Menorrhagia

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

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).

Nearly 30% of all hysterectomies performed in the United States are performed to alleviate heavy menstrual bleeding. Definitive surgical correction has been the mainstay of treatment for menorrhagia. Modern gynecology dictates the trend toward conservative therapy for cost containment and because many women desire to preserve their uteruses. Alternatives to hysterectomy also are the result of statistics revealing that nearly 50% of uterine pathology findings from hysterectomies for menorrhagia are free of disease and histopathologic abnormalities.

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 usually is evaluated subjectively by each patient, making positive outcome measurement difficult.

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Pathophysiology: 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.

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.

Frequency:
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• In the US: While 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.

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.

Sex:

• Only females are affected by menorrhagia.

Age:

• Any woman of reproductive age who is menstruating may develop menorrhagia. Most patients with menorrhagia are older than 30 years. 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.

CLINICAL

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History: 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 should include the following:

• Exclusion of pregnancy

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

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• 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.

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

• 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.

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• 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.

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

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• 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.

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• 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.

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

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• 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.

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

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

WORKUP

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Lab Studies:
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• Complete blood 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.

• 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.

Imaging Studies:
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• 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.

• 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).

Other Tests:
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• 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.

Procedures:
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• 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.

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• A biopsy sample should be taken, regardless of the endometrial appearance.

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• The histologic diagnosis is missed in less than 2% of patients who undergo hysteroscopy with directed biopsy.

• 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.

Histologic Findings: 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.

TREATMENT

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Medical Care: Medical therapy must 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 also are factored in because they may play a direct role in patient compliance.

• Nonsteroidal anti-inflammatory drugs
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  • Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line medical therapy in ovulatory menorrhagia.
  • Studies show an average reduction of 25-35% in menstrual blood flow.
  • NSAIDs reduce prostaglandin levels by inhibiting cyclooxygenase and increasing 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 much as 60% due to endometrial atrophy.
  • OCPs suppress pituitary gonadotropin release, preventing ovulation.
  • Common adverse effects include breast tenderness, breakthrough bleeding, nausea, and, possibly, related weight gain in some individuals.

• Progestin therapy
  • Progestin is the most frequently prescribed medicine for menorrhagia.
  • Therapy with progestin results in a 15% reduction in menstrual blood flow when used alone.
  • If administered to a patient with an IUD, the reduction in blood loss is as high as 86%.
  • 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.

• 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
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  • 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
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  • 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.

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

• Dilatation and curettage
  • A D&C should be used for diagnostic purposes, although studies have shown that less than 50% of the endometrium is sampled during a D&C. 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.

• Transcervical resection of the endometrium
  • 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 but achieves an 84% satisfaction or success rate.
  • The primary risk is uterine perforation.

• Roller-ball endometrial ablation
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  • 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
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  • Endometrial laser ablation requires Nd:YAG (neodymium-doped:yttrium aluminum garnet) laser 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.
  • Of patients, 50% have amenorrhea and another 30% have hypomenorrhea, resulting in an overall success rate of nearly 80%.

• Endometrial ablation or resection preparation
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  • 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.

• Uterine balloon therapy
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  • 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. This success rate is slightly higher than the other techniques described above, but the rate is based on short-term studies. Long-term studies are in place but have not been completed because this technique has not been available for as long as the others.

• Hysterectomy
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  • 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 usually is 40%.
  • Risks include those usually associated with major surgery.

• Microwave endometrial ablation alternative
  • Microwave endometrial ablation (MEA) 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.
  • This procedure was developed and has been used in Europe since 1996.

FOLLOW-UP

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Complications:
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• Treatment 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.

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

Patient Education:
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• 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.

MISCELLANEOUS

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Medical/Legal Pitfalls:
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• Every patient presenting with uterine bleeding should first undergo pregnancy testing. Threatened or incomplete abortion, ectopic pregnancy, or retained products of conception must be considered before any imaging studies may be ordered.

• Every high-risk or postmenopausal patient with uterine bleeding first must be evaluated for endometrial or other gynecological malignancy.

• When treating patients with progestin therapy of any form, they must be informed that this is not a form of birth control. Pregnancy is possible, especially if ovulation is induced by the cycling of the progesterone.

• All medications and procedures must be administered only after informed consent of all benefits and risks.