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

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 disturbed 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.

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.

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.