Menorrhagia

Menorrhagia is defined as menstruation at regular cycle intervals but with excessive flow and 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[13] or menses lasting longer than 7 days.[14] The World Health Organization reports that 18 million women aged 30-55 years perceive their menstrual bleeding to be exorbitant.[15] Reports show that only 10% of these women experience blood loss severe enough to cause anemia or be clinically defined as menorrhagia.[14, 16, 17] In practice, measuring menstrual blood loss is difficult. Thus, the diagnosis is usually based upon the patient's history.

A normal menstrual cycle is 21-35 days in duration, with bleeding lasting an average of 7 days and flow measuring 25-80 mL.[18]

Menorrhagia must be distinguished clinically from other common gynecologic diagnoses. These include metrorrhagia (flow at irregular intervals), menometrorrhagia (frequent, excessive flow), polymenorrhea (bleeding at intervals < 21 d), and dysfunctional uterine bleeding (abnormal uterine bleeding without any obvious structural or systemic abnormality).[18]

Nearly 30% of all hysterectomies performed in the United States are performed to alleviate heavy menstrual bleeding.[11] Historically, definitive surgical correction has been the mainstay of treatment for menorrhagia. Modern gynecology has trended toward conservative therapy both for controlling 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 regimens must address the specific facet of the menstrual cycle the patient perceives to be abnormal, (ie, cycle length, quantity of bleeding). Finally, treatment success is usually evaluated subjectively by each patient, making positive outcome measurement difficult.

Knowledge of normal menstrual function is imperative in understanding the etiologies of menorrhagia. Four phases constitute the menstrual cycle, follicular, luteal, implantation, and menstrual.

In response to 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 an increase in endometrial thickness. 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.

If fertilization occurs, the implantation phase is maintained. Without fertilization, estrogen and progesterone withdrawal results in menstruation.

Etiologic causes are numerous and often unknown. Factors contributing to menorrhagia can be sorted into several categories, including organic, endocrinologic, anatomic, and iatrogenic.

If the bleeding workup does not provide any clues to the etiology of the menorrhagia, a patient often is given the diagnosis of dysfunctional uterine bleeding (DUB). Most cases of DUB 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 end result is asynchronous breakdown of the endometrial lining at different levels. This also is why anovulatory bleeding is heavier than normal menstrual flow.[19]

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. 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.

Anatomic defects or growths 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. The resulting prolonged bleeding time causes menorrhagia that can be very tenuous to treat.

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

Etiologies of menorrhagia are divided into 4 categories, organic, endocrinologic, anatomic, and iatrogenic.

Organic causes

Organic causes of menorrhagia include infection, bleeding disorders, and organ dysfunction. Consider the following:

• Infections can be of any genitourinary origin. The aforementioned sexually transmitted diseases are of greater concern in the teenage and early adult population. Bleeding from the urethra or rectum always must be considered in the workup, especially in the postmenopausal woman who has negative findings after a workup for vaginal bleeding.

• 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 thromboasthenia.[20]  See more on bleeding disorders below.

• Organ dysfunction causing menorrhagia includes hepatic or renal failure. Chronic liver disease impairs production of clotting factors and reduces hormone metabolism (eg, estrogen). Either of these problems may lead to heavy uterine bleeding.

Endocrine causes

Endocrine causes of menorrhagia include thyroid and adrenal gland dysfunction, pituitary tumors, anovulatory cycles, PCOS, obesity, and vasculature imbalance. Note the following:

• Both hypothyroidism and hyperthyroidism 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.[21]

• Prolactin-producing pituitary tumors cause menorrhagia by disrupting (GnRH) secretion. This leads to decreased LH and FSH levels, which ultimately cause hypogonadism. Interim stages of menorrhagia result until hypogonadism manifests.

• The most common etiology of heavy uterine bleeding is anovulatory cycles. The finding of menorrhagia at irregular intervals without any known organic etiology confirms the clinical diagnosis. This is most common in adolescent and perimenopausal populations.

• The hallmarks of PCOS are anovulation, irregular menses, obesity, and hirsutism. Insulin resistance is common and increases androgen production by the ovaries.

• Hyperinsulinemia is a direct consequence of obesity. This overproduction of insulin leads to ovarian production of androgens, as occurs in PCOS.

• Vasculature imbalance is theorized to be the result of a discrepancy between the vasoconstricting and aggregating actions of prostaglandin F2 (alpha) and thromboxane A2 and the vasodilating actions of prostaglandin E2 and prostacyclin on the myometrial and endometrial vasculature.

Anatomic causes

Anatomic etiologies for menorrhagia include uterine fibroids, endometrial polyps, endometrial hyperplasia, and pregnancy. Note the following:

• Fibroids and polyps are benign structures that distort the uterine wall and/or endometrium. Either may be located within the uterine lining, but fibroids may occur almost anywhere on the uterus.

• 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. Fibroids may enlarge to the point that they outgrow their blood supply and undergo necrosis. This also causes a great deal of pain for patients.

• Endometrial hyperplasia usually results from unopposed estrogen production, regardless of the etiology. 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 y). If a woman takes unopposed estrogen (without progesterone), her relative risk of endometrial cancer is 2.8 compared to nonusers.[22]

Iatrogenic causes

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

• IUDs can cause increased menstrual bleeding and cramping due to local irritation effects.

• Steroid hormones and chemotherapy agents disrupt the normal menstrual cycle, which is restored easily upon cessation of the products.

• Anticoagulants decrease clotting factors needed to cease any normal blood flow, including menses. This type of menorrhagia also is easily reversible.

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.[23]  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.

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.[17]

Age-related demographics

Any woman of reproductive age who is menstruating may develop menorrhagia. Most patients with menorrhagia are older than 30 years.[18]  This is because the most common cause of heavy menses in the younger population is anovulatory cycles, in which bleeding does not occur at regular intervals.[24]

With proper workup, diagnosis, treatment, and follow-up care, prognosis is excellent.

Mortality/morbidity

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 as a result of their blood loss. Menorrhagia is the most common cause of anemia in premenopausal women. This usually can be remedied by simple ingestion of ferrous sulfate to replace iron stores. If the bleeding is severe enough to cause volume depletion, patients may experience shortness of breath, fatigue, palpitations, and other related symptoms. This level of anemia necessitates hospitalization for intravenous fluids and possible transfusion and/or intravenous estrogen therapy. Patients who do not respond to medical therapy may require surgical intervention to control the menorrhagia.

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.[21]

Complications

Complications of menorrhagia include the following:

• Treatment of menorrhagia must be individualized to treat each patient's specific symptoms. Cost, dosing, and patient compliance can play major roles.

• If bleeding does not subside within the expected time frame, have the patient keep a menstrual calendar to better assess the resulting bleeding pattern.

• If a specific treatment fails, investigate all possibilities, including noncompliance, medication dosing, diagnosis, patient age, and comorbid conditions.

Reassure patients that most bleeding stops, but not immediately. Provide literature on the treatment of choice, including expectations and adverse effects.

Many patients appreciate reassurance that they do not have cancer and are not alone in their plight.

Reassure patients who experience a treatment failure that other options are available.

Symptoms related 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

This is the most common cause of irregular bleeding in women of reproductive age.

Pregnancy should be the first diagnosis to be excluded before further testing or medications are instituted.

Quantity and quality of bleeding

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.

Quality of bleeding involves the presence of clots and their size.

Patient age

Young patients, from menarche to the late-teen years, most commonly have anovulatory bleeding due to the immaturity of their hypothalamic-pituitary axis. If bleeding does not respond to usual therapy in this age group, a bleeding disorder must be considered.

Women aged 30-50 years may have organic or structural abnormalities. Fibroids or polyps are frequent anatomical findings. Organic causes can be anything from thyroid dysfunction to renal failure.

Postmenopausal women with any uterine bleeding should receive an immediate workup for endometrial cancer.

Endometrial hyperplasia must be considered in women who are obese, aged 70 or older, nulliparous, or have diabetes.

Pelvic pain and pathology

Knowing if a patient has any long-standing diagnosis or known pathology (eg, fibroids) is helpful.

Records from other physicians or hospitalizations may prevent redundancy in ordering lab work or diagnostic imaging.

Menses pattern from menarche

If a young patient has had irregular menses since menarche, the most common etiology of her bleeding is anovulation.

Anovulatory bleeding is most common in young girls (aged 12-18 y) and common in obese females of any reproductive age.

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 may present with heavier bleeding attributed primarily to the copious discharge mixed with the blood.

Chlamydia is a common cause of postpartum endometritis, leading to vaginal bleeding in the weeks following a delivery.

A postpartum infection (eg, endometritis) also may be due to organisms unrelated to sexual activity.

Contraceptive use(intrauterine device or hormones)

Commonly, an intrauterine device (IUD) causes increased uterine cramping and menstrual flow.

If a patient has recently discontinued birth control pills, she may return to her "natural" menses and report an increase in flow. This actually is normal because most 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 and in an anovulatory 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 complaining of a milky discharge from either breast (while not pregnant, postpartum, or breastfeeding) needs a prolactin level to rule out a 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 her first menses.

This is a very common presentation for an undiagnosed bleeding disorder (von Willebrand disease) in a young girl.

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.

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:

• 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 is a locale for 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): This usually points to polycystic ovarian syndrome (PCOS), leading to anovulatory bleeding (see Presence of hirsutism).

• Ecchymosis: This usually is a sign of trauma or a bleeding disorder.

• Purpura: This also is a sign of trauma or a possible bleeding disorder.

• Pronounced acne: This is a sign of PCOS.

General examination should include evaluation of the following:

• Visual fields

• Bleeding gums

• Thyroid evaluation

• Galactorrhea

• Enlarged liver or spleen

Pelvic examination should evaluate for the presence of external genital lesions.

Vaginal/cervical discharge: Look for a copious discharge indicating infection, and confirm the actual site of the bleeding (if present). Assess as follows:

• Uterine size, shape, and contour: An enlarged irregularly shaped uterus suggests fibroids if the patient is aged 30-50 years. An enlarged uniformly shaped uterus in a postmenopausal patient with bleeding suggests endometrial cancer until proven otherwise.

• Cervical motion tenderness: This is a common symptom of pelvic inflammatory disease (PID) that usually is caused by gonorrhea or chlamydia. This 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 pelvic ultrasound.

CBC count

The CBC count may be used as a baseline for hemoglobin and hematocrit or to rule out anemia. Use the platelet count in conjunction with a peripheral smear if a coagulation defect is suspected.

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).[25]

Human chorionic gonadotropin

Pregnancy remains the most common cause of abnormal uterine bleeding in patients of reproductive age. Bleeding usually denotes threatened abortion, incomplete abortion, or ectopic pregnancy.

Thyroid function tests and prolactin level

These tests can rule out hyperthyroidism or hypothyroidism and hyperprolactinemia. All of these conditions 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

LH, FSH, and androgen levels help diagnose patients with suspected PCOS.

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.

Cervical specimens should be obtained if the patient is at risk for an infection.

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 the best noninvasive imaging study to assess uterine shape, size, and contour; endometrial thickness; and adnexal areas.[26]

Sonohysterography (saline-infusion sonography): Fluid infused into the endometrial cavity enhances intrauterine evaluation. One advantage is the ability to differentiate polyps from submucous leiomyomas (ie, fibroids).

MRI as a second-line test is to be used when the diagnosis from pelvic ultrasonography is unclear. In fact, adenomyosis is best diagnosed by MRI, although it can be detected with transvaginal ultrasonography.[27]

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 by close contact. 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.[28]

Endometrial biopsy

This procedure is used in women who are at risk for endometrial carcinoma, polyps, or hyperplasia.

High-risk patients who should be biopsied include those with hypertension, diabetes, chronic anovulation (eg, PCOS), obesity, atypical glandular cells (AGUS) 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 dilatation and curettage (D&C). Both tests are accepted as equal in value and are approximately 98% accurate.[28]

Understanding EMB results is essential for any physician treating menorrhagia.

If no tissue is returned after an EMB is performed, most likely the endometrium is atrophic and requires estrogen.

Simple proliferative endometrium is normal and does not require treatment.

Endometrial hyperplasia (except atypical adenomatous) requires progesterone on timed 12-day regimens outlined in the Treatment. Endometrial hyperplasia with atypia (especially atypical adenomatous hyperplasia) generally is considered equivalent to an intraepithelial malignancy, and hysterectomy usually is advised.

Any biopsy that reveals endometrial 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.

Medical therapy for menorrhagia should be tailored to the individual. Factors taken into consideration when selecting the appropriate medical treatment include the patient's age, coexisting medical diseases, family history, and desire for fertility. Medication cost and adverse effects are also considered because they may play a direct role in patient compliance.[29]  Options for hormonal therapy include combined oral contraceptive pills, combined hormonal patches, 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.[30]

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.[31] NSAIDs reduce prostaglandin levels by inhibiting cyclooxygenase and decreasing the ratio of prostacyclin to thromboxane. NSAIDs are ingested for only 5 days of the entire cycle, limiting their most common adverse effect of stomach upset.

Oral contraceptive pills

Oral contraceptive pills (OCPs) are a popular first-line therapy for women who desire contraception. Menstrual blood loss is reduced as effectively as NSAIDs secondary to endometrial atrophy.[32] OCPs suppress pituitary gonadotropin release, preventing ovulation.

Common adverse effects include breast tenderness, breakthrough bleeding, nausea, and, possibly, related weight gain in some individuals.

A long-term combination of oral estradiol valerate and dienogest was found to be highly effective when compared with placebo in the treatment of women with heavy menstrual bleeding.[33] In 2012, dienogest/estradiol valerate (Natazia) was the first oral contraceptive approved by the FDA for heavy menstrual bleeding.

Progestin therapy

Progestin is the most frequently prescribed medicine for menorrhagia. 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 down-regulation. Common adverse effects include weight gain, headaches, edema, and depression.

Levonorgestrel intrauterine system

The levonorgestrel intrauterine system reduces menstrual blood loss by as much as 97%.[34] It is comparable to transcervical resection of the endometrium for reduction of menstrual bleeding.[35, 36, 37] Adverse effects include uterine bleeding or spotting, headache, ovarian cysts, vaginitis, dysmenorrhea, and breast tenderness.

A study by Kim et al indicated that the presence of a large myoma increases the likelihood of treatment failure with either thermal balloon ablation or the levonorgestrel intrauterine system. The study involved 106 women with menorrhagia and either intramural or submucosal myomas, including 67 patients who underwent thermal balloon ablation and 39 who were treated with the levonorgestrel intrauterine system; follow-up lasted more than 12 months.[38]

The investigators found that treatment failure (ie, hysterectomy at some time during follow-up or recurrence or persistence of menorrhagia within one year of treatment) for thermal balloon ablation for women with myomas of under 2.5 cm was 12%, compared with 28% for women with myomas that were less than 5 cm but greater than or equal to 2.5 cm, and 56% for women whose myomas were at least 5 cm in size. Those figures for women treated with the levonorgestrel intrauterine system were 14%, 29%, and 25%, respectively.[38]

In the ECLIPSE trial, which compared the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system with standard medical care (ie, tranexamic acid, mefenamic acid, combined oestrogen-progestogen or progesterone alone) for menorrhagia, investigators noted that although both treatment groups had improved scores as measured by the Menorrhagia Multi-Attribute Scale (MMAS), significantly greater improvement occurred in the levonorgestrel intrauterine system group over a 2-year period.[39] However, the differences between treatment groups were no longer significant at 5 years, and there was a similarly low proportion of women who required surgery in the groups. The investigators also indicated that the levonorgestrel intrauterine system was cost-effective in the short and medium term.[39]

Gonadotropin-releasing hormone agonists

These agents are used on a short-term basis due to high costs and severe adverse effects. GnRH agonists are 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.

Danazol

Danazol competes with androgen and progesterone at the receptor level, causing amenorrhea in 4-6 weeks. Androgenic effects cause acne, decreasing breast size, and, rarely, lower voice.

Conjugated estrogens

These agents are given intravenously every 4 hours in patients with acute bleeding. A D&C procedure may be necessary if no response is noted in 24 hours. If menses slows, follow up with estrogen-progestin therapy for 7 days. This is followed by OCPs for 3 months.

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.

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.[40] Common adverse effects include menstrual discomfort, headache, and back pain.

A Cochrane study reviewed data from a non-randomized study that found value in combining desmopressin and tranexamic acid, however, these results need further study.[41]

Surgical management has been the standard of treatment in menorrhagia due to organic causes (eg, fibroids) or when medical therapy fails to alleviate symptoms.[42] Surgical treatment ranges from a simple D&C to a full hysterectomy.

Dilatation 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.

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

Transcervical resection of the endometrium[3]

Transcervical resection of the endometrium (TCRE) has been 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.

The primary risk is uterine perforation.

Roller-ball endometrial ablation[4]

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).

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

Thermal balloon therapy[5, 6]

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% satisfaction rate and a 25% amenorrhea rate. Long-term studies are ongoing.

Heated free fluid[7]

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.

This procedure requires only local anesthesia.

HTA may be used in patients with irregularly shaped endometrial cavities and/or fibroids.

Vaginal and skin burns are the most reported complications.

Cryoablation[8]

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 postprocedure.

Risks include perforation and suboptimal ablation of the entire uterine cavity.

Microwave endometrial ablation alternative[9]

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.[43]

In a Japanese study, investigators found that multiple MEAs in the same region in women with adenomyosis and menorrhagia was more effective than conventional single ablation treatment, as well as resulted in higher patient satisfaction rates.[44]

Radiofrequency electricity[8]

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.

Endometrial ablation or resection preparation

A trial of medical therapy should have failed in patients considered for this therapy. The endometrium should be properly sampled and evaluated before surgery.

Patients should be pretreated with danazol or a GnRH analogue for 4-12 weeks before surgery to atrophy the endometrium, reducing surgical difficulty and time.

Success rates are similar to laser ablation techniques.

A 2005 Cochrane Review (updated in 2009) concluded that "overall the existing evidence suggests that success rates and complication profiles of newer techniques of ablation compare favorably with TCRE, although technical difficulties with new equipment need to be ironed out."[9, 45]

In an observational study (2010-2012) of 235 German women aged 18 years and older with menorrhagia and high or low surgical risk of complications who underwent radiofrequency endometrial ablation (RFEA), RFEA appeared to improve quality of life as well as resulted in high satisfaction among both groups of women.[46] High-risk factors included anemia, coagulopathy, anticoagulation, thromboembolism, obesity, transplantation, malignancy, and severe cardiovascular/pulmonary disease.[46]

Surgical techniques

Myomectomy[10]

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[11, 12]

Hysterectomy provides definitive cure for menorrhagia.

This procedure is more expensive and results in greater morbidity than ablative procedures.

The mortality rate ranges from 0.1-1.1 cases per 1000 procedures.

The morbidity rate is usually 40%.

Risks include those usually associated with major surgery.

A study by Roberts et al reviewed the cost effectiveness of first-generation and second-generation endometrial ablative techniques, hysterectomy, and the levonorgestrel-releasing intrauterine system (Mirena) for the treatment of heavy menstrual bleeding.[47] Although the authors did not define "heavy menstrual bleeding," their analysis concluded that the most cost-effective initial treatment for menorrhagia that yielded the best quality of life was hysterectomy.

Acute menorrhagia requires prompt medical intervention. This is bleeding that will compromise an untreated patient.

Successful treatment of chronic menorrhagia is highly dependent on a thorough understanding of the exact etiology. For instance, acute bleeding postpartum does not respond to progesterone therapy, while anovulatory bleeding worsens with high-dose estrogen.

Class Summary

Block formation of prostacyclin, an antagonist of thromboxane, which is a substance that accelerates platelet aggregation and initiates coagulation. Prostacyclin is produced in increased amounts in menorrhagic endometrium. Because NSAIDs inhibit blood prostacyclin formation, they might effectively decrease uterine blood flow.

Naproxen (Anaprox, Naprelan, Naprosyn)

Used for relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

Diclofenac (Cataflam)

Inhibits PG synthesis by decreasing activity of enzyme cyclooxygenase, which in turn decreases formation of PG precursors.

Class Summary

OCPs containing estrogen and progestin used to treat acute hemorrhagic uterine bleeding.

Dienogest/estradiol valerate (Natazia)

Negative feedback decreases GnRH amounts resulting in reduced LH and FSH secretion from the pituitary gland and anovulation. Indicated for treatment of heavy menstrual bleeding not caused by any diagnosed conditions of the uterus in women who choose an oral contraceptive for contraception.

Class Summary

Occasional anovulatory bleeding that is not profuse or prolonged can be treated with progestins, antiestrogens given in pharmacologic doses. Inhibit estrogen-receptor replenishment and activate 17-hydroxysteroid dehydrogenase in endometrial cells, converting estradiol to the less-active estrone.

Medroxyprogesterone (Depo-SubQ Provera 104, DepoProvera, MPA)

Short-acting synthetic progestin. Works as an antiestrogen by minimizing estrogen effects on target cells. Endometrium is maintained in an atrophic state. Effective against hyperplasia and has modest effects on serum lipids (ie, lowering HDL). 

Megestrol (Megace, Megace ES)

It is active against uterine hyperplasia without significantly altering serum lipid levels. 

Levonorgestrel intrauterine (Liletta, Mirena)

Indicated for heavy menstrual bleeding for up to 5 years in women who choose to use intrauterine contraception as a method of contraception. 

Class Summary

Work by reducing concentration of GnRH receptors in the pituitary via receptor down-regulation and induction of postreceptor effects, which suppress gonadotropin release. After an initial gonadotropin release associated with rising estradiol levels, gonadotropin levels fall to castrate levels, with resultant hypogonadism. This form of medical castration is very effective in inducing amenorrhea, thus breaking the ongoing cycle of abnormal bleeding in many anovulatory patients.

Leuprolide (Lupron)

Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.

Class Summary

Certain androgenic preparations have been used historically to treat mild-to-moderate bleeding, particularly in ovulatory patients with abnormal uterine bleeding. Use might stimulate erythropoiesis and clotting efficiency. Alters endometrial tissue so that it becomes inactive and atrophic.

Danazol (Danocrine)

Synthetic steroid analog with strong antigonadotropic activity (inhibits LH and FSH) and weak androgenic action. Competes with androgen and progesterone at receptor level, resulting in amenorrhea within 3 mo.

Class Summary

Indicated in patients with thromboembolic disorders.

Desmopressin (DDAVP)

Has been used to treat abnormal uterine bleeding in patients with coagulation defects. Transiently elevates factor VIII and von Willebrand factor.

Class Summary

Effective in controlling acute, profuse bleeding. Exerts a vasospastic action on capillary bleeding by affecting the level of fibrinogen, factor IV, and factor X in blood and platelet aggregation and capillary permeability. Estrogen also induces formation of progesterone receptors, making subsequent treatment with progestins more effective.

Conjugated equine estrogen (Premarin)

Only controls bleeding acutely but does not treat underlying cause. Appropriate long-term therapy can be administered once the acute episode has passed.