Obstet Gynecol Clin N Am 35 (2008) 219234

Management of Dysfunctional Uterine Bleeding

Yovanni Casablanca, MD
Department of Obstetrics & Gynecology, David Grant Medical Center, 101 Bodin Circle, Travis AFB, CA 94535, USA

Abnormal menstrual bleeding is one of the most common complaints that gynecologists and primary care physicians confront in their oce practice. Dysfunctional uterine bleeding is the term applied to the abnormal bleeding patterns that occur in women secondary to anovulation or oligoovulation and is often referred to as anovulatory bleeding. Exclusion of anatomic pathology and medical illness is important before applying this classication. Bleeding is noncyclic in nature and can range from light to excessive in volume. Dysfunctional bleeding can, in almost all cases, be treated medically by reversing the endometrial abnormalities that lead to heavy and prolonged menstrual ow and subsequently restore cycle predictability and regularity. The causal mechanisms for dysfunctional uterine bleeding vary; however, they all result in departure from the normal hormonal sequence that underlies the regular, ovulatory menstrual cycle. Recognizing which mechanism is responsible is fundamental for successful treatment of the abnormal bleeding. Primarily, a careful menstrual history and physical examination are necessary to rule out other conditions that can lead to similar symptoms. When anatomic pathology is suspected or initial treatment of dysfunctional uterine bleeding fails, further evaluation is necessary.

The normal menstrual cycle Ovulation and the ordered sequence of endocrine signals characterize the menstrual cycle, leading to regularity, predictability, and consistency of menses [1]. During the follicular phase of the cycle, estrogen levels rise in the body as the dominant ovarian follicle matures. In response to this rise

E-mail address: yovanni.casablanca@travis.af.mil 0889-8545/08/$ - see front matter. Published by Elsevier Inc. doi:10.1016/j.ogc.2008.03.001

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in estrogen, the endometrium, after being shed the previous menses, grows and proliferates. After ovulation, the corpus luteum from the ovarian follicle continues to secrete estrogen but, more importantly, also secretes progesterone. During the luteal phase, because of the action of estrogen and progesterone, the endometrium transforms and prepares itself for implantation of a new pregnancy. If pregnancy does not occur, the corpus luteum regresses and, as a result, estrogen and progesterone levels rapidly fall, resulting in endometrial degradation and the beginning of menses. This pattern produces predictable menstrual ow, volume, and timing [2]. Variations in menstrual ow and timing often occur at the extremes of reproductive age because of the prevalence of anovulatory cycles. Menarche is typically followed by longer cycles that eventually decrease in length and become more regular as the hypothalamic-pituitary-gonadal axis matures [1,3]. As menopause approaches, however, ovulation occurs less often, which leads to an increased variability of the cycle length. Underlying this occurrence is a steady trend toward mean cycle lengths longer than 35 days [4]. In general, variations in cycle length reect dierences in the length of the follicular phase of the cycle, because the luteal phase is generally consistent. Although it is the most reported intermenstrual interval, only approximately 15% of cycles in women of reproductive age are actually 28 days in length [5]. Less than 1% of women have a regular cycle less than 21 days or more than 35 days [5]. The usual duration of ow is 4 to 6 days, with an average volume of blood loss of 30 mL, with more than 80 mL being abnormal [6]. Abnormal patterns that have ow heavier than 80 mL, last for 7 or more days, or have intervals less than 21 days can result in anemia. Because volume of ow is dicult to determine, most practitioners refer to the amount of pads or tampons used or soaked throughout per day as a quantifying measure. Bleeding that interferes with daily activities or causes anxiety warrants evaluation and treatment. Specic terminology can be used among practitioners to describe bleeding patterns. Oligomenorrhea is dened as menses with intermenstrual intervals longer than 35 days. The term polymenorrhea applies to periods with regular intervals less than 21 days. Metrorrhagia is dened as irregular bleeding or bleeding between periods. Menorrhagia is dened as regular cycles with excessive ow (technically O80 mL of volume) or duration longer than 7 days [6]. Menometrorrhagia is bleeding with irregular intervals and excessive ow or duration. In general, dysfunctional uterine bleeding leads to the pattern of oligomenorrhea, metrorrhagia, or menometrorrhagia.

Cause of anovulatory bleeding Unlike the organized pattern of estrogen and progesterone stimulation and withdrawal that is seen in regularly ovulating women, women with

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anovulation experience disorganized and unpredictable patterns of hormone production that lead to irregular menstrual bleeding. By denition, the anovulatory woman is always in the follicular phase of the ovarian cycle. There is no luteal phase because ovulation does not occur. The end result is constant estrogen stimulation that is followed by increasing proliferation of the endometrium. The levels of estrogen rise and fall as each new group of follicles begins to grow, loses its momentum, and then eventually regresses. Although the levels of estrogen uctuate, the end result is growth of the endometrium. Over time, the endometrium thickens to the point of becoming fragile. Without the support of progesterone to organize and stabilize it, focal areas within the endometrium begin to break down and bleed. Although some areas heal secondary to continued estrogen stimulation, other areas desquamate. Vascular structures increase in number, fragility, and predilection for rupture. Because tissue loss is supercial and does not reach the basal endometrial layer, vasoconstriction of the basal and myometrial vessels does not occur, leading to continued bleeding. Alterations in endometrial prostaglandin synthesis and balance also result in less vasoconstriction and more blood loss [3]. Dierential diagnosis Dysfunctional uterine bleeding is a diagnosis of exclusion (Table 1). The most common reason for a divergence from a pattern of regular menses is pregnancy or a complication of pregnancy, such as ectopic pregnancy or threatened or incomplete abortion. After pregnancy is ruled out, other anatomic conditions, particularly benign conditions such as cervical or endometrial polyps, adenomyosis, or uterine leiomyomas, are considered. Other possibilities include precancerous changes or malignancies of the cervix or endometrium. Chronic endometritis also can lead to irregular bleeding. Endocrine disorders, most notably hypo- or hyperthyroidism, also can impart menstrual changes. Disorders of coagulation should be considered in women with menorrhagia, particularly in adolescents. A history of postpartum bleeding or excessive bleeding during surgery, dental procedures, or trauma can be a sign of an underlying bleeding disorder. Less common reasons for abnormal bleeding include systemic disease and medications such as anticoagulants, tamoxifen, and herbal supplements with estrogenic activity. In some cases, foreign bodies or genital trauma are possibilities. Diagnostic evaluation A thorough menstrual history is the most essential tool for dierentiating anovulatory bleeding from other causes. The regularity and length of intermenstrual intervals, volume, and duration of ow should be sought for the

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Table 1 Dierential diagnosis of abnormal uterine bleeding Pregnancy Abortion, ectopic pregnancy, trophoblastic disease Retained products, placental site involution, lactation Anovulation Perimenarchal or perimenopausal Hyperandrogenic (PCOS, CAH, androgen-producing tumor) Hypothyroidism Hyperprolactinemia Premature ovarian failure Hypothalamic dysfunction (eg, anorexia) Leiomyoma Endometrial or cervical polyp Adenomyosis Chronic endometritis Endometrial hyperplasia or malignancy Cervical or vaginal neoplasia Blood dyscrasia Iatrogenic/medications Systemic disease Abbreviations: PCOS, polycystic ovarian syndrome; CAH, congenital adrenal hyperplasia.

womans normal and abnormal cycles. The onset of the abnormal bleeding should be determined precisely and whether there is any association with intercourse, contraception, weight changes, or pregnancy. The amount of pads or tampons used and the frequency with which they are changed should be assessed, as should the presence of clots or episodes of ooding onto clothes or bedding. The physician should inquire about moliminal symptoms, occurrence of pain, or other body changes in association with the bleeding. As is important in all history taking, discussion of other systemic illness and medications is necessary. In most women, history can establish the diagnosis with sucient condence. Women with infrequent, unpredictable, irregular bleeding that varies in amount, duration, and character are most likely experiencing anovulatory bleeding. These women do not typically describe moliminal symptoms. Anovulation is most often observed in teenagers, perimenopausal women, obese women, and women with polycystic ovarian syndrome. Women with menorrhagia are more likely have anatomic lesions or bleeding diasthesis. Physical examination should be performed to evaluate for any obvious sources of bleeding in the vagina or cervix and dene whether the uterus is of normal size, shape, and consistency. Foreign bodies and evidence of trauma become readily apparent on examination. Cervical biopsies can be done for any obvious cervical lesions. The presence of acne, hirsutism, or virilization should be noted. Body weight or body mass index can be used to distinguish which clinical syndrome is most likely.

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Laboratory testing is not always necessary but can be helpful in many cases to exclude other diagnoses. A pregnancy test is important to rule out any complication of pregnancy. A complete blood count evaluates for anemia and thrombocytopenia and is important to obtain in women with prolonged, heavy, or frequent bleeding. Serum progesterone levels drawn in the luteal phase can conrm whether ovulation has occurred; however, when bleeding is erratic, proper timing can be dicult. In adolescents or women with a history suspicious for a blood dyscrasia, coagulation studies should be performed. Preference of assays depends on the hematologist but usually includes assessment of quantity and activity of von Willebrands factor and factor VIII. A serum thyroid-stimulating hormone level can evaluate for any underlying thyroid disorder. A fasting prolactin level can rule out hyperprolactinemia. Obtaining a follicle-stimulating hormone level is most useful if ovarian failure or hypothalamic dysfunction is suspected by history; however, its routine use can be confusing in the setting of erratic bleeding because of diculty in assessing proper test timing. Metabolic or hepatic functional panels are reserved for persons who are suspected of having systemic disease. Endometrial biopsy in the oce can diagnose endometrial hyperplasia or cancer with excellent accuracy [7]. A woman older than age 35 with abnormal uterine bleeding should undergo an endometrial biopsy because of the increasing incidence of endometrial cancer with age; however, younger, obese women who have prolonged periods of unopposed estrogen stimulation or anovulation are also at risk. Women younger than age 30 have developed endometrial cancer in this setting [8]. The small, exible suction cannulas that are used to perform biopsies in the oce are fairly well tolerated and do not require muchdif anydcervical dilation. Biopsy also can detect the presence of secretory endometrium, which would be evidence of ovulation, as long as there has been no recent use of progestin agents. Structural abnormalities of the uterus, such as leiomyomas, polyps, and adenomyosis, can be the cause of abnormal uterine bleeding. Radiologic imaging should be considered in women with regular monthly cycles with increasing volume or duration of bleeding, abnormal bleeding despite objective evidence of ovulation (determined by serum progesterone or by endometrial biopsy), or new-onset intermenstrual bleeding (in the absence of vaginal or cervical lesions) or in women in whom empiric medical management has failed. Standard abdominal and endovaginal ultrasound usually can detect the location and size of myomas and evaluate the endometrium by measuring the thickness of the endometrial stripe. Based on literature obtained from postmenopausal women, an endometrial stripe that measures 4 mm or less has an unlikely risk of endometrial hyperplasia and cancer, and biopsy is often considered unnecessary before treatment [9]. Women with a normal endometrial stripe (512 mm) may require biopsy, particularly if there is history of unopposed estrogen stimulation. When the endometrial stripe is larger than 12 mm, a biopsy should be performed.

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Saline sonohysterography, which involves endovaginal ultrasound and instillation of saline into the endometrial cavity, can readily demonstrate intracavitary polyps or myomas. The combination of endometrial biopsy with sonohysterography provides high sensitivity and high negative predictive value for detection of pathologic conditions in women with abnormal bleeding [10]. Hysteroscopy is the denitive way to detect intrauterine lesions, but it is usually reserved for treating lesions that were detected by other less invasive means. Small-diameter hysteroscopes (23 mm) can be used in the oce setting under local anesthesia for diagnostic and minor surgical procedures. Larger lesions require traditional operative hysteroscopic equipment with a larger diameter, uid management systems, and anesthesia capabilities. Hormonal medical treatment If anovulation is strongly suspected as the cause of abnormal bleeding, after pregnancy is ruled out, empiric medical management can be initiated with the expectation of improvement in a short amount of time. If the abnormal bleeding does not improve, further evaluation is necessary before increasing the dosage or changing to another regimen. If other disorders, such as uterine pathology or coagulopathy, are suspected, laboratory testing, endometrial biopsy, and radiographic imaging should be performed before medical management. The goal of treatment for dysfunctional uterine bleeding is to restore the natural cycle of orderly endometrial growth and shedding. Cyclic progestin therapy works well in women who are completely anovulatory by restoring the normal sequence of steroid stimulation to the endometrium: estrogen, followed by estrogen and progestin, followed by withdrawal. Orderly withdrawal bleeding can be induced by use of a progestin such as medroxyprogesterone acetate, 5 to 10 mg daily, for 2 weeks every month. The interval can be xed to the calendar by beginning on a specic day of the month (ie, the rst of every month) or at the onset of menses (beginning day 15 or 16 after the rst day of the last progestin-induced menses). If menses does not follow progestin withdrawal, pregnancy or hypoestrogenic disorders should be considered. Cyclic progestins are typically ecacious for anovulatory women; however, in women who still occasionally ovulate and do not want to conceive, a combined oral contraceptive is a better option. Cyclic progestin therapy does not suppress the hypothalamic-pituitary-ovarian axis enough to prevent ovulation. When women ovulate intermittently, the treatment may not coincide with endogenous progesterone production and may lead to bleeding that does not correlate with the predicted pattern. On the other hand, because they suppress endogenous hormone production, combined oral contraceptives should prevent this from occurring. Oral contraceptives also increase sex-hormone binding globulin, which further reduces bioavailable androgens in women with hyperandrogenic anovulation [11]. Oral

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contraceptives also reduce menstrual ow in women with heavy menstrual ow, even if broids or adenomyosis is present [12]. The transdermal contraceptive patch and the vaginal ring can be used in a similar fashion. Cyclic progestin supplementation in the luteal phase also has been used with some success for women with menorrhagia. The results lead to decrease in menstrual blood ow, but it is often not well tolerated because of gastrointestinal side eects and weight gain. Longer durations of progestin treatment can be used with an even greater decrease in menstrual blood loss, but they are not as eective or as well tolerated as other regimens, such as the progestin intrauterine device (IUD) [13]. In women who present with episodes of heavy bleeding, combined estrogen-progestin treatment is the best option. To slow or stop a heavy bleed, a taper can be performed with any of the low-dose monophasic pills. Treatment regimens vary but often begin with three pills per day for 3 days, followed by two pills per day for 3 days, and then one pill per day thereafter until the placebo week. The patient can be told to skip the initial placebo week and proceed straight through to a second pill pack to prolong the relief from bleeding. Bleeding slows or stops within 24 to 48 hours, but high-dose levels of hormone should be maintained for the initial 5 to 7 days. Women often experience nausea and vomiting with the initial boost of hormones; prescribing an antiemetic for use during this time should be considered. If there is contraindication to estrogen, progestin can be used instead, but high doses are usually needed (medroxyprogesterone, 20 mg, or norethindrone, 5 mg, daily). If either treatment fails, further diagnostic evaluation is required. For the short-term, the decidual changes induced by the aforementioned treatments provide stability to a fragile, overgrown endometrium. Unfortunately, a substantial amount of tissue still may remain to be shed once treatment is stopped. The patient should be informed to expect a heavy, painful bleeding within 2 to 4 days after treatment is withdrawn or during the placebo week of her pills. Maintenance therapy with a cyclic combination contraceptive (pill, transdermal patch, or vaginal ring) can begin after the initial withdrawal bleed, and each successful menses should be lighter and less painful. If treatment is not continued and the pathophysiology underlying the chronic anovulation is not resolved, heavy or prolonged bleeding is likely to recur. Another alternative for maintenance therapy is depot-medroxyprogesterone acetate (Depo-Provera), 150 mg intramuscularly, every 3 months. It can be used for women who have contraindication to estrogen or suer side effects that prevent estrogen use. Although this regimen cannot be used in the setting of acute heavy bleeding, it eventually leads to a thin endometrium. Some patients experience episodic breakthrough bleeding while on DepoProvera when the progesterone eect outweighs the estrogen eect on the endometrium. When this occurs, intermittent bleeding can occur (usually light), and it is commonly treated with short courses of estrogen.

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Low-dose courses of estrogen can be used when bleeding occurs from an attenuated or grossly denuded endometrium. Ultrasound can help distinguish when this is the case with visualization of an endometrium less than 4 mm in thickness. This is commonly seen when breakthrough bleeding occurs with low-dose contraceptive pills, progesterone-only contraceptives, Depo-Provera, or progestin implants, such as the etonorgestrel implant (Implanon). In these patients, the progestin thins the endometrium to atrophic levels, which results in light spotting or staining unless there is sucient endogenous or exogenous estrogen to eectively balance its eects. These lesser, lighter bleeds respond to a single, daily dose of estrogen (eg, 1.25 mg conjugated estrogens for 710 days). If treatment fails, further evaluation is recommended with ultrasound or saline sonohysterography to identify a causative polyp or myoma. If no anatomic cause is found, changing the dose or type of contraceptive is indicated. Occasionally patients present with acute, heavy, active bleeding that may require inpatient treatment and close observation. In these cases, high-dose estrogen is used because it promotes rapid endometrial growth and covers denuded endometrial surfaces. Intravenous estrogen (25 mg conjugated equine estrogens every 4 hours for 24 hours or until bleeding diminishes signicantly) is the usual regimen and has been shown to be successful in most cases [14]. In the rare case that a woman presents with hemodynamic instability and acute bleeding, or if bleeding does not respond to the rst two doses of intravenous estrogen, intrauterine Foley bulb placement or operative hysteroscopy with dilation and curettage is indicated [3]. When bleeding is heavy but does not require inpatient treatment, oral estrogens can be used as an alternative (1.25 mg conjugated estrogens or 2.0 mg micronized estradiol every 46 hours for 24 hours). Gradual tapering is performed down to one dose per day for 7 to 10 days after the bleeding is controlled. All of these initial estrogen treatments should be followed by progestin treatment or combination contraceptives to stabilize the estrogen-stimulated endometrial growth. Importantly, elevated doses of estrogen (more than one oral contraceptive per day or several doses of oral or intravenous estrogen in 24 hours) can increase the risk of thromboembolism. It is dicult to quantify the absolute risk associated with these short-term courses of high-dose estrogen. In general, low doses of estrogen for short periods of time pose little additional risk, even in women with risk factors; however, in women with history of thrombosis or a family history of thromboembolism, high doses should be avoided if possible. In the end, the decision to use the treatment should be made after the benets of the treatment are weighed against the risks and alternatives are considered. Alternative hormonal management For many patients, alternate methods of combined hormone treatment can be used in place of traditional oral contraceptives. The transdermal or

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vaginal administration of estrogen and progestin is a more attractive alternative because of less frequent dosing and more stable circulating levels of hormones. There is improved compliance with these methods with elimination of the timed daily dosage and elimination of some of the side eects associated with oral medication. Theoretically, there might also be an advantage to removal of the rst-pass eect in the liver. The transdermal patch (Ortho Evra) delivers 20 mg ethinyl estradiol and 150 mg norelgestromin when applied to locations on the torso and upper arm [15]. The serum concentrations are in ranges equivalent to an oral formulation of 35 mg ethinyl estradiol and 250 mg norelgestromin; however, the kinetics dier secondary to avoidance of daily uctuations that are experienced when using pills. As a result, systemic steady state hormone levels are 60% higher and peak concentrations are 35% lower [16]. The patch is to be worn for a week, followed by removal and application of a new patch on a dierent site for another week. After 3 weeks of use, no patch is worn on the fourth week, which leads to a withdrawal menses. The patch also can be used continuously, which eliminates the withdrawal week (and thus menses), until a later time. Breakthough bleeding occurs in some women on continuous therapy. A small percentage of women also have problems with detachment, local skin reactions, breast discomfort, and nausea and vomiting [16]. Recent attention to the thromboembolic risk associated with the patch has led to concern regarding its use. Epidemiologic, case control studies have been performed using health care claims data to evaluate the risk of venous thromboembolism among women who used the patch compared with women who used oral contraceptives that contained 35 mg of ethinyl estradiol and norgestimate. These studies used slightly dierent designs and reported odds ratios ranging from 0.9 to 2.4 [1719]. Until further study is done, the patch has the same absolute and relative contraindications as a combined oral contraceptive pill. The vaginal contraceptive ring (NuvaRing) consists of a exible, soft, transparent ring that contains etonorgestrel and ethinyl estradiol. The ring is made as one size ts all and releases 15 mg ethinyl estradiol and 120 mg etonorgestrel per day [15]. The hormone levels reach maximum levels 7 days after insertion and remain stable for 35 days without much uctuation [15]. The patient self-inserts the ring into the vagina and wears it for 3 weeks. Removal in the fourth week leads to a withdrawal menses, after which the patient inserts a new ring. Continuous use is also an eective option, and it allows menstrual bleeding to be postponed, with breakthrough bleeding as a possible side eect. Estradiol exposure is 3.4 times lower with the ring than the patch and 2.1 times lower than in pill users; however, it still eectively inhibits ovulation [15]. This is likely the reason for fewer estrogenic side eects, such as nausea and breast tenderness. Discontinuation generally occurs because of vaginal discomfort or sensation of the ring in place, problems with intercourse, or expulsion. Insertion and removal are

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generally easy, and even if the ring is felt during intercourse, this is not a usual reason for discontinuation. The levonorgestrel IUD (Mirena) is the only progestin-releasing IUD available in the United States, and it is approved for 5 years of use. Menstrual blood loss can be reduced approximately 75% to 95% with Mirena in place and it seems to be superior to other treatments for menorrhagia, such as cyclic progestins [20]. When compared with ablation, although amenorrhea is achieved less frequently, women were equally satised [20]. The use of gonadotropin-releasing hormone agonist (GnRHa), such as leuprolide acetate, can achieve short-term relief of bleeding and is often used to bridge women to surgical treatment such as ablation, myomectomy, and hysterectomy for abnormal uterine bleeding. The amenorrhea achieved by use of GnRHa provides relief of bleeding, which allows hemoglobin levels to rise and decreases the risk of transfusion in subsequent surgery [21,22]. GnRHa also decreases the size of broids by as much as 35% to 65%, which may allow a vaginal route for a hysterectomy that otherwise may have had to be performed abdominally [21,22]. When myomectomy is the planned procedure, GnRHa decreases the need for a vertical incision and lowers operative blood loss but may lead to diculty with assessing tissue planes around the broids [21]. The thinning eect of the endometrium caused by GnRH agonists can improve visualization during hysteroscopy and may improve the short-term outcome of endometrial ablation [23]. Because of the high cost, eect on bone density, and other side eects from estrogen deciency (eg, hot ashes and night sweats), long-term use of these medications is not generally recommended. Nonhormonal medical treatments Prostaglandins are found in high concentrations in the menstrual endometrium. Nonsteroidal anti-inammatory drugs (NSAIDs) inhibit prostaglandin synthesis and decrease menstrual blood loss when compared with placebo [24]. NSAIDs also may alter favorably the ratio between thromboxane A2 (a vasoconstrictor and promoter of platelet aggregation) and prostacyclin (a vasodilator and platelet inhibitor). In general, NSAIDs reduce blood loss by approximately 20% to 40% in most women and may result in a greater reduction in women with menorrhagia [25]. Side eects are diminished with use only in the premenstrual or menstrual time frame with the advantage of diminishing dysmenorrhea as well [26]. They can be considered rst-line treatment in ovulatory women with no obvious pathologic conditions. There is no evidence of a dierence between individual NSAIDs, such as naproxen and mefenamic acid, in reducing menorrhagia [24,27]. Tranexamic acid, a medication commonly used in Europe, can be used for menorrhagia and acts as an antibrinolytic agent. It seems to work better than NSAIDs, but large doses are required and side eects are common [28].

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Endometrial hyperplasia Endometrial hyperplasia is a possible consequence of chronic anovulation and is categorized as simple or complex based on its architectural pattern and as with or without nuclear atypia. The presence of atypia signicantly increases the risk of current presence or future occurrence of malignancy, whereas lesions without atypia are similar to exaggerated proliferative endometrium [29]. Lesions without atypia should regress with curettage or with progestin treatment and have little risk of progression to adenocarcinoma. In contrast, when atypia is present, the endometrium can be resistant to curettage or progestin treatment and can have signicant risk of progression to adenocarcinoma [29,30]. Atypical lesions are precancerous and are distinguished from cancer by lack of stromal invasion. Treatment of hyperplasia without atypia consists of cyclic progestin therapy similar to that used for anovulation (medroxyprogesterone acetate, 10 mg daily, for 1014 days per month for 3 to 6 months) or even combined oral contraceptives [30]. Micronized progesterone (100200 mg) in a vaginal cream is also an alternative when used from the tenth to the twenty-fth day of the cycle for 3 to 6 months [31]. The use of the levonorgestrel IUD has been shown to be an eective treatment option [32,33]. For women who wish to conceive, ovulation induction is also an option for treatment. Hyperplasia with atypia is best treated surgically with hysterectomy. If the diagnosis is made by endometrial biopsy, dilation and curettage should be performed to rule out concurrent adenocarcinoma, which may be present in 42% of these cases [34]. If the diagnosis is conrmed and no carcinoma is present, in women who strongly desire to retain their reproductive capability, high-dose progestins can be used, such as megestrol acetate, 40 to 80 mg daily, or medroxyprogesterone, 600 mg daily, for 3 to 6 months [35,36]. Resolution of atypical hyperplasia also has been seen after insertion of the levonorgestrel IUD [33,37]. Repeat biopsies need to be performed at 3-month intervals to conrm response to treatment and resolution. Most cases respond to medical treatments [35,36]. Women who respond to treatment should be encouraged to achieve pregnancy as soon as possible and, in the interim, be monitored closely because recurrence is not uncommon [37]. Women who delay childbearing should be maintained on progestin treatment and undergo sampling of the endometrium every 6 to 12 months. Women who do not respond to medical treatments should be treated with higher or longer doses of progestins or oered hysterectomy.

Treatment of other causes of abnormal uterine bleeding When women experience abnormal bleeding for reasons other than those discussed previously, other conditions, such as chronic endometritis, should be considered. In chronic endometritis, endometrial biopsy demonstrates variable numbers of plasma cells within the endometrial stroma [38].

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Women may experience intermenstrual bleeding, spotting, postcoital bleeding, menorrhagia, or amenorrhea [38]. Endometritis may be caused by several processes, including infections, intrauterine foreign bodies or growths, and radiation therapy; however, a signicant number of patients have no obvious cause. This condition is seldom the direct cause but may be a secondary or contributing cause of bleeding. Inammatory cells in this condition produce proteolytic enzymes that delay normal healing and damage the endometrium, which makes it fragile and prone to erosions. These inammatory cells also can release prostaglandins and platelet-activating factors, which are potent vasodilators. Chronic inammation related to foreignbody reaction is the most likely cause for heavier bleeding associated with the copper IUD. Chronic endometritis may be one of the causes of abnormal bleeding in women with leiomyomas or polyps. The treatment consists of antibiotics, such as doxycycline, 100 mg, twice a day for 1014 days [39]. Fibroids are common, and in symptomatic women, abnormal uterine bleeding is the most common symptom. Because broids are common and most often asymptomatic, they cannot always be regarded as the cause of abnormal bleeding when they are found. Endovaginal ultrasound can help delineate broid size, location, and number, and sonohysterography demonstrates if there is impingement on the endometrial cavity. Fibroids that are submucosal or large enough to cause the overlying endometrium to stretch may cause friction, inammation, or even ulceration, which lead to bleeding [1]. Some myomas also have larger vessels on their surface, which can rupture and lead to heavy bleeding. Women with a grossly enlarged broid uterus, with multiple large broids distant to the endometrium, may have menorrhagia simply because of the larger surface area of the endometrium. Intervention is initially medical, usually beginning with a combined estrogen-progestin treatment. Oral contraceptives decrease the volume and duration of blood loss during menses [12]. NSAIDs and GnRHa also can help reduce menstrual blood volume and size of broids [21,24]. Surgical management for broids is common, with technique determined by the size, location, and number of broids and patient age and future fertility desires. Endometrial polyps result in abnormal uterine bleeding caused by the associated fragility of the endometrial vasculature, chronic inammation, and surface erosions. Metrorrhagia is the most common bleeding pattern they cause; however, many polyps are asymptomatic [40]. Polyps are relatively easy to identify on sonohysterography; however, sometimes they can be detected on endometrial biopsy. When polyps are identied, hysteroscopically guided removal is relatively straightforward and eective [41]. Adenomyosis, the ectopic presence of endometrial glands and stroma within the myometrium, is a relatively common nding in women with menorrhagia and dysmenorrhea that is not caused by myomas or endometrial pathology. The pathogenesis is unknown; however, it is believed that the ectopic endometrial tissue seems to induce hypertrophy and hyperplasia of the surrounding myometrium, which results in a diusely

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enlarged uterus. Adenomyosis can be suspected when myometrial cysts are seen on ultrasound or an increased junctional zone thickness on MRI [42]. Treatments include medical management with combined oral contraceptive pills, transdermal patch, vaginal ring, depot-medroxyprogesterone, GnRHa, or progestin IUD. Denitive therapy is hysterectomy, however. Bleeding disorders In women with unexplained menorrhagia, there is a substantial association with inherited coagulation defects, and screening coagulation studies are recommended [43]. Von Willebrands disease is the most common inherited bleeding disorder in women with menorrhagia. In this disorder, there can be quantitative or qualitative derangements of the von Willebrands factor, a protein necessary in platelet function and clot formation at sites of vascular injury. Von Willebrands factor also serves as a carrier for factor VIII in the circulation. The disease has several dierent variations that result in disorders of diering severity of bleeding tendency between individuals. The treatment is desmopressin, a synthetic analog of vasopressin, which is available in intravenous forms and nasal preparations [44]. Treatment leads to rapid increase in factor VIII and von Willebrands factor and helps reduce bleeding. Of note, tranexamic acid also has been used successfully in this disorder, as have traditional treatments for menorrhagia, such as oral contraceptive pills [44]. Surgical management In cases in which persistent bleeding does not respond to medical or more conservative measures, or in cases in which women have completed childbearing, surgery is an option. Hysterectomy achieves high levels of satisfaction but is associated with more perioperative morbidity and is a poor choice for women with medical conditions that signicantly increase the risks of surgery [45]. Endometrial ablation, which involves destruction of the endometrium while leaving the uterus in situ, is less invasive and leads to similar rates of patient satisfaction [45]. Technology continues to advance for the purpose of endometrial ablation. The initial methods involved hysteroscopic use of the Nd:YAG laser; however, this method evolved into the use of a resection loop or roller ball to destroy the endometrium. Newer global techniques have been developed that involve many dierent methods. Global systems have been developed that use bipolar or microwave energy, cryotherapy, or hydrothermal techniques. Most of these newer techniques are easy to perform, take less time, and require less anesthesia than hysterectomy. Many providers are moving this procedure to the clinic and performing it in an oce setting, which is acceptable to many patients [46].

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Success with endometrial ablation is high, with 80% to 90% of patients reporting reduced bleeding and 25% to 50% achieving amenorrhea, depending on technique [47]. Most womend70% to 80%dreport less menstrual pain; however, up to a third of patients may require reoperation within 5 years [45]. It seems that results are initially best when performed in the early follicular phase and if the endometrium is pretreated with progestin agents or GnRHa. Whether this approach aects long-term outcome is less clear, however [23]. A major concern regarding this procedure is that cases of cryptic endometrial adenocarcinoma have developed after endometrial ablations in the past [48]. In such cases, presentation and diagnosis can be delayed by overlying scar tissue, and cancer might grow to an advanced stage before detection. This possibility reinforces the need for thorough preoperative evaluation, including endometrial biopsy, and proper patient selection. References
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