Dysfunctional uterine bleeding (DUB) is defined as abnormal bleeding in the absence of intracavitary or uterine pathology. Most commonly, DUB is associated with anovulatory menstrual cycles and systemic or medical conditions, but may coexist with intrauterine pathology. Half of all hysterectomies in the United States are performed to treat abnormal uterine bleeding. Approximately 20% of hysterectomies are performed in women with a normal uterine size.¹

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 is lost with each menstrual cycle, this will rarely result in anemia in women with adequate intake of dietary iron. More than 50% of women who complain of menorrhagia may 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.

The following definitions describe menstrual patterns associated with abnormal uterine bleeding:

• Oligomenorrhea: cycle length greater than 35 days
• Polymenorrhea: cycle length less than 21 days
• Amenorrhea: absence of menses for 6 months or absence of menstrual cycle for three cycles
• Menorrhagia: heavier and increased amount of flow occurring at regular intervals or loss of more than 80mL of blood
• Metrorrhagia: irregular episodes of bleeding
• Menometrorrhagia: longer duration of flow occurring at unpredictable intervals
• Postmenopausal bleeding: bleeding that occurs more than 12 months after the last menstrual cycle

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.

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. This type of bleeding can be episodic or continuous. Patients with anovulatory cycles typically do not experience premenstrual tension syndrome-breast discomfort, increased mucoid vaginal discharge, or premenstrual cramping and bloating-characteristic of ovulatory cycles. Anovulatory cycles may coexist with intracavitary lesions. The most common causes of anovulatory cycles include polycystic ovary syndrome (PCOS), hypothalamic amenorrhea, premature ovarian failure, and hyperprolactinemia.³ Anovulatory cycles are characterized with fragile, vascular, and unsupported endometrial stroma. Bleeding if often noncyclic, variable in amount and volume, and unpredictable. Ovulatory cycles are predictable but may coexist with intracavitary lesions, including polyps or fibroids, and cause erratic bleeding.

Puberty and the perimenopausal years are typically associated with anovulatory menstrual cycles. The immature hypothalamic-pituitary axis does not develop the necessary hormonal feedback to sustain the endometrium. Likewise, the decline of inhibin levels and rise in follicle-stimulating hormone (FSH) levels reflect the loss of follicular activity and competence as the perimenopausal transition occurs.

Abnormal bleeding is a frustrating problem for women and is associated with an array of symptoms. Frequent complaints include heavier or prolonged menstrual flow, social embarrassment, diminished quality of life, sexual compromise, and alteration in lifestyle. Pain is not a common presenting symptom, unless associated with passage of large blood clots.

Incessant menstrual blood loss can be associated with anemia. Typical complaints of anemia include fatigue, lassitude, unusual food cravings (pica), and headaches. Severe anemia may cause fainting, congestive heart failure, exercise-induced fatigue, shortness of breath, and the inability to perform routine activities. DUB is rarely associated with the need for a blood transfusion unless it is a chronic condition. Hemorrhagic shock and death is a rare sequelae for DUB.

Diagnosis has three main components. The physician should note the presence of galactorrhea, weight, acanthosis nigricans, evidence of hypo or hyperthyroidism,virilization and acne. First, a detailed medical history and thorough review of systems must be obtained. Eliciting a detailed clinical history will alert the astute physician to systemic and medical conditions that cause menstrual dysfunction (Table 1). Inherited and acquired coagulation disorders and liver and renal diseases frequently present 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 guidelines (ACOG) eliminates costly and unnecessary laboratory testing.⁴

Pregnancy testing must always be performed in sexually active women. Women with profuse menorrhagia and a normal uterine size should be screened for von Willebrand's disease because 13% to 20% of women who are candidates for surgical intervention may 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).⁵ Obviously, hysterectomy or surgical therapy should not be the first option; rather, medical therapy is paramount for these women.

Liberal use of endometrial biopsy is encouraged in women older than 35 years of age with 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 ovarian syndrome.

Special Categories of Abnormal
Uterine Bleeding:

Adolescent
The adolescent patient with irregular and heavy menses should be evaluated more thoroughly for coagulopathies because 20% to 30% may have a major bleeding diathesis.⁶ The yield percentage is higher if the presenting hemoglobin level is less than 10g/dL or if hospitalization is required. 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 gonadotrophin, level (HCG)
• bleeding time,
• prothrombin time and partial thromboplastin time,
• complete blood count (CBC) with platelets, and
• vWF

Perimenopause
Women entering the perimenopause may 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 FSH, and menstrual cycles that can be episodically ovulatory.⁷ Myriad menstrual complaints occur during the perimenopause, including menometrorrhagia, amenorrhea, and oligomenorrheic cycles. Additionally, decreased mental clarity, diminished concentration, vaginal dryness, decreased libido, hot flashes, and night sweats are classic hallmarks of perimenopause.

Oral contraceptive therapy is quite useful during perimenopause and should be the first line of therapy rather than conventional hormone replacement therapy.⁸ Traditional 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 of age, oral contraceptive pills regulate menstrual cycles, decrease vasomotor symptoms, improve bone mineral density, and decrease the need for surgical intervention for DUB. Additionally, endometrial and ovarian cancer rates are reduced in women using oral contraceptive therapy. Generally, oral contraceptives are well tolerated and enhance menstrual health and quality of life for the perimenopausal woman.

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. Focal intracavitary lesions, including polyps, submucosal fibroids, and endometrial hyperplasia, account for 20% to 40% of cases of abnormal uterine bleeding.⁹

THERAPY

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 polypectectomy are quick, safe, and effective treatment modalities and are associated with a high level of patient satisfaction.¹⁰

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 is dependent 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 recently developed 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, MA, polyvinyl alcohol beads, PVA coils, or Gelfoam causes cessation of blood flow to the fibroid. Shortly thereafter, the fibroid necroses and shrinks in size and volume. Menorrhagia patients treated with uterine artery embolization may have an 85% to 95% chance that their menorrhagia-related symptoms will resolve.¹¹

Additionally, 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 currently available. Factors influencing the surgical route include the number, size, and location of fibroids; concomitant pelvic pathology; and surgical skill of the physician.

Dilatation 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.¹² Currently, 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 work-up. 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 will be become amenorrheic, 65% to 70% hypomenorrheic, and 5% to 10% will not respond to treatment. About 30% of patients treated with endometrial ablation will require a subsequent surgical procedure.¹³

Medical Therapy:

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 or progesterone therapy are the mainstay 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 mg to 800 mg daily as well as a less traditional schedule of 50 mg to 100 mg daily is helpful. Typical side effects of danazol therapy include weight gain, acne, and potential alteration of lipids.¹⁴

Treatment with gonadotropin-releasing hormone(GnRH) (Depo Lupron or Synarel) creates a hypoestrogenic, menopausal-like condition. Cessation of menstruation usually occurs within 3 months of therapy initiation. Menopausal symptoms, including hot flashes, night sweats, vaginal dryness, bone loss, joint pain, decreased concentration, and diminished libido, may occur with therapy. Compliance to therapy is generally good, despite these symptoms. Because osteoporosis is the biggest risk of prolonged therapy, treatment is limited to 6 months unless estrogen add-back is instituted. 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 Depo Lupron therapy in women with uterine fibroids provides an additional a mean additional 9 months of symptom control (range, 2 to greater than 25 months).¹⁵

Recently introduced in the United States, the levonorgestrel-releasing intrauterine system (Mirena) provides another effective treatment option for DUB. This new intrauterine device produces a dramatic decline in menstrual blood loss (65% to 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 may play an important role for women who have menorrhagia but who also need contraception, have a normal uterine size, and wish to avoid surgery.¹⁶

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 NSAID use.¹⁷ 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 have many roles in the treatment of menorrhagia and DUB. Short-term high-dose therapy is used when excessive bleeding results in an emergency situation. It successfully stops heavy menstrual bleeding in the adolescent and perimenopausal woman. Any low-dose (30 µg to 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 will provide a regular menstrual cycle as well as contraception. Low-dose therapy is safe and effective for contraception. It can be used in women older than 35 years of age who do not smoke and who do not have a history of thromboembolic disease.

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

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

In summary, 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. Medical therapy is the main hallmark for initial treatment. When this fails, more aggressive surgical options are considered.⁴

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 work-up.¹⁸

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.

SIS
SIS infuses saline into the endometrial cavity during TVUS to enhance the image. Many alternate terms have been used to describe this technique, including echohysteroscopy, hydrosonography, sonohysterography, sonohysterogram, sonohysterosaliniogography, and sonoendovaginal ultrasound. The author has chosen the term saline infusion sonography and its acronym SIS because it provides a more exact definition of the technique.¹⁸ 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.

Increasingly, gynecologists are using the concept of one-stop evaluation¹⁹ for menstrual disorders by combining the physical exam and basic laboratory studies such as a CBC and TSH (unless clinical history dictates otherwise) with TVUS. If TVUS is indeterminate, then the evaluation proceeds to SIS. Endometrial biopsy is performed in women older than 40 years who have a suspicious TVUS. Direct referral to surgery can be made when this evaluation suggests that surgical intervention is required rather than medical therapy. This streamlined procedure-oriented approach facilitates patient care.

Hysteroscopy
Office hysteroscopy has also revolutionized the practice of gynecology. Thin operative hysteroscopes with outer diameter sizes ranging from 3 mm 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. Office hysteroscopy accurately diagnoses many conditions associated with abnormal bleeding. When the endometrial cavity is normal, aggressive medical therapy can be considered.

DUB is usually well categorized after the initial history, physical examination, and laboratory evaluation. Medical management is the mainstay unless uterine pathology is present. Most patients respond favorably to hormonal manipulation with oral contraceptive therapy or progesterone treatment. Fortunately for those patients who cannot tolerate medical therapy, the new levonorgestrel-releasing intrauterine system is effective in the treatment of abnormal menstruation. Patients with intrauterine polyps and submucosal fibroids have excellent relief of symptoms following operative hysteroscopy. Finally, surgical therapy with endometrial ablation offers 90% success for the treatment of menorrhagia and dysfunctional bleeding in women with a normal uterine cavity who do not desire children but have negative work-up results. Fortunately, hysterectomy is the last resort for DUB in this era of many alternative medical and surgical treatments.

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