Quantitative Assessment of Endometrial Thickness, Intrauterine Lesions, and Intracavitary Fluid

The EMT is the maximum measurement in the sagittal plane and includes both endometrial layers (double EMT). The endometrium should be measured where it appears the thickest perpendicular to the endometrial midline, with the calipers placed at the level of the two opposite endometrial-myometrial interfaces in an appropriately magnified image. The total double-layer thickness is reported in millimeters, rounded off to one decimal point. When intracavitary fluid is present, the thicknesses of both single layers are measured and reported separately ( Fig. 35.6 ), and the amount of intracavitary fluid is defined by its largest measurement in the sagittal plane. If the endometrium is thickened asymmetrically, the largest anterior and posterior EMTs should be measured and reported separately. When the endometrium cannot be seen clearly in its entirety, it should be reported as “nonmeasurable,” and no attempt should be made to measure it. The proportion of cases in which the endometrium cannot be measured may be as high as 10% in perimenopausal women. It is likely much higher in postmenopausal women, although this has not been adequately studied. When intracavitary pathology is present, other than an intracavitary myoma, the total EMT including the lesion is measured and recorded. If an intracavitary myoma is present, it is not included in the EMT measurement, and the three perpendicular measurements are obtained and recorded. In myomas, the distance between the outer peripheral edge of the myoma to the serosa should be measured for consideration of surgical resection.

Spontaneous fluid within the endometrial cavity in two postmenopausal patients.

When intracavitary fluid is present, the thicknesses of both single layers (Ut-Endom.Th.) are measured and reported separately, and the amount of intracavitary fluid is defined by its largest measurement in the sagittal plane. If the endometrium is thickened asymmetrically, the largest anterior and posterior endometrial thicknesses should be measured and reported separately.

Qualitative Assessment of the Endometrium

The endometrium consists of three layers: stratum basalis (basal layer), stratum compactum, and the stratum spongialis. The stratum compactum and stratum spongialis develop into the stratum functionalis (functional layer) during the proliferative phase of the menstrual cycle. The appearance of the endometrium on ultrasound varies in a relatively characteristic pattern throughout the cycle. The endometrium is relatively thin, 3 to 5 mm, in the postmenstrual early follicular phase of the cycle and is a single, hyperechogenic line ( Fig. 35.7 ). The endometrium increases in thickness throughout the follicular phase of the menstrual cycle in response to endometrial proliferation induced by E ₂ and is accompanied by the induction of ER and PRs. The endometrium gradually thickens with the functional and basal layers visually differentiated during the mid-to-late follicular phase (see Fig. 35.7 ). In the late follicular phase and periovulatory period, the endometrium assumes a trilaminar appearance with a central echogenic line of opposing hypoechogenic functional layers and slightly hyperechoic basal layers more peripherally. Mean preovulatory trilaminar EMT measurements vary based on stimulation protocol used for the ovulation induction; however, the measurements are approximately 8 mm in spontaneous cycles, 9 to 10 mm in cycles with oral induction agents, and approximately 12 mm in cycles stimulated with exogenous gonadotropins. In the luteal phase of the menstrual cycle, the endometrium appears homogeneous, hyperechoic with the endometrial glands branching and expanding under the influence of progesterone. In pregnancy, the echogenicity and EMT are maintained as decidual reaction progressed to implantation. In the absence of pregnancy, with a sharp decline in progesterone levels due to demise of the corpus luteum, the endometrium regresses with shedding of the functional layer.

Appearance of the Endometrium through the phases of the menstrual cycle.

(A) Early follicular phase endometrium is a single, hyperechogenic line (arrow) . (B) Mid-to-late follicular phase, the endometrium gradually thickens with the functional and basal layers visually differentiated (arrow) . (C) Late follicular phase and periovulatory period, the endometrium assumes a trilaminar appearance with a central echogenic line of opposing hypoechogenic functional layers (arrow) , and slightly hyperechoic basal layers more peripherally. (D) In the luteal phase of the menstrual cycle, the endometrium appears homogeneous, hyperechoic (arrow) with the endometrial glands branching and expanding under the influence of progesterone.

EMT is a biomarker for endometrial receptivity, yet EMT in itself does not reflect endometrial function. Investigation into the molecular, proteomic, and genetic aspects of endometrial physiology have provided interesting information with regard to the window of implantation, but are not yet clinically applicable. Many reports have analyzed the correlation between EMT and the ability of embryos to implant, and there is general consensus that the higher the EMT (>9 mm), the better the chance of implantation. EMT and sonographic echogenic patterns have been compared with pregnancy rates in in vitro fertilization (IVF) cycles, with most authors agreeing that a thin EMT, defined as 7 mm or less, is correlated with a lower implantation rate. A systemic review and meta-analysis of 22 studies was published in 2014 and reported a virtually absent discriminatory capacity of EMT in the prediction of occurrence of pregnancy in ART cycles (pregnant vs. not pregnant). A trend towards lower ongoing pregnancy and live birth rates for women with EMT 7 mm or less was observed (OR, 0.38; 95% CI, 0.09 to 1.5), with the probability of a clinical pregnancy for an EMT 7 mm or less significantly lower compared with cases with EMT greater than 7 mm (23.3% vs. 48.1%; OR, 0.42; 95% CI, 0.27 to 0.670). Another observation of the authors in the meta-analysis was that the overall incidence of an endometrial echo thickness of less than 7 mm is low (2.4%) compared with the overall rate of implantation failure, and thus a thin endometrium may explain implantation failure in only a small subset of patients. These authors suggested clinicians refrain from clinical decisions based solely on EMT measurement.

While a thin endometrium increases the likelihood of no conception, it does not eliminate the chance for pregnancy. Others have described implantation with minimum EMT threshold values of 4 to 5 mm, demonstrating a thin endometrium does not necessarily exclude the chance of pregnancy. The etiology for low conception rates with a thin endometrium is poorly understood, but endometrial vascular function is considered to be important in blastocyst implantation. It has been proposed that a thin endometrium would expose an implanting embryo closer to the spiral arteries and the alteration in oxygen tension would be detrimental to the implanting blastocyst. Severe treatments have been proposed to encourage endometrial proliferation at the time of ART cycles in those patients with low EMT, including extended estrogen, aspirin, granulocyte-colony stimulating factor, vaginal sildenafil citrate (Viagra), pentoxifylline, and tocopherol (vitamin E). As a rule, data are contradictory or based on too few individuals to support any specific treatment regimen.

Endometrial receptivity may be reflected by the ultrasonographic endometrial echo pattern, but meta-analysis is hampered because different classification systems to describe these echo patterns have been utilized in independent studies. Some studies found an association between endometrial pattern and IVF outcome, while other studies show no significant correlation. A tri-laminar endometrial echo pattern on the day of hCG administration is associated with higher clinical pregnancy rates in IVF cohorts, but not necessarily throughout the range of endometrial echo thickness.

Three-dimensional (3D) TVS is increasingly common in ART. This technique provides accurate contrast between the myometrium and the endometrium for calculating an endometrial volume, or a specific targeted portion of the total volume within the endometrial cavity. Volume calculation by 3D US is performed utilizing a post image acquisition computer aided program—Virtual Organ Computer-Aided Analysis (VOCAL)—a combination of voxels and geometric information of surfaces in a 3D data set. VOCAL has been utilized with high reproducibility and intraobserver reliability for OV, power Doppler indices, and endometrial volume. Total endometrial volume as calculated may be a more accurate assessment of endometrial receptivity, but to date, studies have documented a range of volume thresholds (<1 mL to 3.9 mL) under which conception does not occur. Yet again, too few individuals to date have been included to make a definitive assessment of the use of 3D endometrial volume as a predictor of pregnancy in ART.

The definitions suggested to qualitatively assess the endometrium in daily practice by the IETA are noted in Table 35.2 . In suggesting standardized terminology, the study group hoped to facilitate data comparisons between future studies and facilitate multicenter studies. While EMT may be an important marker for pathology, endometrial morphology may prove equally as useful. An evaluation of endometrial morphology includes an assessment of the endometrial echogenicity, characteristics of the endometrial midline, and descriptors of the endometrial-myometrial junction. The echogenicity of the endometrium is described as hyper-, hypo-, or isoechoic, as compared with the echogenicity of the myometrium, and “uniform” (homogeneous with symmetrical anterior and posterior sides) and includes the tri-layer pattern, as well as homogeneous hyperechogenic, hypoechogenic, and isoechogenic endometrium. The echogenicity is defined as nonuniform if the endometrium appears heterogeneous, asymmetrical, or cystic. The endometrial midline is “linear” (straight with a clear interface is detected), “nonlinear” if a waved interface is visualized, and “irregular” or “not defined” in the absence of a distinct interface. A “bright edge” is the echo formed by the interface of an intracavitary lesion and the surrounding endometrium. The endometrial-myometrial junction is described as regular, irregular, interrupted, or not defined. Synechiae are defined as strands of tissue crossing the endometrium, while intracavitary fluid is described as anechogenic or low-level echogenicity, “ground glass,” or mixed echogenicity.

Color and Power Doppler Assessment

The IETA standard definitions describe color and power Doppler assessment of the endometrium and immediate surrounding myometrium. An image of the midsagittal section of the uterus should be magnified with the color and power Doppler box placed to include the endometrium and the surrounding myometrium. The suggested settings (ultrasound frequency of at least 5.0 Mhz, pulse repetition frequency 0.3 to 0.9 kHz, wall filter 30 to 50 Hz, color power Doppler gain reduced until all color artifacts disappear) ensure maximum sensitivity to blood flow. The color score is a subjective semiquantitative assessment of the amount of blood flow present and is based on color content score first suggested by the International Ovarian Tumor Analysis (IOTA) color score applied previously to ovarian masses. The color score is 1 (not zero by convention) when there is no flow within the endometrium, a score of 2 when minimal color can be detected, a score of 3 when moderate color is present, and a score of 4 when abundant color is detected ( Fig. 35.8 ).

The color score in an ovarian, myometrial, or endometrial lesion is a subjective semiquantitative assessment on color Doppler of the amount of blood flow present and is based on color content score first suggested by the International Ovarian Tumor Analysis color score applied previously to ovarian masses.

When there is no flow within the endometrium the color score is 1 (not zero by convention), a score of 2 when minimal color can be detected, a score of 3 when moderate color is present, and a score of 4 when abundant color is detected.

In the IETA endometrial terminology, the vascular pattern is then further defined within the endometrium with respect to the presence or absence of “dominant vessels,” or of another specific vascular pattern. “Dominant vessels” are defined as one or more distinct vessels (arterial and/or venous) traversing the endomyometrial junction. The dominant vessel may show branching within the endometrium and is further characterized as either orderly or disorderly/chaotic. Dominant vessels may present as a single vessel (formerly known as the “pedicle artery sign”) with or without branching. Multiple dominant vessels may be “focal origin,” or “multifocal origin,” at the endometrial-myometrial junction. Lastly, other vascular patterns within the endometrium include scattered vessels (dispersed color signals within the endometrium but without visible origin at the myometrial-endometrial junction), and circular flow.

Qualitative Assessment of Endometrial Morphology and Intrauterine Lesions at Sonohysterography

SHG, or saline infusion sonohysterography (SIS), is the instillation of isotonic saline into the uterine cavity to create greater contrast to delineate and outline intracavitary filling defects and uterine shape abnormalities (Video 35.1 ). It is a simple, accurate, well-tolerated, efficient outpatient tool in the assessment of endometrial cavity pathologies such as endometrial polyps, submucous myomas, intrauterine adhesions, and congenital uterine anomalies. In a recent systematic review conducted of 20 studies comparing SHG with hysteroscopy in the detection of all intracavitary abnormalities in the subfertile woman, Seshadri et al. reported a pooled sensitivity of SHG of 0.88 (95% CI, 0.85 to 0.90), and a pooled specificity of 0.94 (95% CI, 0.93 to 0.96). The positive and negative likelihood ratios were 20.93 (95% CI, 9.06 to 48.34) and 0.15 (95% CI, 0.10 to 0.22), respectively. SHG had good accuracy in the detection of all intrauterine abnormalities (area under the summary receiver operating curve [sROC] = 0.97 ± 0.01). SHG also had a high-pooled sensitivity and specificity in the detection of congenital uterine anomalies, 0.85 (95% CI, 0.79 to 0.90) and 1.00 (95% CI, 0.99 to 1.00), respectively. These results are consistent with those of de Kroon et al., who performed a systematic review and meta-analysis of 24 studies comparing SHG and surgical findings (hysteroscopy or hysterectomy) in pre- and postmenopausal women suffering with abnormal uterine bleeding (AUB). In this analysis, the pooled sensitivity and pooled specificity of SHG in uterine cavity evaluation for AUB were 0.95 (95% CI, 0.93 to 0.97) and 0.88 (95% CI, 0.85 to 0.92), respectively; the likelihood ratios were, respectively, 0.91 (95% CI, 0.89 to 0.94) and 0.07 (95% CI, 0.04 to 0.10). The overall success rate of performance of an SHG was 93% (95% CI, 0.92 to 0.94), with the success rate among postmenopausal women significantly lower ( P < .01; success rate 86.5%; 95% CI, 0.832 to 0.899) than that of the success rate of premenopausal women (success rate 95%, 95% CI 0.94 to 0.96). In this study, the 7% of uterine cavity abnormalities undetected by SHG as compared with hysteroscopy or hysterectomy were polyps, perhaps small, the clinical significance of which is unknown.

Indications for SHG include but are not limited to the evaluation of AUB; assessment of intracavitary polyps, fibroids, and synechiae; assessment of focal and diffuse endometrial abnormalities; and congenital abnormalities of the uterus, in the assessment of the subfertile patient and in those with recurrent pregnancy loss. SHG should not be performed in a woman who is pregnant. In cases of intermittent or prolonged AUB, treatment with a short course of progestin may enable appropriate timing of the procedure. SHG should not be performed in patients with existing pelvic infection, unexplained pelvic tenderness, or if pelvic infection is suspected. The routine use of antibiotic prophylaxis is not recommended, but consideration should be given to administering antibiotics based on individual risk (e.g., the presence of nontender hydrosalpinges or a past history of pelvic inflammatory disease). A pregnancy test is advised when clinically indicated. Active vaginal bleeding is not a contraindication to the procedure but may make the interpretation more challenging due to clots often mimicking focal lesions.

Technique of Sonohysterography

A complete transvaginal ultrasound should be performed prior to SHG. The cervix is visualized and prepped with an antiseptic solution such as povidone-iodine or chlorhexidine gluconate solution. A variety of suitable catheters are available, with small diameter catheters; some with a stylet, which may be helpful for the small os and in cases of cervical stenosis; and some with a balloon or acorn catheter, in the presence of a patulous cervix, a uterus enlarged with fibroids, and when tubal patency assessment is a goal of the study. Saline has been the traditional distension media of choice for uterine cavity evaluation. A 10-mL syringe prefilled with saline is used to preflush the catheter to remove all air from entering the cavity and contributing to image distortion. If using a balloon catheter, fill the balloon with saline to avoid acoustic distortion.

More recently the use of gel infusion sonohysterography (GIS) has gained interest and has been demonstrated to be equal to saline infusion with respect to clinical feasibility in the assessment of the uterine cavity. Gel infusion sonography is performed with either a 2.0-mm neonatal suction catheter or insemination catheter through which a sterile gel preparation of hydroxyethyl cellulose and glycerol with chlorhexidine and lidocaine (2 g in 100 g of gel) (Instillagel, FARCO-PHARMA GmbH, Köln, Germany), or without lidocaine (Endosgel, FARCO-PHARMA GmbH). These gels have long been used for vaginal, intrauterine, and intraurethral instillation prior to cystoscopy and have been reported as safe. Hydroxyethyl cellulose and glycerol are considered to be safe in cases of intravasation or intraabdominal application. Some authors have suggested utilizing hydroxyethyl cellulose gel without chlorhexidine and lidocaine, citing no additional value of either of these substances. Gel has additional useful physical properties; it offers the same negative contrast as saline, but its viscosity is much higher than saline, resulting in less backflow through the cervix and more stable filling of the uterine cavity, and thus obviating the need for a more expensive balloon catheter. Because of its higher viscosity and smaller instillation volume (range 2 to 10 mL as compared to 5 to 20 mL), trans-tubal spillage is less likely to occur. The gel’s high viscosity can be modulated for instillation through a 2-mm thin catheter by warming it to 37°C. Disadvantages of GIS are blood clots and debris, which are not flushed out by the gel and may mimic a polyp or myoma. In a prospective observational cohort study including 551 consecutive patients with AUB, Van den Bosch et al. found GIS (149 women) and SHG (402 women) similar techniques in terms of technical feasibility, and with no significant difference in the detection of focal endometrial lesions as compared with those findings determined at surgical pathologic evaluation.

Evaluation of the endometrial and intracavitary morphological features at SHG is described as noted in Table 35.3 . Uterine distention at SHG is defined as “optimal” if fluid or gel clearly distends the cavity, “suboptimal” if the cavity is barely distended, and “failed” if the cavity cannot be distended with fluid. The EMT is measured on either side of the fluid, with the fluid excluded, and the total thickness reported as the total of the anterior and posterior endometrial measurement, yet each individual thickness is noted and recorded. The endometrial outline is defined as smooth if the endometrial surface facing the endometrial cavity appears regular, as having endometrial folds (multiple thickened “undulating” areas, “moguls” with a regular profile), or as “polypoid” if there are deep indentations ( Fig. 35.9 ). The endometrium is described as “irregular” if the surface facing the uterine cavity is cauliflower-like or sharply toothed (“spiky”). The endometrial-myometrial junction is described as noted in Table 35.3 .

Sonohysterography in a patient presenting with postmenopausal bleeding demonstrating “undulating” endometrial folds (arrows) .

Any intracavitary lesion with anything that protrudes into the uterine cavity on SHG or GIS is by convention called an intracavitary lesion, and is further described as either endometrial or lesions arising from the myometrium. The extent of the endometrial lesion is estimated subjectively by the sonographer and is classified as “extended” if it involves 25% or more of the endometrial surface, or “localized” if less than 25%. A “localized” endometrial lesion is either “pedunculated” (diameter of the base/maximum transverse diameter of the lesion) if less than 1, or “sessile” if the diameter of the base/maximum diameter of the lesion is 1 or more. The outline of the lesion within the cavity is described as “regular” or “irregular” (e.g., spiky or cauliflower-like).

The presence of intracavitary lesions arising from the myometrium (most commonly myomas) is defined by the grade (proportion of the myoma extending into the cavity) and the echogenicity. Submucosal (SM) myomas are graded according to the description of Leone et al., G0: pedunculated myoma, completely intracavitary, and lacking in intramural extension; G1: submucous myoma with intramural extension less than 50%; and G2: SM myoma with intramural extension higher than 50% ( Fig. 35.10 ). The echogenicity of the lesion is described as “uniform” or “nonuniform.” Synechiae are thin or thick strands of tissue crossing the endometrial cavity and may be the same echogenicity as the myometrium, and are attached to both uterine walls. Often the uterine cavity will not distend completely at SHG in the presence of synechiae ( Fig. 35.11 ). The color score (subjective assessment from 1 to 4) is outlined under the unenhanced ultrasound examination.

Sonohysterography to map the location and extent of myometrial invasion of intracavitary lesions.

The presence of intracavitary lesions arising from the myometrium is defined by the grade (proportion of the myoma extending into the cavity) and the echogenicity. Submucosal myomas are graded according to the description of Leone et al. (A) G0: Pedunculated myoma, completely intracavitary and lacking in intramural extension (thick arrow) ; (B) G1: submucous myoma with intramural extension less than 50% (thin arrow) ; and (C) G2: submucosal myoma with intramural extension higher than 50% (angled arrow) .

Tomographic ultrasound imaging of uterus demonstrating the presence of thick intrauterine synechiae strands of tissue crossing the endometrial cavity and may be the same echogenicity as the myometrium and are attached to both uterine walls.

On sonohysterography the mid uterine cavity is noted to be contracted and not to distend completely despite adequate pressure and fluid volume (arrows) .

Leiomyoma (AUB-L)

On ultrasound, uterine fibroids appear as solid, well-defined round lesions within the uterine corpus, and rarely within the cervix. The myomas often have an inhomogeneous echo-architecture, may be hypo- or hyperechoic, and characterized with variable degrees of acoustic shadowing and refractive artifacts ( Fig. 35.18A and B ). The echogenicity of the lesion varies with cellular content of muscle, fibrous stroma, calcification, and the degree of cystic, lipomatous, hemorrhagic, or hyaline degeneration. Myomas associated with fatty degeneration (see Fig. 35.18C ), and those with dense calcium deposits, appear hyperechoic. Myomas typically demonstrate diffuse, but mostly peripheral flow on color or power Doppler ( Fig. 35.19 ). Both TAS and TVS may be needed to adequately evaluate the uterus; large or pedunculated myomas may be missed by TVS alone. A pedunculated myoma may be suspected when a solid pelvic mass is visualized, separate from the ovaries, and demonstrates a narrow vascular stalk with Doppler flow extending from the uterus to an isoechoic mass (see Fig. 35.18D ). These pedunculated masses may “slide” against the ultrasonographic probe.

Uterine fibroids appear as solid, well-defined round lesions within the uterine corpus.

(A) Longitudinal view of the uterus with three hypoechoic myomas with acoustic shadowing in the posterior wall (arrows) . (B) Transverse view of the uterus with a myoma with a calcified echogenic ring. (C) Transvaginal sonography retroverted uterus with a fundal myoma with lipomatous degeneration (arrow) . (D) A pedunculated myoma with color Doppler flow demonstrating flow contiguous with the uterus (double headed arrow) .

Myomas typically demonstrate mostly peripheral flow on color or power Doppler.

(A) Transverse view of a uterus with a fundal myoma demonstrating a rounded, well-defined lesion with acoustic shadowing; (B) on color Doppler a myoma has diffuse, but mostly peripheral flow.

Given the prevalence of these lesions, up to 70% in Caucasians and up to 80% in women of African ancestry, they may be present and asymptomatic, and thus not causal of the patient’s AUB. Myomas are classified as intramural, subserosal, subendometrial, or a combination of these. In the PALM-COEIN classification system, the clinician is required to (1) document the presence of absence of 1 or more myomas; (2) distinguish leiomyomas involving the endometrial cavity (SM) from others (O), because it is generally held that SM lesions are more likely to contribute to the etiology of AUB; and (3) categorize intramural, subserosal, and possible parasitic lesions based on the criteria of Wamsteker and accepted by the European Society of Human Reproduction and Embryology (ESHRE; Fig. 35.20 ).

Based on International Federation of Gynecology and Obstetrics Leiomyoma subclassification system.

(From Wamsteker K, Emanuel MH, de Kruif JH: Transcervical hysteroscopic resection of submucous fibroids for abnormal uterine bleeding: results regarding the degree of intramural extension. Obstet Gynecol 82:736-740, 1993; and from Munro MG, Critchley HO, Broder MS, et al: FIGO classification system [PALM-COEIN] for causes of abnormal uterine bleeding in nongravid women of reproductive age . Int J Gynaecol Obstet 113:3-13, 2011.)

The mechanism of how leiomyomata contribute to HMB is not completely understood. There is a fourfold increase in the expression of plasminogen activator inhibitors (PAI), a reduction of antithrombin III and thrombomodulin within the endometrium of women that have fibroid associated HMB. Leiomyoma secrete transforming growth factor (TGF-β), a cytokine that acts as a stimulator of angiogenesis. The location of myomata plays a role in the likelihood of development of HMB. SM and intrauterine myomas, which increase the endometrial surface area available for withdrawal bleeding, are more commonly associated with HMB.

Malignancy and Hyperplasia (AUB-M)

Although EC is thought to be a cancer of the postmenopausal years, 14% of cases are diagnosed in premenopausal women, and 5% of who are younger than 40 years. Premalignant hyperplastic and malignant processes of the endometrium arising during the investigation of women of reproductive age with AUB is classified as AUB-M. The PALM-COEIN classification system for AUB-M in reproductive age women did not seek to replace the 1994 World Health Organization (WHO) 1994 and FIGO classification systems for “endometrial hyperplasia and neoplasia.”

The 94WHO classification system has been widely used and segregates endometrial hyperplasia by architecture (simple vs. complex) and cytology (atypical vs. nonatypical). This four-part category system (simple hyperplasia, complex hyperplasia, simple hyperplasia with atypia, and complex hyperplasia) is limited by poor diagnostic reproducibility, the four separate categories do not correspond to distinct biologic entities, and the individual categories do not suggest specific management algorithms. “Endometrial hyperplasia” is a term that has historically been implemented with several qualifiers to encompass both clonal premalignant lesions and benign field effects of the endometrium in response to prolonged and/or excessive estrogen exposure.

In the schema developed by the International Endometrial Collaborative Group, histomorphologic, genetic, clinical, and biological data were used to develop quantitative pathologic criteria for three disease categories: (1) benign endometrial hyperplasia, (2) endometrial intraepithelial neoplasia (EIN; premalignant), and (3) endometrial adenocarcinoma, endometrioid type, well differentiated (malignant; Table e35.4 ). A diagnosis of EIN is rendered when a lesion has a minimum dimension of 1 mm, the area of glands exceeds the area of stroma, the cytology is changed relative to background, and both benign mimics (polyps, secretory endometrium, and effects of exogenous estrogen) and cancer can be excluded ( Table e35.5 ). It has been demonstrated that clinical outcome prediction and interobserver reproducibility with the EIN classification system is greater than the 94WHO schema.

True benign endometrial “hyperplasias” are polyclonal proliferations involving endometrial glands and stroma that develop in response to the systemic effects of an abnormal estrogenic stimulus. The morphology of these benign endometrial proliferations changes with duration and dose of exposure and is dependent upon the patient and her medical history. These polyclonal proliferations are categorized in the EIN schema as “benign endometrial hyperplasia.”

As the majority of patients with hyperplasia and EC will present with PMB, the imaging characteristics of EIN and endometrial carcinoma will be addressed in the section of PMB.

Coagulopathy (AUB-C)

Deficiencies in coagulation factors or abnormalities in platelet function are commonly associated with abnormally excessive or prolonged uterine bleeding. Undiagnosed bleeding disorders, in particular von Willebrand disease (vWD) and platelet function disorders, can be an underlying cause of HMB. In a recent systemic review incorporating 11 studies, an overall prevalence of 13% of vWD was reported in t > 900 women presenting with HMB. There was even a higher prevalence, up to 20% in adolescents presenting with acute HMB at menarche. vWD is characterized by deficient or defective von Willebrand factor (vWF), a glycoprotein that promotes platelet adhesion to vessel walls after vessel injury. vWF plays a critical role in platelet adhesion and platelet plug formation during primary hemostasis and serves as a carrier protein for factor VIII. Deficiencies in vWF may result in mucosal bleeding in the oropharynx, gastrointestinal, and genitourinary tract in all patients, and in women, HMB is a common symptom in up to 80%.

HMB is also reported in high prevalence in carriers of hemophilia and disorders of platelet function. Chronic liver disease results in a global deficiency of the clotting factors synthesized by the liver. Women with HMB on chronic therapeutic anticoagulation also fall within this category. HMB is a relatively common occurrence with the use of chronic anticoagulation (low-molecular-weight heparin, heparin, and warfarin). The attributable mechanism of HMB in this instance is the impairment of the formation of an adequate “plug” or “clot” within the vascular lumen. Women using such agents essentially have a systemic disorder of hemostasis. Although in this case the AUB could be considered iatrogenic and classified accordingly, Munro and colleagues determined it would be more appropriate to classify women affected with HMB associated with chronic anticoagulation use as having a coagulopathy (AUB/HMB-C). There are few available studies of platelet disorders, including thrombocytopenia in the acute setting of menorrhagia, and thus the prevalence may be underestimated. Based on the reports available, immune thrombocytopenia purpura (ITP) may be one of the most common causes of acute menorrhagia in adolescents.

Ovulatory Dysfunction (AUB-O)

Anovulatory bleeding is common in the extremes of the reproductive life span, a common etiology in adolescence and in the perimenopausal transition. The bleeding pattern associated with ovulatory dysfunction can manifest as unpredictable timing and varying in the amount of flow to HMB. The disorders of ovulation may present as a spectrum of menstrual abnormalities, ranging from amenorrhea and extremely light and infrequent bleeding to episodes of unpredictable and extremely HMB requiring medical or surgical intervention. During the first 12 to 18 months after the onset of menstruation, the immaturity of the hypothalamic-pituitary axis frequently is the cause of AUB-O. Obesity is becoming an important comorbid condition in the evaluation of the adolescent with AUB-O. Although many disorders of ovulatory function elude a defined etiology, the differential diagnosis includes excessive exercise, obesity, hypothalamic suppression related to stress, anorexia, hypothyroidism, hyperprolactinemia, and premature ovarian insufficiency. In some instances of AUB-O, the ovulatory dysfunction may be related to the use of gonadal steroids or medications that impact the central dopaminergic metabolism by reducing serotonin uptake such as phenothiazines and tricyclic antidepressants. It has been proposed that the resulting reduced inhibition of PRL release causes prolactin-related disruption in the hypothalamic-pituitary-ovarian axis and impacts ovulatory function.

Endometrial (AUB-E)

The normal cessation of menstrual bleeding is achieved by endometrial hemostasis via platelet aggregation, fibrin deposition, and thrombus formation. Local endocrine, immunological, and hemostatic factors interact at the molecular level to control endometrial hemostasis. Abnormalities of uterine bleeding can result from an imbalance of hemostatic factors. Tissue factor (TF) and thrombin play a key role locally in the cessation of menstrual bleeding through the activation of factors involved in coagulation. Alternatively, fibrinolysis prevents clot organization within the uterine cavity, while PAI and thrombin-activatable fibrinolysis inhibitors control plasminogen activators and plasmin activity.

HMB, without another identifiable cause, may be a primary disorder of endometrial hemostasis. The development of antifibrinolytics in the treatment of AUB is based on the understanding of the local hemostatic factors within the endometrium. Tranexamic acid (TA; amino-methyl-cyclohexane-carbolic acid) is such an agent. In women with HMB, treatment with TA was associated with a 54% reduction in menstrual blood loss and is known to be associated with a significant reduction in endometrial tissue plasminogen activator levels.

Iatrogenic (AUB-I)

Unscheduled uterine bleeding that occurs as a result of the use of medication, or an inert intrauterine system, is termed AUB-I. This category includes prescribed therapy that directly impacts the endometrium, interferes with coagulation mechanisms, or influences the process of ovulation. Gonadal steroids-estrogens, progestins, and androgens act systemically by influencing the action of the central access, the ovary, and have a direct impact on endometrial homeostasis. Other potential causes of iatrogenically induced bleeding include anticonvulsants and antibiotics that may alter the circulating levels of endogenous steroid hormones. Unscheduled bleeding in the first 3 to 6 months of use of the levonorgestrel IUS is a common complaint. Other medications that impact the central axis have been discussed under the section AUB-O.

Not Yet Classified (AUB-N)

The intent of the AUB-N within the PALM-COEIN system is to provide a category for entities that have not been shown conclusively to contribute to AUB—for example, chronic endometritis, arteriovenous malformations (AVMs), and myometrial hypertrophy—and for those entities not yet identified that might contribute to AUB.

Acute Versus Chronic Abnormal Uterine Bleeding

AUB can be further classified as acute or chronic. Acute uterine bleeding is defined as AUB in nonpregnant women that, in the opinion of the clinician, is of sufficient quantity to require immediate intervention to prevent further blood loss. Acute AUB can be defined as HMB or intermenstrual bleeding (IMB), occurring in a woman of childbearing age requiring emergency treatment excluding pregnancy, postpartum hemorrhage, trauma, or malignancy. Acute AUB can occur as a new event or may occur in the setting of chronic AUB. Chronic AUB is defined as bleeding from the uterine corpus that is abnormal in volume, regularity, and/or timing, and has been present for the majority of the past 6 months. IMB is defined as bleeding between clearly defined cyclic and predictable menses.

Pelvic ultrasound is an essential tool in the investigation of the patient with AUB, with the laboratory and imaging investigation tailored to the nature of the bleeding (acute vs. chronic), amount and duration of flow, and based on the clinical presentation a targeted clinical assessment based on age. The basic structure of the suggested investigations includes an assessment of the duration of flow, a measurement of hemoglobin and/or hematocrit, a pelvic ultrasound, an assessment of the endometrial cavity, and at least a structured medical history to assess for possible coagulopathy ( Table 35.5 ).

Ultrasound Imaging of Endometrial Cavity in Acute Abnormal Uterine Bleeding

In the nonpregnant women with acute AUB, a TVS that demonstrates a thin endometrial lining in combination with an absence of leiomyomata near the endometrial echo has been associated with normal results at hysteroscopic assessment of the uterine cavity. In the setting of acute AUB, TVS is a suitable screening tool, but the results may be hindered by echogenic clot or debris with mixed echogenicity within the endometrium. Routine TVS is less sensitive than an SHG (SIS) or hysteroscopy in the detection of intrauterine lesions such as polyps; thus once the vaginal bleeding has remitted, a further assessment of the detail of the anatomy of the uterine cavity may be warranted.

Hormonal Treatment of Acute Abnormal Uterine Bleeding

Once the patient has been resuscitated, a variety of treatment options are available to diminish bleeding ( Tables 35.7 and 35.8 ). Once the acute bleeding has slowed, these regimens are tapered to a maintenance dose. TA is a synthetic derivative of the amino acid lysine and exerts its antifibrinolytics effect through the reversible blockade of lysine-binding sites on plasminogen molecules. Both IV and oral formulations are available. IV conjugated equine estrogen is effective in treating acute AUB and is generally used as 25 mg IV every 4 hours up to 24 hours to obtain the cessation of bleeding. Patients should then be transitioned to a regimen of monophasic multidose oral contraceptives (OCs), or to moderate- or high-dose progestin regimens. Monophasic, combination OCs have been used successfully in the treatment of acute AUB, with the cessation of bleeding on average 3 days after the initiation of therapy. An alternative to the combination OCs, and reported to be equally effective, is a regimen of medroxyprogesterone acetate 20 mg administered three times a day for a week, followed by a gradual taper.

Table 35.8

Medical Management Regimens for Acute Abnormal Uterine Bleeding

Medication	Route	Protocol for Acute Menstrual Cessation	Contraindications
Tranexamic acid	IV Oral	10 mg/kg Q8 h 20–25 mg/kg Q8 h 1.3 g TID *	Disseminated intravascular coagulation, venous or arterial thromboembolism, macroscopic hematuria, color blindness
Conjugated estrogen	IV	25 mg Q 4–6 h until bleeding stops, re-evaluated need at 48 h	Pregnant, active or previous venous or arterial thromboembolic disease, breast cancer, use with caution in obese women
30 µg ethinyl estradiol/0.3 mg norgestrel (or other 30 or 35 µg combination pill)	Oral	One tablet Q 6 h until bleeding stops, re-evaluate at 48 hours, then taper dose over several weeks	Pregnant, smoking (aged ≥35 years and ≥15 cigarettes/day), history of malabsorptive bariatric surgery, multiple risk factors for arterial cardiovascular disease, hypertension, active or previous venous or arterial thromboembolic disease, known thrombogenic mutations, current or past heart disease, systemic lupus erythematosus with vascular disease, nephritis, or antiphospholipid antibodies, headache with aura, current or past history of breast cancer, diabetic neuropathy, retinopathy, nephropathy, or diabetes ≥20 years, liver cirrhosis, or tumor
50 µg ethinyl estradiol/0.5 mg norgestrel (or other 50 µg combination pill)	Oral	One tablet Q 6 h until bleeding stops, re-evaluate at 48 hours, then taper dose over several weeks	Same as 30 to 30 µg pill
Norethindrone acetate	Oral	20 mg three times a day for 7 days, may taper as bleeding stops, taper over several weeks	Pregnant, history of malabsorptive bariatric surgery, liver disease or tumor, breast cancer, current or past ischemic heart disease
Medroxyprogesterone	Oral	10 mg Q 4 h (up to 80 mg/day) until bleeding stops then taper over several weeks	Same as norethindrone acetate

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