Definition

Dysfunctional uterine bleeding (DUB) is defined as abnormal bleeding in the absence of intracavitary or uterine pathology.

Most menstrual cycles occur every 22 to 35 days. Normal menstrual flow lasts 3 to 7 days, with most blood loss occurring within the first 3 days. The menstrual flow amounts to 35 mL and consists of effluent debris and blood. Patients with menorrhagia lose more than 80 mL of blood with each menstrual cycle and often develop anemia. In general, most normal menstruating women use five or six pads or tampons per day. Although approximately 16 mg of iron are lost with each menstrual cycle, this rarely results in anemia in women with adequate intake of dietary iron.

More than 50% of women who complain of menorrhagia might not actually have heavy menses. Some patients change their sanitary products more often for hygienic reasons or because of personal preference or concern for toxic shock syndrome than because of heavy flow. Social obligations, sexual activity, hobbies, work, and travel are not interrupted with normal menstrual function.

Menstrual patterns associated with abnormal uterine bleeding are defined in Box 1.

Prevalence

Approximately 9% to 30% of reproductive-age women have menstrual irregularities requiring medical evaluation.¹ Approximately 15% to 20% of scheduled office gynecologic visits are for evaluation of abnormal uterine bleeding, exceeded only by vaginitis as a chief complaint.

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Pathophysiology

Simplistically, normal menstrual bleeding results from fluctuations in the hypothalamic-pituitary-adrenal-ovarian axis, leading to predictable denudation and sloughing of the endometrium. Hemorrhage followed by prompt hemostasis and repair causes stabilization and regrowth of the endometrium. Physiologically, constant low levels of estrogen prime the endometrium. Normal secretion of progesterone from the corpus luteum stabilizes the endometrium, decreases vascular fragility, and supports the endometrial stroma. Patients with menorrhagia typically have an imbalance of prostaglandin levels and increased fibrinolytic activity.

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Abnormal uterine bleeding generally can be categorized as anovulatory bleeding or ovulatory dysfunctional bleeding. Anovulatory DUB is caused by failure of the corpus luteum to sustain the developing endometrium. Patients with anovulatory cycles typically do not experience premenstrual syndrome—breast discomfort, increased mucoid vaginal discharge, or premenstrual cramping and bloating—characteristic of ovulatory cycles. Anovulatory cycles can coexist with intracavitary lesions. The most common causes of anovulatory cycles include polycystic ovary syndrome (PCOS), hypothalamic amenorrhea, premature ovarian failure, and hyperprolactinemia.² Bleeding is often noncyclic, variable in amount and volume, and unpredictable. Ovulatory cycles are predictable but might coexist with intracavitary lesions, including polyps or fibroids, and cause erratic bleeding.

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Diagnosis

History and Examination

The diagnosis has three main components. The physician should note the presence of galactorrhea, weight gain, acanthosis nigricans, evidence of hypothyroidism or hyperthyroidism, virilization, and acne. First, a detailed medical history and thorough review of systems must be obtained. Eliciting a detailed clinical history alerts the astute physician to systemic and medical conditions that cause menstrual dysfunction (Box 2). Inherited and acquired coagulation disorders and liver and renal diseases often manifest with symptoms of abnormal uterine bleeding. Second, the physical examination must be detailed and complete, even in the presence of heavy bleeding. The gynecologic examination must be performed with specific attention to the vagina, cervix, uterus, and adnexa to exclude pathology. Finally, appropriate laboratory studies should be ordered based on the clinical history obtained. Following the American College of Obstetrics and Gynecology (ACOG) guidelines eliminates costly and unnecessary laboratory testing.³

Pregnancy testing must always be performed in sexually active women. Women with profuse menorrhagia and a normal-size uterus should be screened for von Willebrand’s disease because 13% to 20% of women who are candidates for surgical intervention have the subtle form (type 1 disease). Successful medical options for treatment of women with von Willebrand’s disease include oral contraceptive therapy (88% successful), desmopressin acetate, antifibrinolytic agents, and plasma-derived concentrates rich in the high-molecular-weight multimers of von Willebrand’s factor (vWF).⁴

Liberal use of endometrial biopsy is encouraged in women older than 35 years who have increased risk factors for endometrial hyperplasia and endometrial cancer. Risk factors include diabetes, prolonged steroid use, obesity, long history of irregular cycles, unopposed estrogen therapy, and suspected polycystic ovary syndrome.

Special Categories of Abnormal Uterine Bleeding

Adolescence

The adolescent patient with irregular and heavy menses should be evaluated more thoroughly for coagulopathies because 20% to 30% might have a major bleeding diathesis.⁵ Specifically, adolescents need to be evaluated for von Willebrand’s disease with a ristocetin cofactor assay for vWF before hormonal therapy is initiated to prevent false-negative results. This assay is the best single screening test for von Willebrand’s disease. Laboratory testing in the adolescent should include serum human chorionic gonadotropin level (hCG), bleeding time, prothrombin time and partial thromboplastin time, complete blood count (CBC) with platelets, and vWF.

Perimenopause

Women entering the perimenopause might have recurrent bouts of DUB and associated physical complaints due to changes in the hypothalamic-pituitary axis. The hormonal milieu is associated with decreased inhibin levels and variable estradiol levels, normal follicle-stimulating hormone (FSH), and menstrual cycles that can be episodically ovulatory.⁶ Myriad menstrual complaints occur during the perimenopause, including menometrorrhagia, amenorrhea, and oligomenorrheic cycles. Additionally, decreased mental clarity, diminished concentration, vaginal dryness, decreased libido, hot flushes, and night sweats are classic hallmarks of perimenopause.

Oral contraceptive therapy is quite useful during the perimenopause and should be the first line of therapy rather than conventional hormone replacement therapy.⁷Traditional doses of postmenopausal hormone replacement therapy do not suppress ovulation or prevent pregnancy as do traditional oral contraceptive pills. In healthy nonsmoking women older than 35 years, oral contraceptive pills regulate menstrual cycles, decrease vasomotor symptoms, improve bone mineral density, and decrease the need for surgical intervention for DUB.

Menopausal Bleeding

Bleeding occurring more than 1 year after cessation of menses or during hormone replacement therapy or tamoxifen use requires thorough evaluation. Although the most common cause of postmenopausal bleeding is atrophy, intracavitary pathology and cancer must be excluded. Approximately 10% of women with postmenopausal bleeding have endometrial cancer. The likelihood of endometrial cancer increases with each decade and must be aggressively excluded.

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Treatment

Once the cause of DUB is identified, appropriate therapy can be instituted. Medical therapy with oral contraceptives or progesterone is a mainstay in the treatment of anovulatory menstrual cycles. Patients with ovulatory DUB must be evaluated for intracavitary uterine pathology because hormonal dysfunction is not likely the cause of bleeding. Patients with anatomic causes associated with abnormal bleeding can be treated surgically.

Operative Hysteroscopy

Submucosal Fibroids and Endometrial Polyps

Submucosal fibroids and endometrial polyps vary in number, location, and size. When patients have intracavitary pathology, an altered endometrial surface area, increased endometrial fragility and vascularity, endometrial irregularities, and abnormal prostaglandin levels contribute to DUB. Intracavitary lesions can coexist with anovulatory and ovulatory cycles. Office hysteroscopy and saline infusion sonography (SIS) are the most accurate methods to detect intracavitary lesions. Outpatient hysteroscopic myomectomy and polypectomy are quick, safe, and effective treatment modalities and are associated with a high level of patient satisfaction.⁸

Intramural Fibroids

Intramural fibroids also can cause disturbances in menstrual flow. The mechanisms are unclear but may be attributable to topographic endometrial abnormalities, endometrial glandular atrophy overlying the fibroid, venous congestion, increased endometrial surface area, and alteration in prostaglandin levels.

Several treatment options are available for symptomatic intramural fibroids. The treatment decision depends on whether the patient desires to become pregnant or to preserve the uterus. When a woman wishes to remain fertile, an abdominal or laparoscopic myomectomy may be recommended. The surgical route for myomectomy depends on the number, size, and location of the fibroids as well as on the physician’s surgical skill.

When pregnancy is not desired and fibroids contribute to heavy menstrual bleeding, the patient can be offered a minimally invasive outpatient procedure called uterine artery embolization. Transcutaneous insertion of a catheter through the femoral artery and subsequent occlusion of the uterine artery with Embospheres (Biosphere Medical, Rockland, Mass), polyvinyl alcohol beads, polyvinyl alcohol coils, or Gelfoam causes cessation of blood flow to the fibroid. Shortly thereafter, the fibroid necroses and shrinks. Menorrhagia-related symptoms resolve in 85% to 95% of menorrhagia patients treated with uterine artery embolization.⁹

Hysterectomy offers definitive therapy for patients with uterine fibroids who have completed childbearing and who do not desire to preserve the uterus. Laparoscopic, vaginal, or abdominal hysterectomy are surgical options. Factors influencing the surgical route include the number, sizes, and locations of fibroids; concomitant pelvic pathology; and surgical skill of the physician.

Dilation and curettage is no longer acceptable as the single surgical treatment for menorrhagia or DUB. In the past, this procedure was commonly used to treat menstrual aberrations; however, its inaccuracy often resulted in missed diagnoses, incomplete removal of intracavitary pathology, failure to treat DUB, and high false-negative rates.¹⁰ Operative hysteroscopy coupled with directed hysteroscopic endometrial sampling is the gold standard to evaluate the uterine cavity in the surgical suite. This evaluation can be performed in the presence of heavy bleeding, and coexisting intrauterine pathology can be removed.

Endometrial Ablation

Endometrial ablation is an alternative to hysterectomy for women with DUB. It usually is recommended after unsuccessful medical therapy for women with a normal uterine cavity who have completed childbearing and have a negative laboratory workup. Hysteroscopic and global endometrial ablation procedures destroy the basalis layer of the endometrium, preventing regeneration and thereby altering menstrual flow. This results in Asherman’s syndrome, which is characterized by hypomenorrhea, eumenorrhea, or amenorrhea. Endometrial ablation is an outpatient procedure associated with a rapid return to work, minimal complications, and high patient satisfaction rates. Approximately 20% to 30% of patients who undergo endometrial ablation become amenorrheic, 65% to 70% become hypomenorrheic, and 5% to 10% do not respond to treatment.

Medical Treatment

DUB due to anovulatory cycles is best treated medically. Surgery should be reserved for patients who do not respond to medical therapy or for whom medical therapy is contraindicated.

Several medical strategies are effective in treating this disabling condition. Therapy should be individually tailored after a review of the risks, benefits, concerns, and contraindications. Generally, oral contraceptives and progesterone therapy are the mainstays of medical treatment for women who do not desire children.

Danazol therapy creates a hypoestrogenic state and decreases menstrual blood loss by 70% to 80%. A conventional dosing schedule of 400 to 800 mg daily as well as a less-traditional schedule of 50 to 100 mg daily is helpful. Typical side effects of danazol therapy include weight gain, acne, and potential alteration of lipid levels.¹¹

Treatment with gonadotropin-releasing hormone (GnRH) (Depo Lupron or Synarel) creates a hypoestrogenic, menopause-like condition. Cessation of menstruation usually occurs within 3 months of initiating therapy. Menopausal symptoms, including hot flushes, night sweats, vaginal dryness, bone loss, joint pain, decreased concentration, and diminished libido, can occur with therapy. Compliance with therapy is generally good, despite these symptoms. Because osteoporosis is the biggest risk of prolonged therapy, treatment is limited to 6 months unless estrogen is added. GnRH is a great option for the woman in late perimenopause who has significant contraindications to other medical therapy. Halting menses is a relief to these patients, and after therapy, many women spontaneously transition into menopause. Additionally, intermittent depot leuprolide (Lupron) therapy in women with uterine fibroids provides a mean additional 9 months of symptom control (range, 2 to >25 mo).¹²

The levonorgestrel-releasing intrauterine system (Mirena) provides another effective treatment option for DUB. This intrauterine device produces a dramatic decline in menstrual blood loss (65%-98%) within 12 months of use. There is little systemic absorption of progesterone. The device, imbedded with 20 µg of levonorgestrel, causes pseudodecidual changes and amenorrhea. It can play an important role in women who have menorrhagia but who also need contraception, have a normal-size uterus, and wish to avoid surgery.¹³

Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease rates of dysmenorrhea and significantly reduce clotting and menstrual blood loss. Some studies have demonstrated a 50% to 80% reduction in blood loss with proper use of NSAIDs.¹⁴ Patients are advised to begin therapy 1 to 2 days before expected menstruation and to continue therapy throughout the menses. NSAID therapy also can be combined with oral contraceptives, if needed.

Oral contraceptives clearly play many roles in the treatment of menorrhagia and DUB. Short-term high-dose therapy is used when excessive bleeding results in an emergency. It successfully stops heavy menstrual bleeding in adolescents and perimenopausal women. Any low-dose (30-35 µg) ethinyl estradiol product can be taken every 6 hours for 5 days to rapidly stop heavy menstrual bleeding. Once bleeding has stabilized, a single daily maintenance dose provides a regular menstrual cycle as well as contraception.

Progesterone therapy is effective in women with anovulatory menstrual cycles. It stabilizes the proliferative endometrium and induces regular sloughing. Cyclic progesterone therapy is useful in women with contraindications to estrogen therapy (women older than 35 years who smoke, have a history of deep venous thrombosis, or have high risk factors for cardiovascular disease). Generally, medroxyprogesterone acetate 10 mg for 10 to 14 days each month induces a regular withdrawal bleed. This dosage does not provide contraception.

Long-acting progesterone therapy in the form of medroxyprogesterone acetate (MDPA) SR (Depo-Provera) stops menses in most patients. Standard dosing involves MDPA 150 mg administered intramuscularly every 3 months. Approximately, 80% to 90% of patients completing 12 months of MDPA therapy become amenorrheic. Side effects can include weight gain, irregular bleeding, and depression.

ACOG practice bulletin guidelines mandate thorough evaluation and medical treatment of noncyclic uterine bleeding. Treatment depends on desire for future fertility, tolerance of medical therapy, age, and severity of symptoms. When medical therapy fails, more-aggressive surgical options are considered.³

Clinical Tools to Evaluate the Endometrium

Historically, medical therapy is instituted for 3 months; when response to therapy is unsuccessful, additional evaluation is warranted. These ACOG guidelines are appropriate for hemodynamically stable patients with normal laboratory evaluation. Increasingly, an imaging evaluation is being used with the initial workup.¹⁵

Endometrial biopsy is generally performed in the office with a pipelle. The procedure can be performed quickly, is associated with few complications, and is generally well tolerated by the patient. Biopsy has a high sensitivity for detecting endometrial cancer and hyperplasia but a low sensitivity for detecting intracavitary lesions, including polyps and submucosal fibroids. Lesions encompassing a small surface area are likely to be missed. The biopsy instrument samples only 10% to 25% of the endometrial cavity. Patients with persistent symptoms despite normal biopsy results need further evaluation.

Transvaginal Ultrasound

Transvaginal ultrasound (TVUS) is extremely helpful in evaluating women with postmenopausal bleeding. TVUS permits rapid assessment of size, position, and presence of uterine fibroids. Adnexal pathology can be assessed. The endometrial echo measurement is critical in evaluating the health of the endometrium. If uterine size is greater than 12 gestational weeks, then transabdominal scanning is preferred. Measurement of the endometrial echo in the postmenopausal woman is very helpful in determining whether endometrial biopsy or further imaging studies are necessary. Normally, the endometrial echo measures less than 5 mm. Increased endometrial thickness is associated with endometrial hyperplasia, endometrial polyps, fibroids, and endometrial cancer. When the endometrial echo is greater than 5 mm or is indistinct or indeterminate, an enhanced view is required with SIS or hysteroscopy. An endometrial echo of less than 5 mm is associated with malignancy in less than 0.5% of cases.

Saline-Infusion Sonography

SIS infuses saline into the endometrial cavity during TVUS to enhance the image. (This technique is also called echohysteroscopy, hydrosonography, sonohysterography, sonohysterogram, sonohysterosalinogography, and sonoendovaginal ultrasound. The term saline-infusion sonography provides a more exact definition of the technique.¹⁵ ) SIS allows the clinician to evaluate the uterus for intracavitary lesions more accurately than TVUS. Causes of increased endometrial thickness can be clearly differentiated with saline infusion.

Current indications for SIS include abnormal bleeding in premenopausal or postmenopausal patients; evaluation of an endometrium that is thickened, irregular, immeasurable, or poorly defined on conventional TVUS; irregular-appearing endometrium with TVUS in women using tamoxifen; the need to differentiate between sessile and pedunculated masses of the endometrium; and presurgical evaluation of intracavitary fibroids.

Hysteroscopy

Thin operative hysteroscopes with outer diameter sizes ranging from 3 to 5 mm can easily and comfortably be used in the office. Hysteroscopy permits full visualization of the endometrial cavity and endocervix. Rapid visual inspection permits accurate diagnosis of atrophy, endometrial hyperplasia, polyps, fibroids, and endometrial cancer. Direct endometrial biopsies are possible with some hysteroscopes. When the endometrial cavity is normal, aggressive medical therapy can be considered.

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Outcomes

DUB is usually well categorized after the initial history, physical examination, and laboratory evaluation. Medical management is the mainstay unless uterine pathology is present. Patients with intrauterine polyps and submucosal fibroids have excellent relief of symptoms following operative hysteroscopy. Surgical therapy with endometrial ablation offers 90% success for treating menorrhagia and dysfunctional bleeding in women with a normal uterine cavity who do not desire children but have negative workup results. Fortunately, hysterectomy is the last resort for DUB in this era of many alternative medical and surgical treatments.

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Summary

• The evaluation of abnormal uterine bleeding requires a complete physical examination, detailed medical history, and laboratory testing.
• The endometrial cavity can be evaluated with office hysteroscopy or saline infusion sonography.
• Uterine fibroid embolization is an excellent alternative to hysterectomy in appropriately triaged patients.
• Dilation and curettage is no longer the first choice for evaluating the endometrial cavity.
• The levonorgestrel intrauterine system provides an excellent means to control abnormal uterine bleeding in patients with a normal uterine cavity.

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Suggested Readings

• Carlson KJ, Nichols DH, Schiff I. Indications for hysterectomy. N Engl J Med. 1993, 328: 856-860.
• Jones H. Clinical pathway for evaluating women with abnormal uterine bleeding. Obstet Gynecol Surv. 2002, 57: 22-24.