What does the term “Bleeding Kansas†refer to?
Best Pract Res Clin Obstet Gynaecol. 2016 Jul; 34: 54–65.
Abnormal uterine haemorrhage
Abstract
Abnormal uterine bleeding (AUB) is a mutual and debilitating condition with loftier direct and indirect costs. AUB frequently co-exists with fibroids, only the relationship betwixt the two remains incompletely understood and in many women the identification of fibroids may exist 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 (Polyp, Adenomyosis, Fiftyeiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Due northot otherwise classified) classification system will facilitate accurate diagnosis and inform handling options. Office hysteroscopy and increasing sophisticated imaging will assist provision of robust bear witness for the underlying cause. Increased availability of medical options has expanded the choice for women and many volition no longer need to recourse to potentially complicated surgery. Handling must remain individualised and encompass the impact of pressure symptoms, desire for retention of fertility and contraceptive needs, likewise as address the management of AUB in order to accomplish improved quality of life.
Keywords: aberrant uterine bleeding (AUB), fibroids, FIGO PALM-COEIN classification of AUB
Background
Abnormal uterine bleeding (AUB) is a meaning clinical entity. AUB and its sub group, heavy menstrual bleeding (HMB), are common atmospheric condition affecting 14–25% of women of reproductive age [ane], [ii] and may have a pregnant bear on on their concrete, social, emotional and material quality of life [3]. In the United kingdom, over 800,000 women seek aid for AUB annually [3]. Along with the straight impact on the woman and her family, at that place are significant costs to both economy and wellness service. A US study reported financial losses of >$2000 per patient per annum due to work absence and dwelling house management costs [iv]. AUB is the 4th most common reason for referral to Uk gynaecological services [v]. 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 amend) at the prospect of current menstrual symptoms continuing, as currently experienced, for the side by side five years [6]. 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 virtually mutual neoplasm of women; past the historic period of 50, almost seventy% of white women and >lxxx% of black women will accept developed at to the lowest degree one coarse [7]. Fibroids are associated with subfertility, miscarriage, preterm labour and obstruction of labour. In addition, they may crusade 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 dumb renal function and venous thromboembolism, respectively. Conversely, many women with fibroids will be entirely asymptomatic [8]. However, many women most normally present to gynaecological services with AUB and associated fe-deficiency anaemia. For women with uterine fibroids, everyday life is often disrupted and fibroids remain a leading indication for hysterectomy [nine], [10]. Conservative estimates of annual direct treatment costs and indirect costs from lost piece of work hours every bit a result of fibroids are $iv.1–9.4 billion and $1.55–17.two billion, respectively [11]. 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 arroyo 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) [12], ∗[13]. This was in society to standardise definitions, classification and the underlying categories of aetiology. It was hoped that this would facilitate ease of investigation and comparison of like 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 'haemorrhage from the uterine corpus that is aberrant in book, regularity and/or timing that has been present for the majority of the concluding 6 months' [xiii]. Values outwith the accustomed 5–95th percentiles indicated aberration (Tabular array i).
Table 1
Suggested Normal limits for menstrual parameters. Adapted from Fraser et al. [12].
| Clinical Parameter | Descriptive term | Normal limits (5–95th percentiles) |
|---|---|---|
| Frequency of menses (days) | Frequent Normal Exceptional | <24 24–38 >38 |
| Regularity of menses, cycle to cycle (Variation in days over 12 months) | Absent Regular Irregular | No bleeding Variation ± 2–twenty days Variation >20 days |
| Elapsing of menstruation (days) | Prolonged Normal Shortened | >viii.0 4.v–eight.0 <iv.5 |
| Volume of monthly claret loss (mL) | Heavy Normal Low-cal | >80 5–fourscore <5 |
With regard to book, 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'south physical, social, emotional and/or textile quality of life' [3], as an indication for investigation and treatment options. Every bit such, objective measurements of book are normally the preserve of research studies and surrogates such a pictorial blood-loss cess chart (PBAC) scores are non recommended in routine clinical practise.
FIGO classification of cause: 'PALM-COEIN'
Once bleeding is defined equally existence abnormal, the acronym PALM-COEIN is now existence increasingly used for categorising causes: Polyp, Adenomyosis, 50eiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Due northot otherwise classified [13]. The 'PALM' are assessed visually (imaging and histopathology) and the 'COEIN' are not-structural (Fig. ane).
FIGO classification of causes of AUB; 'PALM COEIN'.
Depending on the site, leiomyoma (fibroids) are farther subdivided into submucosal (SM) and other (O) and so into nine tertiary categories adapted from the Wamsteker classification [fourteen] (Fig. ii). These have been adopted by the European Society for Human Reproduction and Embryology (ESHRE) and used by the European Society for Gynaecological Endoscopy (ESGE).
Tertiary nomenclature of AUB-L (adapted from Munro et al. [13]).
Contribution of fibroids (leiomyoma) to AUB
The relationship betwixt AUB and fibroids remains incompletely understood. The obvious paradox is that many women take fibroids simply too take entirely normal bleeding patterns. Fibroids are besides highly prevalent in women presenting with AUB.
Previous postulated theories include an increased endometrial surface surface area and the presence of fragile and engorged vasculature in the perimyoma environment [15]. The increase in vascular flow observed along with these enlarged vessels can overcome platelet activeness [16]. At that place is increasing knowledge regarding the complex cellular and molecular changes found in association with fibroids, with impact on angiogenesis, amending in vasoactive substrates and growth factors every bit well as alteration in coagulation [16]. The effect of fibroids on endometrial function is now thought to represent a field change within the uterine crenel rather than limited to regions overlying the myoma(s). Some of these changes may take an impact on endometrial receptivity and implantation as well as AUB [17], ∗[xviii].
Matrix metalloproteinase (MMP) ii and 11 levels are increased in fibroids (with MMP one and 3 unchanged) [xix], [20], but the touch on on endometrial bleeding is unclear. Expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), heparin-bounden epidermal growth factor, platelet-derived growth cistron (PDGF), parathyroid hormone-related protein (PTHrP) and prolactin is altered in women with fibroids [16]. VEGF, bFGF, PDGF and PTHrP all have potential angiogenic effects but their specific function inside the endometrium in women with fibroids has even so to be determined [17].
There is alteration of plasminogen modulators and this may impact on endometrial haemostasis and repair [16]. Transforming growth factor beta (TGF-β) is produced in backlog in the endometrium in women with fibroids and is associated with reduced levels of plasminogen activator inhibitor-1 (PAI-1), thrombomodulin and antithrombin 3, both in vivo and in endometrial stromal cells treated in vitro with TGF-β [18]. 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 [21]. Whether these variations touch immune function and inflammation implicated in endometrial breakdown and repair remains unknown.
With regard to the location of fibroids, information technology was previously thought that those women with SM fibroids, particularly with those distorting the cavity, were more than probable to nowadays with HMB [15]. There is current debate that women with pregnant cavity distortion represent additional therapeutic challenges.
Other causes of AUB
The PALM-COEIN classification system accepts that women may have more than than 1 underlying aetiology and also that oftentimes in the instance of structural abnormalities, many women may in fact exist asymptomatic.
Polyps (AUB-P)
Endometrial polyps are epithelial proliferations arising from the endometrial stroma and glands. The bulk are asymptomatic. The contribution of polyps to AUB varies widely ranging from three.7% to 65% [22], [23], but it is widely accepted [24]. The incidence of polyps as with fibroids increases with age and both pathologies may frequently co-be, or suspected polyps visualised on transvaginal ultrasound scanning (TV-USS) may be mistaken for SM fibroids and vice-versa [25].
Adenomyosis (AUB-A)
The relationship between adenomyosis and AUB remains unclear [26], 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 exist both focal and lengthened and it may exist harder to establish diagnosis if fibroids are also present [27].
Malignancy (AUB-Chiliad)
Endometrial cancer is the about common gynaecological malignancy in the western world. Historically, endometrial cancer has rarely occurred in premenopausal women; however, with increasing obesity and ascent 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 historic period-standardised rates of uterine cancer in the Britain take increased by 48% [28]. With the reclassification by the WHO from hyperplasia to endometrial intraepithelial neoplasia (EIN), the electric current prevalence of premalignant affliction is unknown. The evaluation of the endometrium may exist affected by distortion of the uterine crenel 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 take been reported as rare (3–7/100,000 in the USA) [29] but possibly a cause of AUB-M. A recent meta-analysis reported that leiomyosarcoma are unexpectedly diagnosed following surgery for anticipated 'benign' myomas in ii.94 per k women (i in 340 women) [thirty], [31]. Race is the just commonality between leiomyosarcoma and leiomyoma with black women having an approximately twofold increased risk [29]. The risk of development of leiomyosarcoma is reported to increase with age with <1 case per 500 among women anile under 30 years to ane in 98 amid women in the historic period range 75–79 years [30], [31]. Other risk factors for uterine leiomyosarcoma include the long-term use of tamoxifen [32], previous pelvic radiation therapy [33] and rare inherited disorders such as hereditary leiomyomatosis and renal jail cell carcinoma (HLRCC) [34].
Interestingly, the previously held view was that a apace enlarging uterus would raise the suspicion for malignancy. This is now no longer held to exist truthful as benign fibroids can abound rapidly and sarcomas grow slowly [35], [36]. Still, more than objective investigations are all the same 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 [37]. The lack of a robust pre-surgical predictor/biomarker has recently altered surgical practice because morcellation of an unsuspected leiomyosarcoma increases dissemination [38].
If malignancy or premalignancy is found along with AUB nomenclature, the pathology should be described and staged utilising the appropriate WHO/FIGO systems [39].
Coagulopathy (AUB-C)
Coagulopathies are reported to affect xiii% [40] of the women presenting with HMB. The majority of these women suffer from Von Willebrand affliction [40]. Systemic disorders of haemostasis may be identified in 90% of women using a structured history [41], ∗[42] (Tabular array 2).
Table 2
Structured history for coagulopathy screen. Adapted from Koudies et al. [42].
| Criteria |
|---|
| 1. Heavy bleeding since the menarche |
2. Ane of the post-obit:
|
3. Two or more of the following:
|
If ane, 2 or iii (see Table 2) is ascertained, it indicates positive screen, and further referral for appropriate investigation should be considered.
Anticoagulant and antiplatelet therapy hitherto has been considered as a part of 'AUB-C' (rather than AUB-I). Compression acquired by a large fibroid uterus may atomic number 82 to venous thromboembolism (VTE). Bleeding previously deemed every bit AUB-L may be exacerbated by subsequent anticoagulation and presents additional management challenges.
Ovulatory (AUB-O)
Anovulatory cycles may contribute to AUB past unopposed oestrogen effects on the endometrium causing marked proliferation and thickening resulting in HMB along with an altered frequency of menstruation. This is observed at the extremes of reproductive age; however, impact on the HPO axis along with endocrinopathies is likewise present. The latter include polycystic ovarian syndrome (PCOS), hyperprolactinaemia, hypothyroidism as well as factors such as obesity, anorexia, weight loss, mental stress and extreme exercise. Typically, women in this group have menstrual cycles that fall out with 38 days or have a variation of >21 days. Drugs that affect dopamine levels, with their attendant furnishings on the HPO axis, also currently fall nether this category rather than AUB-I. In women with fibroids, the co-existing ovulatory dysfunction may exacerbate menstrual loss.
The FIGO AUB classification organization is a dynamic organisation with feedback and contemporary debate informing futurity revisions [13]. The position of drug therapies affecting AUB is currently under review with regard to whether anticoagulant/antiplatelet therapies and drugs affecting the HPO axis may be better placed in 'AUB-I'.
Endometrial (AUB-East)
AUB that occurs in the context of a structurally normal uterus with regular menstrual cycles without evidence of coagulopathy is likely to accept an underlying endometrial crusade. Endometrial part in the context of menstruation and its disorders is still not fully understood and remains an surface area of active scientific enquiry, specially the complexities of the sequence of events triggered by progesterone withdrawal (due to demise of the corpus luteum in the absence of pregnancy). Hypoxia, inflammation, haemostasis and angiogenesis all play crucial roles in the shedding and subsequent scarless repair of the functional upper layer of the endometrium. Perturbation of local glucocorticoid metabolism, abnormal prostaglandin synthesis and excessive plasminogen (resulting in premature clot lysis) take all been implicated in AUB [43].
AUB-E may exist implicated in many women with AUB, but a lack of clinically available specific tests or biomarkers means that practical testing for such disorders is not still feasible. As such, diagnosis depends on careful history taking and exclusion of other contributors. The high prevalence of potential endometrial dysfunction means that it is highly likely that those with AUB-L will often have an chemical element of AUB-E contributing to increased/aberrant menstrual blood loss with its attendant implication for therapy.
Iatrogenic (AUB-I)
Iatrogenic causes of AUB include exogenous therapy than may lead to unscheduled endometrial bleeding. This is typically associated with continuous oestrogen or progestin therapy (systemic or intrauterine commitment routes) or those interventions that deed on ovarian steroid release such every bit gonadotropin-releasing hormone (GnRH) agonists and aromatase inhibitors. Selective oestrogen receptor modulators (SERMs) and more rarely selective progesterone receptor modulators (SPRMs) may cause AUB through direct activity on the endometrium.
The use of an intrauterine device (IUD) may cause a low-grade endometritis which may also contribute to AUB.
Not otherwise classified (AUB-North)
It is inevitable that there will be pathologies that are either rare or poorly defined that do not easily fit within the categories described earlier. Examples include arteriovenous malformations, endometrial pseudoaneurysms, myometrial hypertrophy and chronic endometritis (not precipitated by an IUD). All of these can co-be with AUB-Fifty.
The planned regular review of the FIGO PALM-COEIN classification organization every 3–v years through FIGO [xiii] will allow reassessment, in particular, of this category. Further areas considered for future sub-classification include AUB-P and AUB-A.
Assessment of the patient presenting with AUB and fibroids
Equally described before, all of the other causes of AUB may co-be with fibroids. As such, information technology is crucial when a patient with known or suspected fibroids presents with AUB, she is appropriately assessed for the presence of other aetiologies. Misdiagnosis volition have an impact on treatment options and efficacy, and in the event of undiagnosed coagulopathy, return surgical intervention disproportionately chancy.
As office of structured history, factors such as co-morbidities, polypharmacy, torso mass index (BMI), previous surgery and most crucially fertility desire and impact of pressure symptoms must exist assessed every bit these significantly affect treatment approach. A structured arroyo is shown in Fig. 3.
Structured approach for assessing the patient presenting with AUB.
An accurate menstrual history and associated symptoms will place a probable AUB-O cause. Equally described before, a structured screen for coagulopathies volition identify 90% of those women with disorders of systemic haemostasis (Tabular array 2). History will also place contributors to AUB-I.
Combined history and examination will advise possible AUB-P/-A/-L and should be confirmed with subsequent imaging. Television-USS remains the near acceptable and validated beginning-line investigation. The increasing use of saline infusion ultrasonography (Sis) and selected hysteroscopy will meliorate sensitivity and specificity for diagnosis of polyps and SM fibroids ∗[37], ∗[44]. The optimal way of imaging for suspected adenomyosis has however to exist established [45]. Furthermore, women with fibroids may have them confused for focal adenomyosis and vice-versa using conventional imaging [27]. The increased use of i-stop clinics with access to outpatient hysteroscopy improves patient satisfaction and facilitates timely investigation and direction [46].
MRI plays a role in selected patients with AUB and fibroids, likewise in the cess of suitability for uterine avenue embolisation (UAE). Equally previously discussed, it is relatively poor at providing reassurance of the absenteeism of sarcomatous modify.
Endometrial sampling
In the U.k., NICE recommend endometrial sampling in women with persistent inter-menstrual bleeding or aged ≥45 years with treatment failure [three]. This has been highlighted in the RCOG guidelines with an exception of reducing the historic period of sampling in the context of treatment failure to 40 [47]. With the marked increase in endometrial cancer, the authors would encourage all gynaecologists to continue to excise their clinical judgement for those women aged <40 years with HMB who have risk factors for premalignant change such equally obesity and PCOS. Endometrial sampling may be more challenging if fibroids distort the cavity, and access to concurrent outpatient hysteroscopy can facilitate timely exclusion of endometrial pathology.
Approach to management
Management of AUB-Fifty should accost fertility desire, impact of pressure symptoms, co-morbidities, and any other AUB contributors. Handling should exist individualised. No one-size-fits-all approaches are available with regard to initial and subsequent handling options, and there is a relative paucity of big robust clinical trials providing head-to-caput information rather to placebo.
In those with other underlying AUB causes co-existing with fibroids, targeted treatment of these may ameliorate bleeding, and in the absence of pressure symptoms or sub-mucosal myoma-related infertility, all the treatments may be required. Specific treatments for other causes are shown in Table 3.
Table 3
Specific treatment options for individual PALM-COEIN causes of AUB.
| AUB Sub-classification | Specific treatment |
|---|---|
| Polyp | Resection |
| Adenomyosis | Surgery: hysterectomy; adenomyomectomy (not oftentimes performed) |
| Malignancy | Surgery +/− adjuvant treatment High-dose progestogens (if surgery non possible) Palliation (including radiotherapy) |
| Coagulopathy | Tranexamic acid DDVAP |
| Ovulation | Lifestyle modification Cabergoline (if hyperprolactinaemia) Levothyroxine (if hypothyroid) |
| Endometrial | Specific therapies await further delineation of underlying mechanisms |
| Iatrogenic | Refer to FSRH CEU guidance on problematic bleeding with hormonal contraception [56] |
| Non otherwise classified | Antibiotics for endometritis Embolisation of AV malformation |
Otherwise, treatment should be tailored depending on the bear on of related symptoms, fertility requirements and cavity baloney (Fig. 4). It should be remembered that a conservative approach (incorporating oral atomic number 26 replacement if indicated) may be an entirely acceptable treatment approach, especially in the peri-menopausal stage with amenorrhea and regression of fibroid size imminent.
Symptom-based approach for direction of AUB in the context of fibroids.
In AUB, in the absenteeism of pressure level symptoms, medical treatment may be more appropriate, specially when fertility preservation is required. Tranexamic acid and NSAIDs (e.g. mefenamic acid) remain the only fully non-contraceptive medical options [3]. Whilst the risk of expulsion of a levonorgestrel-releasing intrauterine system (LNG–IUS) is without uncertainty higher in the context of fibroids, there is still evidence for efficacy [48] although cavity baloney may preclude the use of LNG–IUS.
The current Cochrane review for the SPRMs is limited to mifepristone [49] and a future review incorporating other members of the SPRM class is underway. GnRH analogues are constructive in reducing both size of fibroids and amelioration of bleeding, but their side effects and impact on bone density limit their longer-term utility, and rebound of symptoms is rapid on abeyance [fifty]. GnRH agonists oft are beneficial every bit a short-term handling prior to IVF or surgery, but given the findings in the PEARL Ii written report, there is good evidence that the SPRM ulipristal acetate (UPA) is better tolerated in those women pre-surgery without loss of efficacy [51]. There is no robust evidence for alternative therapies such equally acupuncture or herbal remedies for the handling of fibroids [52], [53].
With regard to interventional radiological (uterine avenue embolisation, UAE) and surgical options, the anticipated outputs of the FEMME study [54] will hopefully provide robust show for touch on on symptoms and other qualitative measures betwixt myomectomy and UAE. MR-guided focussed ultrasound (MRgFUS) is not a widely available technique. Its office in the management of symptomatic fibroids remains to be established. Hysterectomy is a definitive handling, and in the context of management options for HMB, information technology remains equally a therapeutic option with the highest patient satisfaction and cost-effectiveness for >v years [55]. Hysterectomy, however, is often a challenging surgery in women with loftier potential blood losses and chance of ureteric injury due to anatomical distortion in the pelvis. With increasing obesity, the complexity of surgery is compounded. Whilst culling treatment strategies are under development, a cohort of women whose fertility plans are complete and for whom definitive surgery, that is, hysterectomy, becomes the most appropriate management will remain.
Conclusions
AUB is a common and debilitating condition with high directly and indirect costs. Symptoms of AUB often co-exist with fibroids, but the relationship betwixt AUB and fibroids remains incompletely understood. In many women, fibroids may exist an incidental innocent bystander in the underlying aetiology of a menstrual haemorrhage complaint. A structured approach to establishing the cause using the FIGO PALM-COEIN classification organization will facilitate accurate diagnosis and inform treatment options. The classification system, however, nonetheless lacks effective biomarkers for 'AUB-E'. Office hysteroscopy and the increasingly sophisticated imaging volition assist provision of robust evidence for the underlying crusade. The increased availability of medical options has expanded the selection for women. Many volition no longer need to recourse to potentially complicated surgery. Treatment must remain individualised and encompass the bear on of pressure symptoms, want for retentivity of fertility and contraceptive needs, as well as accost the management of their AUB in order to reach improved quality of life.
Conflict of interest argument
LW has no conflict of interest. HODC has clinical inquiry support for laboratory consumables and staff from Bayer Pharma AG and provides consultancy communication (but with no personal remuneration) for Bayer Pharma AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc.
Acknowledgements
We are nearly grateful to Mrs Sheila Milne for her help with manuscript training and Mr Ronnie Grant for graphical assistance. We thank Professors Mac Munro (Usa), Alistair Williams (UK), Dr Jane Walker and Dr Alison Murray for provision of several of the images in Fig. 1. HC has grant back up from the Medical Enquiry Quango (MR/J003011/one and G1002033) and NIHR (12/206/52). LW is supported by the Medical Enquiry Council (MR/J003011/one and G1002033).
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970656/
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