Hypoxia inducible factor (HIF-1) and endometrial remodelling: relevance to menstrual bleeding

Lead Research Organisation: University of Edinburgh
Department Name: Edinburgh Research and Innovation

Abstract

Menstrual disorders impose a major impact on quality of life for healthy women and are one of the four most common reasons for seeking advice from a general practitioner. Heavy menstrual bleeding (menorrhagia) is one of the commonest indications for referral to a gynaecologist. Management typically involves invasive surgery. Current medical treatment options are often associated with side effects such as unscheduled breakthrough bleeding. We still do not know why some women experience problematic menstrual bleeding. Enhancement of our understanding of the mechanism of normal menstruation will provide an opportunity to identify novel targets for potential therapeutic development. Our proposal aims to examine the cascade of events that occur in cells of the womb-lining (endometrium) and triggered by withdrawal of the hormone, progesterone (P). This occurs at the end of each monthly cycle prior to a period or as a consequence of treatment with long-acting progestogen treatment, such as the levonorgestrel- intrauterine system (LNG-IUS). As a consequence of P-withdrawal, enzymes that are involved in the manufacture of substances known as prostaglandins (PGs) are increased in cells of the endometrium. In turn, other factors in these cells are also switched on. In the context of our study we wish to study the factors that switch on production of the molecule, HIF-1alpha and as a result the end products of this cascade that orchestrate blood vessel growth and repair in the endometrium; both necessary events to prepare for the next menstrual cycle. Further if these events are disturbed abnormal menstrual bleeding is a likely consequence. We therefore will seek participation from women attending with menstrual complaints and ask to examine small samples of the endometrium from these patients for molecular and cellular studies. Information about these molecular and cellular pathways will help us identify points in the pathway which could be new targets for treatment, especially if these treatments could be delivered directly to the uterus.

Technical Summary

Menstrual disorders impose a significant impact on quality of life for women. It is essential to understand mechanisms involved in uterine bleeding if improved medical treatments are to be developed and
surgery (hysterectomy) avoided. Progesterone withdrawal is the trigger for menstruation, and is associated with increased expression and generation of potent vaso-active prostaglandins. We describe a case for the prostaglandin EP2 receptor, epidermal growth factor receptor (EGFR) and signalling pathway associated with their regulation of HIF-1alpha, as potential novel therapeutic targets (perhaps by local
administration) for menstrual bleeding disorders.
The functional role of HIF-1alpha in human endometrium is unknown; it may be critical to the regeneration phase of the menstrual cycle.
Tissue regeneration requires angiogenesis and matrix remodelling, processes clearly relevant to known HIF-1alpha target genes.
We propose to undertake a proof of concept study that will, in human endometrium, establish whether progesterone withdrawal and elevated prostaglandin synthesis and signalling initiate local events that lead to HIF-1alpha expression and downstream angiogenic gene expression (VEGF, CTGF, ET, Ang-2). This provides a coordinated mechanism for endometrial regeneration, that when dysregulated could result in heavy menstrual bleeding (menorrhagia). We aim to test these hypotheses in functional assays using human endometrial tissue explants derived from women with measured normal and heavy menstrual blood loss (MBL).
Our proposal addresses the following hypotheses:
(1) women with heavy menstrual bleeding have elevated endometrial HIF-1alpha expression compared to women with normal MBL.
(2)Endometrial tissue from women with heavy bleeding exhibits an altered vasculogenic potential compared to women with normal MBL. For this we will use a functional angiogenesis assay using endometrial tissue explants. (3) Novel agents (inhibitors of PGE2-EGFR-HIF-1 pathway) reduce angiogenesis in a functional explant assay through attenuated angiogenic gene expression and may represent new therapy for disorders of abnormal menstrual bleeding.

Publications


10 25 50
Critchley HO (2011) Molecular and cellular causes of abnormal uterine bleeding of endometrial origin. in Seminars in reproductive medicine
Fauser BC (2011) Sex steroid hormones and reproductive disorders: impact on women's health. in Reproductive sciences (Thousand Oaks, Calif.)
Horne AW (2009) Attenuated sex steroid receptor expression in fallopian tube of women with ectopic pregnancy. in The Journal of clinical endocrinology and metabolism
Horne AW (2011) Placental growth factor: a promising diagnostic biomarker for tubal ectopic pregnancy. in The Journal of clinical endocrinology and metabolism
King AE (2010) Oestrogen and progesterone regulation of inflammatory processes in the human endometrium. in The Journal of steroid biochemistry and molecular biology
King AE (2010) Oestrogen and progesterone regulation of inflammatory processes in the human endometrium. in The Journal of steroid biochemistry and molecular biology
Maybin J (2014) Repair and regeneration of the human endometrium in Expert Review of Obstetrics & Gynecology
Maybin JA (2011) Inflammatory pathways in endometrial disorders. in Molecular and cellular endocrinology
 
Description Contributed to FIGO endorsed classification of Abnormal Uterine Bleeding (AUB)
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Aim is to streamline classification of menstrual bleeding disorders MRC funded Research has contributed to the molecular & cellular understanding of menstrual bleeding disorders - a component within this classification. PI on MRC funded work is co-chair of this initiative Publications relevant are: PMID:22386064;PMID:22065326;PMID:22065324; PMID:21496802;PMID:21345435
URL http://europepmc.org/abstract/MED/22386064
 
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
 
Description Dr J Maybin (PhD funded through MRC Grant G0600048) has gone on to be awarded a Wellcome Trust Postgraduate Training Fellowship (Clinical Academic)
Amount £247,472 (GBP)
Funding ID 100646/Z/12/Z 
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 08/2013 
End 07/2015
 
Description MRC Centre application (G1002033)
Amount £1,086,000 (GBP)
Funding ID G1002033 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2011 
End 03/2016
 
Description MRC Developmental Clinical Studies Grant
Amount £1,642,538 (GBP)
Funding ID MR/J003611/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 08/2012 
End 07/2016
 
Description MRC Project Grant 0900550
Amount £726,874 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2010 
End 01/2013
 
Title Endometrial microarray data from women with heavy bleeding 
Description Human endometrial samples categorised across the menstrual blood loss spectrum have provided resource for microarray studies and thus RNA dataset from women with heavy menstrual bleeding 
Type Of Material Biological samples 
Provided To Others? No  
Impact Human endometrial samples categorised across the menstrual blood loss spectrum have provided RNA dataset from women with heavy bleeding -- this will permit detailed in silico analyses and pathway analyses that will direct future studies in women heavy menstrual bleeding 
 
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 Human endometrial samples categorised across the menstrual blood loss spectrum 
Description Human endometrial samples categorised across the menstrual blood loss spectrum 
Type Of Material Biological samples 
Year Produced 2009 
Provided To Others? Yes  
Impact Provided opportunity for microarray analyses and thus generation of RNA data sets Tissue Resource for further collaborative studies -initially with other groups within local research environment 
 
Title Human female reproductive tract tissue resource 
Description Female reproductive tract tissue archive (human endometrium and ovarian surface/ peritoneal surface epithelium) complemented with a computerised detailed dataset of consent records and patient characteristics for study participants since 2001. 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact Invaluable resource to identify well-characterised cases for future re-use of stored tissue (with patient consent). Credible centralised source data for on-going, current and archived human female reproductive tract tissues. We now have a "tissue bank approval" since 2011 for this resource 
 
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 Anti-inflammatory and pro-resolution mediators of endometrial repair 
Organisation Medical Research Council (MRC)
Department MRC Human Reproductive Sciences Unit
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution Exchange of expertise, laboratory reagents and intellectual input to facilitate continuation of collaborative research
Collaborator Contribution Exchange of expertise, laboratory reagents and intellectual input to facilitate continuation of collaborative research
Impact Co-investigator on research grant
Start Year 2006
 
Description Development of animal models of menstruation 
Organisation Faculty of Medicine, Nursing and Health Sciences
Department Department of Obstetrics and Gynaecology
Country Australia, Commonwealth of 
Sector Academic/University 
PI Contribution Provided opportunity for undergraduate medical student elective project -- subsequent sharing of data generated Provided preliminary data to support development of xenograft model of menstruation
Collaborator Contribution Provided preliminary data to support xenograft model of menstruationShared intellectual exchange Opportunity for medical student elective project to generate pilot data for future grant applications
Impact Provided opportunity for undergraduate medical student elective project Generation of preliminary data to support development of xenograft model of menstruation Murine models of menstruation have now been established in MRC Centre for Reproductive Health in Edinburgh
Start Year 2008
 
Description Development of animal models of menstruation 
Organisation University of Melbourne
Department Department of Obstetrics and Gynaecology
Country Australia, Commonwealth of 
Sector Academic/University 
PI Contribution Provided opportunity for undergraduate medical student elective project -- subsequent sharing of data generated Provided preliminary data to support development of xenograft model of menstruation
Collaborator Contribution Provided preliminary data to support xenograft model of menstruationShared intellectual exchange Opportunity for medical student elective project to generate pilot data for future grant applications
Impact Provided opportunity for undergraduate medical student elective project Generation of preliminary data to support development of xenograft model of menstruation Murine models of menstruation have now been established in MRC Centre for Reproductive Health in Edinburgh
Start Year 2008
 
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 Research collaboration with Bayer Pharma AG 
Organisation Bayer
Country Germany, Federal Republic of 
Sector Private 
PI Contribution All studies will be conducted at University of Edinburgh
Collaborator Contribution Research grant to develop animal models of menstruation - thereby providing opportunity for intellectual exchange with research scientists at Bayer Pharma AG and access to novel steroid agonists and antagonists plus other pharmacological agents for research studies
Impact New collaboration from Sept 2010 Life Sciences Workshop on Abnormal uterine bleeding: Berlin Nov 10-12 2010 Via human reproductive tract tisse resource - enabled sharing of endometrial RNA (human) resource for detailed gene microarray studies
Start Year 2010
 
Description Studies on female reproductive tract injury and repair 
Organisation Medical Research Council (MRC)
Department MRC Centre for Inflammation Research
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution Exchange of ideas and expertise and continuation of a joint collaborative research programme
Collaborator Contribution Exchange of ideas and expertise and continuation of a joint collaborative research programme
Impact MRC British Lung Foundation Capacity Building PhD studentship
Start Year 2006
 
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
 
Description Studies on human fallopian tube and ectopic pregnancy 
Organisation University of Edinburgh
Department Centre for Reproductive Biology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Provision of intellectual input and exchange of ideas - expertise in uterine biology Opportunity to study female reproductive disorders due to ready access to clinical primary tissue resource
Collaborator Contribution Intellectual input and exchange of ideas. Development of collaborative research programme
Impact Mentorship of trainee clinical academic who subsequently has been awarded an MRC Clinician Scientist Fellowship 2009-13 Successful joint grant awarded from Wellbeing of Women 2008-10 Joint publications: 19864448; 20047737; 20651036; 20864676; 20978183; 21047920; PMID:22685224
Start Year 2006
 
Description Studies on human female reproductive tract tissues (endometrium, ovarian surface epithelium, fallopian tube, peritoneum) 
Organisation Medical Research Council (MRC)
Department MRC Centre for Inflammation Research
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution Provision of intellectual input and exchange of ideas - technical (molecular & cellular study expertise) Opportunity to study female reproductive disorders due to access to clinical primary tissue resource
Collaborator Contribution Collaborative discussions have generated opportunity for joint research grant applications and shared supervision of PhD students Opportunity to share reagents and technical laboratory expertise
Impact Joint successful grant application to MRC [2009-2012. MRC Project Grant. £700870 "Postovulatory ovarian repair: a role for LOX in scar-free adult healing] Through Research collaboration with Bayer Pharma - sharing of endometrial RNA resource
Start Year 2006
 
Description Studies on uterine immune cells 
Organisation Medical Research Council (MRC)
Department MRC Centre for Inflammation Research
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution Opportunity to study isolated immune cells from primary human uterine tissues
Collaborator Contribution Exchange of ideas and expertise (molecular and cellular)
Impact Novel preliminary data necessary for preparation of collaborative grant applications. Co-supervision of current PhD student. Publications: 19196802 and PMID:23108100
Start Year 2008
 
Title EP receptor antagonists 
Description Use of antagonists for receptors of prostaglandin E2 (EP2 and EP4) for treatment of benign endometrial pathologies. Our collaborative studies have demonstrated receptors of prostaglandin E2 are elevated in a number of endometrial pathologies. Suppression of receptor function reduces/ inhibits these pathways with potential for therpeutic benefit. 
IP Reference US2008206309 
Protection Patent granted
Year Protection Granted 2008
Licensed No
Impact Unknown
 
Title FP receptor antagonist 
Description FP receptors are elevated in several endometrial pathologies 
IP Reference US2007004620 
Protection Patent granted
Year Protection Granted 2007
Licensed No
Impact Unknown
 
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 Invited speaker and participant Scientific Workshop (Bayer Schering Pharma Ag) 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Scientific Meeting, Scientific Workshop on "IUS and Uterine Bleeding", Bayer Schering Pharma AG, Berlin 9-10 June 2008 Invited speaker: Human endometrial function: role of progesterone withdrawal in endometrial (breakthrough) bleeding.

Raised profile to industry of importance of menstrual bleeding problems and impact of menstrual disorders of health and quality of life to many women
Year(s) Of Engagement Activity 2008
 
Description Invited speaker MRC Showcase Programme (Edinburgh) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact MRC Showcase Programme, Physiological Systems and Clinical Sciences Board, 11 - 12 September 2007. Edinburgh. Inflammation Invited speaker: Injury and repair in the female reproductive tract. Audience was mixture of scientists from academia and industry

FIGO international meeting Rome; topic abnormal uterine bleeding; Audience was mixture of scientists and clinicians from academia, industry and in clinical practice


Co-organiser & speaker at industry (Bayer Schering Pharma) forum on abnormal uterine bleeding, Berlin Germany -- 20-30 international experts (academia & industry)

Speaker at Nordic Ob/GYN society (Norway) annual meeting (approx 100 participants)

Discussions with scientists working in industry
Year(s) Of Engagement Activity 2007,2010,2011,2012
 
Description Invited speaker and participant Life Science Workshop (Bayer Schering Pharma Ag) 2010 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Scientific Meeting, Scientific Workshop on "Abnormal Uterine Bleeding", Bayer Schering Pharma AG, Berlin 10-12 November 2010. Invited speaker: Heavy Menstrual Bleeding: evidence for disturbed "injury and repair".

Raised profile to industry of importance of menstrual bleeding problems and impact of menstrual disorders of health and quality of life to many women
This "Life Sciences" workshop also explored potential mechanistic pathways for future therapeutic targets
Year(s) Of Engagement Activity 2010
 
Description Invited speaker and participant Scientific Meeting (Preglem 2012) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Scientific Meeting on "SPRMs and a new treatment for uterine fibroids", Preglem , Leeds 22 May 2012. Invited speaker: Progesterone receptor modulators (PRMs), effects on the endometrium.

Raised profile to indudstry of importance of menstrual bleeding problems and impact of menstrual disorders of health and quality of life to many women.
Year(s) Of Engagement Activity 2012
 
Description Max Perutz Science writing prize 2009 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Annual MRC science writing award [Max Perutz prize] awarded to Clinical Research Fellow studying for PhD and funded from this grant

Further exposure in the media: BBC interview on Radio 4 [Leading Edge BBC radio program]. Further radio invitation from BBC Radio "Moments of Genius" to celebrate the international year of science in 2010. Its a two minute slot to discuss a moment of genius in science. Scientists and famous people have been asked to take part. They are to be used as fillers in the Today programme.
Year(s) Of Engagement Activity 2009
 
Description Pathways to Professions Public Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Pathways to Professions Public Lecture

xx Work experience
Year(s) Of Engagement Activity 2015
 
Description Public Lecture (2012) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact MRC Centre for Reproductive Health Public Talk, Edinburgh 25 January 2012. Invited speaker: Heavy menstrual bleeding: a period drama. 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.
Year(s) Of Engagement Activity 2010
 
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 Public lecture (2008) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Centre for Reproductive Biology Public lecture series, Edinburgh Invited speakers: Periods: a bleeding pain! Will it ever be possible to make every week of the month bearable? Audience mainly school students and the public

Audience mainly school students 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
Year(s) Of Engagement Activity 2008
 
Description Public lecture (2010) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Centre for Reproductive Biology Public lecture series, Edinburgh Invited speaker: A womb with a view: a closer look at endometriosis and fibroids.
Opportunity to disseminate information to a lay audience about importance of understanding basis for problematic monthly bleeding.

Audience mainly school students 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
Year(s) Of Engagement Activity 2010
 
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