40 Abnormal Uterine Bleeding
Dipa Joshi
Roxanne Marie Jamshidi
The evaluation of abnormal uterine bleeding (AUB) requires characterization and quantification of the bleeding, specifically the onset, duration, frequency, amount, pattern, and associated symptoms.
MENSTRUAL DIMENSIONS
The mean menstrual blood loss in women with normal hemoglobin and iron levels is 35 mL, with 95% of women losing 7 days
Shortenedbgcolor=white>Perimenopausal
Adapted from Shwayder JM.
Pathophysiology of abnormal uterine bleeding. Obstet Gynecol Clin North Am 2000;27:219-234, with permission.P.528
Diagnostic Testing
Order laboratory urine (or serum) human chorionic gonadotropin (β-hCG) to assess for pregnancy, thyroid-stimulating hormone (TSH), prolactin, and complete blood count.
In patients with history or physical exam suggesting genital tract infection, cervical or vaginal swabs to assess for sexually transmitted infections such as chlamydia, gonorrhea, herpes, or trichomonas can be of use.
In women with risk factors for neoplastic processes, a tissue diagnosis is required (i.e., endometrial biopsy).
In women at risk for coagulopathy, targeted screening of bleeding disorders is recommended (discussed later in this chapter).
Imaging can be ordered to look for an anatomic cause of bleeding (e.g. fibroid, endometrial polyp).
Perimenopause Abnormal Uterine Bleeding
Perimenopausal AUB is most commonly due to anovulation and structural abnormalities (e.g., fibroids, polyps), however may be attributed to hyperplasia or malignancy.
History, Exam, and Testing
In addition to routine history obtained for women of other ages, menopausal symptoms (e.g., vasomotor symptoms, sleep disturbances, mood disturbances) should be explored.
Order TSH, follicle-stimulating hormone, and prolactin.
Imaging should evaluate for fibroids. See Chapter 37.
Obtain tissue specimens/biopsies (e.g., cervical, endometrial) if indicated.
Infectious workup is recommended in patients at risk.
Postmenopause Abnormal Uterine Bleeding
Postmenopausal AUB is primarily caused by endometrial and vaginal atrophy. However, as approximately 15% of these women will have some form of hyperplasia and 7% to 10% will have endometrial cancer, AUB in the age group suggests malignancy until proven otherwise.
As with very young patients, careful attention should be paid to determine the source of bleeding, such as the rectum.
Tissue sampling and imaging in this population are essential.
Infectious workup is recommended in patients at risk.
EVALUATION OF ABNORMAL UTERINE BLEEDING
Ultrasonography
Transvaginal ultrasonography (TVUS) is useful to evaluate for the presence of fibroids, polyps, intrauterine pregnancy, and ectopic pregnancy. In the workup for possible malignant processes, sonography can be used to search for a thickened endometrium and masses within the uterus, adnexa, or cervix.
TVUS is a better diagnostic tool in postmenopausal than premenopausal women, with a sensitivity of 94% and specificity of 78% in diagnosing an endometrial abnormality in this population using a cutoff of 5 mm for the endometrial echo.
On the other hand, for reproductive age women, as useful as TVUS is at assessing the myometrium, it is only 56% sensitive and 73% specific for assessment of the intrauterine cavity.
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Saline infusion sonography, or sonohysterography, involves distention of the uterine cavity with sterile saline to enhance visualization of the endometrial surface during TVUS. Sonohysterography is the most sensitive noninvasive method of diagnosis for endometrial polyps and submucous myomata. However, it does not distinguish between benign and malignant processes.
Hysteroscopy
The gold standard for evaluating the endometrial cavity is hysteroscopy. The advantage of this procedure is that it provides direct visualization of the endometrial cavity and can be performed in the office setting or operating room. It can be both diagnostic and operative, allowing for directed biopsies and excision of polyps and small myomas. Office hysteroscopy with targeted biopsies has a sensitivity and specificity of 98% and 95%, respectively, compared with histologic findings at the time of hysterectomy.
Magnetic Resonance Imaging
Pelvic magnetic resonance imaging (MRI) can be useful in the diagnosis of adenomyosis and can accurately localize and measure fibroids, facilitating determination of the best treatment (e.g., embolization, resection, hysterectomy).
Endometrial Sampling
The American College of Obstetricians and Gynecologists (ACOG) recommends endometrial sampling in women older than age 45 years as a first-line test. Women younger than 45 years with risk factors for unopposed estrogen (e.g., obesity, polycystic ovarian syndrome), those who have failed medical management or have persistent AUB, are also recommended by ACOG to undergo endometrial sampling.
Endometrial sampling is a rapid, safe, and cost-effective procedure that can be performed in the office to evaluate AUB. A potential drawback is that the biopsy does not sample the entire endometrium and a localized lesion may be missed: The posttest probability of endometrial cancer from an office endometrial biopsy is approximately 80% for a positive test result and 1% for a negative test result.
Dilation and Curettage
Dilation and curettage (D&C) can be both diagnostic and therapeutic but incurs the cost of an operating room and carries the risks of anesthesia. However, D&C may be indicated in women with nondiagnostic endometrial biopsies, biopsies with insufficient tissue for analysis, or women with cervical stenosis making an office procedure unsuccessful.
SPECIFIC CAUSES OF ABNORMAL UTERINE BLEEDING
Pregnancy-Associated Bleeding
Pregnancy should be suspected in any woman in her reproductive years.
If urine β-hCG is positive, a pelvic examination must be performed and an ultrasonographic study obtained. The differential includes ectopic pregnancy or threatened, inevitable, incomplete, or missed abortion. A quantitative serum β-hCG test is needed if an intrauterine pregnancy is not first confirmed by ultrasound, and Rh status is needed in all of these cases.
Any patient who is hemodynamically unstable, bleeding heavily, or septic requires surgical intervention.
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Women with missed or incomplete abortions who are stable and not bleeding heavily may be offered expectant management or treated medically with misoprostol, which has a success rate of approximately 84%.
Dysfunctional Uterine Bleeding
Dysfunctional uterine bleeding (DUB) is a diagnosis of exclusion for AUB without a demonstrable pathologic cause and is found in approximately one third of all patients evaluated. The predominant causes of DUB are anovulation or oligoovulation. Anovulation is multifactorial and related to alterations of the hypothalamicpituitary-ovarian axis. The use of the terminology dysfunctional uterine bleeding is falling out of favor with major professional organizations such as ACOG and the International Federation of Gynecology and Obstetrics (FIGO).
With long-term anovulation, estrogen production occurs without the progesterone normally produced from a corpus luteum, thus creating an unopposed estrogen state. Therefore, these women are at risk for endometrial hyperplasia. Anovulation is also associated with polycystic ovary syndrome, which also places women at risk for endometrial hyperplasia. Morbid obesity can also cause DUB. Peripheral conversion of androstenedione to estrone occurs in adipose tissue producing elevated estrogen levels. Occasionally, DUB may be associated with ovulatory cycles.
The optimal treatment will relieve symptoms and improve quality of life with minimal side effects. It is directed toward stabilizing the endometrium and treating the underlying hormonal alterations. T reatment is usually long-term because symptoms tend to return when therapy is discontinued. Various medical therapies are available (Table 40-2).
Administration of progestins may be especially useful in patients with contraindications to combined oral contraceptive pills (COCs), such as smokers older than age 35 years. Although progestin therapy does not result in ovulation, it does prevent the negative sequelae of unopposed estrogen and regulates bleeding. However, very little data are available and no consensus exists on type of progestin or dosage. Side effects of progestins include breast tenderness, weight gain, and headaches.
The levonorgestrel-releasing intrauterine system (Mirena) has been shown to decrease blood loss by up to 90% in women with menorrhagia. COCs also regulate menses and often decrease flow. Extended-use regimens may be especially useful in this population.
Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce menstrual volume in women with menorrhagia by at least 20% to 40% and need to be taken during menses only.
Danazol has been shown to significantly reduce menstrual blood loss (~50%) and may induce amenorrhea. However,
androgenic side effects limit its use.
Antifibrinolytic medications (e.g., tranexamic acid) decrease menstrual blood flow by 50% and similar to NSAIDs need to be taken only during menses. Some practitioners have been reluctant to prescribe antifibrinolytics because of their prothrombotic potential; however, studies have not shown increased incidence of thrombosis in treated women versus the general population. Antifibrinolytics may be especially useful in women who cannot tolerate hormonal treatments.
Gonadotropin-releasing hormone (GnRH) agonists have limited use for treating AUB long-term and have significant side effects, such as hot flashes, osteopenia, and vaginal dryness. Symptoms return shortly after discontinuation. GnRH agonists can reduce uterine volume by 30% to 50%, which may facilitate less invasive surgery (i.e., vaginal vs. abdominal hysterectomy). Add-back therapy, which typically includes a progestin or a progestin plus low-dose estrogen, alleviates menopausal symptoms.
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TABLE 40-2 Pharmacologic Management of Abnormal Uterine Bleeding
Hormonal Management
Progestins
Medroxyprogesterone (Provera) 10 mg 3?Zd for 14 d (days 12-25) or for 5-10 d
Norethindrone acetate (Aygestin) 5 mg 3?Zd for 14 d (days 12 and 25) for anovulatory bleeding or on days 5-25 for ovulatory bleeding
Medroxyprogesterone acetate injection (Depo Provera) 150 mg IM every 12 wk
Levonorgestrel-releasing intrauterine system (Mirena)
Combined estrogen and progestins
Oral contraceptives
T ransdermal preparations
Vaginal ring
Hormone replacement therapy
Androgenic steroids
Danazol 200 mg/d
Gonadotropin-releasing hormone (GnRH) agonists
Leuprolide (Lupron) 3.75 mg IM/mo or 11.25 mg every 3 mo
Goserelin (Zoladex) 3.6 mg SQ every 4 wk
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Mefenamic acid 500 mg 3x/d
Ibuprofen 600-800 mg every 6 hr
Meclofenamate sodium 100 mg 3?∕d
Naproxen sodium 550 mg ? 1, then 275 mg every 6 hr
Antifibrinolytic Agents
T ranexamic acid 1,300 mg tid for up to 5 d during monthly menstruation
IM, intramuscularly; SQ, subcutaneously; tid, three times a day. Adapted from Singh RH, Blumenthal P. Hormonal management of abnormal uterine bleeding. Clin Obstet Gynecol 2005;48:337-352; Roy SN, Bhattacharya S. Benefits and risks of pharmacological agents used for the treatment of menorrhagia. Drug Safety 2004;27:75-90, with permission.
Surgical Treatment for Dysfunctional Uterine Bleeding
Surgical treatment may be warranted in patients who fail medical management.
D&C may be an initial step in treating AUB but does not typically have a sustained therapeutic effect.
Endometrial ablation is designed to ablate the full thickness of the endometrium. A variety of modalities are available, including thermal ablation, microwave, laser, cryocautery, and radiofrequency, each with its own advantages and disadvantages.
Before performing endometrial ablation, endometrial hyperplasia or carcinoma must be ruled out. It should be used to treat AUB in women with no intrauterine pathology, although some of the devices are approved for women with submucosal or intracavitary fibroids.
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Across all methods, the overall success rate is approximately 80% to 90%, with 30% to 50% of women reporting amenorrhea 6 months postprocedure. Still, within 5 years, 15% will have a second ablation and 20% will have a hysterectomy. Although endometrial ablation is not recommended in women who desire future fertility, contraception should be addressed for patients undergoing ablation.
Hysterectomy provides definitive treatment for menorrhagia and may be a reasonable option in women with severe menorrhagia, refractory to medical and less radical surgical therapy, who have completed their childbearing.
Coagulation Disorders
Menorrhagia during adolescence should be attributed to a coagulation disorder until proven otherwise. Bleeding from multiple sites (e.g., nose, gingiva, intravenous sites, gastrointestinal, and genitourinary tracts) may suggest coagulopathy. There is a higher prevalence of bleeding disorders in women with menorrhagia.
Von Willebrand Disease
Von Willebrand disease (vWD) is the most common inherited bleeding disorder, affecting 1% to 2% of the population. Low, abnormal, or absent von Willebrand factor (vWF) leads to a spectrum of disease severity with three main types of vWD: types 1,2, and 3. In women with vWD, menorrhagia is the most common manifestation, occurring in 60% to 95% beginning at menarche.
Women with vWD are also likely to report postpartum or postoperative bleeding or bleeding related to dental work. They may also report easy bruising, epistaxis, or family history of bleeding symptoms. The frequency of vWD in women with menorrhagia is 5% to 20%.
Other coagulopathies may also cause AUB, including platelet abnormalities, idiopathic thrombocytopenic purpura, and hematologic malignancy (e.g., leukemia).
Testing for vWD should be considered in women with a history of unexplained menorrhagia beginning at menarche. ACOG recommends screening for vWD in adolescents with severe menorrhagia before starting hormonal therapy and in adult women with significant unexplained menorrhagia.
vWF levels vary over time and are affected by various physiologic, genetic, and pharmacologic factors. Several tests are performed to diagnose vWD: factor VIIIC activity, vWF antigen, ristocetin cofactor activity (i.e., vWF activity), platelet function tests, and bleeding time. vWF multimer tests are subsequently performed to distinguish among subtypes.
The ristocetin cofactor assay may be the best single screening test.
Therapy usually involves treating the underlying cause and may require administration of blood products.
Little data are available regarding treatment of menorrhagia in women with vWD. Oral contraceptives, desmopressin, and antifibrinolytic agents are options. Nasal desmopressin appears to be an effective treatment for vWD.
Endocrine Disorders
Endocrinopathies can cause anovulation, producing an environment of unopposed estrogen. In the absence of progesterone, the endometrium eventually breaks down, which may or may not lead to the formation of hyperplasia. Hypothyroidism and hyperprolactinemia are common disorders that can lead to anovulation.
See Chapters 13 and 41.
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Hepatic Dysfunction
Decreased metabolism of estrogen and decreased clotting factor synthesis are common ramifications of liver failure. Anovulation may also ensue. Menometrorrhagia is common.
Liver function tests are necessary to make the diagnosis. Physical examination findings of jaundice, ascites, hepatosplenomegaly, palmar erythema, pruritus, and spider angioma are suggestive of liver failure. See Chapter 17.
If possible, the underlying cause should be treated. If the patient is coagulopathic and hemorrhaging, administration of packed red blood cells and fresh frozen plasma may be indicated. Progestin therapy may also be beneficial.
Medication Side Effects
Psychotropic Medications
Certain medications used in the treatment of psychiatric patients can affect the hypothalamic-pituitary axis and interfere with ovulation.
Antipsychotic medications (i.e., dopamine antagonists) most commonly cause hyperprolactinemia and subsequent abnormalities in menstruation.
Phenothiazines and antidepressants, particularly tricyclics, also interfere with the normal menstrual cycle.
Hormone Medications
Medroxyprogesterone acetate (Depo Provera). Approximately 50% of the patients taking this medication experience amenorrhea after 1 year of use, 80% after 5 years. Irregular bleeding also may be experienced.
Combination oral contraceptive pills. Intermenstrual (breakthrough) bleeding is a side effect associated with COCs use that often leads to discontinuation. With long-term use, AUB may result from endometrial atrophy.
Progestational agents. High doses of progestins often are used in the treatment of AUB and endometrial hyperplasia. Prolonged use of these agents may result in endometrial atrophy, which itself can cause AUB.
Other Medications
Anticoagulants. If the dosage of anticoagulants is too high, the patient can experience AUB.
Digitalis, phenytoin, and corticosteroids have been implicated as causes of AUB.
Over-the-counter medications that may contribute to AUB include motherwort, gingko, and ginseng.
Intrauterine Devices
Copper-containing intrauterine devices, unlike the levonorgestrel-releasing Mirena intrauterine system, increase average monthly blood loss by approximately 35%.
Such bleeding is often treated successfully with NSAIDs.
Genital Infection
AUB is not a common presenting symptom of either endometritis or cervicitis. If present, bleeding associated with endometritis is most commonly intermenstrual, whereas bleeding associated with cervicitis is usually postcoital.
Endometritis is diagnosed by uterine tenderness and sometimes fever. Any recent history of instrumentation of the uterus adds to the suspicion of endometritis. Chronic endometritis may be diagnosed by endometrial biopsy as evidenced by the
P.534 presence of plasma cells. Cervicitis is diagnosed by clinical examination and results of cervical cultures. See Chapter 28.
Benign Pathology
Leiomyomata
Leiomyomata (fibroids) are the most common uterine neoplasm and are the number one indication for hysterectomy in the United States. See Chapter 37.
AUB is the most common presenting symptom in women with leiomyomata.
Although submucosal fibroids, followed by intramural fibroids, are most likely to cause bleeding, fibroids of any size and in any location can cause abnormal bleeding.
Polyps
Generally, benign endometrial lesions tend to be asymptomatic but may be present in 10% to 33% of women with complaints of bleeding, typically metrorrhagia.
Diagnosis can be made by saline infusion sonogram or hysteroscopy.
Bleeding secondary to polyps may respond to hormonal therapy. When found in postmenopausal women, they should be removed via operative hysteroscopy. Cervical polyps can be removed by grasping them with forceps, twisting them off, and cauterizing the base as needed.
Endometrial Hyperplasia
Endometrial hyperplasia, a precursor to endometrial carcinoma, is classified into simple or complex, based on architectural features, and typical or atypical, based on cytologic features. Endometrial hyperplasia tends to occur during periods of longterm unopposed estrogen exposure, either secondary to anovulatory cycles or exogenous use. AUB is the most common presenting symptom.
An endometrial tissue sample, obtained either from an endometrial biopsy or D&C, is required to diagnose endometrial hyperplasia.
T reatment depends on age, desire for future fertility, surgical risk, and presence of atypia in the pathology specimen.
Hyperplasia without atypia may be managed by long-term follow-up with repeat endometrial sampling if abnormal bleeding recurs.
ξ Cyclic medroxyprogesterone acetate is recommended (10 mg/day for 12 to 14 days/cycle for 3 to 6 months) in young anovulatory women to induce monthly withdrawal bleeding and subsequently normalize the endometrium, which occurs in approximately 86% of patients on this regimen.
ξ Local progesterone administration via the levonorgestrel-releasing intrauterine system (Mirena) and combined oral contraceptives are also options.
ξ Postmenopausal women with endometrial hyperplasia without atypia who are on estrogen replacement therapy should discontinue estrogen and may then be treated with medroxyprogesterone and repeat D&C.
Atypical endometrial hyperplasia is more likely to progress to carcinoma, and therefore, more aggressive treatment is needed. Atypical hyperplasia concomitantly exists with endometrial carcinoma in up to 25% to 50% of cases. Thus, a significant number of women diagnosed with atypical hyperplasia on curettage will be found to have invasive carcinoma if hysterectomy is performed.
For patients who wish to retain their fertility, progestational therapy is an acceptable approach. T reatment with continuous regimens of megestrol acetate (40 mg two to four times daily) is associated with a regression rate of 94%.
P.535 Treatment is continued for 6 months with endometrial biopsies performed at 3 and 6 months. Dosing is increased if regression is not observed. This approach also may be used in women who are poor surgical candidates. If regression does not occur, megestrol dose can be increased to 200 mg/day. Once regression occurs, maintenance therapy should begin with either megestrol, cyclic medroxyprogesterone acetate, or a levonorgestrel-releasing intrauterine system.
It must be emphasized that conservative therapy in women with complex atypical hyperplasia involves risk and close follow-up is necessary. Progesterone withdrawal regimens are not consistently effective and should not be used in the treatment of atypical hyperplasia. Also see Chapter 47.
Malignancy
Endometrial Cancer
Endometrial carcinoma is rare in patients younger than age 40 years. Postmenopausal bleeding, however, should be assumed to represent endometrial cancer until proven otherwise.
In a postmenopausal woman not receiving hormone replacement therapy, the presence of a thickened endometrial stripe (>5 mm) on ultrasonography is considered abnormal. Tissue sampling is then required. See Chapter 47 for further discussion.
Cervical Cancer
Cervical carcinoma is a disease of both the relatively young and the old. Almost all cervical lesions that cause abnormal bleeding are visible on examination. The most common bleeding patterns associated with cervical carcinoma are intermenstrual and postcoital bleeding. See Chapters 45 and 46 for screening and treatment.
Ovarian Cancer
Estrogen-producing ovarian tumors, such as a granulosa-theca cell tumor, can produce endometrial hyperplasia and AUB. See Chapter 48.
SUGGESTED READINGS
American College of Obstetricians and Gynecologists. ACOG committee opinion no. 451: Von Willebrand disease in women. Obstet Gynecol 2009;114:1439-1443.
American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 14: management of anovulatory bleeding. Int J Gynaecol Obstet 2001 ;72(3):263-271.
American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol 2012;120(1):197-206.
Casablanca Y. Management of dysfunctional uterine bleeding. Obstet Gynecol Clin North Am 2008;35(2):219-234, viii.
Hashim A. Medical treatment of idiopathic heavy menstrual bleeding. What is new? An evidence based approach. Arch Gynecol Obstet 2013;287(2):251 -260.
Lacey JV Jr, Chia VM. Endometrial hyperplasia and the risk of progression to carcinoma. Maturitas 2009;63(1 ):39-44.