Abnormal uterine bleeding in the reproductive years. Part I—Pathogenesis and clinical investigation

November ] 999, Vol. 6, No. 4

The Journal of the American Association of Gynecologic Laparoscopists

CME Approved Article Abnormal Uterine Bleeding in the Reproductive Years. Part I--Pathogenesis and Clinical Investigation Malcolm G. Munro, M.D.

Objectives After reading this article the reader should: 1. Understand the physiology of menstruation, including factors in volved in attaining and maintaining endometrial hemostasis. 2. Distinguish between dysfunctional uterine bleeding and that caused by structural or organic pathologic processes. 3. Distinguish between ovulatory and anovulatory dysfunctional uterine bleeding, including differences in pathophysiology and clinical investigation. 4. Determine when to perform endometrial biopsy, ultrasound, sonohysterography, hysteroscopy, and magnetic resonance imaging in investigating abnormal uterine bleeding in the reproductive years.

Instructions for Obtaining CME Category 1 Credits The following article will allow you to assess your understanding and knowledge of the material and earn continuing medical education (CME) credit. Review articles will be published in many issues of the Journal of the American Association of Gynecologic Laparoscopists. They will be designated as course reading and offer you a chance to earn up to 1 CME credit hour per article. To obtain 1 CME credit hour, you must take the entire examination that appears after the article and cornplete the answer sheet. Please make a copy of your answer sheet, as it will not be returned to you. Send the completed answer sheet and all other requested information to the Journal of the American Association of Gynecologic Laparoscopists at the address below. The American Association of Gynecologic Laparoscopists is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. For more information, please contact the Association at 13021 East Florence Avenue, Santa Fe Springs, CA 90670-4505; telephone 800 554 2245 or 562 946 8774, fax 562 946 9204.

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Pretest Questions 1. 2. 3. 4. 5.

What are the local endometrial events that trigger the onset of normal menstrual bleeding? How does physiologic menstrual bleeding stop? What is the difference between ovulatory and anovulatory dysfunctional uterine bleeding? What are the recognized or suspected endometrial causes of ovulatory dysfunctional uterine bleeding? What potential etiologies should be considered when evaluating a woman for anovulatory dysfunctional uterine bleeding?

6.

Name the known organic causes of abnormal uterine bleeding. 7. Do all leiomyomas cause abnormal uterine bleeding? If not, which ones do and how? 8. What is the difference between structural and histological evaluation of the endometrial cavity? 9. What are the relative advantages and disadvantages of hysteroscopy and sonohysterography in the evaluation of women with abnormal uterine bleeding?

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Abnormal Uterine Bleeding in the Reproductive Years. Part !

Pathogenesis and Clinical Investigation

Malcolm G. Munro, M.D.

Introduction

Physiology of Menstruation

Abnormal uterine bleeding (AUB) is a clinical problem of great magnitude--affecting women of all ages. Sequelae include anemia, lassitude and associated social, economic and psychological consequences that result in a diminished quality of life. Yet, as the 20 ~ century comes to a close, women still suffer both from the disorder and the costs and side effects of therapy. Hysterectomy remains the dominant intervention for chronic AUB, largely because many perceive medical therapies to be ineffective, expensive, inconvenient and fraught with undesirable or unacceptable side effects. To date, minimally invasive surgery has not experienced wide acceptance for numerous reasons including technical difficulty, cost, reimbursement issues and the perception that it may not be effective in many individuals. This is the first of three articles discussing contemporary understanding ofAUB. The first will build a foundation for sound clinical management by facilitating understanding of the physiology of menstruation and the pathogenesis of disorders that manifest in a complaint of abnormal bleeding. This basic knowledge will be extended to clinical practice by reviewing the principles of clinical investigation of these patients. The second and third installments will discuss medical and surgical management of both dysfunctional uterine bleeding (DUB) and that secondary to structural abnormalities of the uterus.

The normal, non-pregnant, reproductive aged woman ovulates every 21 to 35 days and, in the absence of pregnancy has menstrual periods with the same interval. Menstrual periods usually last for 4+2 days, during which an average of 35-40 ml of blood is lost, an amount equivalent to 16 mg of iron. Whereas the stated upper limit of normal is 80 ml, an amount that can be replaced by the recommended monthly dietary intake of iron, the average woman has been reported to become anemic if she loses more than 60 ml/month.t The mechanisms involved in the induction and control of physiologic menstrual bleeding are complex and still not yet fully delineated. Nevertheless, it is clear that this monthly phenomenon is orchestrated by the systemic and cyclically variable release of estrogens and progesterone from the ovary, which, in turn, are a manifestation of the variable production of gonadotropins from the pituitary, itself under control of the hypothalamus. These interactions have been well described, but less is known about the local factors involved in the induction of menstruation and subsequent endometrial hemostasis. From a simplistic perspective, endometrium responds to the cyclically produced ovarian gonadal steroids, balancing and cyclically shifting factors that favor hemorrhage with those that promote hemostasis. In the proliferative and early luteal phases, hemostasis is the desired

From the Department of Obstetrics and Gynecology, School of Medicine, University of California, Los Angeles. Address reprint requests to Malcolm G. Munro, M.D., Department of Obstetrics and Gynecology, UCLA School of Medicine, Olive View--UCLAMedical Center, 14445 Olive View Drive, Suite 2B-163, Sylmar, CA 91342-1495; fax 818 364 3255. Accepted for publication August 1, 1999.

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environlnent, favoring ultimate successful implantation and consequent development of the early embryo. From the middle to late luteal phase, in the absence of implantation, the reduction and then withdrawal of systemic and local progesterone results in a milieu that culminates in endometrial sloughing and resultant menstrual bleeding. Subsequent menstrual hemostasis is a process that requires a delicate balance of numerous systemic and local factors, knowledge of which is necessary to understand medical management strategies. Vascular Anatomy of the Uterus The uterus receives its principal blood supply from the ovarian and uterine arteries. The paired uterine arteries are branches of the anterior division of the internal iliac arteries and bifurcate, usually just before their arrival at the uterus, into an ascending branch and a descending, or vaginal branch. As they course cephalad, the two ascending uterine arteries give off 6 to 10 arcuate arteries, posteriorly and anteriorly, each of which anastamose with corresponding vessels from the contralateral side, thereby forming a stacked series of vascular rings. The myometrium receives its blood supply from centrifugal and centripetally oriented branches of the arcuate arteries that are oriented in a radial fashion, perpendicular to the serosal surface. When the centripetally oriented radial arteries cross the myoendometrial junction they give rise to the smaller caliber basal arteries that continue on toward the endometrial surface as the spiral arteries that provide blood supply to the functional endometrium. The coiled spiral arteries have a cross sectional appearance that varies depending upon the time in the cycle, with increased coiling characteristic of progression through the proliferative, and, especially, the luteal phases. These arteries supply separate narrow, longitudinally oriented areas of the functional endometrium, each of which is 4 to 9 mm 2 in area. 2 The contribution of the ovarian artery to the uterine blood supply is less well established, but seems to vary according to the time of the menstrual cycle and the location of the corpus luteum. Color Doppler sonography has been used to demonstrate that ovarian arterial blood flow increases during the luteal phase in the vessel ipsilateral to the ovary with the corpus luteum suggesting a gonadal steroid related influence on arterial blood flow between the uterus and ovary.

Induction of Menstruation The endometrium is a regenerative layer of glands and stroma that lines the uterine cavity functioning to provide an environment in which nutrition and oxygen can be delivered to the developing embryo and fetus. It comprises a number of layers. Permanent, lower layers (zones l and 2), which reside next to the myometrium, are collectively called the basalis, and overlying superficial layers (zones 3 and 4) that regularly slough in the absence of pregnancy are called the functionalis. In the reproductive years, in ovulatory women, the endometrium undergoes monthly cycles of proliferation, differentiation and subsequent transition to secretory activity in response first to estrogens and then to the addition of progesterone, each from the ovary. In the absence of conception and implantation, the functionalis layer breaks down and is discharged during menstruation. Whereas it seems clear that progesterone withdrawal from an estrogenically primed endometrium is the systemic trigger of menstrual bleeding, the local mechanisms involved in this process remain unclear. Until recently, the presumed sole etiology of menstruation was spiral artery vasoconstriction with resultant ischemia and necrosis as proposed by Markee in the 1940s based upon his work with endometrial transplants in the anterior chamber of the monkey e y e ) Indeed, it is likely that this mechanism is but one component of the process, with the vasoactivity of the spiral arteries modulated by a number of agents known to exist in the endometrium and superficial myometrium around the time of menses. Prostaglandins (PGs) are produced in the endometrium throughout the menstrual cycle, most notably in the late luteal and menstrual phases, coincident with the declining levels of systemic and local progesterone (Figure 1). The endometrium is rich in the phospholipases necessary for the conversion of fatty acid precursors to arachadonic acid, and, at least in the late luteal phase, the cyclooxygenase necessary for transforming arachadonic acid to prostaglandins. 4 Dominating the prostaglandin milieu of the late luteal phase is PG F2a, a potent vasoconstrictor produced predominantly in the endometrium, particularly in the gland cells. 5'6 However, it is apparent that prostaglandins with vasodilating activity are also measurable in the endometrial stroma (PGE2) 7 and superficial myometrium (PGI2). 8 These substances

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FIGURE 1. Schematic of cyclic events in the endometrium. The top panel shows systemic production of 17g-estradiol and progesterone over a stylized endometrium that first responds to unopposed estrogens with growth, and then stabilizes under the influence of the combination of estrogens and progestins from the corpus luteum. Whereas both estrogen (ER) and progesterone (PR) endometrial receptors rise in the proliferative phase of the cycle, the progestagenic influence results in a decrease in both by the later parts of the luteal phase. The bottom five panels shows various endomyometrial biochemical events in the cycle. Panel 1 portrays menstruation. Bleeding volume depends on primary hemostasis provided by vasoconstrictors like PGF2a and endothelin-1 (ET-1), which is antagonized by endometrial PGE2 and myometrial PGI2. Estradiol, plasminogen activator inhibitor (PAl), and tissue factor (TF) promote secondary hemostasis, angiogenesis, and reepithelialization. Panel 2 shows hemostatic midfollicular endometrium with continuing angiogenesis and growth of glands, stroma, and the extraceUular matrix (ECM). In panel 3, the transition from follicular to luteal phase occurs, with increased coiling of the spiral arteries, continued production of stromal PGE2, and appearance of migratory cells including mast cells. The midluteal endometrium in panel 4 is prepared for implantation, but in the absence of conception the pieces are in place for induction of endometrial regression and menstruation, shown in panel 5. With reduced progestagenic influence, cytokines interlukin-1 and tumor necrosis factor-a (TNFa) induce decidualized endometrial stromal cells to produce matrix metalloproteinases (MMP). Levels of OAI and TF decrease in association with rising levels of plasminogen activators (PAs). Collectively, PAs and MMPs break down components of the ECM, including blood vessels. Vasoconstriction of spiral arteries is induced by ET-1 from stromal cells and PGF2a predominantly from endometrial glands and results in ischemia, necrosis, and sloughing of components of the functional layer of endometrium. Bleeding results from a combination of effects of free radicals, MMPs, and vasodilating agents such as PGE2 and PGI2.

may be present in greater abundance in women with ovulatory menorrhagia as discussed below. More recently, another vasoconstrictive agent, endothelin-1 (ET-1) was discovered in the late luteal and premenstrual decidualized endometrial stroma that clusters around the sprial arteries. 9 It is likely that this substance, produced in quantity with the withdrawal of progesterone, in combination with PG F2o~, largely contributes to spiral artery vasospasm.

The resulting ischemia may potentiate production of greater amounts of the vasoconstrictive substances, particularly PG F2~, thereby setting up a positive feedback loop. In the last decade of this century, additional components to the menstrual paradigm have been developed following demonstration of the dramatic release of matrix metalloproteinase (MMP) and other proteolytic enzymes in the stroma of late secretory

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Abnormal Uterine Bleeding in the Reproductive Years Munro

endometrium and the association of these substances with the onset of menstruation.l~ A number of MMPs exist, at least three of which seem to be involved with the induction of menstruation by a process of degradation of specific components of the endometrial stromal extracellular matrix. For example, MMP-1 functions as an interstitial collagenase (types I,II and III) by cleaving the helical structure of the molecule; MMP-2 is a gelatinase, attacking basement membrane collagens (types IV and V) as well as already denatured interstitial collagens, or gelatins; and MMP-3 is a stromolysin that degrades extracellular matrix proteins like proteoglycans, glycoproteins, fibronectin, and laminin, as well as basement membrane collagens type IV and V. 11,12'13Each of the MMPs are derived from precursor zymogens (pro-MMP I, II, III) manufactured by endometrial stromal cells. The secretion of two of these (MMP-I, III) is inhibited by progesterone and increased with the withdrawal of progesterone, at least in in-vitro models. 14Consequently, the current hypothesis is that estrogens and progesterone stabilize the perivascular endometrial extracellular matrix by suppressing the expression of MMPs from endometrial stromal cells until late in the luteal phase. At that time, if pregnancy does not occur, with the removal of the estrogens and progesterone of luteal origin, MMP expression increases, endometrial extracellular matrix degrades, and the functional layer of endometrium is sloughed. The specific mechanisms controlling MMP production and release are not completely clear. There is evidence that mast cells, a component of the endometrial migratory cell population noted to increase late in the luteal phase, may be involved. Mast ceils produce cytokines, including interlukin-1 (IL-1) and tumor necrosis factor alpha (TNF-cz), which individually and collectively increase the production of MMPs in vitro. 15 Other substances are produced in abundance in the late luteal phase stroma that possess proteolytic activity. The family of plasminogen activators (PAs) are proteases that increase with MMP in the late luteal and early menstrual phases of the cycle, while their inhibitors plasminogen activator inhibitors (PAIs), decrease around menses. Indeed, PAs may even contribute to the activation of at least some of the MMPs and potentially are involved in the induction of menstruation in a way that is synergistic with the action of M M P s . x6'17

Endometrial Hemostasis With the onset of menstrual sloughing and bleeding comes the requirement for local hemostasis, a process that depends upon a variety of factors. In most tissues, the initial process involves formation of the primary platelet plug (primary hemostasis), which is stabilized after activation of the coagulation cascade and the resultant, thrombin-induced conversion of fibrinogen to fibrin. However, studies of endometrial clots in animal models suggest that platelet involvement is relatively low while features dependent upon the clotting cascade are of greater importance.58 While these findings cannot necessarily be applied to the human, it is likely that local vasoconstriction plays the dominant role in securing hemostasis early in the menstrual cycle. Thromboxane (from vascular endothelial and platelet origins), ET- 1, and PG F2ot each contribute to the induction of vasospasm in the spiral arteries of the endometrium (Figure 1). Conversely, excess production of PG E2 and PG I2 can result in vasodilation of the same vessels. Evidence exists that women with menorrhagia have higher PG E2:F2cz ratios than those with normal periods. 19 Such women also have been demonstrated to have greater endometrial levels of PG I2. 8 These therapeutic responses to agents with antiplatelet activity serve to underscore the relative importance of vasoactivity over platelet aggregation, at least in the pathogenesis of some cases of ovulatory menorrhagia. Nitric oxide (NO) is another potent vasodilator and inhibitor of platlet aggregation that has been localized in the endometrial glands and decidualized stromal cells and which has potential influence on menstrual hemostasis in a fashion similar to PG I2. However, to date, there are no published data relating NO levels to the volume or duration of menstrual bleeding. The coagulation cascade is likely important for secondary hemostasis after day 1 of the cycle. Historically, the coagulation cascade was depicted as comprising two distinct pathways, extrinsic and intrinsic, each of which was independently capable of activation of factor X to Xa, which, under the influence of activated factor V, catalyzes the conversion of prothrombin to thrombin. 2~ In this model the intrinsic pathway is initiated by factor XII and other contact agents, whereas the extrinsic pathway is activated by

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Endometrial Repair and Regeneration

tissue factor, which, together with factor Xa, results in factor VII activation. Recently, the concepts of the coagulation cascade have been modified to be consistent with recently recognized regulatory steps and p a t h w a y s 21 (Figure 2). Most important is the recognition of the important role of the factor VII-tissue factor complex of the extrinsic pathway which appears to activate factor IX of the intrinsic pathway, a feature that provides crosstalk between the two, formerly distinctly perceived systems. An important part of the natural history of a vascular clot is the process of fibrinolysis that is mediated by the generation of plasmin from plasminogen after its activation by PA. While such fibrinolysis is physiologic, and therefore necessary, enhanced fibrinolysis may impede the attainment of local hemostasis. Enhanced levels of fibrinolysis have been demonstrated in menorrhagic women, who frequently respond with normal menstrual volumes when antifibriniolytic agents are employed.22,23 Intrinsic Pathway

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After acquisition of primary hemostasis by vasoconstriction and then secondary hemostasis with thrombin-induced plug formation, the process of endometrial regeneration begins. Details are far from clear, but the process appears to fall under the control of local thrombin and of estrogen originating from the developing follicle, first stimulating epithelialization and then proliferation of the various cell types of the endometrium, including stromal, glandular, and epithelial cells. Angiogenesis (the development of capillaries from preexisting vessels) is critical to endometrial regeneration. One factor thought to stimulate angiogenesis is estrogen, an effect that may be inhibited in the presence of progesterone.24However, these data are somewhat controversial for other investigators have not found differences in microvascular structure 2s or endometrial proliferation at varying times in the cycle. 26 Thrombin is thought to affect angiogenesis via surface mediated effects on various types of PA, as well as PAI- 1.

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In the reproductive years, AUB may be related to local or systemic disorders that affect the frequency, timing, and/or volume of endometrial bleeding, that are collectively called dysfunctional uterine bleeding (DUB). Alternatively, such abnormal bleeding may occur secondary to definable organic etiologies within the uterus that affect endometrial hemostasis, such as polyps, leiomyomas, and endometrial hyperplasia. Coagulopathies are uncommon but important entities that may initially manifest in heavy menstrual bleeding, particularly around the time of menarche.

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Pregnancy Uterine bleeding may occur in association with ectopic pregnancy, gestational trophoblastic disease, and normal or abnormal intrauterine gestations. When associated with ectopic pregnancy, uterine bleeding is generally considered to originate from the endometrium, secondary to inadequate progestational support from the corpus tuteum, a consequence of subnormal production of r-human chorionic gonadotropin (~-hCG) from the abnormally located gestation.

"Secondary" hemostasis: the coagulation cascade and fibrinolysis. Whereas both extrinsic and intrinsic pathways remain, it is now apparent that "cross-talk" occurs with factor IX from the intrinsic pathway capable of activation by the factor Vlla-tissue factor complex of the extrinsic pathway. Fibrinolysis is stimulated by plasminogen activator (PA) and inhibited by plasminogen activator inhibitor (PAl) (Modified from Roberts H,/ozier J. Hospital Practice FIGURE 2.

27:97-112,1992).

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Abnormal Uterine Bleeding in the Reproductive Years Munro

Abnormal intrauterine pregnancies comprise more than 50 % of all gestations and are an extremely common cause of uterine bleeding, a frequent harbinger of spontaneous abortion. Bleeding may also occur in the presence of normal intrauterine gestations. As the early embryo implants itself into the decidualized endometrium, the developing trophoblast encounters enlarging sinusoidal lakes as it seeks to develop the interface between the developing fetal and maternal circulation. In some instances, this normal process results in bleeding, frequently referred to as nidation bleeding, usually occurring in the second or third week following conception, or at about the time of the anticipated menses. Another cause of uterine bleeding associated with otherwise normal intrauterine pregnancy is subchorionic hemorrhage, an early gestational event analogous to placental abruption. There are also other causes of bleeding in early gestation that are intrauterine in location (such as an endometrial or endocervical polyp) but wholly unrelated to the gestation itself.

clinical examination may not be the cause of the bleeding experienced by the patient, particularly if they do not involve the endometrial cavity (Figure 3).

Polyps Polyps are generally benign localized tumors that arise either from the endometrium or the columnar epithelium of the cervix. In some instances cervical polyps are visible on speculum examination, most reside in the cervical canal where they may only be visualized with sonographic or hysteroscopic imaging. Although many polyps are asymptomatic, those that bleed do so because of their vascular and friable structure. The resulting bleeding pattern is generally random and frequently not necessarily associated with menstruation. Rarely, such polyps are malignant.

Inflammation When the columnar endothelial surfaces of the uterus are infiammed, AUB may result. Cervicitis occurs secondary to a definable infection such as

Leiomyomas Uterine leiomyomas are an extremely common finding, especially in women in the fourth and fifth decades of life. Although they are frequently associated with AUB, most are present in asymptomatic women. Myomas that involve the endometrial cavity probably cause or contribute to menorrhagia, because of inhibition of local hemostasis or expansion of the surface area of the endometrium or both. The bleeding is thought to be endometrial in origin as spontaneous bleeding from the leiomyoma itself is thought to be uncommon. Little additional information regarding the cause of myoma associated bleeding has been produced since Samson's hypothesis of disordered vasculature in 19 12. Nevertheless, evidence indicates possible local disorders in basic fibroblast growth factor, vascular endothelial growth factor, heparinbinding epidermal growth factor, platelet-derived growth factor, transforming growth factor-l], parathyroid hormone-related protein and prolactin. Further work in this area may provide more specific therapies for myoma-associated AUB.27 The clinician must remember that myomas that involve the endometrial cavity are often impossible to feel on manual examination. Consequently, the uterus, normal to manual examination, may indeed harbor a myoma that is causing the abnormal uterine bleeding. On the other hand, the myomas that are felt on

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E FIGURE 3. Myoma-related or dysfunctional bleeding? (A) Normal uterus, typical for an individual with either ovulatory or anovulatory DUB. (B) The uterus is normal to clinical palpation but harbors a myoma detectable only by imaging. (C) The enlarged uterus contains myomas that would likely explain bleeding. However, (D) the uterinemyomatous complex contains a normal endometrial cavity. Such women are frequently asymptomatic, or, in the face of abnormal bleeding are most likely to have DUB. (E) The uterus is identical to that in D, but only the submucous, intracavitary myoma is the likely source of abnormal bleeding.

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chlamydia trachomatis, or may be idiopathic. 28'29 Women with chlamydial infection seem most likely to experience contact bleeding, such as that which occurs with intercourse or the positioning of a contraceptive diaphragm Chronic and non-specific endometritis tend to occur in the absence of a detectable organism, either idiopathically, or following instrumentation or pregnancy. In such instances, at the time of endometrial biopsy or curettage, stromal edema, increased stromat density, and pleomorphic stromal inflammatory infiltrate dominated by lymphocytes is generally found in addition to a dense plasma cell infiltrate. 28 Similar inflammation may occur in the presence of an intrauterine contraceptive device (IUD) as discussed below.

Intrauterine Devices Both inert and copper-containing IUDs are known to frequently result in increased menstrual bleeding and irregular bleeding between menses. The mechanism of menorrhagia is thought to be related to one or a combination of local inflammatory reaction and foreign body induced enhancement of endometrial fibrinolytic activity. However, there is some evidence suggesting that irregular bleeding associated with IUD use may indeed be related to bacterial infection of the endometrium.3~Progestin IUDs generally reduce menstrual bleeding, and may cause amenorrhea, but in some instances may result in intermenstrual bleeding (metrorrhagia).

Endometrial Hyperplasia and Neoplasia Exposure of the endometrium to prolonged levels of unopposed estrogen stimulation is thought to frequently result in the development of endometrial hyperplasia, even in the premenopausal years. Consequently, ovulatory women rarely develop endometrial hyperplasia, whereas those with long-term anovulation are at risk, regardless of age. 31Hyperplasia may be simple or complex and with or without atypia. Each entity places the patient at increased risk for endometrial cancer; complex hyperplasia with atypia is associated with endometrial adenocarcinoma in about 25% of cases.

endometrial glands and stroma within the myometrium. The adenomyotic tissue is usually evenly dispersed throughout at least the superficial myometrium and, in such instances, is said to cause symmetric enlargement of the uterus. However, in some cases the glands and stroma can develop in one or a number of myometrial foci that, in some instances, may mimic leiomyomas. The diagnosis can only be confirmed by histological examination of a significant specimen of the myometrium. Consequently, adenomyosis is usually not confirmed until a hysterectomy is performed. Attempts to obtain biopsy specimens of the myometrium for diagnostic purposes have yielded mixed results. Whereas adenomyosis is said to cause both menorrhagia and dysmenorrhea, its true significance is yet to be determined. For example, Valvilis et al found a high incidence of menstrual disorders and dysmenorrhea in 116 women diagnosed with adenomyosis at hysterectomy.32 However the disorder is frequently found at hysterectomy in women without such symptoms. Owolabi and Strickler found adenomyosis in 161 of 1619 consecutive hysterectomy specimens, a diagnosis made prior to surgery 10% of the time? 3 They were unable to relate a consistent group of symptoms to patients with the disorder. Similar conclusions were reached by Kilkku and investigators in a cohort of 212 women, 28 of whom had adenomyosis on histological examination of their hysterectomy specimens? 4 Unfortunately and traditionally, the diagnosis of adenomyosis has been limited to the examination of hysterectomy specimens, a circumstance that prevents an understanding of the prevalence of the disorder in asymptomatic women. Imaging techniques with potential for non-operative diagnosis (ultrasound; magnetic resonance imaging), together with the possibility of myometrial biopsy, via hysteroscopy or ultrasound directed needle biopsy, offer opportunity to gain a better understanding of the relationship of adenomyosis to clinical medicine.

Coagulopathies Congenital or acquired systemic disorders of hemostasis are uncommon but important, and often unrecognized causes of AUB. For discussion purposes, they may be categorized into disorders of primary or secondary hemostasis.

Adenomyosis Adenomyosis is a rather enigmatic disorder of unknown etiology, characterized by the presence of

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Defects in Primary Hemostasis These affect the formation of the initial clot, or platelet plug. Although platelet plugs may have a secondary importance in endometrial hemostasis] 8 it is clear that, in some instances, defects in primary hemostasis may contribute to the genesis ofAUB. Such primary defects occur secondary to quantitative or qualitative platelet abnormalities, defects in yon Willebrand factor (vWF), or from abnormal blood vessel wall components. Thrombocytopenia may result from a number of congenital and acquired conditions including bone marrow failure, cytotoxic drugs, and hypersplenism secondary to portal hypertension, lymphoma, and a spectrum of metabolic diseases. Platelet numbers can be reduced by conditions that increase peripheral destruction, including nonimmune causes such as vasculitis and thrombotic thrombocytopenic purpura, as well as the more common immune etiologies such as autoimmune thrombocytopenia purpura. Qualitative platelet abnormalities are most conmaonly iatrogenic and related to the use of nonsteroidal antiinflammatory drugs that block the production of thromboxane, one of the factors necessary for platelet aggregation. The fact that such agents usually either reduce menstrual bleeding or have no impact on bleeding volume serves to underscore the likelihood that platelets are of secondary importance in endometrial hemostasis. Von Willebrand disease (vWD) is the most common genetic coagulopathy found in women (0.1%0.8% of the general population) and is actually a spectrum of disorders that occur because of defects in vWF synthesis or structure. 35Type 1 vWD is the most common of the three types and four subtypes, which are defined by a sophisticated array of laboratory tests. The characteristics of type lvWD include a 50% to 70% reduction in vWF and reductions in factor VIII. The disorder is autosomal dominant, but variable penetrance frequently makes it difficult to identify patients by family history. A structurally abnormal vWF protein characterizes the less common type 2 vWD, while type 3 patients are virtually devoid of measurable vWE The first patient described by Erik von Willebrand was a thirteen-year-old who eventually died of uncontrollable menstrual bleeding. 36Patients with the disease typically present around menarche, which is often the first time that the young woman has had to secure hemostasis from a relatively large surface area. Since

adolescent women are usually anovulatory, the endometrial concentrations of PG F2o~, ET-1 and other progesterone dependent vasoconstrictive substances are low, a circumstance that potentiates the hemorrhagic process even further. The amount of bleeding generally correlates with circulating levels of vWF, which are affected by factors that include ABO blood type, age, and endocrine status. At least in type 1 vWF, these factors collectively are potential explanations for the variable penetrance of the type 1 vWF gene.

Defects in Secondary Hemostasis Deficiencies in coagulation factors VIII, XIII, and fibrinogen have been reported in association with menorrhagia but are uncommon? 7"3s However, reproductive-age women receiving oral anticoagulant therapy relatively commonly experience heavy menstrual bleeding. 38 Another cause of defects in secondary hemostasis is advanced liver disease, including cirrhosis, which results in a depletion of hepatic dependent factors such as prothrombin.

Arteriovenous Malformations A rare cause of AUB is the uterine arteriovenous malformation (AVM), fewer than 100 of which have been documented in the literature. 39These lesions are ostensibly congenital in origin, but may be acquired and can present any time throughout life ranging from the premenarchial to the post menopausal years. Congenital AVMs are generally complex, involving a number of blood vessels as well as the surrounding muscle. On the other hand, acquired AVMs, which likely result from trauma (usually surgical), malignancy or infection, are usually characterized by a connection between a single artery and an adjacent vein. Hemorrhage is the usual presenting complaint.

Iatrogenic Causes Many iatrogenic causes of AUB exist, including IUDs and anticoagulants. Perhaps the most common is the use of oral, implantable, or injectable gonadal steroids, which, in the reproductive years are usually administered for contraception. Tamoxifen is used for prophylaxis and treatment of breast cancer and has weak estrogenic activity that may contribute to AUB, and has been linked to the genesis of endometrial hyperplasia and adenocarcinoma. In addition, psychotropic drugs such as tricyclic antidepressants and

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phenothiazines, may contribute to anovulation. Uterovaginal bleeding of limited duration is a frequent consequence of colposcopy, electrosurgical or cold knife excision of the cervix and dilation and curettage (D&C) or hysteroscopic ablation or resection of the endometrium, polyps, or leiomyomas.

women of reproductive age have menstrual blood loss of more than 80 ml/cycle4~ and that up to 20% of women are affected by excessive menstrual bleeding. t Menorrhagia accounts for over half of all hysterectomies in the United Kingdom. at Kjerulff and colleagues reported that menstrual disorders, 90% of which could be classified as DUB, were the most common group of gynecologic disorders at 53 cases/ 1,000 women, and this rate is similar for AfricanAmericans and whites. 42 Dysfunctional uterine bleeding, especially when associated with heavy bleeding, is frequently associated with symptoms such as fatigue, discomfort, and depression as well as a general decrease in quality of life, including activity limitation and changes in sexual function.

Systemic Disease Systemic diseases are covered in other areas of these articles, but some disorders deserve separate mention. Chronic liver disease that is not severe enough to result in a coagulopathy may contribute to AUB because of the reduced ability to metabolize estrogen. Resulting increased systemic levels of estrogens may result in hyperstimulation of the endometrium and consequent AUB.

Ovulatory DUB

Dysfunctional Uterine Bleeding Dysfunctional uterine bleeding (DUB) occurs in women of reproductive age and is diagnosed when abnormal bleeding occurs unrelated to demonstrable congenital or acquired causes. Ovulatory DUB is generally excessive bleeding associated with progesterone withdrawal, thereby manifesting predictable menses 21 to 35 days apart. Anovulatory DUB occurs in the absence of the cyclic production of ovarian progesterone and, consequently, is usually erratic in nature resulting in a mixture of amenorrhea and bleeding that is irregular in both timing and volume. Anemia is a frequent consequence of either type of DUB, and may develop with less blood loss in women whose iron intake is low. Bleeding that women consider excessive or unacceptable and for which they seek care covers a broad range of volume and predictability. Although some physicians assert that anemia is a prerequisite for clinical significance, there are many inconvenienced nonanemic women who would challenge such a contention. Most European and Australasian investigators and clinicians consider DUB to be restricted to being ovulatory. In contrast, many North American textbooks minimize or even deny the existence of ovulatory DUB as an entity. These international and regional differences in nomenclature and clinical perspective lead to some confusion and apparent conflict in interpreting the results of clinical investigation. Precise prevalence data on DUB are difficult to obtain; however, it is estimated that 9 % to 14% of

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Ovulatory DUB occurs when there is loss of local endometrial hemostasis. The woman experiences regular and predictable menstruation, usually retaining any existing molimina associated with ovulation such as dysmenorrhea, mid-cycle pain, and premenstrual symptoms such as breast tenderness, bloating, and irritability. Although the exact mechanisms involved in this deficit are unknown there exist a substantial body of data regarding potential causes. The ratio of PG F2~ to E2 is decreased in menorrhagic women 43 and levels of prostacyclin (PG 12) are increased) ,44In addition, fibrinolytic activity is significantly elevated in most women with ovulatory DUB.22'45The levels of MMPs in ovulatory DUB have not been reported.

Anovulatory DUB The mechanisms involved in anovulatory DUB are uniquely different from those with ovulatory DUB. Local hemostatic mechanisms are rendered deficient secondary to the absence of cyclical production of progesterone and the related biosynthesis of prostaglandins and other substances necessary to control blood loss. In addition, the absence of ovulation makes bleeding unpredictable in both timing and volume, a circumstance that can negatively affect the woman's lifestyle due to constant concern about unexpected bleeding. Finally, anovulatory DUB creates an endocrinologic endornetrial milieu of unopposed estrogen, known to facilitate the development of endometrial hyperplasia and endometrial adenocarcinoma.

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It is frequently difficult to determine the etiology of anovulation in any given woman. In the perimenarcheal female, immaturity of the hypothalamicpituitary-ovarian axis is usually touted as the principal reason for anovulatory cycles that frequently characterize the first six to 12 months of reproductive life. 46 However, a number of factors and entities are known or suspected to affect the normal function of the hypothalamic-pituitary-ovarian axis. Perhaps the most defined disorders are a group of endocrinopathies led by hyper-, or, more commonly hypothyroidism, which is frequently otherwise subclinical. 47 Clinical or subclinical hypothyroidism may impact ovulation via the resultant increased levels of thyrotropin releasing hormone, which, in turn, appear to directly increase the production of prolactin. 48 Hyperandrogenic anovulatory states include ovarian or adrenal tumors, congenital adrenal hyperplasia, and, the most commonly diagnosed entity, polycystic ovarian syndrome ( P C O S ) . 49 Occult or overt insulin resistance has recently been associated with PCOS and should be considered in women so diagnosed) ~Hyperprolactinemia is another cause of anovulation and may be idiopathic, secondary to a pituitary prolactinoma, or associated with the use certain drugs such as metoclopramide51or psychotropic agents such as phenothiazines and tricyclic antidepressants22 The most notable cause of reversible anovulation is contraception with gonadal steroids, which are commonly associated with abnormal bleeding. Recent evidence indicates that serum cortisol levels are increased in women who have idiopathic anovulation, a finding that may suggest that stress is involved in the development of at least some irregular uterine bleeding? 3 However, studies evaluating job-related stress and its relationship to anovulation have reported conflicting results, with some suggesting that stress inhibits ovulation, while others have failed to find such an association) 4'55 Nevertheless, most such studies have found that stress does at least affect cycle length, usually by reducing the number of days in a cycle. Eating disorders, including anorexia nervosa and bulimia nervosa, have been strongly linked to anovulatory states, and may initially manifest in anovulatory bleeding. 56,57Strenuous exercise, particularly that associated with endurance athletic training, will frequently cause reversible anovulation and either AUB or amenorrhea. 58

The impact of obesity on ovulatory function is difficult to evaluate because of other associated variables. For example, one recently published study found that the incidence of anovulation was increased in women with central obesity, but, most of these subjects also had insulin resistance, similar to that seen in many cases of PCOS. 59 Nevertheless, obesity remains at least a marker for one or a number of related syndromes that individually or collectively may result in anovulation and anovulatory DUB. Other contributors to the genesis of anovulation are, undoubtedly not yet appreciated. One might be cigarette smoking, which has recently been linked to anovulatory cycles. 6~

Clinical Investigation Introduction Abnormal uterine bleeding consists of one or a combination of disorders in frequency, predictability, duration, and rate of flow, and may be accompanied by related symptoms of fatigue and dysmenorrhea. A confusing array of terms and definitions are used to describe these symptoms, which are sometimes misperceived as diagnoses. Menorrhagia is a term that should generally be used in the context of ovulatory cycles and is defined as the loss of 60 to 80 ml or more of blood per cycle. 61 Oligomenorrhea occurs when menses are more than 35 days apart, while polymenorrhea is said to exist when the "cycle" is less than 21 days in duration. Metrorrhagia is bleeding between cyclic menses. When heavy bleeding is interspersed with light bleeding menometrorrhagia is said to exist. As mentioned, some clinicians, as well as managed care organizations, suggest that bleeding that does not result in anemia is clinically irrelevant. This approach ignores the inconvenience experienced with unpredictable or heavy bleeding that may not result in depletion of iron stores. Methods used to quantify menstrual volume have little practical use in clinical medicine; they include pad pictograms, alkaline hematin extraction, and radioactive isotope scanning. The evaluation of a woman with abnormal bleeding must first focus on determining the site of bleeding. Bleeding perceived by the patient to be genital tract in origin indeed may arise from extragenital sites, including urinary and gastrointestinal sources. Genital tract bleeding may originate in the vulva, vagina or

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cervix, and, rarely, the fallopian tubes. Consequently, the history, the physical examination, and indicated ancillary tests should be conducted in a way that allows comprehensive evaluation of all possible sources of bleeding. As discussed in the section on pathogenesis, the presence or absence of ovulation is a key to identifying the etiology of the bleeding, determining appropriate investigations, and, in many instances, choosing among options for management. This distinction has not received enough attention, particularly in the textbooks and publications that originate from North America. Anovulation should stimulate the clinician to pursue an investigative path that seeks to expose causes of the systemic malfunction, and to direct therapy accordingly. On the other hand, bleeding associated with ovulation is an indication of disordered hemostasis. In rare circumstances the disordered hemostasis is systemic, secondary to a congenital or acquired coagulopathy. However, in most cases it is localized to the endometrium, either related to a definable organic lesion such as a submucous myoma, or the factors involved in ovulatory DUB. Clinical "red herrings" may be found in the evaluation. Consequently, it is always necessary to relate the findings to the pattern of bleeding. The evaluation may be divided into three components: history and physical examination, laboratory investigation, and structural and histologic evaluation of the endometrial cavity. Whereas history and physical examination are necessary for all women with AUB, the extent of laboratory and endometrial investigation depends upon the specific clinical circumstances, the judgement of the clinician, and the desires of the patient.

circulating intravascular volume. It is important always to evaluate for pregnancy with one or a combination of history, physical examination and urine or serum [3-hCG assay. The usual clinical investigation starts with a detailed menstrual history, not only to evaluate for pregnancy and ovulatory status, but to determine the impact of the clinical problem on the woman's life and life style. Ovulatory status, is most cost-effectively determined by the history. At least 95% of women with cyclic, predictable menses every 21 to 35 days are ovulatory. Molimina may provide clues additionally suggestive of ovulation, and may include dysmenorrhea, mid-cycle unilateral pelvic pain, and premenstrual symptoms, such as breast tenderness, that are relieved by menses. Anovulatory bleeding patterns are typically irregular in timing and flow, and are often, but not always, interspersed with episodes of amenorrhea of varying duration. The first anovulatory bleed may be extremely heavy and can follow an extremely short or even non-existent period of amenorrhea. The history may provide clues to the cause of anovulation by searching for subjective features of the circumstances and clinical entities described above in the discussion of causes of anovulation. The clinician should also screen for evidence of a congenital or acquired coagulopathy by reviewing the family history and the patient's own medical history. The physical examination starts with a general examination of the patient and should be directed in a way that allows comprehensive but efficient evaluation for the cause of the abnormal bleeding. For ovulatory women, it should focus on acquiring evidence of coagulopathy by looking for bruising and petechiae, as well as for features such as hepatopathy and splenomegaly that could suggest systemic disease. For anovulatory women, the integument and general bodily habitus may provide some clues as to the etiology of the disorder. Obesity is commonly associated with anovulation, and formerly obese women who lose weight relatively suddenly may experience amenorrhea and/or unpredictable anovulatory bleeding. Extremely thin women, including those who have lost weight, will also be susceptible to anovulation. For them, the clinician should redouble efforts to identify sources of stress, psychiatric disorders, and systemic organic disease. Discrete disease entities known to cause anovulation may be suggested by hirsutism, thyromegaly, and galactorrhea. Acanthosis nigricans

History and Physical Examination Occasionally, patients with AUB will present with severe anemia, and/or in a hemodynamically unstable state with tachycardia and orthostatic or frank hypotension. They usually have a ruptured ectopic pregnancy or impending spontaneous abortion, but even nonpregnant patients may, in certain circumstances, lose large volumes of blood before they can reach medical care. In such instances, the clinician must initially abbreviate the history, confining it to the information required for successful resuscitation and restoration of

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is frequently associated with insulin resistance and, in combination with anovulatory bleeding is suggestive of PCOS .62 Careful inspection of the perineum and perianal area should identify non-genital tract causes of bleeding such as lacerations, tumors, anal fissures, and urethral caruncles. A careful speculum examination generally reveals vaginal lesions such as lacerations and tumors. However, the blades of the speculum may obscure such lesions, particularly on the anterior and posterior vaginal walls. Consequently, the clinician should carefully visualize those areas as the speculum is slowly withdrawn. Visual examination of the portio vaginalis of the cervix may reveal evidence consistent with pregnancy (dusky hue), exocervical dilation in the event of inevitable abortion, or tissue in the cervical canal or vaginal vault secondary to incomplete or complete abortion. Exclusive of pregnancy, cervical ectropion, a polyp, or a lesion suspicious of a malignant tumor may be noted. A friable ectropion is most often related to chronic cervicitis, but it may be a sign of Trichomonas vaginalis, or C. trachomatis infection, the latter particularly if purulent cervical mucous is present. In such instances an antigen test for C. trachomatis should be performed. For those who are competent colposcopists, examination of the cervix under magnification with appropriate staining (acetic acid, Lugols solution) may provide reassurance, or allow the performance of a directed biopsy. Regardless, macroscopically visible cervical polyps or lesions suspicious for malignancy should be biopsied. The manual examination should be conducted in a logical progression focusing on the clinical problem. All aspects of the vagina should be palpated digitally to evaluate any lesions found during the speculum examination, and searching for those that might have been missed. The cul-de-sac and lateral fornices are examined for fullness that might suggest hematoperitoneum or a pelvic mass. Then the cervix should be moved laterally, first to one side and then to the other, seeking evidence of the unilateral "stretch" tenderness often associated with ectopic gestation. Careful bimanual examination of the corpus is performed for evidence of symmetric enlargement that might be found with pregnancy, adenomyosis, or a centrally located intramural myoma. Asymmetric enlargement suggests leiomyoma(s) but can be a finding encountered in nodular adenomyosis. Finally, the adnexa are carefully palpated, particularly evaluating for the tenderness,

fullness, or mass that may provide evidence of an ectopic gestation.

Laboratory Investigation A hemoglobin and hematocrit should be considered the only routine laboratory assessments, with other ancillary investigations guided by the history and physical examination. A sensitive urinary assay for pregnancy should be liberally performed particularly in women who have a relatively short bleeding history or who are at risk for pregnancy. For those with associated mucous membrane bleeding (gums, epistaxis), bruising without petechiae, and a family history of abnormal bleeding, particularly with surgery or menses, vWD should be considered. Women who develop such problems without the family history and long after menarche are m o r e likely to harbor an acquired coagulopathy. In such patients, and for others who are at risk for coagulopathy, including perimenarcheal girls, the investigation should include a platelet count, peripheral smear, prothrombin time (PT) and activated partial thromboplastin time (APTT). The APTT is a screening test that reflects deficiencies in factors II, V, VIII, IX, X, XI; factors II, V, VII, and X are also measured by the PT. The normal range of the APTT varies from laboratory to laboratory so it is important to use the laboratory reference to determine whether the result is normal or abnormal. The APTT would remain normal until factors V, VIII, IX, and XII are 30% of normal. A similar situation exists for PT, which remains normal until deficiencies in factors II, V, VII, and/or X are below 40% of normal. Consequently, if a woman has findings suggestive of vWD, further studies should be done even if the PT and APTT are normal. While a bleeding time may be useful if positive, it may still be normal in vWD. As a result a factor VIII assay and a ristocetin cofactor assay should be considered, the latter a measure of vWF. Levels of vWF vary with blood type. For example those with type AB have 60 % to 70% higher levels of vWF than do those with type O. There are a number of other tests that may be employed in the evaluation of women with suspected coagulopathies that are covered in an excellent review by L u s h e r . 63 If the diagnosis of ovulation is uncertain, luteal phase progesterone is measured. For women who are anovulatory, a thyroid stimulating hormone (TSH) assay will evaluate thyroid function and serum

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prolactin and serum testosterone may be ordered as indicated by the clinical picture.

be. Consequently, many suggest the routine use of preprocedural oral analgesia and/or one or a combination of the local anesthetic techniques described below for diagnostic hysteroscopy. Administration of local anesthesia is particularly valuable when the cervix is stenotic or if the patient experiences pain with the initial introduction of the catheter or dilator. Occasionally, cervical stenosis does not allow dilation, either at endometrial biopsy or D&C. In such instances, transvaginal or abdominal ultrasound may allow successful and safe completion of the procedureY The yield of endometrial hyperplasia or endometrial cancer may be extremely low in women with ovulatory DUB, regardless of age. 31 However, for those with chronic anovulation, endometrial hyperplasia and cancer may be detected in the fourth and even the third decade of life, a circumstance that is more likely in obese women. Persistent abnormal bleeding, despite normal sampling, suggests the potential for localized pathology that can be seen only with sonographic or endoscopic imaging.

Endometrial Evaluation

Histology The principle reasons for sampling the endometrium are to evaluate the patient for the presence of endometrial hyperplasia and carcinoma and to diagnose acute or chronic endometritis. In postmenopausal women, not taking hormone replacement, sonographically measured thickness of the endometrial echo complex (often called the endometrial stripe) helps define those at extremely low risk for endometrial neoplasia, thereby avoiding endometrial sampiing. However, to date, such data have not been validated in women in the reproductive years. Consequently, endometrial sampling, the standard for decades, remains advisable women who require histologic assessment of the endometrium. Endometrial samples may be obtained by several methods. Many women still undergo routine institution-based D&C, often under general anesthetic, despite abundant evidence that such an approach is not superior to office-based techniques. Office endometrial sampling using disposable catheters has been demonstrated equivalent to formal D & C . 64-66 The Vabra aspirator is the device originally involved in clinical trials comparing endometrial biopsy outcomes with traditional D&C, and evidence suggests that it may sample greater proportions of the endometrium than devices like the Pipelle disposable catheter.67However, the Vabra aspirator is more expensive, cumbersome to use, painful for the patient, and has not been shown to be more reliable at diagnosis. 68In addition, Stovall showed that 97.5% of a cohort of 40 patients with endometrial adenocarcinoma were correctly diagnosed with the Pipelle. 69Whereas some physicians feel that the toothed, non disposable Novak endometrial biopsy instrument is superior to disposable systems, at least two randomized trials suggest that the two have equivalent sensitivity, with the Pipelle device causing less pain. 7~ Other disposable devices exist for endometrial sampling, but none have been demonstrated superior to the Pipelle device for sampling accuracy, although some seem to cause less pain. 72-74 With endometrial biopsy catheters, pain associated with office endometrial sampling is generally minimal: however, some women experience substantial discomfort, although it is difficult to predict who they will

Transvaginal Sonography Transvaginal sonographic measurement of the endometrial echo complex is extremely sensitive for the detection of endometrial hyperplasia and carcinoma (96%, 95% C190% to 98%) in postmenopausal women when the endometrial thickness (both layers) is measured to be greater than 5 millimeters. Its sensitivity remains even in women taking hormone replacement therapy, although, in such instances, its specificity declines from 92% to 77%. 76 However, there are few data regarding ultrasonographic assessment of the premenopausal endometrium. Whereas a thin endometrium likely predicts the absence of endometrial hyperplasia or cancer, the physiologic impact of ovarian estrogens likely reduces the specificity of the test. Color Doppler sonography which evaluates blood flow within a targeted structure, is said to be effective in determining whether, for example, ovarian tumors are totally benign or potentially malignant. Such an approach, if validated, would have potential value when asymptomatic endometrial polyps are found at the time of ultrasound or sonohysterographic examination, thereby eliminating the need for interventions in a cohort of women. A recent paper from Getafe University in Madrid, Spain, described this approach to identify a group of 65 women with asymptomatic

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endometrial polyps. The lesions were not removed because each were determined by color doppler to be devoid of flow. v7At three years, 59 of these remained asymptomatic and unchanged, whereas six developed symptoms and had the polyps removed. Although this paper falls short of proving the utility and safety of expectant management, the technique deserves further study with longer followup.

Structural Evaluation of the Endometrial Cavity Blind instrumentation of the endometrial cavity occasionally suggests the presence of a structural abnormality such as a submucous leiomyoma, however, it is inadequate when hysteroscopy is used as the standard as polyps, leiomyomas and localized adenocarcinomas may be identified, vs-8~ Consequently, imaging by radiological or ultrasonographic techniques or direct evaluation via hysteroscopy is necessary. Magnetic resonance imaging may be an effective way to identify adenomyosis or to distinguish adenomyosis from leiomyomas.

Imaging Hysterography The hysterogram is performed under fluoroscopic guidance using oil or water based radioopaque dye injected via a transcervical catheter into the endometrial cavity. Unfortunately, although it is valuable for determining tubal patency, controversy surrounds its efficacy for cavity evaluation. For example, in a retrospective study of 400 women who underwent both hysteroscopy and hysterography, radiological imaging was found equivalent to endoscopy. 81However, most studies suggest that hysterography is less accurate. For example, when hysteroscopy and sonohysterography were performed in 40 women with abnormal cavity structure on hysterogram, 9 were demonstrated to have a normal cavity,s2 In a similar study of 323 women, the false positive rate for hysterography was 11.7% while the false negative rate was 13.3%. s3 Goldberg et al found that five of 26 women with filling defects on radiological hysterography were normal when examined by both sonohysterography and hysteroscopy,s4

tural abnormalities that may cause AUB, including leiomyomas and polyps. Although it is not consistently useful for evaluating congenital abnormalities such as defects in mullerian fusion or resorption, these anomalies are not known to cause abnormal uterine bleeding. Unlike many imaging techniques, this assessment is dynamic, and therefore its sensitivity and specificity depend largely on the training, skill and experience of the sonographer. Abnormal uterine bleeding is common in pregnancy and may signal either an ectopic or non-viable intrauterine gestation. The use of ultrasound, in combination with assays of the ~-hCG in the management of women with bleeding in early pregnancy is beyond the scope of this manuscript. In non-pregnant women with AUB, a thin endometrial stripe in combination with an absence of leiomyomas near the endometrial cavity is strongly associated with a negative hysteroscopic examination. a5 Transvaginal ultrasound has been compared with hysteroscopic evaluation and successfully predicted a normal cavity in 135 of 139 women with abnormal uterine bleeding; 16 of 121 deemed to be abnormal by ultrasound, were found to be normal at hysteroscopy. These features make transvaginal sonography a suitable screening test for evaluation of the endometrial cavity in women with AUB. In the presence of a thick endometrial stripe or when myomas appear suspiciously close to the endometrial stripe, additional evaluation with sonohysterography or hysteroscopy is necessary. A thickened endometrial stripe may indicate unopposed estrogen effect, including hyperplasia or adenocarcinoma, or may suggest an endometrial polyp, similar in consistency to the endometrium itself.

Sonohysterography Limitations of simple sonography of the uterus can be largely overcome by instilling saline or other suitable fluid into the endometrial cavity. Sonohysterography (SHG) is perhaps the most common term for the technique, but a number of synonyms are in widespread use including hysterosonography and saline infusion sonography. Most have ceased use of the term "hysterosonogram" because of the potential for confusion with hysterosalpingograrn. The technique was introduced by Nannini et al in 1981 using transabdominal scanning following the transcervical introduction of fluid contrast, s6 However, in this form, the technique was not widely

Transvaginal Ultrasound Transvaginal ultrasound is extremely useful to evaluate the uterus for pregnancy and for struc-

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utilized, at least in North America, until the introduction of the transvaginal approach in the early 90s. 87 Compared with office hysteroscopy, SHG seems, in most studies, to have at least equal sensitivity in detecting intrauterine pathology, including polyps, myomas, and synechiae and it causes less pain for the patient. 88's9 In some instances, it is less specific at distinguishing between polyps and myomas than hysteroscopy, but ultrasonic evaluation is more accurate in determining the size and myometrial extent of leiomyomas.90A limitation to sonohysterography is that it does not allow simultaneous removal of selected visualized lesions such as polyps and small myomas, a disadvantage when compared to diagnostic hysteroscopy. Patient preparation is minimal. Women with valvular heart disease or a history suggestive of previous pelvic infection require periprocedural prophylactic antibiotics. Administration of non-steroidal antiinflammatory agents such as ibuprofen or sodium naproxen is an option to diminish discomfort. Because a full bladder is not necessary, the patient should void prior to the procedure to reduce posterior deflection of the uterus. A conventional transvaginal ultrasound is performed with the patient in a modified dorsal lithotomy position during which the uterus and adnexal structures are evaluated. An open-sided speculum is then positioned in the vagina to expose the cervix that is cleansed with an appropriate antiseptic solution. After this a long (usually about 25 cm) intrauterine insemination catheter is flushed with saline or other sterile liquid (eg. saline, glycine, Ringer's lactate) and positioned in the endometrial cavity. Before insertion, the catheter is primed to prevent introduction of bubbles that would obscure sonographic assessment. Cervical dilation is rarely required. When the cervical canal has an old laceration or is patulous, a balloon-tipped catheter may be necessary to contain the fluid in the endometrial cavity. 91 After the catheter is introduced, the endometrial cavity is slowly distended with fluid (usually 5-30 ml) using an attached 60-ml syringe and the uterus is systematically examined in real time. Sonohysterography is extremely useful in determining the presence or absence of polyps or intracavitary leiomyomas that may contribute to AUB. It also provides information about the myometrium and its involvement with myomas not possible with hysteroscopic imaging. Its major deficiency, compared to hysteroscopy, is the inability to allow removal of selected lesions with the same instrumentation.

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Endoscopy Diagnostic laparoscopy has limited utility in evaluating the uterus in women with AUB, as it is difficult to determine which, if any identified myomas contribute to the clinical problem. Diagnostic hysteroscopy, on the other hand, is an office or clinic-based procedure that allows detection of intracavitary myomas, polyps, and other lesions that may cause bleeding. Furthermore, at the time of hysteroscopy, targeted tissue samples may be obtained from the endometrium; and, in some instances, the lesion, such as a polyp or small myoma, may be removed at the same time. Pantaleoni first described hysteroscopy in the nineteenth century for the evaluation of a postmenopausal woman with AUB.92 He described chemical cauterization to eradicate an endometrial polyp. Diagnostic hysteroscopy has received relatively lukewarm response from North American clinicians for a number of reasons including the capital cost of equipment, poor anesthetic technique, and a lack of familiarity with the technique educational institutions.

Utility of Diagnostic Hysteroscopy Diagnostic hysteroscopy provides information not predictably obtainable by blind endometrial sampling. 79'~~ Its utility in diagnosing intrauterine lesions is particularly valuable in women of reproductive age with ovulatory AUB. Fraser described leiomyomas in 20% of 182 such women, only 60% of whom had a normal endometrial cavity.99 However, curettage can provide information (endometritis, hyperplasia) not obtainable by hysteroscopic evaluation, either alone, or with directed biopsy. 79'8~176176Consequently, the principal advantage of diagnostic hysteroscopy over blind sampling is that structural anomalies are more likely detected and defined. Whereas hysteroscopy is superior to blind instrumentation for determining structural defects, it is comparable with SHG, in identifying myomas and polyps.

Procedure Site and Instrumentation In most patients, diagnostic hysteroscopy can be performed in an office or clinic setting, quickly, safely and with minimal discomfort.l~176176 This is a particular advantage because it reduces cost. In one US cost analysis (including anesthesiologist fees; excluding surgeon fees) hospital charges were nearly 30 times those incurred when the procedure is performed in an office ($1799 vs. $62 US). ~~ In very few patients, concerns about comfort, aspects of anatomy, or

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medical condition may preclude performing an officebased hysteroscopic procedure. Office-based hysteroscopy requires appropriate training, suitable equipment, and supplies that include distending media, tubing, and analgesics and anesthetics. A suitable light source is required, as is an appropriate distension medium. Either CO2 or Hyskon (32% dextran 70) was used extensively in the past, but saline is becoming the medium of choice. Saline is inexpensive, available, comfortable for the patient, capable of flushing out blood or debris from the endometrial cavity, and not associated with the carmelization of instruments that occurs with dextran 70. Hysteroscopes may be rigid or flexible, and diagnostic instruments now are available with outside diameters ranging from less than 3.0 mm to 7.0 mm. Smaller diameter instruments now provide an adequate image, with reduced need for dilation and anesthesia, thus reducing the time required for the procedure and providing increased comfort for the patient. If directed biopsy or removal of lesions is to be performed, CO2 should not be the distending medium, to minimize the risk of gas embolus and to facilitate visualization. Hysteroscopically directed biopsy or excision also requires larger-diameter instruments to allow the passage of grasping, cutting, or coagulating tools. In such instances, there are advantages to having continuous flow instrumentation to keep the visual field clear of blood and debris. Regardless of the procedure contemplated, the clinician must be prepared to dilate the cervix, using a cervical expander (e.g. laminaria) or by active dilation, preferably after local anesthesia. Anesthesia One of the barriers to successful diagnostic hysteroscopy is the ability prevent or manage the pain and discomfort that a number of women experience. There are a number of techniques that have been individually evaluated for diagnostic hysteroscopy. Topical anesthesia, which is the introduction of local anesthetics into the cervical canal and/or the endometrial cavity, is effective. 1~176 Paracervical anesthesia has had limited evaluation, and the results are conflicting. In a double-blind, placebo-controlled randomized trial (Class I), Cicinelli et al demonstrated that 10 ml of 1.5% mepivicaine in or near each uterosacral ligament significantly reduced vasovagal reactions as well as both procedure and post procedural pain scores, u~

However, Vercellini and coworkers found no improvement in pain scores in another well designed Class I study comparing paracervical block with placebo. TM Intracervical anesthesia has been demonstrated successful in non-hysteroscopic instrumentation of the uterus,"2 but the only published study on hysteroscopy by Broadbent et al, showed no significant differences when compared to placebo.l~3 Differences in technique may explain the differences in the outcomes of these studies, the most obvious of which is the time allowed for the anesthesia to take effect before the procedure was commenced. The Cicinelli group allowed at least 10 minutes to pass whereas the Vercellini and Broadbent groups performed hysteroscopy as soon as five minutes after administering the anesthetic. This flaw is commonly encountered in clinical practice; few gynecologists would allow a dentist to start drilling only 5 minutes after injection of the anesthetic. It is important to allow at least 10 minutes, and to test the patient's response, being prepared to wait longer, or add additional anesthetic if the initial instrumentation causes pain. Local anesthetic complications include allergy, neurologic effects and impaired cardiac conduction, the last two usually consequences of overdose or intravascular injection. Typical symptoms of allergy are agitation, palpitations, pruritis, coughing and shortness of breath; urticaria, bronchospasm, shock and convulsions may occur. Treatment includes oxygen, isotonic intravenous fluids, intramuscular or subcutaneous adrenaline, and intravenous prednisolone and aminophylline. Cardiac effects are related to impaired myocardial conduction and include bradycardia, cardiac arrest, shock, and convulsions. Emergency treatment includes administration of oxygen, intravenous atropine 0.5 mg, intravenous adrenaline, and appropriate cardiac resuscitation. The most common central nervous system manifestation is paresthesia of the tongue. Other effects are drowsiness, tremor and convulsions. Options for therapy include intravenous diazepam and respiratory support. Overdose is prevented by avoiding intravascular injection and by respecting the maximum recommended doses (lidocaine 4 mg/kg, mepivicaine 3 mg/kg). A vasoconstrictor reduces the amount of systemic absorption of the agent, allowing the maximum dosage to increase by about 100 %. The discussion of complications of general and regional anesthesia is beyond the scope of this paper.

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Complications Besides those related to anesthesia, potential risks of diagnostic hysteroscopy include uterine perforation, infection, excessive bleeding, and complications related to the distention medium. The last includes CO2 embolus and pulmonary edema secondary to over infusion of 32% dextran 70 or low viscosity fluids, such as glycine and sorbitol, neither of which is commonly used for office-based procedures. Prevention of most complications requires a full understanding of uterine anatomy, the instrumentation and the effects of distension media. Published series of office-based diagnostic hysteroscopy report low complication rates ranging from none 93to less than 1 % . 95 However, these series generally describe the experience of experts in the technique and may not accurately reflect that of physicians with tess experience and training.

a study from Kyoto University in Japan, histopathologic findings were correctly predicted in 92 of 93 cases including 71 with leiomyomata, 15 with adenomyosis, and six with a combination of the t w o . 119 The one case missed had a diagnosis of adenomyosis after the MRI predicted leiomyomas. These data suggest that, at present, MRI is more accurate at distinguishing leiomyomas from adenomyosis than is transvaginal sonography. However, management algorithms integrating the two imaging modalities have not yet been developed. Nevertheless, because leiomyomas, unlike adenomyosis, are amenable to local excision, MRI seems valuable when one or a combination of clinical symptoms and transvaginal ultrasound results suggests possible adenomyosis. A number of women would be spared the time, cost, and trauma associated with a laparoscopy or laparotomy-based myomectomy.

Myometrial Evaluation

Myometrial Biopsy Myometrial biopsy is a relatively new, and little used modality that has undergone investigation as a method for the diagnosis of adenomyosis. One method of obtaining myometrial samples is transcervical needle biopsy, reported by Verecellini to have high specificity (96%) but poor sensitivity (45%) compared with histopathologic examination of hysterectomy specimens. 115 Others have reported a per specimen specificity o f 100% but a sensitivity of only 8 to 18% using either laparoscopically- or ultrasonographicallydirected technique.~2~ Whereas these techniques, seem, at least for the moment, to have limited clinical applicability, hysteroscopic endomyometrial biopsy may have a place in identifying patients less likely to undergo successful endometrial ablation or resection. In one technique, an endomyometrial strip is taken from the posterior wall of the endometrial cavity with a resectoscope and a loop electrode. Women with deep endometriosis (> 1ram) had a significantly increased chance of treatment failure with respect to both dysmenorrhea and menorrhagia.~2~.m

The myometrium is assessed to determine the extent of submucous myoma involvement and to identify adenomyosis or to distinguish between leiomyomas and adenomyomas. Detection of adenomyosis remains imprecise, and the clinical significance of adenomyosis itself is controversial.

Transvaginal Sonography Ultrasound is useful for evaluating myomas in the myometrium, although variations in echogenicity can, in some instances, reduce its sensitivity. Transvaginal ultrasound is effective in diagnosing diffuse adenomyosis with a sensitivity of 81% and specificity of 74% in one cohort of women who subsequently underwent hysterectomy for ovulatory menorrhagia and an enlarged u t e r u s . TM Some have reported a specificity of 83% and a sensitivity of 6 7 % 115 while others have described essentially opposite results--sensitivity 80%; specificity 50%). 116Perhaps because of these inconsistent results and uncertainty regarding the clinical significance of the disorder, the current utility of ultrasound in the clinical diagnosis of adenomyosis is limited.

Investigative Strategy

Magnetic Resonance Imaging

A successful investigative strategy requires conscientious, judicious, and appropriate use of the tactics and techniques described above. First a careful history, physical examination, and appropriate laboratory

Magnetic resonance imaging (MRI) for evaluating the myometrium for leiomyomas "7 and adenomyosis z~8was first described in the middle 1980s. In

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Abnormal Uterine Bleeding in the Reproductive Years Munro

investigations are performed to evaluate for hemodynamic instability, pregnancy, ovulatory status, and extrauterine causes of the bleeding. The subsequent steps depend, not only on the ovulatory status, but also on the resources readily available to the clinician, and the wishes of the patient after she has undergone appropriate counseling following the initial assessment. Consequently, the order of the following steps may vary. For women with ovulatory AUB, an experienced sonographer performs transvaginal ultrasound (Figure 4). If the ultrasound reveals a normal endometrial echo complex without involvement of the cavity with a submucosal myoma, the tentative diagnosis of ovulatory DUB is likely and a trial of medical therapy is justified. Alternatively, or should medical therapy fail, an endometrial biopsy may be obtained, searching in particular for chronic endometritis, or the rare endometrial hyperplasia or adenocarcinoma that occurs despite

an ovulatory history. If the sonogram suggests that the endometrial echo complex is abnormally thick, or if a submucous myoma is suspected, either office hysteroscopy or SHG is performed. If resources and expertise are readily available, these procedures may be performed during the same visit. 123 If a polyp or myoma is identified, the patient is counseled regarding appropriate surgical management. Many such polyps can be removed concurrent with the diagnostic hysteroscopy. For women in whom hysteroscopy identifies a submucous myoma with uncertain myometrial extension, SHG may be an appropriate test to determine the best surgical route or technique. When no intracavitary lesions are identified with SHG or hysteroscopy, endometrial biopsy should be obtained if it has not been clone previously. Indeed, in ovulatory bleeding, the endometrial biopsy may be considered optional or positioned anywhere in the algorithm, for the likelihood of a neoplasm is extremely low. For the same reason, a trial of medical therapy may be appropriate at any time, such as oral contraceptives, low dose danazol, non steroidal antiinflammatory agents, antifibrinolytics, and local progestins delivered by an IUD. Should the clinical examination suggest that the patient has chronic anovulatory DUB, an attempt is made to determine the cause of the anovulation (Figure 5). ATSH is usually ordered to provide information regarding thyroid function, and, depending upon the clinical findings, serum prolactin, and androgens (free

1

l :i!t

i

FIGURE 4. Investigation of ovulatory AUB. A transvaginal ultrasound (TVUS) is performed and if there is no cavitary involvement, a diagnosis of ovulatory DUB is made. The hatched line allows for optional performance of an endometrial biopsy that could detect endometritis, or the rare case of hyperp|asia or adenocarcinoma in an apparently ovulatory woman. If screening TVUS suggests a lesion that involves the endometrial cavity, a sonohysterogram or hysteroscopy, or both, is performed. A normal cavity allows a diagnosis of ovulatory DUB with the caveat regarding endometrial biopsy as described above. Should an intracavitary lesion be present, it may be removed concurrently (polyp or small myoma). Larger myomas are determined to be hysteroscopically resectable or unresectable depending on factors that include the size and number of the lesions, and extent of myometrial involvement.

FIGURE 5. Investigation of anovulatory AUB. When the menstrual history suggests anovulation, evaluation of its etiology should be comprehensive. In the face of long-standing ovulation, usually more than a year, endometrial biopsy is generally suggested.

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and total testosterone) may be obtained. The history may provide the clinician with information regarding the patient's psychosocial, nutritional, or exercise/training routines that may provide a clue as to the reason for the onset of anovulation. Furthermore, the use of psychotropic drugs or other pharmacological agents may be determined to have an impact on the genesis of the anovulation. Any of these historical features or clinical findings may provide direction as to the etiology-specific management of the patient's anovulatory DUB. Endometrial biopsy is generally recommended as an initial part of the investigation in those with chronic anovulation. The only available data that can provide guidance as to the definition of chronic anovulation for these purposes are those that relate to postmenopausal hormone replacement. Unopposed estrogen is rarely associated with adenocarcinoma after 1 year of therapy, but endometrial hyperplasia has been described. 124'125Consequently, I recommend consideration of endometrial biopsy in women with a history of more than one year of anovulation, regardless of age. Summary

Women with chronic anovulatory DUB present the clinician an opportunity to detect an array of clinical entities ranging from significant endocrinopathies to serious psychosocial pathology. Chronic anovulation creates the milieu necessary for development of endometrial neoplasia including hyperplasia and adenocarcinoma. Consequently, evaluation of these women should focus on endometrial histology and the reason for the systemic disorder. Such a rigorous but tailored approach to AUB is necessary to provide women with a full range of therapeutic options. Management can evolve from the traditional, often unsatisfactory, empiric approach, dominated by hysterectomy, to an individualized strategy that offers women a variety of expectant, medical, and surgical options tailored to their particular needs.

References 1. Hallberg L, Hogdahl A, Nilsson L, et al: Menstrual blood loss - a population study. Acta Obstet Gynecol Scand 45:320-351, 1966 2. Bartelmez GW: Histologic studies on the menstruating mucous membrane of the human uterus. Contrib. Embryol. 142:142, 1933

A number of mechanisms are involved in the genesis AUB including disorders of pregnancy, structural abnormalities such as polyps or submucous myomas, anovulation, and abnormalities in local endometrial hemostatic mechanisms. The patient's personal and family history are extremely important for triage, and measurement of [3-hCG is essential to determine pregnancy. Ovulatory status is a critically important component of the clinical assessment as it affects both selection of further analytic tests and patient counseling regarding expectant and therapeutic options. The physical examination may be misleading when evaluating for causative leiomyomas. Palpable masses suggestive of leiomyomas may not involve the endometrial cavity and therefore may not contribute to the etiology of the bleeding. Furthermore, although uncommon, such masses may actually be manifestations of nodular adenomyosis. On the other hand, the uterus, normal to palpation, may harbor small but clinically significant submucous myomas or other focal or generalized pathology such as polyps or endometritis that could explain the AUB. As a result, and particularly in the presence of ovulatory AUB, the clinician should judiciously rely on imaging techniques.

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CME TEST 006 Abnormal Uterine Bleeding Part l (Test valid through May 2000) The American Association of Gynecologic Laparoscopists (AAGL) is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. The AAGL designates this continuing medical education activity for 1 credit hour in category 1 of the Physician's Recognition Award of the American Medical Association. Instructions: Read the article on abnormal uterine bleeding beginning on page 97, and select all answers for each of the following questions. Record your answers by circling the appropriate letter on the test form located on the next page.

1.

The late luteal phase endometrium is characterized by:

3.

a. Reduced levels of estrogen and progestin receptors b. Increased levels of matrix metalloproteinases c. Decreased levels of plasminogen activator inhibitor. d. All of the above e. None of the above

2.

Menstrual bleeding volume is thought to be increased by which of the following? a. b. c. d. e.

4.

PGE2 PGI2 Plasminogen activator All of the above None of the above

Consider the following statements regarding adenomyosis.

a. Vasospasm secondary to increased endometrial PGF2o~and endothelin factor (ET-1) b. Matrix metalloproteinases from endometrial stromal cells c. Progesterone withdrawal d. Tissue factor

a. The disorder causes diffuse and symmetric, but not nodular, enlargement of the uterus. b. Magnetic resonance imaging is the most accurate means of making a preoperative diagnosis. c. Adenomyosis predictably causes pelvic pain and menorrhagia. d. It is characterized by the presence of endometrial glands and stroma within the myometrium.

1. 2. 3. 4. 5.

1. 2. 3. 4. 5.

Factors contributing to the initiation of menstruation are thought to include:

Only a, b, and c are true. Only a and c are true. Only b and d are true. Only d is true. All are true.

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Only a, b, and c are true. Only a and c are true. Only b and d are true. Only d is true. All are true.

.

Which of the following is (are) true regarding ovulatory dysfunctional uterine bleeding (DUB)?

8.

a. The diagnosis can be made with reasonable certainty from the history alone. b. Women with anovulatory DUB are at enhanced risk for endometrial neoplasia. c. Anovulatory DUB can occur in the presence of uterine leiomyomata. d. The endometrium of women with anovulatory bleeding is rich in PGF2a.

a. It is due to defects in endometrial hemostatic mechanisms. b. Endometrium contains higher PGF2~:PGE2 ratios and lower levels of PGI2. c. Ovulatory DUB does not occur in the presence of uterine leiomyomas. d. All of the above. e. None of the above.

6.

1. 2. 3. 4. 5.

Which of the following statements about von Willebrand disease is (are) true? a. Bleeding time is invariably abnormal and is therefore a good screening test. b. Among typical peripheral findings are skin bruises with petechiae. c. The amount of bleeding is generally unrelated to circulating levels of yon Willebrand factor. d. Type 1 disease is autosomal dominant with variable penetrance. 1. 2. 3. 4. 5.

7.

Which of the following statements regarding anovulatory DUB is (are) true?

9.

Only a, b, and c are true. Only a and c are true. Only b and d are true. Only d is true. All are true.

Which of the following is true regarding dilation and curettage (D&C)? a. It is superior to endometrial sampling with a biopsy catheter. b. It provides no reliable information regarding uterine structure. c. It is necessary in all instances Of abnormal ovulatory uterine bleeding. d. All of the above. e. None of the above.

Only a, b, and c are true. Only a and c are true. Only b and d are true. Only d is true. All are true.

10. Regarding hysteroscopy and local anesthesia: a. Topical anesthesia is effective compared with placebo. b. Most local anesthetics achieve maximum effect 3 to 5 minutes after administration. c. Paracervical block can reduce pain associated with hysteroscopy or endometrial biopsy. d. Injection of anesthesia near the insertion of the cardinal ligaments predictably reduces pain of hysteroscopy.

Evaluation of the uterus in cases of abnormal uterine bleeding consists of: a. Assessment of endometrial histology with endometrial sampling b. Screening evaluation of the endometrial cavity by ultrasound c. Selective examination of the endometrial cavity with either sonohysterography or hysteroscopy d. All of the above e. None of the above.

t. 2. 3. 4. 5.

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Only a, b, and c are true. Only a and c are true. Only b and d are true. Only d is true. All are true.

The Journal of the American Association of Gynecologic Laparoscopists, CME Test 006. Abnormal Uterine Bleeding Part I

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