Abnormal uterine bleeding (AUB) is a common and debilitating condition with high direct and indirect costs. AUB frequently co-exists with fibroids, but the relationship between the two remains incompletely understood and in many women the identification of fibroids may be incidental to a menstrual bleeding complaint. A structured approach for establishing the cause using the Fédération International de Gynécologie et d’Obstétrique (FIGO) PALM-COEIN ( P olyp, A denomyosis, L eiomyoma, M alignancy (and hyperplasia), C oagulopathy, O vulatory disorders, E ndometrial, I atrogenic and N ot otherwise classified) classification system will facilitate accurate diagnosis and inform treatment options. Office hysteroscopy and increasing sophisticated imaging will assist provision of robust evidence for the underlying cause. Increased availability of medical options has expanded the choice for women and many will no longer need to recourse to potentially complicated surgery. Treatment must remain individualised and encompass the impact of pressure symptoms, desire for retention of fertility and contraceptive needs, as well as address the management of AUB in order to achieve improved quality of life.
Highlights
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The FIGO ‘PALM COEIN’ classification of AUB is considered in this review
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Mechanisms by which fibroids contribute to AUB are elucidated.
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A structured approach to management of the patient with fibroids and AUB is proposed.
Background
Abnormal uterine bleeding (AUB) is a significant clinical entity. AUB and its sub group, heavy menstrual bleeding (HMB), are common conditions affecting 14–25% of women of reproductive age and may have a significant impact on their physical, social, emotional and material quality of life . In the UK, over 800,000 women seek help for AUB annually . Along with the direct impact on the woman and her family, there are significant costs to both economy and health service. A US study reported financial losses of >$2000 per patient per annum due to work absence and home management costs . AUB is the fourth most common reason for referral to UK gynaecological services . A recent national audit in England and Wales (RCOG HMB audit) reported that at 1-year post referral, only a third of women (including those managed with surgery) were ‘satisfied’ (or better) at the prospect of current menstrual symptoms continuing, as currently experienced, for the next 5 years . While there may be relief from HMB during pregnancy and lactation, and an end to the problem at menopause, women affected will tend to suffer the adverse impacts of AUB over what should be the prime years of their lives.
Fibroids (leiomyoma) represent the most common tumour of women; by the age of 50, almost 70% of white women and >80% of black women will have developed at least one fibroid . Fibroids are associated with subfertility, miscarriage, preterm labour and obstruction of labour. In addition, they may cause discomfort and pressure symptoms, typically urinary. In rare circumstances, at larger sizes, they may cause compression of the renal tract and pelvic vasculature leading to impaired renal function and venous thromboembolism, respectively. Conversely, many women with fibroids will be entirely asymptomatic . However, many women most commonly present to gynaecological services with AUB and associated iron-deficiency anaemia. For women with uterine fibroids, everyday life is often disrupted and fibroids remain a leading indication for hysterectomy . Conservative estimates of annual direct treatment costs and indirect costs from lost work hours as a result of fibroids are $4.1–9.4 billion and $1.55–17.2 billion, respectively . The mechanisms, however, linking AUB and fibroids remain incompletely understood.
As women increasingly defer pregnancy, fertility preservation is critical and newer medical options offer genuine effective relief for both AUB and other symptoms associated with fibroids. This review addresses the causes of AUB and approach to assessment and general principles of management of the pre-menopausal woman with fibroids.
Definitions
AUB was redefined by Fédération International de Gynécologie et d’Obstétrique (FIGO) in 2009 by the FIGO Menstrual Disorders Group (FMDG) . This was in order to standardise definitions, nomenclature and the underlying categories of aetiology. It was hoped that this would facilitate ease of investigation and comparison of similar patient populations and thereby aid research and improve evidence-based care; this would also be a practical tool for assessing contributing aetiologies.
Chronic AUB was defined as ‘bleeding from the uterine corpus that is abnormal in volume, regularity and/or timing that has been present for the majority of the last 6 months’ . Values outwith the accepted 5–95th percentiles indicated abnormality ( Table 1 ).
| Clinical Parameter | Descriptive term | Normal limits (5–95th percentiles) |
|---|---|---|
| Frequency of menses (days) | Frequent Normal Infrequent | <24 24–38 >38 |
| Regularity of menses, cycle to cycle (Variation in days over 12 months) | Absent Regular Irregular | No bleeding Variation ± 2–20 days Variation >20 days |
| Duration of flow (days) | Prolonged Normal Shortened | >8.0 4.5–8.0 <4.5 |
| Volume of monthly blood loss (mL) | Heavy Normal Light | >80 5–80 <5 |
With regard to volume, however, both the Royal College of Obstetricians and Gynaecologists (RCOG) and American College of Obstetricians and Gynecologists (ACOG) prefer the patient-centred definition of HMB, ‘excessive menstrual blood loss which interferes with a woman’s physical, social, emotional and/or material quality of life’ , as an indication for investigation and treatment options. As such, objective measurements of volume are usually the preserve of research studies and surrogates such a pictorial blood-loss assessment chart (PBAC) scores are not recommended in routine clinical practice.
Definitions
AUB was redefined by Fédération International de Gynécologie et d’Obstétrique (FIGO) in 2009 by the FIGO Menstrual Disorders Group (FMDG) . This was in order to standardise definitions, nomenclature and the underlying categories of aetiology. It was hoped that this would facilitate ease of investigation and comparison of similar patient populations and thereby aid research and improve evidence-based care; this would also be a practical tool for assessing contributing aetiologies.
Chronic AUB was defined as ‘bleeding from the uterine corpus that is abnormal in volume, regularity and/or timing that has been present for the majority of the last 6 months’ . Values outwith the accepted 5–95th percentiles indicated abnormality ( Table 1 ).
| Clinical Parameter | Descriptive term | Normal limits (5–95th percentiles) |
|---|---|---|
| Frequency of menses (days) | Frequent Normal Infrequent | <24 24–38 >38 |
| Regularity of menses, cycle to cycle (Variation in days over 12 months) | Absent Regular Irregular | No bleeding Variation ± 2–20 days Variation >20 days |
| Duration of flow (days) | Prolonged Normal Shortened | >8.0 4.5–8.0 <4.5 |
| Volume of monthly blood loss (mL) | Heavy Normal Light | >80 5–80 <5 |
With regard to volume, however, both the Royal College of Obstetricians and Gynaecologists (RCOG) and American College of Obstetricians and Gynecologists (ACOG) prefer the patient-centred definition of HMB, ‘excessive menstrual blood loss which interferes with a woman’s physical, social, emotional and/or material quality of life’ , as an indication for investigation and treatment options. As such, objective measurements of volume are usually the preserve of research studies and surrogates such a pictorial blood-loss assessment chart (PBAC) scores are not recommended in routine clinical practice.
FIGO classification of cause: ‘PALM-COEIN’
Once bleeding is defined as being abnormal, the acronym PALM-COEIN is now being increasingly used for categorising causes: P olyp, A denomyosis, L eiomyoma, M alignancy (and hyperplasia), C oagulopathy, O vulatory disorders, E ndometrial, I atrogenic and N ot otherwise classified . The ‘PALM’ are assessed visually (imaging and histopathology) and the ‘COEIN’ are non-structural ( Fig. 1 ).
Depending on the site, leiomyoma (fibroids) are further subdivided into submucosal (SM) and other (O) and then into nine tertiary categories adapted from the Wamsteker classification ( Fig. 2 ). These have been adopted by the European Society for Human Reproduction and Embryology (ESHRE) and used by the European Society for Gynaecological Endoscopy (ESGE).
Contribution of fibroids (leiomyoma) to AUB
The relationship between AUB and fibroids remains incompletely understood. The obvious paradox is that many women have fibroids but also have entirely normal bleeding patterns. Fibroids are also highly prevalent in women presenting with AUB.
Previous postulated theories include an increased endometrial surface area and the presence of fragile and engorged vasculature in the perimyoma environment . The increase in vascular flow observed along with these enlarged vessels can overcome platelet action . There is increasing knowledge regarding the complex cellular and molecular changes found in association with fibroids, with impact on angiogenesis, alteration in vasoactive substrates and growth factors as well as alteration in coagulation . The effect of fibroids on endometrial function is now thought to represent a field change within the uterine cavity rather than limited to regions overlying the myoma(s). Some of these changes may have an impact on endometrial receptivity and implantation as well as AUB .
Matrix metalloproteinase (MMP) 2 and 11 levels are increased in fibroids (with MMP 1 and 3 unchanged) , but the impact on endometrial bleeding is unclear. Expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), heparin-binding epidermal growth factor, platelet-derived growth factor (PDGF), parathyroid hormone-related protein (PTHrP) and prolactin is altered in women with fibroids . VEGF, bFGF, PDGF and PTHrP all have potential angiogenic effects but their specific role within the endometrium in women with fibroids has yet to be determined .
There is alteration of plasminogen modulators and this may impact on endometrial haemostasis and repair . Transforming growth factor beta (TGF-β) is produced in excess in the endometrium in women with fibroids and is associated with reduced levels of plasminogen activator inhibitor-1 (PAI-1), thrombomodulin and antithrombin III, both in vivo and in endometrial stromal cells treated in vitro with TGF-β . This may represent a putative mechanism for some cases of AUB observed in the context of fibroids and may in the future offer a potential therapeutic target.
In women with fibroids, alterations in the blood plasma levels of circulating interleukin (IL)-13, IL-17 and IL-10 have been reported . Whether these variations affect immune function and inflammation implicated in endometrial breakdown and repair remains unknown.
With regard to the location of fibroids, it was previously thought that those women with SM fibroids, particularly with those distorting the cavity, were more likely to present with HMB . There is current debate that women with significant cavity distortion represent additional therapeutic challenges.
Other causes of AUB
The PALM-COEIN classification system accepts that women may have more than one underlying aetiology and also that often in the case of structural abnormalities, many women may in fact be asymptomatic.
Polyps (AUB-P)
Endometrial polyps are epithelial proliferations arising from the endometrial stroma and glands. The majority are asymptomatic. The contribution of polyps to AUB varies widely ranging from 3.7% to 65% , but it is widely accepted . The incidence of polyps as with fibroids increases with age and both pathologies may frequently co-exist, or suspected polyps visualised on transvaginal ultrasound scanning (TV-USS) may be mistaken for SM fibroids and vice-versa .
Adenomyosis (AUB-A)
The relationship between adenomyosis and AUB remains unclear , particularly with regard to wide variations in histopathological diagnosis reflecting variations in criteria used and also improved radiological diagnosis. Typically, adenomyosis is associated with increasing age and may co-exist with fibroids. Furthermore, adenomyosis may be both focal and diffuse and it may be harder to establish diagnosis if fibroids are also present .
Malignancy (AUB-M)
Endometrial cancer is the most common gynaecological malignancy in the western world. Historically, endometrial cancer has rarely occurred in premenopausal women; however, with increasing obesity and rising prevalence of the metabolic syndrome, the endocrine-driven subset of endometrial malignancy has markedly increased in frequency. Between 1992–1994 and 2009–2011, the European age-standardised rates of uterine cancer in the UK have increased by 48% . With the reclassification by the WHO from hyperplasia to endometrial intraepithelial neoplasia (EIN), the current prevalence of premalignant disease is unknown. The evaluation of the endometrium may be affected by distortion of the uterine cavity by fibroids, and as such, the co-existing pathology may delay diagnosis.
The diagnosis of cervical cancer should be considered, particularly with persistent intermenstrual bleeding, and rarely ovarian cancer may present with AUB.
Uterine sarcoma have been reported as rare (3–7/100,000 in the USA) but maybe a cause of AUB-M. A recent meta-analysis reported that leiomyosarcoma are unexpectedly diagnosed following surgery for anticipated ‘benign’ myomas in 2.94 per 1000 women (one in 340 women) . Race is the only commonality between leiomyosarcoma and leiomyoma with black women having an approximately twofold increased risk . The risk of development of leiomyosarcoma is reported to increase with age with <1 case per 500 among women aged under 30 years to one in 98 among women in the age range 75–79 years . Other risk factors for uterine leiomyosarcoma include the long-term use of tamoxifen , previous pelvic radiation therapy and rare inherited disorders such as hereditary leiomyomatosis and renal cell carcinoma (HLRCC) .
Interestingly, the previously held view was that a rapidly enlarging uterus would raise the suspicion for malignancy. This is now no longer held to be true as benign fibroids can grow rapidly and sarcomas grow slowly . However, more objective investigations are still lacking. Both ultrasound scanning (USS) and magnetic resonance imaging (MRI) do not as yet have robust criteria to accurately predict differentiation between leiomyoma and leiomyosarcoma . The lack of a robust pre-surgical predictor/biomarker has recently altered surgical practice because morcellation of an unsuspected leiomyosarcoma increases dissemination .
If malignancy or premalignancy is found along with AUB classification, the pathology should be described and staged utilising the appropriate WHO/FIGO systems .
Coagulopathy (AUB-C)
Coagulopathies are reported to affect 13% of the women presenting with HMB. The majority of these women suffer from Von Willebrand disease . Systemic disorders of haemostasis may be identified in 90% of women using a structured history ( Table 2 ).
