Developmental Clinical Studies - Reversing endometrial glucocorticoid deficiency in heavy menstrual bleeding

Lead Research Organisation: University of Edinburgh
Department Name: School of Clinical Sciences

Abstract

Heavy periods are literally a monthly 'curse' for millions of women. Menstrual complaints have a broad negative impact on the lives of women - affecting their everyday activities, including work, family life and relationships. Menstrual problems can occur any time between 12 and 55 years of age, but heavy menstrual bleeding (HMB) is most common between 30 and 50 years of age, which is also the stage when women have numerous aspirations, roles and responsibilities, which would be severely curtailed by menstrual complaints. The regular impact of menstruation (about a quarter of a woman's life - 7 days out of 28) can lead to low mood, which can in turn impact further on quality of life and fulfilment of roles. For those in families with low income, the cost of sanitary protection for HMB can also be a recurring burden on the family budget.
A million women a year seek medical help for their condition, consuming considerable NHS resource, in terms of consultations with GPs (or attendances at hospital clinics) and tests and prescriptions. Unfortunately the treatments on offer are often ineffective and many women complain of unacceptable side effects. Although hysterectomy can solve the problem of heavy bleeding most women would rather avoid taking this 'irreversible' step which is not surprising as close to half of all babies born in the UK have mothers aged 30 or older . There is therefore an urgent requirement for development of novel, effective, medical treatments for heavy periods.
Our plan builds on previous research comparing the lining of the womb in women with and without heavy bleeding. This has provided compelling evidence that the activity of glucocorticoids in the endometrium of women with HMB is deficient..We believe this deficiency results in altered structure of the blood vessels of the womb, which could lead to increased menstrual bleeding.
We hope to demonstrate that a glucocorticoid (dexamethasone; Dex), already in common use for other conditions, will reverse the observed endometrial glucocorticoid deficiency, and hence be beneficial in women requesting treatment for HMB. Dex will be given to women in the second half of their menstrual cycle, in the week prior to their expected period (menses) and we expect Dex given over this time period will improve the ability of blood vessels in the endometrium to efficiently constrict when menses commences, and hence reduce menstrual bleeding. While this is a novel use of Dex, it is in wide-spread use eg .glucocorticoids are used to treat medical conditions in early pregnancy including asthma and rheumatoid arthritis. A lot is already known about the side-effects that can occur with Dex and that they depend upon the duration of treatment as well as the dose. This leads us to expect that Dex will be unlikely to be cause problems during the short courses of treatment we plan to use in this study.
We hope this new medical treatment will benefit women of reproductive age suffering from heavy bleeding by reducing their blood loss improving their quality of life, allowing them to participate in family activities and avoid time off work. Our beneficiaries will thus be the women, their families and employers, and in terms of costs saved, society and the economy.

Technical Summary

Treatment of menstrual bleeding complaints has a major impact on health care costs. The proposed studies will provide proof of concept of efficacy of the glucocorticoid Dex, together with pharmacodynamic data concerning optimal endometrial Dex concentrations required for efficacy in treatment of women with heavy menstrual bleeding (HMB). The data generated will justify further investment in a phase III trial and new intrauterine delivery systems.
A sequence of two studies is proposed with outcome in each being reduction in objectively measured menstrual blood loss (MBL). Study A is an initial open uncontrolled dose-ranging study to assess the effect of Dex on MBL and will explore a range of therapeutic doses. Study B is a follow-on phase II double blind crossover RCT, comparing Dex (at two doses, selected using findings of Study A) to placebo treatment.
Assessments to be used are: Patient Clinical History; Recruitment Questionnaire of HMB problem; MBL estimated from daily menstrual bleeding pictogram diaries and objective measurement of MBL measured in 'no treatment' baseline cycles and 2nd of a pair of cycles for each treatment/dose; Menstrual diary (allowing recording of medication consumption, adverse events); Questionnaire report of treatment effect. Endometrial response to luteal phase administration of Dex will be evaluated (including vascular morphology and differentiation) and endometrial Dex concentration assayed by (LCMS/MS). Ovarian function will be monitored by measurement of urinary sex steroid metabolites. Endometrial function will be assessed with DCE-MRI (dynamic contrast-enhanced MR imaging): images will be analysed using pharmacokinetic modelling techniques that monitor changes in uterine permeability kinetics and plasma volume fraction. MR Fluorine Spectroscopy will be used to measure dexamethasone concentrations in endometrium and this will be used simultaneously with MR blood flow measurements.

Planned Impact

Strategic importance: Heavy menstrual bleeding (HMB) is a chronic complaint that impacts on quality of life and well-being of a large proportion of reproductive age women, often over many years, and typically at a time when they should be at their most active/productive (30 to 49 years of age). There are shortcomings in the currently available medical therapies and surgical options are not always appropriate (eg as compromise fertility), involve risks, and are more costly. This research addresses an area of unmet clinical need and has the potential to translate to clear patient, family and societal benefits.
Our proposal fits with a number of MRC strategic objectives:
- Improve human health
- Promote translation of basic research discoveries into new/ improved healthcare
- Encourage commercial exploitation, for the benefit of the UK's health and economy
- Attract and train first-rate researchers (the study clinical research fellow)
Specifically, our proposal meets the MRC five year Strategic Plan (2009-2014), in particular with respect to Strategic Aims:
1: 'Picking Research that Delivers' - in respect of themes:
(i) 'Resilience, repair and replacement' by utilising knowledge about the biology of human tissue and by translating knowledge of tissue repair into new treatment strategies (healing of injured endometrium post-menstruation in HMB)
(ii) Mental health and wellbeing: seeking to improve wellbeing/mental health by ameliorating disease processes.
2. 'Living a long and healthy life - Life course perspective': by gathering an interdisciplinary team with aim of improving the health/ well-being of women in their reproductive years.
3. 'Research to people': in terms of 'Translation of research' ie aiming to bring the health impacts of fundamental research to people more quickly.
4. 'Supporting Scientists' - by contributing to 'Capacity' in terms of skilled research workforce/ research leaders.
Who benefits and how:
End users are women of reproductive age seeking treatment for HMB; many will desire to retain their uterus (and fertility). Beneficiaries will be the women, their families and employers, and in terms of costs saved, society and the economy.
Patients/ Patient families: There is a direct impact of menstrual symptoms and limitations on well-being and family/ social roles (often at a time when there may be additional responsibilities ,i.e. caring for/supporting young children and elderly relatives). Menstrual symptoms may also impact on career and earning potential, and hence well-being. Patients with HMB will benefit from the treatment, not solely in terms of amelioration of HMB, but also via improved quality of life, capacity to optimise their productivity in employment and to participate in family activities.
Employers: It is well known that there are impacts on industry and the UK economy not just through absenteeism (due to menstrual problems), but also in the case of 'presenteeism', when a woman with menstrual problems nevertheless presents herself for work, but performance /productivity is affected by her symptoms.
The NHS budget: Curtailing costs/ consultation rate at GPs and clinics.
Clinicians: Past research has identified that GPs regard menstrual complaints as difficult to manage due to the absence of effective medical treatments. Similarly community gynaecology clinicians would welcome an effective medical treatment.
Research Community: Our research will benefit research communities investigating mechanisms involved with menstruation/menstrual bleeding problems. In addition the data generated on glucocorticoid modulation of vascular development will benefit researchers in the wider fields of vascular and inflammation biology, and MR imaging technologies.
Industry: Data generated from our proposal, along with our extensive expertise/ know-how in women's health and HMB will be crucial for our aim to partner with a third party pharmaceutical company to move to commercialisation

Publications

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Iredale JP (2016) BREXIT and science, where do we go from here. in QJM : monthly journal of the Association of Physicians

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Maybin JA (2016) Medical management of heavy menstrual bleeding. in Women's health (London, England)

 
Description Industry advisory committee (Bayer Schering Pharma AG)
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description Launch of Advice Paper on Women, Work and Care at Royal Society of Edinburgh
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Title Development of a Bayesian response-adaptive dose-finding study 
Description Utilisation of an integrated approach to the development of a Bayesian response-adaptive dose-finding study using SAS and WinBUGS. Data presented at 2013 Clinical Trials Methodology Conference, Edinburgh International Conference Centre, 18-19 November.in the Adaptive Designs session. 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact This integrated approach to develop a Bayesian response-adaptive dose-finding study will now inform protocol development for clinical trials 
 
Title Endometrial tissue resource after exposure to exogenous oral low dose glucocorticoid 
Description Endometrial tissue resource after exposure to exogenous oral low dose glucocorticoid 
Type Of Material Biological samples 
Provided To Others? No  
Impact Opportunity to work cross- discipline (endocrinology & gynaecology) 
 
Title Human Female Reproductive Tract Tissue Resource 
Description Archive and prospective tissue resource with & tissue bank approval; 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact Multiple collaborations: local, some international and with industry Tissue bank approval (since 2011) for this resource 
 
Title Phamacokinetic models to describe dynamic-MRI data in the human uterus 
Description We have developed robust imaging and analysis protocols for acquisition of MRI data of the endometrium and myometrium using our dedicated 3T research MRI system based at the University of Edinburgh Clinical Research Imaging Centre. We have optimised phamacokinetic models to describe dynamic-MRI data acquired during the administration of a standard clinical MRI contrast agent. These models allows us to model flow and permeability in the various compartments of the uterus. In particular we have demonstrated that we have the temporal resolution required to dynamically model vascular supply to the endometrium and myometrium and the spatial resolution to readily identify both of these structures. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact These models allow us to model flow and permeability in the various compartments of the uterus. 
 
Title Human female reproductive tract tissue resource 
Description Human female reproductive tract tissue resource -- archival tissue resource (endometrium) = well-characterised/ phenotyped 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact valuable human female reproductive tract tissue resource -- archival tissue resource (endometrium) = well-characterised/ phenotyped 
 
Description FIGO Menstrual Disorders Working Group 
Organisation International Federation of Gynecology and Obstetrics (FIGO)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution Current member FIGO menstrual disorders committee (previously Co-Chair with colleagues from USA and Australia).
Collaborator Contribution Established a FIGO endorsed classification for abnormal uterine bleeding. Within this classification is a sub-classification "Endometrium" molecular and cellular causes of abnormal uterine bleeding and studies arising from this MRC funding have helped inform endometrial biology in this area. Also within this classification is a sub-classification for fibroids
Impact Publications: PMID 22386064 PMID 22068978 PMID 22065329 PMID 22065324
 
Description Our study is supported by the Scottish Primary Care Research Network (SPCRN) 
Organisation Scottish School of Primary Care SSPC
Department Scottish Primary Care Research Network (SPCRN)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We work with Scottish Primary Care Research Network (SPCRN) and Clinical Research Network (CRN) to help identify potential study recruits thereby raising awareness amongst GP colleagues of opportunity for their patients with menstrual complaints to consider study participation.
Collaborator Contribution Engagement with this network [Scottish Primary Care Research Network (SPCRN) and Clinical Research Network (CRN) is helping to identify potential study recruits and raising awareness amongst GP colleagues of opportunity for their patients with menstrual complaints to consider study participation.
Impact multidisciplinary: general practice and gynaecology
Start Year 2016
 
Description Studies on human endometrium 
Organisation Medical Research Council (MRC)
Department MRC Human Reproductive Sciences Unit
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution Provision of intellectual input and exchange of ideas - expertise in endometrial biology Opportunity to study female reproductive disorders due to ready access to clinical primary tissue resource
Collaborator Contribution Collaboration has generated opportunity for successful joint research grant application; shared supervision of PhD students;
Impact Successful joint research grant application to the Wellcome Trust Joint publications: 19955102; 19208787;19196802;18775884; 18032694; 19955102; 20668045; 20885978 IP - patent submitted but not supported beyond first year
 
Title DexFEM 
Description Exploration of first-in-woman use of a short oral course of low-dose dexamethasone to rescue local endometrial glucocorticoid deficiency in women with heavy menstrual bleeding (HMB) 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Study in progress 
 
Description Public Talk (2014) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact MRC Centre for Reproductive Health Public Talk, Edinburgh 19 February 2014. Invited speaker: Blood Vessel Route to Solving Problem Periods. Audience mainly school pupils and the public.

Audience mainly school pupils and the public and event received positive feedback. Discussion with school pupils and general public about impact of research on important women's health clinical complaints. Interest expressed in work experience at Edinburgh Royal Infirmary by one member of audience who subsequently obtained one week work experience placement June 2014.
Year(s) Of Engagement Activity 2014
 
Description Radio interview BBC Scotland's Newsdrive 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed by BBC Scotland Newsdrive programme on subject of studies on helping women with heavy menstrual bleeding.
Year(s) Of Engagement Activity 2016
 
Description media article on menstruation (Why Menstruation Remains a Medical Mystery: https://uk.news.yahoo.com/why-menstruation-remains-medical-mystery-215459035.html) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact media interest in article (peer-reviewed - review type article highlighting research contributions) on menstruation: Live Science.com
https://uk.news.yahoo.com/why-menstruation-remains-medical-mystery-215459035.html
Year(s) Of Engagement Activity 2015
URL https://uk.news.yahoo.com/why-menstruation-remains-medical-mystery-215459035.html