Scholarly article on topic 'Abnormal uterine bleeding'

Abnormal uterine bleeding Academic research paper on "Clinical medicine"

CC BY
0
0
Share paper
Keywords
{"abnormal uterine bleeding (AUB)" / fibroids / "FIGO PALM-COEIN classification of AUB"}

Abstract of research paper on Clinical medicine, author of scientific article — Lucy Whitaker, Hilary O.D. Critchley

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 (Polyp, Adenomyosis, Leiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Not 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.

Academic research paper on topic "Abnormal uterine bleeding"

Abnormal Uterine Bleeding

Accepted Manuscript

Lucy Whitaker, MBChB, MSc, Hilary O.D. Critchley, BSc, MBChB, MD, Professor

S1521-6934(15)00226-6 10.1016/j.bpobgyn.2015.11.012

Reference: YBEOG 1575

To appear in: Best Practice & Research Clinical Obstetrics & Gynaecology

Received Date: 7 November 2015 Accepted Date: 18 November 2015

Please cite this article as: Whitaker L, Critchley HOD, Abnormal Uterine Bleeding, Best Practice & Research Clinical Obstetrics & Gynaecology (2015), doi: 10.1016/j.bpobgyn.2015.11.012.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Abnormal Uterine Bleeding

Authors: Lucy Whitaker MBChB, MSc; Hilary O D Critchley* BSc, MBChB, MD

Affiliation: MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh EH16 4TJ; United Kingdom

Corresponding Author:

Professor Hilary O D Critchley Professor of Reproductive Medicine MRC Centre for Reproductive Health The Queen's Medical Research Institute 47 Little France Crescent EDINBURGH EH16 4TJ

Email: hilary.critchley@ed.ac.uk Tel: +44 (0)131 242 6858 Fax: +44 (0)131 242 6441

Author contact details:

Lucy Whitaker lucy. whitaker@ed .ac.uk

Conflict of Interest Statement:

LW has no conflict of interest. HODC has clinical research support for laboratory consumables and staff from Bayer Pharma AG and provides consultancy advice (but with no personal remuneration) for Bayer Pharma AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc. No of Words: Approx 7000

ABSTRACT

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 to establishing cause using the FIGO PALM-COEIN classification system will facilitate accurate diagnosis and inform treatment options. Office hysteroscopy and increasing sophisticated imaging will assist provision of robust evidence for 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.

Key Words:

• Abnormal uterine bleeding (AUB)

• Fibroids

• FIGO PALM COEIN classification of AUB

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 [1, 2] and may have a significant impact upon their physical, social emotional and material quality of life [3]. In the UK, over 800 000 women seek help for AUB annually [3]. Along with the direct impact on the woman and her family there are significant costs both to the economy and the health service. A US study reported that financial losses of >$2000 per patient per annum due to work absence and home management costs [4]. AUB is the 4th most common reason for referral to UK gynaecological services [5]. 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 [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 most common tumour of women; by the age of 50 almost 70% of white women and more than 80% of black women will have developed at least one fibroid [7]. Fibroids are associated with subfertility, miscarriage, pre-term 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 [8]. However for many women the most

common presentation to gynaecological services is 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 [9, 10]. 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 [11]. The mechanisms however linking AUB and fibroids remain incompletely understood.

As women increasing defer pregnancy, fertility preservation is critical and newer medical options offer genuine effective relief both of 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) [12, 13]. This was in order to standardise definitions, nomenclature and 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 and well as being 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' [13]. Abnormality was defined as outwith accepted 5-95th percentiles (Table 1).

<Insert Table 1 here>

With regards 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 heavy menstrual bleeding (HMB): 'excessive menstrual blood loss which interferes with a woman's physical, social, emotional and/or material quality of life' [3] as a prompt 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 increasing used for categorising cause: Polyp, Adenomyosis, Leiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Not otherwise classified [13]. The "PALM" are assessed visually (imaging and histopathology) and the "COEIN" are non-structural. (Figure 1)

Depending on site, leiomyoma (fibroids) are further subdivided into submucosal (SM) and other (O) and then into 9 tertiary categories adapted from the Wamsteker classification [14] (Figure 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

As with the relationship between fibroids and infertility, 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 peri-myoma environment [15]. The increase in vascular flow seen with these enlarged vessels can overwhelm platelet action [16]. Knowledge is increasing about 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 [16]. 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 upon endometrial receptivity and implantation as well as AUB [17, 18].

Matrix metalloproteinase (MMP) 2 and 11 are increased in fibroids (with MMP 1 and MMP 3 unchanged) [19, 20] but the impact upon 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 are all altered in women with fibroids [16]. 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 [17].

There is alteration of plasminogen modulators and this may impact upon endometrial haemostasis and repair [16]. Transforming growth factor-beta (TGF-P) 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- p [18]. This may represent a putative mechanism for some of the AUB seen in the context of fibroids and may in the future offer a potential therapeutic target.

In women with fibroids alterations in blood plasma levels of circulating interleukin (IL) -13, IL-17 and IL-10 have been reported [21]. It is unknown if these variations impact upon immune function and inflammation implicated in endometrial breakdown and repair.

With regard to location of fibroids it was historically thought that those women with submucosal fibroids, particularly those distorting the cavity were more likely to present with HMB [15]. There is current debate that those women with a 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% [22, 23] but it is widely accepted that they contribute [24]. The incidence of polyps as with fibroids, increases with age and the two pathologies may both frequently co-exist, or suspected polyps visualised on transvaginal ultrasound (TV USS)be mistaken for submucosal fibroids and visa-versa [25].

Adenomyosis (AUB-A)

The relationship between adenomyosis and AUB remains unclear [26], particularly as histopathological diagnosis varies widely reflecting variations in criteria used, and 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 diagnosis may be harder to establish if fibroids are also present [27].

Malignancy (AUB-M)

Endometrial cancer is the most common gynaecological malignancy in the Western world. Historically endometrial cancer has been rare in pre-menopausal women however with increasing obesity and rising prevalence of the metabolic syndrome, the

endocrine driven subset of endometrial malignancy have markedly increased in frequency. Between 1992-1994 and 2009-2011 European age standardised rates of uterine cancer in the UK have increased by 48% [28]. With the reclassification by the WHO from hyperplasia to Endometrial Intraepithelial Neoplasia (EIN) the current prevalence of pre-malignant disease is unknown. The evaluation of the endometrium may be affected by distortion of the uterine cavity by fibroids, and as such 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) [29] but may be 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 (1 in 340 women) [30, 31]. Race is the only commonality between leiomyosarcoma and leiomyoma with black women having an approximately 2-fold increased risk [29]. Risk for development of leiomyosarcoma is reported to increase with age with less than one case per 500 among women aged under 30 years to 1 in 98 among women in the age range 75-79 years [30, 31]. Other risk factors for uterine leiomyosarcoma include long-term tamoxifen use [32], previous pelvic radiation therapy [33] and rare inherited disorders such as hereditary leiomyomatosis and renal cell carcinoma (HLRCC) [34].

Interestingly the previously held view was that a rapidly enlarging uterus was suspicious for malignancy. This is now no longer held to be true as both benign

fibroids can grow rapidly and sarcomas grow slowly [35, 36]. However more objective investigations are still lacking. Both ultrasound scanning (USS) and magnetic resonance imaging (MRI) do not as yet have robust criteria to predict confidently differentiation between leiomyoma and leiomyosarcoma [37]. The lack of a robust pre-surgical predictor / biomarker has recently altered surgical practice due to concern that morcellation of an unsuspected leiomyosarcoma increases dissemination [38].

If malignancy or pre-malignancy is found along with AUB classification the pathology should be described and staged utilising the appropriate WHO/FIGO systems [39].

Coagulopathy (AUB-C)

Coagulopathies are reported to affect 13% [40] of women presenting with HMB. The majority of these women suffer with Von Willebrand Disease [40]. Systemic disorders of haemostasis may be identified in 90% of women using a structured history [41, 42], (Table 2).

<Insert Table 2 here>

A positive screen is if either 1, 2 or 3 (see Table 2) are ascertained and should prompt consideration of further referral for appropriate investigation.

Anti-coagulant and anti-platelet therapy hitherto has been considered part of "AUB-C" (rather than AUB-I). Compression from a large fibroid uterus may precipitate

venous thromboembolism (VTE). Bleeding previous deemed AUB-L may be exacerbated by subsequent anticoagulation and presents additional management challenges.

Ovulatory (AUB-O)

Anovulatory cycles may contribute to AUB by unopposed oestrogen effects on the endometrium causing marked proliferation and thickening resulting in HMB along with altered frequency of menstruation. This is seen at the extremes of reproductive age but also impact on the HPO axis is present with endocrinopathies. The latter include polycystic ovarian syndrome (PCOS), hyperprolactinaemia, hypothyroidism and well as factors such as obesity, anorexia, weight loss, mental stress and extreme exercise. Typically women in this group have menstrual cycles that fall outwith 38 days or have a variation of >21 days. Drugs that impact upon dopamine, with their attendant effects on the HPO axis also currently fall under this category rather than AUB-I. In women with fibroids, co-existing ovulatory dysfunction may exacerbate menstrual loss.

The FIGO AUB classification system is a dynamic system with feedback and contemporary debate informing future revisions [13]. The position of drug therapies impacting AUB is currently under review with regard to whether e.g. anti-coagulant / anti-platelet therapies and drugs impacting the HPO axis may be better placed in "AUB-I".

Endometrial (AUB-E)

AUB that occurs in the context of a structurally normal uterus with regular menstrual cycles without evidence of a coagulopathy are likely to have an underlying endometrial cause. Endometrial function in the context of menstruation and its disorders is still not fully understood and remains an area of active scientific enquiry, particularly the complexities of the sequence of events triggered by progesterone withdrawal (due to demise of the corpus luteum in absence of pregnancy). 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 AUB [43].

AUB-E may be 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 yet 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 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 precipitate unscheduled endometrial bleeding. This is typically associated with continuous administered oestrogen or progestin therapy (systemic or intrauterine delivery routes)

or those interventions that act on ovarian steroid release such as gonadotrophin-releasing hormone (GnRH) agonists and aromatase inhibitors. Selective Estrogen Receptor Modulators (SERMs) and more rarely Selective Progesterone Receptor Modulators (SPRMs) may cause AUB through direct action on the endometrium.

Use of an intrauterine device (IUD) may cause a low grade endometritis which may also contribute to AUB.

Not Otherwise Classified (AUB-N)

It is inevitable that there will be pathologies that are either rare or poorly defined that do not easily fit within the categories described above. Examples include arteriovenous malformations, endometrial pseudo-aneurysms, myometrial hypertrophy and chronic endometritis (not precipitated by an IUD). All of these can co-exist with AUB-L.

The planned regular review of the FIGO PALM-COEIN classification system every 3-5 years through FIGO [13] will allow re-assessment in particular of this category. Further areas considered for future sub-classification include AUB-P and -A.

ASSESSMENT OF THE PATIENT PRESENTING WITH AUB AND FIBROIDS

As described above all of the other causes of AUB may co-exist with fibroids. As such it is crucial when a patient with known or suspected fibroids presents with AUB she is appropriately assessed for the presence of other aetiologies. Misdiagnosis will

impact upon treatment options and efficacy, and in the event of undiagnosed coagulopathy render surgical intervention disproportionately hazardous.

As part of structured history factors such as co-morbidities, polypharmacy, BMI, previous surgery and most crucially fertility desire and impact of pressure symptoms must be assessed as these impact significantly upon treatment approach. A structured approach is shown in Figure 3

An accurate menstrual history and associated symptoms will identify a likely AUB-O cause. As described earlier a structured screen for coagulopathies will identify 90% of those women with disorders of systemic haemostasis (Table 2). History will also identify contributors to AUB-I.

Combined history and examination will suggest possible AUB-P/-A/-L and should be confirmed with subsequent imaging. TV-USS remains the most acceptable and validated first line investigation. Increasing use of saline infusion ultrasonography (SIS) and selected hysteroscopy will improve sensitivity and specificity for diagnosis of polyps and submucosal fibroids [37, 44]. The optimum mode of imaging for suspected adenomyosis has yet to be established [45]. Furthermore women with fibroids may have them confused for focal adenomyosis and vice-versa using conventional imaging [27]. Increased use of one-stop clinics with access to outpatient hysteroscopy improves patient satisfaction and facilitates timely investigation and management [46].

MRI plays a role in selected patients with AUB and fibroids, and has the added benefit of assessing for suitability for uterine artery embolization (UAE). As previously discussed it is relatively poor at providing reassurance of absence of sarcomatous change.

Endometrial sampling.

In the UK NICE recommend endometrial sampling in women with persistent intermenstrual bleeding or aged 45 and over with treatment failure [3]. This is echoed in the RCOG guidance with exception of reducing the age 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 younger than 40 with HMB who have risk factors for premalignant change such as 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-L should address fertility desire, impact of pressure symptoms, co-morbidities, and any other AUB contributors. Treatment should be individualised. There remains no one-size fits all treatment with regard to initial and subsequent treatment options and there is a relative paucity of large robust clinical trials providing head-to-head data 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 may be all the treatment required. Specific treatments for other causes are shown in Table 3.

<Insert Table 3 here>

Otherwise treatment should be tailored depending on impact of related symptoms, fertility requirements and cavity distortion (Figure 4). It should be remembered that a conservative approach (incorporating oral iron replacement if indicated) may be an entirely acceptable treatment approach, particularly in the peri-menopasual phase with amenorrhea and regression of fibroid size imminent.

In AUB in the absence of pressure symptoms medical treatment may be more appropriate, particularly 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 doubt higher in the context of fibroids, there is still evidence for efficacy [48] although cavity distortion may preclude 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 effective at reducing both size of fibroids and amelioration of bleeding but their side effects and impact upon bone density limit their longer-term utility and rebound of symptoms is rapid on cessation [50]. GnRH agonists often have utility as

a short-term treatment prior to IVF or surgery but given the findings in the PEARL II study 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 as acupuncture or herbal remedies for the treatment of fibroids [52, 53].

With regard to interventional radiological (uterine artery embolisation [UAE]) and surgical options then the anticipated outputs of the FEMME study [54] will hopefully provide robust evidence for impact on symptoms and other qualitative measures between myomectomy and UAE. MR-guided focused ultrasound (MRgFUS) remains a technique that is not widely available. Its role in the management of symptomatic fibroids remains to be established. Hysterectomy is definitive treatment and in the context of management options for HMB it remains the therapeutic option with the highest patient satisfaction and cost-effectiveness beyond 5 years [55]. Hysterectomy however is often challenging surgery in these women, with high potential blood losses and risk of ureteric injury due to anatomical distortion in the pelvis. With increasing obesity the complexity of surgery is compounded. Whilst there are alternative treatment strategies under development, there will remain a cohort of women whose fertility plans are complete and for whom definitive surgery, i.e. hysterectomy, becomes the most appropriate management.

CONCLUSIONS

AUB is a common and debilitating condition with high direct and indirect costs. Symptoms of AUB frequently co-exist with fibroids but the relationship between

AUB and fibroids remains incompletely understood. In many women fibroids may be an incidental innocent bystander in the underlying aetiology of a menstrual bleeding complaint. A structured approach to establishing cause using the FIGO PALM-COEIN classification system will facilitate accurate diagnosis and inform treatment options. The classification system however still lacks effective biomarkers for "AUBE". Office hysteroscopy and increasing sophisticated imaging will assist provision of robust evidence for underlying cause. Increased availability of medical options has expanded the choice for women. 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 their AUB in order to achieve improved quality of life.

ACKNOWLEDGEMENTS

We are most grateful to Mrs Sheila Milne for her help with manuscript preparation 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 Figure 1. HC has grant support from the Medical Research Council (MR/J003011/1 and G1002033) and NIHR (12/206/52). LW is supported by the Medical Research Council (MR/J003011/1 and G1002033)

Practice Points

• A structured approach to cause utilizing the PALM COEIN framework to ensure important contributors apart from fibroids are not missed.

• In particular coagulopathies should be verbally screened for in all patients presenting with AUB given their high prevalence in this population and implications for management.

• In view of the rapid increase in endometrial cancer clinical judgement regarding endometrial sampling should be utilised in younger women with AUB with risk factors for EIN and malignancy.

• Treatment should be individualised encompassing impact of pressure symptoms, desire for retention of fertility, contraceptive needs and impact of symptoms on quality of life.

Research Agenda

• Imaging for fibroids, in particular modality for diagnosis of adenomyosis and for discriminating between fibroids and leiomyosarcoma

• Increased evidence base for long-term medical treatments for management of AUB in the context of fibroids, with particular emphasis on quality of life

• Improved evidence for interventional treatments for AUB in context of fibroids

REFERENCES

[1]. Fraser IS, Langham S & Uhl-Hochgraeber K. Health-related quality of life and economic burden of abnormal uterine bleeding. Expert Rev Obstet Gynecol 2009; 4: 179-189.

[2]. Shapley M, Jordan K & Croft PR. An epidemiological survey of symptoms of menstrual loss in the community. Br J Gen Pract 2004; 54: 359-363.

[3].* NICE. Clinical Guideline 44; Heavy menstrual bleeding 2007. National Institute for Health and Clinical Excellence (NICE); Available at: http://www.nice.org.uk/nicemedia/pdf/CG44FullGuideline.pdf.

[4]. Frick KD, Clark MA, Steinwachs DM, et al. Financial and quality-of-life burden of dysfunctional uterine bleeding among women agreeing to obtain surgical treatment. Womens Health Issues 2009; 19: 70-78.

[5]. RCOG. National Heavy Menstrual Bleeding Audit Second Annual Report. London: RCOG; 2012.

[6]. RCOG. National Heavy Menstrual Bleeding Audit Final Report. London: RCOG; 2014.

[7].* Baird DD, Dunson DB, Hill MC, et al. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 2003; 188: 100-107.

[8]. Brahma PK, Martel KM & Christman GM. Future directions in myoma research. Obstet Gynecol Clin North Am 2006; 33: 199-224, xiii.

[9]. Merrill RM. Hysterectomy surveillance in the United States, 1997 through 2005. MedSciMonit 2008; 14: CR24-31.

[10]. Stewart EA. Uterine fibroids. Lancet 2001; 357: 293-298.

[11]. Cardozo ER, Clark AD, Banks NK, et al. The estimated annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol 2012; 206: 211 e211-219.

[12]. Fraser IS, Critchley HO, Broder M & Munro MG. The FIGO recommendations on terminologies and definitions for normal and abnormal uterine bleeding. Semin Reprod Med 2011; 29: 383-390.

[13].* Munro MG, Critchley HO & Fraser IS. The FIGO classification of causes of abnormal uterine bleeding: Malcolm G. Munro, Hilary O.D. Crithcley, Ian S. Fraser, for the FIGO Working Group on Menstrual Disorders. Int J Gynaecol Obstet 2011; 113: 1-2.

[14]. 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 1993; 82: 736740.

[15]. Munro MG. Classification of menstrual bleeding disorders. Rev Endocr Metab Disord 2012; 13: 225-234.

[16]. Stewart EA & Nowak RA. Leiomyoma-related bleeding: a classic hypothesis updated for the molecular era. Hum Reprod Update 1996; 2: 295-306.

[17]. Doherty L, Mutlu L, Sinclair D & Taylor H. Uterine fibroids: clinical manifestations and contemporary management. Reprod Sci 2014; 21: 10671092.

[18].* Sinclair DC, Mastroyannis A & Taylor HS. Leiomyoma simultaneously impair endometrial BMP-2-mediated decidualization and anticoagulant expression through secretion of TGF-beta3. J Clin Endocrinol Metab 2011; 96: 412-421.

[19]. Palmer SS, Haynes-Johnson D, Diehl T & Nowak RA. Increased expression of stromelysin 3 mRNA in leiomyomas (uterine fibroids) compared with myometrium. JSoc GynecolInvestig 1998; 5: 203-209.

[20]. Bogusiewicz M, Stryjecka-Zimmer M, Postawski K, et al. Activity of matrix metalloproteinase-2 and -9 and contents of their tissue inhibitors in uterine leiomyoma and corresponding myometrium. Gynecol Endocrinol 2007; 23: 541-546.

[21]. Wegienka G, Baird DD, Cooper T, et al. Cytokine patterns differ seasonally between women with and without uterine leiomyomata. Am JReprodImmunol 2013; 70: 327-335.

[22]. Dreisler E, Stampe Sorensen S, Ibsen PH & Lose G. Prevalence of endometrial polyps and abnormal uterine bleeding in a Danish population aged 20-74 years. Ultrasound Obstet Gynecol 2009; 33: 102-108.

[23]. Preutthipan S & Herabutya Y. Hysteroscopic polypectomy in 240 premenopausal and postmenopausal women. Fertil Steril 2005; 83: 705-709.

[24]. Lieng M, Istre O, Sandvik L & Qvigstad E. Prevalence, 1-year regression rate, and clinical significance of asymptomatic endometrial polyps: cross-sectional study. J Minim Invasive Gynecol 2009; 16: 465-471.

[25]. Van den Bosch T, Ameye L, Van Schoubroeck D, et al. Intra-cavitary uterine pathology in women with abnormal uterine bleeding: a prospective study of 1220 women. Facts Views Vis Obgyn 2015; 7: 17-24.

[26]. Naftalin J, Hoo W, Pateman K, et al. Is adenomyosis associated with menorrhagia? Hum Reprod2014; 29: 473-479.

[27]. Hulka CA, Hall DA, McCarthy K & Simeone J. Sonographic findings in patients with adenomyosis: can sonography assist in predicting extent of disease? AJR Am J Roentgenol 2002; 179: 379-383.

[28]. CRUK. Uterine Cancer Incidence Statistics: Uterine cancer incidence trends over time (last reviewed May 2014). Available at: http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/uterine-cancer/incidence#ref-2.

[29]. Brooks SE, Zhan M, Cote T & Baquet CR. Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999. Gynecol Oncol 2004; 93: 204-208.

[30]. Lumsden MA, Hamoodi I, Gupta J & Hickey M. Fibroids: diagnosis and management. BMJ 2015; 351: h4887.

[31]. Brohl AS, Li L, Andikyan V, et al. Age-stratified risk of unexpected uterine sarcoma following surgery for presumed benign leiomyoma. Oncologist 2015; 20: 433-439.

[32]. Lavie O, Barnett-Griness O, Narod SA & Rennert G. The risk of developing uterine sarcoma after tamoxifen use. Int J Gynecol Cancer 2008; 18: 352-356.

[33]. Giuntoli RL, 2nd, Metzinger DS, DiMarco CS, et al. Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy. Gynecol Oncol 2003; 89: 460-469.

[34]. Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A 2001; 98: 33873392.

[35]. Peddada SD, Laughlin SK, Miner K, et al. Growth of uterine leiomyomata among premenopausal black and white women. Proc Natl Acad Sci USA 2008; 105: 19887-19892.

[36]. Parker WH, Fu YS & Berek JS. Uterine sarcoma in patients operated on for presumed leiomyoma and rapidly growing leiomyoma. Obstet Gynecol 1994; 83: 414-418.

[37].* Valentin L. Imaging techniques in the management of abnormal vaginal bleeding in non-pregnant women before and after menopause. Best Pract Res Clin Obstet Gynaecol 2014; 28: 637-654.

[38]. FDA. UPDATED Laparascopic Uterine Power Morcellation in Hysterectomy andMyomectpmy: FDA Safety Communication 2014. Available at: http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm424443.htm

[39]. Denny L, Quinn M & Hacker N. FIGO Cancer Report 2012. Int J Gynaecol Obstet 2012; 119 Suppl 2: S89.

[40]. Shankar M, Lee CA, Sabin CA, et al. von Willebrand disease in women with menorrhagia: a systematic review. BJOG 2004; 111: 734-740.

[41]. Kadir RA, Economides DL, Sabin CA, et al. Frequency of inherited bleeding disorders in women with menorrhagia. Lancet 1998; 351: 485-489.

[42].* Kouides PA, Conard J, Peyvandi F, et al. Hemostasis and menstruation: appropriate investigation for underlying disorders of hemostasis in women with excessive menstrual bleeding. Fertil Steril 2005; 84: 1345-1351.

[43].* Critchley HO & Maybin JA. Molecular and cellular causes of abnormal uterine bleeding of endometrial origin. Semin Reprod Med 2011; 29: 400-409.

[44].* Mahmud A, Smith P & Clark J. The role of hysteroscopy in diagnosis of menstrual disorders. Best Pract Res Clin Obstet Gynaecol 2015; [Epub ahead of print].

[45]. Struble J, Reid S & Bedaiwy MA. Adenomyosis; A Clinical Review of a Challenging Gynecologic Condition. J Minim Invasive Gynecol 2015; [Epub ahead of print].

[46]. Maiti S & Naidoo K. Patients' satisfaction survey at the outpatient hysteroscopy service at St Mary's Hospital, Manchester, UK. Menopause Int 2008; 14: 5.

[47]. Standards for Gynaecology. RCOG; 2008: Available at: https://www.rcog.org.uk/globalassets/documents/guidelines/wprgynstandards2 008.pdf.

[48]. Sangkomkamhang US, Lumbiganon P, Laopaiboon M & Mol BW. Progestogens or progestogen-releasing intrauterine systems for uterine fibroids. Cochrane Database Syst Rev 2013; 2: CD008994.

[49]. Tristan M, Orozco LJ, Steed A, et al. Mifepristone for uterine fibroids. Cochrane Database Syst Rev 2012; 8: CD007687.

[50]. Moroni RM, Martins WP, Ferriani RA, et al. Add-back therapy with GnRH analogues for uterine fibroids. Cochrane Database Syst Rev 2015; 3: CD010854.

[51].* Donnez J, Tomaszewski J, Vazquez F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012; 366: 421-432.

[52]. Liu JP, Yang H, Xia Y & Cardini F. Herbal preparations for uterine fibroids. Cochrane Database Syst Rev 2013; 4: CD005292.

[53]. Zhang Y, Peng W, Clarke J & Liu Z. Acupuncture for uterine fibroids. Cochrane Database Syst Rev 2010: CD007221.

[54]. FEMME Trial; Available at: http://www.birmingham.ac.uk/research/activity/mds/trials/bctu/trials/womens/ femme/index.aspx.

[55].* Roberts TE, Tsourapas A, Middleton LJ, et al. Hysterectomy, endometrial ablation, and levonorgestrel releasing intrauterine system (Mirena) for treatment of heavy menstrual bleeding: cost effectiveness analysis. BMJ 2011; 342: d2202.

[56]. Problematic Bleeding with Hormonal Contraception. FSRH; 2015: Available at:

http://www.fsrh.org/pdfs/CEUGuidanceProblematicBleedingHormonalContra ception.pdf.

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 <24

Normal 24-38 V

Infrequent >38

Regularity of menses, cycle to cycle Absent No bleeding

(Variation in days over 12 months Regular Variation +/- 2-20

Irregular days Variation >20 days

Duration of flow (days) Prolonged >8.0

Normal 4.5-8.0

Shortened <4.5

Volume of monthly blood loss (mL) Heavy >80

Normal 5-80

Light <5

Table 2. Structured history for coagulopathy screen. Adapted from Koudies et al [42]

Criteria

1. Heavy bleeding since the menarche

2. One of the following:

• Postpartum haemorrhage

• Surgical related bleeding

• Bleeding associated with dental work

3. Two or more of the following:

• Bruising 1-2 times/month

• Epistaxis 1-2 times per/month

• Frequent gum bleeding

• Family history of bleeding problems

Table 3. Specific treatment options for individual PALM-COEIN causes of AUB.

AUB Sub-classification Specific treatment

Polyp Resection

Adenomyosis Surgery: hysterectomy; adenomyectomy (not frequently performed)

Malignancy Surgery +/- adjuvant treatment High dose progestogens (if surgery not 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]

Not otherwise classified Antibiotics for endometritis Embolisation of AV malformation

FIGURE LEGENDS

Figure 1: FIGO classification of causes of AUB; 'PALM COEIN'.

Figure 2: Tertiary classification of AUB-L Adapted from Munro et al [13].

Figure 3: Structured approach to assessing the patient presenting with AUB

Figure 4: Symptom based approach to management of AUB in the context of fibroids.

ACCEPTED MANUSCRIPT

A: USS view of polyp B: Hysteroscopic view of polyp

C: MRI of adenomyosis D: USS of adenomyosis E: Hysterectomy specimen containing fibroids F: Hysterectomy specimen containing

endometrial cancer G: Histology of endometrioid carcinoma H: Excessive bruising I: USS of polycystic ovary J: Progesterone receptor localisation in

secretory phase K: levonorgestrel-releasing intrauterine system

(LNG-IUS) L: Doppler USS of AV malformation M: Doppler USS of endometrial pseudo-aneurysm

Not otherwise classified

Primary

Secondary Tertiary

Absent

Present

Submucosal

0 Pedunculated intracavity

1 <50% intramural

2 >50% intramural

3 Contacts endometrium

4 Intramural

5 Subserosal >50% intramural

6 Subserosal <50% intramural

7 Subserosal pedunculated

8 Other (eg cervical parasitic)

History

Menstrual

• Menarche

• Last menstrual period

• Menses frequency, regularity, duration and volume

• Intermenstrual bleeding and postcoital bleeding

Symptoms of anaemia

Sexual and Reproductive History

• Past pregnancies and mode of delivery

• Future fertility desire

• Subfertility

• Current contraceptive requirement

• Previous STIs

• Smear history

Associated Symptoms

• Pain

• Discharge

• Bowel and bladder symptoms in particular pressure

Systemic

• Weight change

• Coagulopathy history screen (Table 3)

• PCOS, liver, renal, thyroid, pituitary and adrenal disease

• Drug history: anti-platelet, anti-coagulant, tamoxifen, hormones, HRT, dopamine agonists

Family history: VTE, malignancy

Examination

Basic observations: BP, BMI Pallor

Signs of systemic disease

• Thyroid disease

• Bruising, petechiae

• Cushing's

• Hyperandrogenism

Palpable pelvic mass Speculum and bimanual

If indicated: smear, chlamydia screen, endometrial biopsy Consider PR if appropriate

Investigation

Haemoglobin and consider ferritin

• If indicated: TFTs, gonadotrophins, PRL, HCG, coagulopathy investigations

MRI if required Hysteroscopy if required

Social: impact of symptoms, smoking and occupation

Symptoms

AUB only AUB with pressure symptoms; family complete and no desire to retain fertility AUB symptoms and fertility desire/subfertility

No cavity distortion LNG-IUS Tranexamic acid Mefenamic acid UPA GnRH analogue P UPA GnRH analogue Tranexamic acid Mefenamic acid UPA (short course) GnRH analogue (short course)

UAE EA Hysterectomy UAE (MRgFUS) Myomectomy Hysterectomy Myomectomy UAE (evidence here needed) (MRgFUS)

Cavity distortion Tranexamic acid Mefenamic acid UPA GnRH analogue P UPA GnRH analogue Tranexamic acid Mefenamic acid UPA (short course) GnRH analogue (short course)

TCRF UAE Hysterectomy UAE Myomectomy Hysterectomy TCRF Myomectomy UAE (evidence here needed)

Medical treatment Surgical treatment

LNG-IUS Levonorgestrel-releasing -intrauterine system

UPA Ulipristal acetate

GnRH analogue Gonadotrophin-releasing hormone analogue

P Systemic progestogens • Medroxyprogesterone acetate • Norethisterone • Depo-Medroxyprogesterone acetate

EA Endometrial ablation

UAE Uterine artery embolisation

(MRgFUS) MR-guided focused ultrasound - predominantly experimental at present

TCRF Transcervical resection of fibroid

Highlights

• The FIGO 'PALM COEIN' classification of abnormal uterine bleeding (AUB)

• Mechanisms by which fibroids contribute to AUB

• Structured approach to the assessment and management of the patient with fibroids who presents with AUB