48 Andrew W. Horne and Hilary O.D. Critchley MRC Centre for Reproductive Health, University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh, UK There has been confusion over the various terminologies used for abnormalities of menstrual blood loss. Heavy menstrual bleeding (HMB) is now the preferred symptom description as it is simple and easily translatable into other languages. Use of the word ‘menorrhagia’ is discouraged [1]. The word itself, meaning to ‘burst forth each month’, was first used in English medical texts by William Cullen, a professor at the University of Edinburgh in the late 1700s. The term is confusing, being used as a symptom, sign and diagnosis. Similarly, the term ‘dysfunctional uterine bleeding’ (DUB) should also no longer be used [1]. DUB was traditionally used to describe excessive bleeding (heavy, frequent or prolonged) of uterine origin which was not due to pelvic pathology or systemic disease. Descriptions of menstrual bleeding were standardized in 2009 by the Menstrual Disorders Group (FMDG) of the Fédération International de Gynécologie et d’Obstétrique (FIGO). Definitions of normality were described, nomenclature standardized, and underlying aetiologies classified in a structured manner. HMB is defined as excessive menstrual blood loss (over several consecutive cycles) that has a major effect on a woman’s quality of life [2]. The objective definition of HMB (defined as blood loss of greater than 80 mL per menstruation) is no longer used except for research purposes [2]. It is also important in clinical practice to distinguish between regular and abnormal bleeding, such as intermenstrual and post‐coital bleeding. HMB affects one in three women of reproductive age [2]. The complaint of HMB results in significant morbidity and impact on quality of life. In addition to the direct effect on the woman and her family, there are significant socioeconomic costs. Menstrual bleeding complaints are the fourth most common reason for referral to UK gynaecological services [3]. The recent national audit in England and Wales [3] reported that at 1‐year post referral, only one‐third of women (including those managed with surgery) were ‘satisfied’ (or better) with the current treatment of their menstrual symptoms [3]. Unfortunately, current medical therapy may be associated with undesirable side effects. As many as one in five women discontinue use of progestin therapies (systemic and locally delivered) for HMB on account of unscheduled bleeding [4]. Despite continually emerging new medical therapies, surgery is still favoured by many women with severe symptoms and HMB remains a leading indication for hysterectomy. In the UK, regional differences in surgical rates for HMB have persisted despite changes in practice and improved evidence, suggesting there is still scope for improving the management of HMB within health services. There remains a pressing need for continuing development of effective and acceptable medical treatment options for women with HMB. Correct management is facilitated by careful classification of HMB with the now widely used FIGO PALM‐COEIN system [1] (Fig. 48.1). The ‘PALM’ (Polyp, Adenomyosis, Leiomyoma [fibroids], Malignancy) are assessed visually (imaging and histopathology) and the ‘COEIN’ (Coagulopathy, Ovulatory and Endometrial dysfunction, Iatrogenic and Not otherwise classified) are non‐structural and are identified through meticulous history‐taking and appropriate investigations. The classification system accepts that women may have more than one underlying cause and also that where structural abnormalities are present, many women may in fact be symptom‐free. Fig. 48.1 FIGO PALM‐COEIN classification of causes of HMB. Reproduced from Whitaker L, Critchley HOD. Abnormal uterine bleeding. Best Pract Res Clin Obstet Gynaecol 2016;34:54–65. Creative Commons Attribution License (CC BY 4.0) (https://creativecommons.org/licenses/by/4.0/). Polyps are common (incidence increasing with age), frequently asymptomatic and their exact cause remains unknown. It is important to be aware that both polyps and fibroids may frequently coexist, and that polyps may be mistaken for submucous fibroids on ultrasound. Polyps may cause unpredictable intermenstrual bleeding as well as being associated with an increased volume of bleeding [5]. Any relationship between adenomyosis and HMB is still unclear. Adenomyosis is associated with increasing age and often coexists with endometriosis and fibroids. Adenomyosis is increasingly being diagnosed on MRI and ultrasonography but it is harder to establish the diagnosis of adenomyosis if fibroids are also present. Submucosal and intramural fibroids are the subtype most commonly associated with HMB but the exact number of cases of HMB resulting from fibroids is not known. About 50% of fibroids cause no symptoms. Furthermore, the mechanisms involved in fibroid‐associated HMB are yet to be determined. Theories include an increased endometrial surface area and the presence of fragile and dilated vasculature around the fibroid [6]. Knowledge regarding the complex cellular and molecular changes found in association with fibroids is increasing. Data are emerging on the impact of uterine fibroid presence on angiogenesis, on alteration in the production of vasoactive substances and growth factors, as well as modulation of coagulation. Both endometrial and cervical carcinoma are potential causes of intermenstrual and post‐coital bleeding, and rarely HMB. The most relevant premalignant condition that may cause abnormal bleeding is endometrial hyperplasia. Sarcomas of myometrial origin, such as leiomyosarcoma, are rare but not infrequently present with abnormal bleeding in perimenopausal and postmenopausal women. A recent meta‐analysis reported that leiomyosarcoma was diagnosed unexpectedly following surgery for anticipated ‘benign’ myomas (fibroids) in 2.94 per 1000 women (1 in 340 women) [7]. Age is a risk factor for the development of leiomyosarcoma, with less than one case per 500 among women under 30 years and up to 1 in 98 among women in the age range 75–79 years. As many as 10–20% of women with HMB will have a systemic disorder of haemostasis [6]. These disorders may be inherited or acquired and severity of disorder varies (but the majority are mild to moderate). The overall clinical impact is unknown. The most common inherited disorder is von Willebrand disease, found in 13% of women with HMB. This aetiology should be considered in women who fail to respond to medical management and women who present at a young age. Acquired conditions include severe thrombocytopenia, thrombocytopathies such as Glanzmann’s disease, and other rare bleeding/factor deficiencies. Currently, the use of anticoagulants in women with thromboembolic disease also falls within this category. Anovulatory menstrual cycles may contribute to HMB by the effects of unopposed oestrogen on the endometrium causing marked proliferation. This most commonly occurs at the extremes of reproductive age (adolescence and perimenopause). Anovulatory menstrual cycles are associated with polycystic ovarian syndrome (PCOS), hyperprolactinaemia, hypothyroidism and other factors such as obesity. Women in this group often report menstrual cycles that extend beyond 38 days or vary by more than 21 days. Pharmacological drugs known to impact ovulation by prolactin‐related disruption of the hypothalamic–pituitary–ovarian axis (e.g. tricyclic antidepressants and phenothiazines) currently fall within this category. In the majority of cases of HMB, it is likely that the precise cause of heavy bleeding lies at the level of the endometrium itself. This is a diagnosis of exclusion. Hypoxia, inflammation, haemostasis and angiogenesis all play crucial roles in the shedding and subsequent scar‐less repair of the functional upper layer of the endometrium. Perturbation of local glucocorticoid metabolism, aberrant prostaglandin synthesis and excessive plasminogen (resulting in premature clot lysis) have all been implicated in HMB. However, the exact endometrial mechanisms leading to HMB remain undefined and an area of active research enquiry [8,9]. Iatrogenic causes of HMB include exogenous therapies than may result in unscheduled bleeding. This is typically associated with continuous oestrogen or progestin therapies (intrauterine, systemic or oral delivery). The use of an intrauterine device may cause a low‐grade endometritis which may also contribute to HMB. Inevitably, there are pathologies that do not easily fit within the categories described. Examples include infection and arteriovenous malformations. Data exist to support an association between chronic endometrial infection and abnormal uterine bleeding, both intermenstrual and heavy bleeding [5]. Chlamydia trachomatis has been proposed as a cause of HMB, and the prevalence of C. trachomatis in women with abnormal uterine bleeding may be underestimated. This is confounded by the fact that 85% of cases of chlamydial infection are asymptomatic. Further research is required to determine whether all women with HMB should be screened for C. trachomatis. An arteriovenous malformation (AVM) is a congenital, or acquired, localized collection of abnormally connected arteries and veins. When they occur in the uterus they have been associated with episodes of acute excessive bleeding. Congenital AVMs are rare, as are acquired AVMs, which may occur following uterine curettage after pregnancy. These vascular lesions of the uterus pose difficult management decisions and may present with heavy uterine bleeding following early pregnancy loss. Colour Doppler ultrasound imaging is a useful diagnostic modality if an AVM is suspected. In cases associated with an early pregnancy loss (likely due to sub‐involution of the placental bed), the uterine lesion resolves once the human chorionic gonadotrophin (hCG) level has returned to normal. Acute heavy bleeding from an AVM require management with therapeutic uterine artery embolization or intrauterine balloon tamponade. The primary aim of the history is to determine the full impact that the bleeding is having on the woman’s quality of life and a menstrual diary is often helpful to determine the degree and timing of the bleeding [10], and flooding and clots generally indicate significant loss. An accurate history may also indicate the cause of the bleeding. Intermenstrual bleeding and post‐coital bleeding are suggestive of an anatomical cause whereas associated pressure symptoms, including bowel and urinary symptoms, may indicate the presence of a large fibroid(s). A coagulation disorder may be implicated in the complaint of HMB and a structured history to elicit such is valuable and an onward referral for formal haematological assessment may be indicated [5]. A coagulation disorder is likely if there is: A sexual, smear and contraceptive history are essential and should include questioning about the woman’s desire for future pregnancy as this will affect therapeutic options for future symptom management. A general evaluation of the patient should be performed to exclude signs of anaemia, evidence of systemic coagulopathy (e.g. bruising, petechiae) and thyroid disease (e.g. goitre). An abdominal examination should be performed to reveal a pelvic mass (eg, fibroid); a speculum examination should be performed to assess the vulva, vagina and cervix (this may reveal sources of bleeding, such as a tumour, or a discharge suggesting infection); and a bimanual examination should be performed to elicit uterine enlargement. A full blood count is indicated in all women with HMB. If the history and examination strongly suggests cyclical HMB without the presence of pathology in a woman under 45 years old, it is appropriate to implement first‐line medical treatment without further investigation, so long as no risk factor, such as raised body mass index (BMI), are identified [2]. In older women, and in younger women in whom medical treatment has failed, further investigation is warranted (Table 48.1). Table 48.1 Investigations of patients complaining of heavy menstrual bleeding (HMB). In the UK, current National Institute for Health and Care Excellence (NICE) guidelines advise endometrial sampling and histological assessment of HMB in women aged 45 years and above who have persistent intermenstrual bleeding or treatment failure. With the increase in rates of endometrial cancer, all gynaecologists should use their clinical judgement for those women aged under 45 years with HMB who have risk factors for premalignant change, in particular PCOS and obesity. Blind sampling methodologies (outpatient endometrial biopsy) are reasonable screening techniques but they are ineffective at diagnosing focal lesions. Published research has provided the clinician with high‐quality data regarding the accuracy of pelvic ultrasound and outpatient hysteroscopy in the diagnosis of structural lesions. In the UK, NICE suggests that pelvic ultrasound should be considered the primary investigation of suspected structural lesions, backed up by hysteroscopy for suspected polyps or submucous fibroids (Fig. 48.1). MRI is also now being used in specific clinical scenarios in the evaluation of HMB. This imaging modality will assist in further identification and localization of fibroids and also features of adenomyosis if present. Pelvic MRI is of value in determining the role of embolization as a treatment option. However, future research needs to be directed towards providing effectiveness and cost‐effectiveness data (MRI is expensive) in order to determine the role for this mode of imaging in guiding best clinical practice.
Heavy Menstrual Bleeding
Definition
Prevalence and impact
Aetiology
Polyps
Adenomyosis
Leiomyoma (fibroids)
Malignancy (and hyperplasia)
Coagulopathy
Ovulatory dysfunction
Endometrial dysfunction
Iatrogenic
Not otherwise classified
Clinical evaluation
History
Examination
Investigations
Investigation
Indication
Full blood count
All women with HMB
Coagulation screen
If a structured history is suggestive of a coagulation disorder
Thyroid function tests
Only from women with other symptoms of thyroid disease
Endocervical/high vaginal swabs
If history suggestive of risk of infection
Colposcopic examination
Suspicion of cervical pathology
Histological assessment of the endometrium
Symptomatic women ≥45 years old, younger women when medical treatment has failed, younger women with risk factors (e.g. PCOS, obesity) and all women prior to surgical intervention
Evaluation of the uterine cavity (pelvic ultrasound, MRI, and outpatient hysteroscopy)
Intermenstrual or post‐coital bleeding, irregular HMB, suspected structural pathology, or when medical management has failed
Histological assessment of the endometrium
Evaluation of the uterus and uterine cavity
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