Polycystic Ovarian Syndrome: modelling development, phenotype and progression using a developmental paradigm

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

Abstract

Polycystic ovarian syndrome (PCOS) is common: more than one in twenty young women has this condition. There are many associated health problems including abnormal periods, miscarriages, infertility, excess hair, acne, weight gain and diabetes. As we do not understand what causes PCOS, we can only treat the various symptoms rather than the condition itself. We think that the seeds for PCOS are sown at the beginning of life before birth. Although sheep don?t normally suffer from PCOS, if we change the hormonal environment slightly before birth they develop a lot of features of PCOS as adults. We think similar changes in the environment before birth in women is associated with the development of PCOS. We plan to study the growth and development of these sheep to understand how the different problems of PCOS develop. This will help us understand how PCOS develops and we can use that knowledge to prevent or modify its development. We can then investigate whether there are any changes before puberty that will predict the development of PCOS, study the effects of current treatments and develop and test new treatments.

Technical Summary

Polycystic ovarian syndrome (PCOS) is the commonest endocrine disorder in women, and it presents with heavy infrequent periods, amenorrhoea, hirsuitism, female infertility and recurrent miscarriage. It is also associated with an increased risk of obesity, endometrial carcinoma and type II diabetes mellitus. We do not understand its aetiology or its variable phenotype and current treatment options are limited and largely symptomatic in nature. Twenty percent of women have polycystic ovaries but only some will experience the hyperandrogenism and abnormal gonadotrophins of PCOS, and some of these will be insulin resistant. Recently, a developmental origin of PCOS has been suggested, as female monkeys and sheep exposed to increased androgen concentrations in utero show many of its features when they reach adulthood. We hypothesise that the PCOS phenotype results from abnormal exposure to androgens during development, and a hierarchy of androgen effects results in variable phenotypic penetrance, depending on the level of prenatal androgen exposure. We aim to use the androgen-treated fetal sheep as a model to study the development of the phenotype, and the effect of variable androgen exposure. The ovarian phenotype and function, steroidogenesis, pituitary function, and metabolic phenotype of sheep prenatally exposed to different concentrations androgens will be fully characterised. Androgen and synthesis action in the fetus will be studied by localising androgen receptors and metabolising enzymes. The long-term cellular effects of androgen exposure will be studied using sheep fetuses exposed to variable concentrations of androgens, and the short-term effects studied in fetal tissues in primary culture. Using the androgen treated fetal sheep, the development of the ovarian phenotype will be studied by localising and quantifying the key genes involved in tissue and vascular remodelling in ovarian tissue at different stages of development. This research programme will afford the scientific opportunities to understand the development of PCOS and the medical opportunities for the development and testing of new treatment strategies.

Publications

10 25 50
 
Description CT Project Grant/The Cunningham Trust
Amount £83,131 (GBP)
Funding ID CT09/07 
Organisation The Cunningham Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2010 
End 04/2012
 
Description Models of disease
Amount £672,767 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2008 
End 11/2011
 
Description PhD Studentship/University of Edinburgh
Amount £56,000 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 09/2008 
End 09/2011
 
Description Scottish Senior Clinical Fellowship
Amount £500,000 (GBP)
Organisation Government of Scotland 
Department Scottish Funding Council
Sector Public
Country United Kingdom
Start 03/2009 
End 04/2013
 
Description Translational Research Collaboration
Amount £549,765 (GBP)
Organisation Pfizer Ltd 
Department Wyeth Pharmaceuticals
Sector Private
Country United States
Start 06/2008 
End 05/2010
 
Title Ovine PCOS model biological samples 
Description Multiple tissue and biological samples from an ovine model of PCOS and prenatally androgenised males collected at fetal, prepubertal and adult stages. 
Type Of Material Biological samples 
Year Produced 2009 
Provided To Others? Yes  
Impact Developed new collaborations. Collaborations with Warwick University, University of Dundee and University of Glasgow being developed. Underpinned BSc and MSc research projects and an ongoing PhD project to facilitate training of a new generation of researchers. 
 
Title Ovine model of PCOS 
Description A refined model utilising direct fetal injection of different concentrations of androgen as well as maternal injection to improve, dissect and refine the prenatal androgenisation model of PCOS 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Use in the recently funded MRC programme grant to Professor S. Franks (Imperial College, London). 
 
Description Cardiovascular function in an ovine PCOS model 
Organisation University of Warwick
Department Warwick Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided extra cardiovascular samples and the baseline clinical data from our ovine model of PCOS, stratified for Insulin Resistance, at sacrifice of the adult animals to the researchers from Warwick who were in attendance.
Collaborator Contribution We provided tissue samples from our sheep to investigate cardiovascular pathways. This has extended the research beyond the focus of the award as a value-added exercise.
Impact Collaboration MTA agreement. Multidisciplinary collaboration fostered during a Society for Endocrinology Conference. A collaboration between Obstetrics and Gynaecology at the University of Edinburgh and Medicine at the University of Warwick. Data currently been analysed and combined with view to manuscript.
Start Year 2009
 
Description Ectopic pregnancy 
Organisation University of Edinburgh
Department Centre for Reproductive Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution The molecular capabilities that have developed from this funding have been a starting point to develop an intellectual collaboration with an Edinburgh University Researcher to work on biomarker development in ectopic pregnancy. The initial approach was based on molecules we were studying in the sheep.
Collaborator Contribution This collaboration has brought a human dimension in a different disease to interrogate based on the intellectual skills developed in this project
Impact MRC Clinician Scientist Fellowship PMID: 21047920 PMID: 20651036 PMID: 20199347 PMID: 19933287 PMID: 19321656 PMID: 19282327 PMID: 18381568
Start Year 2007
 
Description Endometriosis 
Organisation University of Aberdeen
Department School of Medicine & Dentistry Aberdeen
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of intellectual input derived from our molecular and cell culture experience which had been further developed by this grant
Collaborator Contribution Brought a translational element in a different disease that benefits from our intellectual and experimental expertise
Impact A Wyeth Translational Research Consortium collaborative grant between The University of Edinburgh and The University of Aberdeen
Start Year 2008
 
Description HSD11B1 activity 
Organisation St George's University of London
Department Obstetrics and Gynaecology St George's
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided samples and developed research questions
Collaborator Contribution Analysis of our tissue using a specialist technique of enzyme kinetics measurement not immediately available in our laboratory
Impact A MTA agreement with St Georges London to analyse some of our tissue samples. THis has been presented at the British Endocrine Society meeting meeting and we are now working on a collaborative publication.
Start Year 2010
 
Description Health Outcomes from Programming & Environment Scotland 
Organisation University of Aberdeen
Country United Kingdom 
Sector Academic/University 
PI Contribution This links us to a Scottish Consortium to share ideas and tissues to co-ordinate our research
Collaborator Contribution This is a link between scientists interested in developmental programming of disease in Scotland. It is a consortium linking The University of Edinburgh, The University of Aberdeen, Edinburgh Napier University and The University of Glasgow with more than 15 members
Impact An preliminary application has been sent to the CSO for formal funding of the HOPES consortium
Start Year 2010
 
Description Microbubble vascular imaging 
Organisation Heriot-Watt University
Department Physics
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual and practical advice and help.
Collaborator Contribution Provision and measurement of assessment tools to study ovarian microvasculature.
Impact MRC grant in models of disease. This is multi-disciplinary involving the Centre for Cardiovascular Research and BHF. It also involved Heriot Watt University, Edinburgh.
Start Year 2008
 
Description Microbubble vascular imaging 
Organisation University of Edinburgh
Department Centre for Cardiovascular Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual and practical advice and help.
Collaborator Contribution Provision and measurement of assessment tools to study ovarian microvasculature.
Impact MRC grant in models of disease. This is multi-disciplinary involving the Centre for Cardiovascular Research and BHF. It also involved Heriot Watt University, Edinburgh.
Start Year 2008
 
Description Ovine model of PCOS 
Organisation Imperial College London
Department Institute of Reproductive and Developmental Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided intellectual, model and practical information and will provide samples and in vivo experiments in the future.
Collaborator Contribution As we have presented our model and initial results at international meetings we were approached to collaborate using our model system and conducting the future ovine experiments in a collaboration ICSTM.
Impact MRC Programme grant awarded ti collaborators at ICTSM . This is a multi-disciplinary liaison with Medical Endocrinology at Imperial College in London.
Start Year 2009
 
Description Ovine nutrition 
Organisation Edinburgh Napier University
Department Life, Sport and Social Sciences Napier
Country United Kingdom 
Sector Academic/University 
PI Contribution We have now analyzed a separate cohort not included in our grant and found nutritional effects could mimic our steroid effects in prenatal programming.
Collaborator Contribution Link with an expert in nutritional effects on ovine fetal development and pancreatic function.
Impact This links to Life Sciences at Napier Edinburgh University and Rowatt at Aberdeen. Presentation at international meeting and manuscript in preparation.
Start Year 2009
 
Description Stress and Fetal Programming 
Organisation University of Edinburgh
Department The Roslin Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution LInking with group studying stress related fetal programming in pigs
Collaborator Contribution Supply of tissues and intellectual discussion
Impact PMID: 21984747
Start Year 2010
 
Description The robo/slit interaction 
Organisation Medical Research Council (MRC)
Department MRC Human Reproductive Sciences Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided samples, intellectual and technical expertise. Initiated experiment and experimental design and analysis.
Collaborator Contribution I was very keen to have outputs from the grant during its lifetime. As the data was still being collected at the end of the grant, the grant outcomes will occur in the years after the completion of the grant. I instigated a collaboration with the MRC HRSU to study our control fetal samples. There was intellectual contribution to this project from scientists in the HRSU.
Impact PMID: 19900988 PMID: 20100881
Start Year 2009
 
Description Invited Presentations at International Meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact At least 500 academic delegates at each meeting

Raised profile of research
Year(s) Of Engagement Activity 2008,2010,2011,2012,2013,2014,2015,2016
 
Description Lecture - Doctors in Training 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact East of Scotland and Scotland -wide meetings for doctors in training. Discussed our research and the novel concepts

Raising awareness. Generating interest in research.
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013,2014,2015
 
Description Lecture - Fertility nurses 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Discussed our research and these concepts with Scottish fertility nurses, support-workers and clinical embryologists at national meeting

Raising awareness within profession
Year(s) Of Engagement Activity 2009,2011,2012,2013
 
Description Lecture - GPs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Education about PCOS and how our research fits is driving understanding

Increased personal referrals to PCOS clinic giving good patient cohort for future studies
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013,2014,2015
 
Description Lecture - UK Consultants 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Discussion of our research with consultant gynaecologists in a national meeting.

Raising awareness of novel concepts and findings.
Year(s) Of Engagement Activity 2008,2010,2012,2013,2015
 
Description MRCOG reproductive endocrinology 
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 Talked to over 300 clinicians in training

Invited to write review about our concepts for the non specialist
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014,2015
 
Description Patient Round Table 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact After the public lecture I held a question and answer workshop for patients and women with PCOS. There was approximately 15 attenders of this session and there was a vibrant discussion.

Word of mouth spread to other patients had not attended but who discussed the public lecture with me when I saw them in clinic.
Year(s) Of Engagement Activity 2010
 
Description Presentations at International Conferences 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact At least three abstracts presented each year from the research in the laboratory

Increasing the training of the postgraduate students, their reputation and the reputation of the laboratory
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011,2012,2013,2014,2015
 
Description Reproduction research 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Article about research in Reproduction for Public Service Review

Public Service Review EU 20:204-207
Year(s) Of Engagement Activity 2010
 
Description School engagement 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Part of the panel talking to School Children during the Fertility 2017. Supported by the Scottish Government
Year(s) Of Engagement Activity 2017