Androgens and women's health: developing new therapies to treat endometrial disorders

Lead Research Organisation: University of Edinburgh
Department Name: MRC Centre for Inflammation Research

Abstract

Endometriosis is a chronic incurable disease that affects an estimated 176 million women worldwide, similar to the number of women affected by diabetes mellitus or asthma (approximately 1.5 million women in the UK). It is associated with debilitating pelvic pain, painful periods, pain with sexual intercourse and infertility. Endometriosis costs the UK economy £8.2 billion per year. The causes of endometriosis are not known but genetic, environmental and anatomical factors may all contribute. Up to 90% of patients with endometriosis suffer from 'peritoneal disease' caused by the presence of small pieces of tissue ('endometrium' or womb lining) that have 'escaped' into and stuck onto the wall of the pelvic cavity. Once embedded on the peritoneal wall these 'endometriosis lesions' attract nerves, and immune cells that interact with each other and relay 'pain' messages to the brain. Endometriosis is managed by surgical excision of lesions (with its inherent risks) or drugs, but symptoms recur after surgery in up to 75% of women and available medical treatments have undesirable side effects. There is an urgent need for new treatments for endometriosis.
Whilst the type of sex steroid classed as 'androgens' are usually considered as 'male hormones', women also have significant amounts of androgens in their body. We have found that the protein that mediates the androgen signal to target tissues, the androgen 'receptor' is present not only in cells within the uterus but also in cells within endometriosis lesions. Our pilot data show that drugs capable of interacting with androgen receptors could offer a new way of treating women suffering from endometriosis and we believe that a newly developed class of drugs, termed selective androgen receptor modulators or SARMs, could be an effective, alternative novel therapeutic.
Our overarching objective is gain a better understanding of the role played by androgens in the regulation of the endometrium, how this role may become disurbed in women with endometriosis and to test a new class of drugs - the selective androgen receptor modulators (SARMs), as a treatment for endometriosis-dependent pain. We will use samples from patients who attend our clinics, capitalise on other resources in our closely associated research environment (including new animal models) as well as using commercially available drugs that we can re-purpose to treat our patients.
Our proven track record in women's health research and world-leading expertise in steroid hormone action will both ensure rapid progress and support a programme of work that spans both discovery science and translational medicine.

Technical Summary

Endometriosis is a chronic, hormone-dependent, inflammatory disorder characterized by growth of endometrial tissue outside the uterine cavity; it affects 1.5 million women in the UK. The pathophysiology of endometriosis is complex and new personalized therapies to treat the chronic pain suffered by patients is needed. There is compelling evidence that androgens have an impact on the pathophysiology of endometriosis. We have shown that endometrium and endometriosis lesions have AR+ cells and that the treatment of human primary cells, or mice, with androgens has an impact on processes implicated in establishment of these lesions (proliferation, cell migration, tissue remodelling). Androgens regulate inflammatory and pain pathways and the synthetic androgen, Danazol, has been successfully used to treat women with endometriosis-associated pain. Danazol is no longer recommended as a front-line therapy because of unacceptable (virilizing) side effects. However the development of a new class of drug - the selective androgen receptor modulators (SARMs) - tested in women for other indications provides us with the unique opportunity to repurpose SARMs as a treatment of endometriosis-associated pain. The programme will use discovery and translational science to develop a fully rounded understanding of the androgen 'steroidome' of women with endometriosis and the androgen microenvironment of endometriotic lesions. We will stratify responses to SARMs using 3D culture systems (primary human cells) and a mouse model of menstruation (inflammation, progenitor recruitment, repair processes) to prioritise one SARM for testing in our innovative mouse model of endometriosis.
The programme will support a wide range of collaborations as well as capacity building in steroids and women's health research by training students and postdoctoral scientists.

Planned Impact

Impact on patients
Endometriosis is a chronic disorder that causes pelvic pain, painful periods, pain with sexual intercourse and infertility. In the UK, ~1.5 million women have endometriosis. Current treatments include surgical excision or hormonal suppression. On average women with endometriosis have >2 surgeries and over 75% receive hormonal treatments. National patient organisations report that women want to avoid surgery and to have access to medical treatments with fewer side effects.
We will test selective androgen receptor modulators (SARMs) as a novel therapeutic option for endometriosis to: a) allow women with endometriosis to avoid surgery, b) avoid the side-effects of current medical therapy options for endometriosis, c) improve the health and quality of life of patients.

Impact on the biomedical research community
Results will be communicated via primary publications, accessible review articles, conferences, our websites and presentations to pharma. We regularly present at national and international meetings attended by clinicians and researchers. At a national level, AWH and PTKS have initiated the formation of an Endometriosis Research Network providing a forum for exchange of ideas/experiences between researchers, health professionals and patients with biannual meetings. Results obtained on the impact of SARMs on primary human endometrial cells and female mice will be of particular interest to biomedical researchers exploring the role of androgen receptors in regulation of gene expression as to date most of these studies have been conducted on prostate cells or in males.

Impact on Policy makers
Endometriosis has received relatively little attention compared with other chronic disorders. In 2014, AWH organised an event (>100 attendees, including politicians, clinicians, patients) in the Scottish Parliament to campaign for better care and research across Scotland for women with endometriosis. AWH and colleagues have established a Scottish Government Endometriosis Short Life working group working closely with Scotland's Chief Medical Officer to take this forward.

Impact on the commercial sector
The University of Edinburgh has a dedicated technology transfer group, responsible for protecting IP and commercializing research. The investigators have already established a fruitful dialogue with Dr Mike Finnen (Chief of Operations, Edinburgh Bioquarter) regarding the translational potential of our studies. PTKS and AWH have spun out a company 'Icthus Therapeutics' founded in partnership with Edinburgh BioQuarter to study novel therapies for treatment of endometriosis pain.

Impact on training and capacity building
We have a strong track record in training PhD students and supporting postdoctoral fellows to obtain independent funding. This programme will provide opportunities for PhD students and staff (including the postdoc) to gain skills in mentorship and supervision. We will use local seminars and informal discussion groups to help trainees gain experience in presenting and defending their research in preparation for national and international conferences. The applicants regularly lecture to clinical and non-clinical students and are committed to offering mini-projects to undergraduate and MSc students so that they can participate in research activity.

Impact on the public and wider society
We will engage with the public via print and a range of digital media including a dedicated webpage [www.exppectedinburgh.co.uk]. PTKS also Tweets and shares information about endometriosis on Facebook. In the recent past our studies have received wide coverage in the press and digital media including the BBC website. We are currently working with BBC Alba to produce a programme about our work with endometriosis patients. We will participate in public events including the Edinburgh Science Festival.

Publications

10 25 50
 
Description Chair Springboard Grants panel
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Grants were given to academics in their first University post to enhance their ability to undertake research led teaching and also to gain further funding for their own research activity
 
Description Endometriosis - James Lind PSP
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Management group of priority setting partnership in endometriosis run under the auspices of the James Lind Alliance. Financial support provided as part of public engagement commitment from grants. Surveys were conducted nationally and results led to publication of a top 10 priority for research - this is being considered by funders including NIHR (phone calls and discussions). High profile publication in the Lancet. Social media activity and engagement with clinical and research community.
 
Description Team Science Follow up meeting - co-chair
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact This was a 2 year follow up report from the Academy of Medical Sciences on the progress made against the goals of the 2016 Team Science Report on challenges faced by biomedical researchers in gaining recognition for their work. The report has been widely circulated to key stakeholders including policy makers, commercial organisations and employers. There was significant interest on social media and articles in specialist and general print media.
URL https://acmedsci.ac.uk/policy/policy-projects/team-science
 
Description Ferring Research Innovation Grant
Amount $70,000 (USD)
Organisation Ferring Pharmaceuticals 
Sector Private
Country Switzerland
Start 06/2017 
End 05/2019
 
Description IMI2-2016-10-03C
Amount € 6,480,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 04/2018 
End 03/2021
 
Description MOMENDO
Amount € 1,000,000 (EUR)
Funding ID 691058 
Organisation European Commission H2020 
Sector Public
Country Belgium
Start 07/2016 
End 07/2019
 
Description MRC Confidence in Concept - Edinburgh
Amount £120,173 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 11/2018 
End 12/2020
 
Title Impact of androgens and SARMs on uterus 
Description In vivo platform for testing impact of androgen receptor agonism in intact uterine tissue. Mice are ovariectomised and androgen or selective androgen receptor modulators administered for 1 or 7 days. Measurement of weight, compartment areas, proliferation and gene expression provide robust and reproducible analysis of AR agonism in an intact tissue regulated by stromal-epithelial interactions. Myometrial area changes additional metric. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2016 
Provided To Others? Yes  
Impact Platform for testing SARMs. Interest from pharma in using the model as basis for drug testing. 
 
Title Tissue and fluid samples from patients with pelvic pain and/or endometriosis 
Description Tissue and fluid samples have been retrieved according to international guidelines (EPHect) with linked annoymised clincial information entered into a customised database (Redcap) - we have harmised our activities/data criteria with those of other international groups. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Collaboration as part of on international consortia investigating epigenetic and genomic causes of endometriosis (follows from publication of research priorities). Extensive collaboration with industry and academic partners (further funding and academic outputs) 
URL http://www.exppectedinburgh.co.uk/
 
Description IMI Grant consortium PainCare 
Organisation European Union
Country European Union (EU) 
Sector Public 
PI Contribution I am leading Work package 10 within the consortium members addressing ' Improving translation in chronic pelvic pain (TRiPP)'. WP10 is focused on improving the translation of new therapies for endometriosis-associated pain by aligning and refining preclinical animal models.
Collaborator Contribution The IMI-PAINCARE Consortium is composed of 40 participants from 14 countries; 6 are EFPIA (European Federation of Pharmaceutical Industries and Associations) participants with strong traditions in pain research and development, 23 are internationally renowned academic and clinical institutions, 5 are specialist SMEs with cutting-edge technologies, 3 are patient organizations and 3 are professional pain/anesthesia societies. The Consortium addresses three important topics: Patient reported outcome measures to improve management of acute and chronic pain (PROMPT); Pharmacological validation of functional pain biomarkers in healthy subjects and animals (BioPain); Improving translation in chronic pelvic pain (TRiPP).
Impact Employment of a posdoctoral fellow for 2 years. Purchase of state of the art in cage monitoring equipment (3R's commitment) Knowledge exchange with leaders in the field of pain including those based in commercial companies (Bayer, Grunenthal)
Start Year 2018
 
Description Studies on Endometriosis 
Organisation Catholic University of Louvain
Country Belgium 
Sector Academic/University 
PI Contribution Academic collaboration sharing ideas for publications and so-supervision of PhD student
Collaborator Contribution Academic collaboration sharing ideas for publications and so-supervision of PhD student
Impact Publications Grant for PhD student
Start Year 2012
 
Description Androgens 2018 Conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was a 3 day symposium which is part of a biannual series hosted at different locations in Europe - the local organising committee included Saunders and Gibson and they organised both the programme and social events. The meeting was attended by more than 80 people a significant number of which were trainees (PhD students and postdocs). Presentations featured data generated from the MRC programme grant. Feedback from trainees was excellent and it also raised the profile of research on androgens within the University of Edinburgh and generated new opportunities for collaboration.
Year(s) Of Engagement Activity 2018
 
Description Media engagement in relation to publication 
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 Press release related to publication in Fertility and Sterility related to role of androgens in fertility. Article in Daily Mail, widespread international and national reporting in social media including twitter. High altmetrics
Year(s) Of Engagement Activity 2018
 
Description Patient Information Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact This was an event targeted at women who suffer from endometriosis (pain, infertility) and their family members. it was run jointly with the UK patient group Endometriosis UK [https://www.endometriosis-uk.org/] who publicised it via their patient support groups. A speaker from Endometriosis UK introduced the event which consisted of talks from a range of health care professionals (University and NHS staff) as well as researchers. There was time for informal discussion and also for a Q&A. The event was widely publicised on social media and there was a lot of positive feedback from participants.
Year(s) Of Engagement Activity 2019