as the menstrual phase.

Hemostasis relies on sufficient vasoconstriction and a functioning coagulation system, and a disruption in either element can affect menstruation.^[15] Hemostasis of the endometrium is directly related to the functions of platelets and fibrin. Deficiencies in either of these components results in menorrhagia for patients with von Willebrand disease or thrombocytopenia.^[18] Thrombi are seen in the functional layers but are limited to the shedding surface of the tissue. These thrombi are known as "plugs" because blood can only partially flow past them. Fibrinolysis limits the fibrin deposits in the unshed layer. Following thrombin plug formation, vasoconstriction occurs and contributes to hemostasis.

Many cases of AUB are secondary to anovulation. Without ovulation, the corpus luteum fails to form, resulting in no progesterone secretion. Unopposed estrogen allows the endometrium to proliferate and thicken. The endometrium finally outgrows its blood supply and degenerates. The result is asynchronous breakdown of the endometrial lining at different levels. This also is why anovulatory bleeding is heavier than normal menstrual flow. Unlike menorrhagia, anovulatory cycles are often described as irregular in timing as well as flow volume.^[19]

Anatomic defects or growths (most typically polyps or fibroids but also malignancy) within the uterus can alter either of the aforementioned pathways (endocrinologic/hemostatic), causing significant uterine bleeding. The clinical presentation is dependent on the location and size of the gynecologic lesion.

Organic diseases also contribute to menorrhagia in the female patient. For example, in patients with renal failure, gonadal resistance to hormones, and hypothalamic-pituitary axis disturbances result in menstrual irregularities. Most women in this renal state are amenorrheic, but others also develop menorrhagia. If uremic coagulopathy ensues, it usually is due to platelet dysfunction and abnormal factor VIII function.

Due to the overwhelming factors that can contribute to the dysfunction of either the endocrine or hematologic pathways, in-depth knowledge of an existing organic disease is just as imperative as understanding the menstrual cycle itself.

• References

Etiology

The International Federation of Gynecology and Obstetrics (FIGO) has created a classification system for abnormal uterine bleeding (AUB) by bleeding pattern as well as bleeding etiology by using the acronym PALM-COEIN (Figure 2). AUB can be paired with descriptive terms to denote bleeding pattern, such as intermenstrual bleeding and heavy menstrual bleeding. The letters are sorted by structural and non-structural causes. The structural categories include polyp, adenomyosis, leiomyoma, malignancy, and hyperplasia, while the non-structural categories include coagulopathy, ovulatory disorders, endometrial disorders, iatrogenic, and those not otherwise classified.^{[20, 21]}

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PALM-COEIN classification system, approved by FIGO, for the causes of abnormal uterine bleeding and associated bleeding patterns (“heavy menstrual ble....

Structural causes

Structural causes of menorrhagia include polyps, leiomyomas, adenomyosis, endometrial hyperplasia, and malignancy. Note the following:

• Leiomyomas, commonly known as "fibroids" are benign smooth muscle neoplasms. Fibroids can be cervical or uterine in origin. Both fibroids and polyps can distort the uterine wall and/or endometrium. The FIGO system classified fibroids by location, including submucosal, intramural, subserosal or other (eg, cervical).^[22]
• The mechanism by which endometrial polyps or fibroids cause menorrhagia is not well understood. The blood supply to the fibroid or polyp is different compared to the surrounding endometrium and is thought to function independently. This blood supply is greater than the endometrial supply and may have impeded venous return, causing pooling in the areas of the fibroid. Heavy pooling is thought to weaken the endometrium in that area, and break-through bleeding ensues. Fibroids located within the uterine wall may inhibit muscle contracture, thereby preventing normal uterine attempts at hemostasis. This also is why intramural fibroids may cause a significant amount of pain and cramping.
• Adenomyosis is characterized by endometrium located within the myometrium, often leading to uterine enlargement, menorrhagia, and dysmenorrhea.
• Endometrial hyperplasia usually results from unopposed estrogen production leading to a proliferative endometrium but is biologically distinct from precancerous lesions of endometrial intraepithelial neoplasia (EIN) or atypical endometrial hyperplasia.^[23] Endometrial hyperplasia can lead to endometrial cancer in 1-2% of patients with anovulatory bleeding, but it is a diagnosis of exclusion in postmenopausal bleeding (average age at menopause is 51). If a woman takes unopposed estrogen (without progesterone), their relative risk of endometrial cancer is 2.8 compared to nonusers.^[16]
• Endometrial carcinoma is the most common gynecologic malignancy in the United States and typically presents in the postmenopausal period with irregular and continuous heavy uterine bleeding. Any patient older than age 45 years with changes in menstrual pattern or age 35 years and BMI greater than 30 should have endometrial sampling.

Nonstructural causes

Nonstructural causes of menorrhagia include coagulopathies, ovulatory disorders, endometrial disorders, iatrogenic, and those not otherwise classified. Consider the following:

• Coagulation disorders can evade diagnosis until menarche when heavy menstrual bleeding presents as an unrelenting disorder. These include von Willebrand disease; factor II, V, VII, and IX deficiencies; prothrombin deficiency; idiopathic thrombocytopenia purpura (ITP); and thrombasthenia.^[1]  See more on bleeding disorders below.
• A common etiology of heavy uterine bleeding is anovulation, which includes varied underlying causes. Anovulation classically presents with menorrhagia at irregular intervals, often several months, without any known etiology. This is most common in adolescent and perimenopausal populations.^{[24, 25]} Polycystic ovary syndrome (PCOS) is the most common cause of chronic anovulation.^[15] The hallmarks of PCOS are anovulation, irregular menses, obesity, and hirsutism. Insulin resistance is common and increases androgen production by the ovaries.
• Organ dysfunction causing menorrhagia includes hepatic or renal dysfunction. Liver dysfunction can impair production of clotting factors and reduces hormone metabolism (eg, estrogen), ultimately disrupting the HPO axis and leading to a proliferative endometrium. Either of these problems may lead to heavy uterine bleeding, which may worsen preexisting chronic anemia associated with chronic organ dysfunction.
• Both hypothyroidism and hyperthyroidism can result in menorrhagia. Even subclinical cases of hypothyroidism produce heavy uterine bleeding in 20% of patients. Menorrhagia usually resolves with correction of the thyroid disorder.^[26]
• Hyperprolactinemia can disrupt GnRH secretion leading to decreased LH and FSH levels, which ultimately cause hypogonadism. Bleeding patterns typically include amenorrhea or oligomenorrhea, though can range to include menorrhagia.

Iatrogenic causes of menorrhagia include intrauterine devices (IUDs), steroid hormones, chemotherapy agents, and medications (eg, anticoagulants). Consider the following:

• Copper IUDs can cause increased menstrual bleeding and cramping due to local inflammatory effects (heavy vaginal bleeding is rarely noted with hormonal IUDs, although patients may report an unpredictable light bleeding pattern).
• Steroid hormones such as prednisone can disrupt the normal menstrual cycle, which is typically restored upon cessation of the products.
• Chemotherapy can affect gonadal cells, impacting hormone production and the menstrual cycle. It is variable whether normal ovarian function returns following completion of chemotherapy depending on the agent, duration, and other patient characteristics.
• Anticoagulants decrease clotting factors needed to cease normal blood flow, including menses. This type of menorrhagia also is easily reversible; however, many patients require anticoagulation for other medical issues.

Bleeding disorders

An international expert panel including obstetrician/gynecologists and hematologists has issued guidelines to assist physicians in better recognizing bleeding disorders, such as von Willebrand disease, as a cause of menorrhagia and postpartum hemorrhage and to provide disease-specific therapy for the bleeding disorder.^[1]  Historically, a lack of awareness of underlying bleeding disorders has led to underdiagnosis in women with abnormal reproductive tract bleeding.

The panel provided expert consensus recommendations on how to identify, confirm, and manage a bleeding disorder. An underlying bleeding disorder should be considered when a patient has any of the following:

• Menorrhagia since menarche
• Family history of bleeding disorders
• Personal history of 1 or more of the following: (1) Notable bruising without known injury; (2) bleeding of oral cavity or gastrointestinal tract without obvious lesion; and/or (3) epistaxis greater than 10 minutes duration (possibly necessitating packing or cautery)

If a bleeding disorder is suspected, consultation with a hematologist is suggested.

• References

Epidemiology

United States statistics

Although menorrhagia remains a leading reason for gynecologic office visits, only 10-20% of all menstruating women experience blood loss severe enough to be defined clinically as menorrhagia.^[14] Abnormal uterine bleeding, including menorrhagia, is one of the leading causes of outpatient gynecologic visits.

Age-related demographics

Any woman of reproductive age who is menstruating may develop menorrhagia. Most patients with menorrhagia are older than 30 years.^[9]  The most common cause of heavy menstrual bleeding in adolescents is persistent anovulation, though other common etiologies include coagulopathies and pregnancy. After adolescence, menorrhagia most frequently results from structural lesions, like leiomyomas, polyps, in addition to anovulatory cycles and endometrial hyperplasia.^[24]

• References

Prognosis

With proper workup, diagnosis, treatment, and follow-up care, prognosis is favorable, though largely depends on the etiology. Menorrhagia can significantly impact a person’s quality of life, ability to perform daily activities, productivity, and relationships.

Morbidity/mortality

Infrequent episodes of menorrhagia usually do not carry severe risks to women's general health.

Patients who lose more than 80 mL of blood, especially repetitively, are at risk for serious medical sequelae. These women are likely to develop iron-deficiency anemia because of their blood loss. Menorrhagia is the most common cause of anemia in premenopausal women. This usually can be remedied by oral ingestion of ferrous sulfate to replace iron stores as well as management of the abnormal bleeding. If the bleeding is severe enough to cause volume depletion, patients may experience shortness of breath, fatigue, palpitations, and other related symptoms. In the most serious of scenarios, anemia can lead to congestive heart failure and death. This level of anemia necessitates hospitalization for intravenous fluids, possible transfusion and prompt medical and/or surgical management.

Other sequelae associated with menorrhagia usually are related to the etiology. For example, with hypothyroidism, patients may experience symptoms associated with a low-functioning thyroid (eg, cold intolerance, hair loss, dry skin, weight gain) in addition to the effects of significant blood loss.^[26]

Complications

Complications of heavy menstrual bleeding depend on the underlying etiology, but can include anemia, infertility, endometrial cancer, and associated complications of medical and/or surgical management. When severe, bleeding can lead to hypotension and even shock if not promptly evaluated and treated.^[15]

• References

Racial and Ethnic Disparities

As previously mentioned, patients with menorrhagia can experience a worse quality of life, including physical, mental, emotional, and social health, compared with those who have normal menstrual bleeding. People with heavy menstrual bleeding have decreased involvement in personal relationships, social activities, and work attendance.^[27]

Menorrhagia and the many conditions that affect menstrual bleeding vary by race, ethnicity, and numerous other socioeconomic characteristics. Patients presenting for their first outpatient gynecology visit who live in more socioeconomically deprived areas report more severe heavy menstrual bleeding symptoms and a poorer quality of life.^[27] Racial disparities with respect to menstrual bleeding are deeply rooted in assumptions of biological or genetic plausibility, without sound evidence and have historically been neglected. Black people experience higher rates of heavy menstrual bleeding compared with non-Hispanic White women. Some attribute differences in symptoms to the increased prevalence of uterine fibroids among Black people, though bias exists at every step of a patient’s experience within the healthcare system.^[28] For example, Black women and those aged 40 years or older were less likely to have documentation of nonsurgical treatment and less likely to receive a laparoscopic hysterectomy compared to other modes of hysterectomy.^[29]

Period poverty is another example of an area where significant disparities exist. Period poverty is the injustice and inequity that people experience due to menstruation, which often results from insufficient access to menstrual supplies and information.^[30] Period poverty most heavily impacts Black and Latina people compared with their counterparts.^[30]

Endometrial cancer can cause menorrhagia and is one of many etiologies where significant racial disparities exist. Black people with endometrial cancer present at higher stage of disease, with more aggressive histology, have higher mortality rates than any other race or ethnicity, and are less likely to receive guideline-concordant care.^[31] Further investigation and effort are needed to better address these disparities.

• References

History

Symptoms experienced by a patient with menorrhagia often can be more revealing than laboratory tests. Considering the lengthy list of possible etiologies that contribute to menorrhagia, taking a detailed patient history is imperative. Inquiries that should be included are discussed below.

Exclusion of pregnancy

Pregnancy should be the first diagnosis to be excluded before further testing or medications are instituted. This is the most common cause of irregular bleeding in women of reproductive age. Bleeding can occur in all trimesters of pregnancy and following pregnancy loss. Bleeding may also indicate a pregnancy complication including ectopic pregnancy or threatened abortion.

Bleeding pattern

Knowing a detailed menstrual history including days of flow, the severity of bleeding, the presence of intermenstrual bleeding, and a patient’s certainty that the bleeding is vaginal can all be helpful. Quantity is a very subjective issue when considering vaginal bleeding. Best estimates usually are the only source clinicians have available to consider. Helpful references for totaling blood loss may include that the average tampon holds 5 mL and the average pad holds 5-15 mL of blood. Asking the patient what type of pad (liner vs overnight) was used and if it was soaked may add some insight into what the patient believes to be heavy bleeding. A menstrual cup theoretically offers a more direct method of collecting and measuring menstrual blood. Quality of bleeding involves the presence of clots and their size.

Patient age

Age plays a large role in determining a differential diagnosis of abnormal uterine bleeding. Young patients, from menarche to the late-teen years, most commonly have anovulatory bleeding due to the immaturity of their hypothalamic-pituitary axis. Heavy uterine bleeding also may be to pelvic infection, pregnancy, and coagulopathies. If bleeding does not respond to typical therapy in this age group, a bleeding disorder should be considered.

Women are more likely to have structural abnormalities during their reproductive-age years through menopause. Fibroids or polyps are frequent anatomical findings. Systemic causes can be anything from thyroid dysfunction to renal failure. Postmenopausal women with any uterine bleeding should receive an immediate workup to rule out endometrial cancer. Endometrial hyperplasia must be considered in women with menorrhagia and history of exposure to unopposed estrogen, such as age, nulliparity, obesity, diabetes, anovulation (eg, PCOS).^[20]

Menses pattern from menarche

If a young patient has had irregular menses since menarche, the most common etiology of their bleeding is anovulation secondary to hormonal axis immaturity. Anovulatory bleeding is most common in young girls (aged 12-18 y) and common in obese females of any reproductive age. Adipose tissue contains the enzyme lipase that can increase circulatory estrogen. If a patient's bleeding normally occurs at regular intervals and the irregularity is new in onset, pathology must be ruled out, regardless of age.

Sexual activity

Simple vaginitis (eg, candidal, bacterial vaginosis) may cause intermenstrual bleeding, while gonorrhea and chlamydia cervicitis may present with heavier bleeding attributed primarily to the copious cervical discharge mixed with the blood. One should also be cognizant of patients with a history of and/or risk factors concerning for sexual assault and trauma, which should be included in the evaluation and management.

Contraceptive use (intrauterine device or hormones)

A copper-containing intrauterine device (IUD) may cause bleeding irregularities, including prolonged and heavier bleeding.^[32]  

If a patient has recently discontinued birth control pills, they may return to their "natural" menses and report an increase in flow. This occurs because most combined oral birth control pills decrease the flow and duration of a woman's menses.

Presence of hirsutism (polycystic ovarian syndrome)

These patients commonly are obese (BMI greater than 35), although patients with any BMI may be affected and in an anovulatory or oligo-ovulatory state. When they do have a period, it may be very heavy and cause concern for the patient. The etiology of this is explained in the Introduction to this article.

Galactorrhea (pituitary tumor)

Any patient who reports a milky discharge from either breast (while not pregnant, postpartum, or breastfeeding) needs a prolactin level to rule out a prolactin-secreting pituitary tumor.

Systemic illnesses (hepatic/renal failure or diabetes)

As explained in the Introduction, organic diseases may affect either the hormonal or hematologic pathways that are involved in the manifestation of menorrhagia. If either the hypothalamic-pituitary axis or the coagulation paths are disrupted, heavy bleeding may result.

Symptoms of thyroid dysfunction

The alteration of the hypothalamic-pituitary axis may create either amenorrhea (hyperthyroidism) or menorrhagia (hypothyroidism).

Excessive bruising or known bleeding disorders

This is especially important in a young patient who does not stop bleeding during their first menses. This is a very common presentation for an undiagnosed bleeding disorder (eg, von Willebrand disease) in an adolescent.

Current medications (hormones or anticoagulants)

Any medication that prolongs bleeding time may cause menorrhagia. A patient treated with any progestin therapy may have a withdrawal bleed after cessation of the medication. This bleeding often is heavy and worrisome to patients if they are not forewarned.

Previous medical or surgical procedures/diagnoses

This also is helpful in preventing duplication of testing.

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Physical Examination

The physical examination should be tailored to the differential diagnoses formulated by the results of the patient's history. Initial inspection should include evaluation for the following (see Table 1):

• Signs of severe volume depletion (eg, anemia): This may help confirm the patient's history of very heavy bleeding and/or prompt immediate inpatient care.
• Obesity: This is an independent risk factor for endometrial cancer. Adipose tissue enzymatic activity causes estrogen conversion. Therefore, the larger the patient, the more increased the risk (and the higher the unopposed estrogen level on the endometrium).
• Signs of androgen excess (eg, hirsutism, acne): This usually points to polycystic ovarian syndrome (PCOS), leading to anovulatory bleeding (see Presence of hirsutism).
• Signs of bleeding diathesis (ecchymosis, purpura, or bleeding gums: This usually is a sign of trauma or a bleeding disorder.
• Visual fields or nipple discharge: This may be associated with a prolactin-secreting pituitary tumor.
• Thyroid evaluation
• Enlarged liver or spleen

Pelvic examination should usually include an external, speculum, and bimanual examination. An external exam is performed to evaluate for the presence of external genital lesions. The speculum exam allows for visualization of the vagina and cervix, at which time Pap testing and infection testing can be performed. The bimanual exam is intended to provide information about the cervix, uterus, and adnexa, while also determining the size, shape, contour, and mobility of these structures. The bimanual exam can assist in making a diagnosis and planning a surgical approach if a hysterectomy is required.^[33]    

• Vaginal/cervical discharge: Look for an abnormal discharge indicating infection and confirm the actual site of the bleeding (if present).
• Uterine size, shape, and contour: An enlarged irregularly shaped uterus may suggest fibroids. An enlarged uniformly shaped uterus in a postmenopausal patient with bleeding is concerning fo malignancy until proven otherwise.
• Cervical motion tenderness: This is a common symptom of pelvic inflammatory disease (PID). It may also be present during other intraabdominal inflammatory processes including appendicitis. Pelvic inflammatory disease is an important diagnosis to exclude, especially in young nulliparous women, because it can lead to pelvic adhesions and infertility.
• Adnexal tenderness or masses: This is especially concerning in patients older than 40 years. Ovarian cancer may present with intermenstrual bleeding as its only symptom. Rare but deadly ovarian tumors also can present in teenage girls. Any suspicion of an adnexal mass should prompt an immediate evaluation with pelvic ultrasound.

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Laboratory Studies

Complete blood cell count

The CBC count may be used to evaluate hemoglobin and hematocrit and determine severity of anemia, if present. Use the platelet count in conjunction with a peripheral smear if a coagulation defect is suspected. An elevated white blood cell count can be followed in treatment of infectious processes.

Iron studies

Total iron-binding capacity (TIBC) and total iron are used to assess iron stores.

Coagulation factors

These studies are used to rule out von Willebrand disease; ITP; and factor II, V, VII, or IX deficiency. These tests should be ordered sparingly because they are expensive tests for rare disorders (usually in the adolescent age group).^[34]

Human chorionic gonadotropin

Pregnancy remains the most common cause of abnormal uterine bleeding in patients of reproductive age. Bleeding can denote threatened abortion, incomplete abortion, ectopic pregnancy, or in rare cases, gestational trophoblastic disease.

Thyroid function tests and prolactin level

These tests can rule out hyperthyroidism, hypothyroidism, and hyperprolactinemia. All of these conditions can cause ovarian dysfunction leading to possible menorrhagia.

Liver function and/or renal function tests

Order liver function tests (LFTs) when liver disease is suspected, such as in persons with alcoholism or hepatitis. BUN and creatinine tests assess renal function. Dysfunction of either organ can alter coagulation factors and/or the metabolism of hormones.

Hormone assays

Total testosterone and sex hormone-binding globulin or free testosterone can assist in diagnosing biochemical hyperandrogenemia in those with suspected PCOS.^[35]

Adrenal function tests (eg, cortisol, 17-alpha hydroxyprogesterone [17-OHP]) delineate hyperandrogenism in women with suspected adrenal tumors. Congenital adrenal hyperplasia (CAH) is diagnosed primarily by testing 17-OHP.

Other tests

Papanicolaou (Pap) smear test results for cervical cytology should be current. If a suspicious vaginal or cervical lesion is present, it may warrant direct biopsy.

Cervical specimens should be obtained if the patient is at risk for an infection. Testing is recommended for both Chlamydia trachomatis and Neisseria gonorrhoeae.

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Imaging Studies

Endometrial biopsy most typically samples an approximate 10% of the uterine lining. Small, focal, irregular, or eccentrically located endometrial lesions may be missed by an in-office endometrial biopsy (EMB). The findings yielded from pelvic examinations may be limited if patients are obese. These limitations can lead to further imaging studies to inspect the uterus, endometrium, and/or adnexa.

Pelvic ultrasound is a noninvasive imaging study to assess uterine shape, size, and contour; endometrial thickness; and adnexal areas.^[36]  Pelvic ultrasound is widely available, cost-effective and a primary diagnostic tool.

Sonohysterography (also known as hysterosonography or saline-infusion sonography) involves instilling fluid into the endometrial cavity and enhances intrauterine evaluation. One advantage is the ability to differentiate polyps from submucous leiomyomas (ie, fibroids). Sonohysterography is best performed in the proliferative phase to minimize false-negative or false-positive results.^[33]

MRI as a second-line test is to be used when the diagnosis from pelvic ultrasonography is unclear. In fact, adenomyosis or fibroids can be diagnosed by MRI, although both can be detected with transvaginal ultrasonography.^[20] Importantly, MRI should only be used if the result will affect treatment, such as in the case of fibroid mapping prior to minimally invasive myomectomy.

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Procedures

Endometrial biopsy

This procedure is used in women who are at risk for endometrial polyps, hyperplasia, or carcinoma, though other pathology may be found. Endometrial sampling should be a first-line test in those with menorrhagia who are older than 45 years and those younger than 45 years with a history of exposure to unopposed estrogen, persistent menorrhagia, and/or failed medical management.^[23] . Other high-risk patients who may need to be biopsied include those with hypertension, diabetes, chronic anovulation (eg, PCOS), obesity, atypical glandular cells on Pap smear, new-onset menorrhagia, and those older than 70 years or any woman older than 35 years with new-onset irregular bleeding (especially if nulliparous).

EMB findings are used to assess the stage and proliferation of the endometrial stroma and glands. Many studies have been done to compare the results of EMB and dilation and curettage (D&C). Both tests are accepted as equal in value and are approximately 98% accurate.^[37] EMB is more accurate for ruling in disease if positive than ruling it out if negative.

Because routine EMB and conventional imaging studies may miss small or laterally displaced lesions, superior methods of assessment must be used in high-risk patients. In addition, performing an in-office biopsy or imaging studies may be limited by patient problems such as obesity or cervical stenosis.

Hysteroscopy

This can be done in the office but may require anesthesia if the patient has a low pain tolerance or adequate visualization is not obtainable.

This technique is used to directly visualize the endometrial cavity after the cavity is distended with a medium, most typically normal saline. A primary advantage of hysteroscopy is the ability to detect and treat focal lesions, such as fibroids and polyps immediately upon visual diagnosis. A biopsy sample should be taken, regardless of the endometrial appearance. The histologic diagnosis is missed in less than 2% of patients who undergo hysteroscopy with directed biopsy.^{[37, 38]}

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Histologic Findings

Understanding EMB results is essential for any physician treating menorrhagia. If no tissue is returned after an EMB is performed, particularly in postmenopausal patients, most likely the endometrium is atrophic and requires estrogen. Simple proliferative endometrium is normal and does not require treatment. If sampling is insufficient or an EMB cannot be performed, a diagnostic hysteroscopy with D&C can be performed. No further sampling is needed for premenopausal women if biopsy results are normal, but further evaluation should be pursued if symptoms persist or the patient is postmenopausal.

Any biopsy that reveals endometrial hyperplasia with atypia or carcinoma should prompt immediate referral to a gynecologic oncologist for treatment outlined by current oncology protocols associated with the grade and stage of the cancer.

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Medical Care

Medical therapy for menorrhagia should be tailored to the individual. Factors taken into consideration when selecting the appropriate medical treatment include the patient’s clinical stability, acuity of bleeding, patient's age, coexisting medical diseases and allergies, family history, and desire for fertility. Medication cost and adverse effects are also considered because they may play a direct role in patient compliance.^[39]  Options for hormonal therapy include combined oral contraceptive pills, GnRH agonists and antagonists, hormonal patches or vaginal rings, progestin-only pills, depot medroxyprogesterone acetate, the levonorgestrel-releasing intrauterine device, and the etonogestrel implant, according to American College of Obstetricians and Gynecologists.^[40] The Centers for Disease Control and Prevention’s Medical Eligibility Criteria for Contraceptive Use and US Food and Drug Administration (FDA) labeling information can be useful in determining the contraindications to hormonal methods based on medical comorbidities.

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line medical therapy in ovulatory menorrhagia. Studies show an average reduction of 20-46% in menstrual blood flow.^[41] NSAIDs reduce prostaglandin levels by inhibiting cyclooxygenase and decreasing the ratio of prostacyclin to thromboxane. NSAIDs are often ingested for the first 5 days of a menstrual cycle, although the use is limited by the most common adverse effect of stomach upset. NSAIDs should be avoided in patients with an allergy or with peptic ulcer and renal disease.

Combined hormonal contraceptives

Oral contraceptive pills (OCPs) are a popular first-line therapy for women who desire contraception in addition to management of abnormal uterine bleeding (AUB). Menstrual blood loss is reduced as effectively as NSAIDs secondary to endometrial atrophy.^[42] OCPs suppress pituitary gonadotropin release and thus ovulation. OCPs can be used in continuous or extended fashion for menorrhagia and multidose regimens for acute AUB. Common adverse effects include breast tenderness, breakthrough bleeding, nausea, and related weight gain in some individuals. The vaginal ring and transdermal patch require less frequent administration than daily OCPs. Both the ring and patch can be used similarly to OCPs, with a standard 28-day cycle, extended cycles, or continuously. Patients should be counseled about the various routes of administration for combined contraceptives and the benefits and disadvantages of each.

Progesterone-only contraceptives

Progestin is the most frequently prescribed medication for menorrhagia likely because of its safety in the setting of other medical comorbidities and its efficacy. Therapy with this drug results in a significant reduction in menstrual blood flow when used alone. Progestin works as an antiestrogen by minimizing the effects of estrogen on target cells, thereby maintaining the endometrium in a state of nonproliferation. Common adverse effects include weight gain, headaches, edema, and depression.

High-dose oral progestin options (eg, norethindrone 5-15 mg daily, medroxyprogesterone 5-30 mg daily) can be taken day 5 to 26 of the menstrual cycle or continuously and have shown to reduce blood loss by >80%.^[43] In contrast to the combined OCPs, low-dose progestin-only pills (POPs) (eg, 0.35 mg norethindrone) typically for contraceptive use are not usually recommended for treatment of menorrhagia as they are associated with irregular and unpredictable blood loss.

Depo-medroxyprogesterone acetate (DMPA) is an injectable long-acting progesterone, administered as an intramuscular injection, typically given every 12-14 weeks. This can be titrated to more frequent dosing if unfavorable spotting occurs. Like other hormonal options, DMPA works to inhibit FSH release, follicle development, and thus, ovulation. DMPA is known to cause a transient reduction in bone mineral density with long-term use and complete restoration is seen after cessation of use. The clinical impact is uncertain, and DMPA is suitable for most women. Other adverse effects include weight changes and unscheduled bleeding.^{[44, 45]}

The etonogestrel implant (Nexplanon) is inserted in the arm with local anesthesia and FDA-approved for use up to 3 years for contraception, though can be continued up to 5 years. The implant is a less effective option for management of menorrhagia, and breakthrough bleeding is common with the implant.^[45]

Levonorgestrel intrauterine device

The levonorgestrel intrauterine system (IUD) reduces menstrual blood loss by as much as 97%.^[46] It is comparable to transcervical resection of the endometrium for reduction of menstrual bleeding.^{[47, 48, 49]} Adverse effects include discomfort with insertion, spontaneous expulsion, and abnormal uterine bleeding or spotting.

Gonadotropin-releasing hormone agonists and antagonists

These agents are used on a short-term basis in selected patients due to high costs and severe adverse effects. GnRH agonists and antagonists can be effective in reducing menstrual blood flow. They inhibit pituitary release of FSH and LH, resulting in hypogonadism. A prolonged hypoestrogenic state leads to bone demineralization and reduction of high-density lipoprotein (HDL) cholesterol. Notably, most patients experience a “flare” in symptomatology with initial treatment that resolves with continued use. Most commonly, GnRH agonists/antagonists are used preoperatively to reduce fibroid volume prior to surgical management.^[43] Studies have shown a volume reduction in fibroids of approximately 30%, which may impact the feasibility of minimally invasive treatment methods and decrease morbidity associated with surgical management. Common adverse effects are attributed to low estrogen levels, which can be managed with “add-back” hormone replacement therapy.

Danazol

Danazol competes with androgen and progesterone at the receptor level, causing amenorrhea in 4-6 weeks. Danazol can effectively reduce heavy menstrual bleeding, though serious adverse effects limit its use. Common adverse effects produce male characteristics and menopausal symptoms, such as acne, decreasing breast size, and, rarely, lower voice.^[43] In addition, danazol is teratogenic and patients need to be counseled about the risks of pregnancy while on this medication.

Conjugated estrogens

Estrogens are given intravenously every 4-6 hours in patients with acute bleeding. A D&C procedure may be necessary if no response is noted in 24 hours. Most typically patients will respond within 1-2 doses with cessation of acute bleeding. If menses slows, patients often transition to OCPs to minimize unopposed estrogen exposure.

Tranexamic acid

Tranexamic acid (Lysteda) was the first nonhormonal product approved by the FDA (in November of 2009) for the treatment of heavy menstrual bleeding. It is a synthetic derivative of lysine that uses antifibrinolytic effects by inhibiting the activation of plasminogen to plasmin. Tranexamic acid’s mechanism of action in treating heavy menstrual bleeding is by prevention of fibrinolysis and the breakdown of clots via inhibiting endometrial plasminogen activator. Most recommend using oral or IV tranexamic acid. Oral tranexamic is commonly given as 1.3 g tablets three times per day for the first 5 days of menses. Tranexamic acid has been shown to reduce bleeding by 30-55% in those with chronic AUB.^[50]

In a double-blind, placebo-controlled study, women taking 3.9 g/d of tranexamic acid showed a significant reduction in menstrual blood loss and an increase in their health-related quality of life compared with those taking placebo.^[51] Common adverse effects include menstrual discomfort, headache, and back pain. A Cochrane study reviewed data from a nonrandomized study that found value in combining desmopressin and tranexamic acid; however, these results need further study.^[52]

• References

Surgical Care

Surgical management has been the standard of treatment in menorrhagia due to structural causes (eg, fibroids) or when medical therapy fails to alleviate symptoms.^[50] Surgical treatment ranges from a simple D&C to a total hysterectomy.

Surgical management is based on the acuity and severity of bleeding, contraindications and response to medical management, and the underlying etiology of bleeding. Choosing a surgical modality is a shared decision-making process, which depends on the previously mentioned considerations, future fertility, and the patient’s goals.

Dilation and curettage

A D&C should be used for diagnostic purposes. It is not used for treatment because it provides only short-term relief, typically 1-2 months, though can be used to stop acute bleeding episodes in specific circumstances. This procedure is used best in conjunction with hysteroscopy to evaluate the endometrial cavity for pathology. It is contraindicated in patients with known or suspected pelvic infection. Risks include uterine perforation, infection, and Asherman syndrome.

Resectoscopic endometrial ablation techniques (first-generation)

Endometrial ablation is a surgical procedure that destroys the endometrium. For many, this procedure provides a minimally invasive and effective option for menorrhagia and can be used for acute uterine bleeding. Ablation is typically considered if a patient has failed medical therapy or desires more definitive management, and/or other options are contraindicated. Techniques are divided into first- and second-generation devices. Clinically, first-generation devices have largely been abandoned in favor of more contemporary methods that yield excellent effects with minimal morbidity but are presented here for context. The endometrium should be properly sampled and evaluated before surgery to rule out malignancy. Most second-generation devices require a relatively normal intrauterine cavity, which can be evaluated preoperatively with imaging and/or at time of surgery with concurrent hysteroscopy. Some may consider pretreating with GnRH agonists, combination oral contraceptives, or progestins for 4-12 weeks before surgery to atrophy the endometrium, reducing surgical difficulty and time. Endometrial ablation should not be used in people who desire future fertility, those with known or suspected premalignant or endometrial carcinoma, or for the sole treatment of fibroids or polyps. Contraception is recommended postoperatively in premenopausal people.^{[53, 54]}

Transcervical resection of the endometrium ^[2]

Transcervical resection of the endometrium (TCRE) was considered the criterion standard cure for menorrhagia for many years. This procedure requires the use of a resectoscope (ie, hysteroscope with a heated wire loop), and it requires time and skill. TCRE can excise concurrent intrauterine pathology such as polyps and leiomyomas. The primary risk is uterine perforation, and TCRE has consequently fallen out of favor as newer techniques have emerged.

Roller-ball endometrial ablation ^[3]

Roller-ball endometrial ablation essentially is the same as TCRE, except that a heated roller ball is used to destroy the endometrium (instead of the wire loop). The goal is to ablate all endometrial surfaces. Ablation often takes 45 minutes for a skilled surgeon. It has the same requirements, risks, and outcome success as TCRE. Satisfaction rates are equal to those of TCRE.

Endometrial laser ablation

Endometrial laser ablation requires Nd:YAG equipment and optical fiber delivery system. The laser is inserted into the uterus through the hysteroscope while transmitting energy through the distending media to warm and eventually coagulate the endometrial tissue. Disadvantages include the expense of the equipment (high), the time required for the procedure (long), and the risk of excessive fluid uptake from the distending media infusion and irrigating fluid. This technique has largely been replaced by the nonresectoscopic systems (discussed below).

Nonresectoscopic endometrial ablation techniques (second-generation)

Second-generation devices confer less surgical risk, surgical time and produce better patient outcomes than first-generation ablation techniques. Hysteroscopy may be utilized to evaluate the uterine cavity prior to ablation, though is often not required.

Thermal balloon therapy ^{[4, 5]}

A balloon catheter filled with isotonic sodium chloride solution is inserted into the endometrial cavity, inflated, and heated to 87°C for 8 minutes. Uterine balloon therapy cannot be used in irregular uterine cavities because the balloon will not conform to the cavity. Studies report a 90% patient satisfaction rate and a 25% amenorrhea rate.

Heated free fluid ^[6]

HydroThermAblator (HTA) is an office procedure in which normal saline is infused into the uterus via the hysteroscope. The solution is heated to 194°F (90°C) for 10 minutes under direct visualization. Hydrostatic pressure remains below minimum pressure needed to spill through fallopian tubes. This procedure requires only local anesthesia. HTA may be used in patients with irregularly shaped endometrial cavities and/or fibroids. Vaginal and skin burns, though rare, are the most reported complications.

Cryoablation ^[7]

Cryoablation is the use of liquid nitrogen to freeze the endometrium. The procedure is performed in approximately 10 minutes under ultrasonographic guidance. Patients usually experience 1 week of watery vaginal discharge post procedure. Risks include perforation and suboptimal ablation of the entire uterine cavity.

Microwave endometrial ablation alternative ^[8]

Microwave endometrial ablation (MEA) was developed and has been used in Europe since 1996. It uses high-frequency microwave energy to cause rapid but shallow heating of the endometrium. Microwaves are selected so that they do not destroy beyond 6 mm in depth. MEA requires 3 minutes of time and only local anesthetic. It is proving to be as effective as TCRE.^[55] In a Japanese study, investigators found that multiple MEAs in the same region in women with adenomyosis and menorrhagia were more effective than conventional single ablation treatment, and also resulted in higher patient satisfaction rates.^[56]

Radiofrequency electricity ^{[7, 53]}

NovaSure system is a detailed microprocessor-based unit with a bipolar gold mesh electrode array. It contains a system for determining uterine integrity based upon the injection of CO₂. The device is placed transcervically, the array is opened, and electrical energy is applied for 80-90 seconds, desiccating the endometrium. The Minerva system is a combined thermal and bipolar radiofrequency ablation device, which uses an electric current to ionize argon gas leading to thermal ablation of the endometrium. Among the second-generation techniques, balloon, microwave, and radiofrequency ablation are the most studied. A meta-analysis reported that radiofrequency and microwave ablation result in higher rates of amenorrhea than thermal balloon ablation 12 months after treatment.

Endometrial ablation outcomes and complications

Overall, most studies report up to 90% improvement in bleeding. Amenorrhea rates vary between 20% and 70%.^[54] There is a higher risk of failure for people younger than 45 years of age. Of those who undergo an endometrial ablation, 24% or more will undergo a hysterectomy within 4 years of the ablation.^[7]

A 2019 Cochrane review of endometrial resection and ablation techniques for heavy menstrual bleeding suggests that compared with first-generation techniques, second-generation approaches offer equivalent efficacy for heavy menstrual bleeding and shorter operating times, and are more often performed under local anesthesia. Insufficient evidence exists to say which second-generation approaches were superior to others.^[53]

Common complications include risk of uterine perforation, hemorrhage, pelvic infection, and damage to surrounding external genitalia with specific devices. The risk of perforation is higher in resectoscope techniques.^[53]

Surgical techniques

Myomectomy ^[57]

Myomectomy involves removing fibroids, often by route of hysteroscopy or transabdominally via minimally invasive techniques or laparotomy depending on location, size, and number of fibroids. Myomectomy can be useful in women who wish to retain their uterus and/or fertility. Since myomectomy can be associated with large blood loss, this procedure is often reserved for cases of a single or few myomas. Risks include large blood loss or recurrence.

Hysterectomy ^{[17, 58]}

Hysterectomy provides a definitive cure for menorrhagia, often utilized for people who do not desire future fertility and have failed medical and/or other surgical options. Hysterectomies can be performed vaginally, laparoscopically (or laparoscopically assisted vaginal hysterectomy), robotically, or abdominally. The route of hysterectomy can be influenced by the size and shape of the uterus, accessibility of the uterus, surrounding pelvic disease, other concurrent procedures, surgeon preference and training, available technology and support, acuity of surgery, patient preference, and many other clinical factors.^[59] The procedure is more expensive and results in greater morbidity than ablative procedures.^[60] The mortality rate ranges from 0.1-1.1 cases per 1000 procedures and 1/30 women will experience a major adverse event.^[43] Risks include those usually associated with major surgery.

Procedural techniques

Uterine artery embolization (UAE)

UAE is considered an acceptable alternative to surgery for menorrhagia associated with fibroids, and research supports treatment of adenomyosis. Common reasons to choose UAE include desiring a nonsurgical approach, medical contraindications to surgery, uterine preservation, faster recovery, and minimally invasive technique. Common complications include fibroid expulsion, premature ovarian failure, infection, DVT, and postembolization syndrome. Given the lack of comprehensive studies, learned societies do not recommend UAE for women desiring to preserve fertility. Further controlled clinical trials are warranted to evaluate the indications and limitations of UAE in patients who desire to procreate.^[61]

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