Polycystic ovary syndrome (PCOS): manipulation of hormonal, metabolic and ovarian phenotypes using a developmental model

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

Abstract

Polycystic ovary syndrome (PCOS) is common: more than one in 1 in 15 young women has this condition. There are many associated health problems including abnormal periods, miscarriages, infertility, excess hair, acne, weight gain, diabetes and heart disease. 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 beginnings of life before birth. Although sheep don?t normally suffer from PCOS if we slightly change the hormonal environment before birth they develop a lot of the features of PCOS as adults. We think that similar changes in the environment before birth in women is associated with the development of PCOS. In order to try to prevent it happening we need to study what happens before birth and what are the initial changes that start the ball rolling towards PCOS as adults. We have developed new techniques to study the very earliest changes so that we can work out how to stop them happening. As well as this we need to ensure that we can develop and test the best treatments for PCOS when it has occurred. We will use these sheep to test new treatments and how treatments focussing on different aspects of PCOS work. Together this research will help us try to reduce the development of this distressing condition and optimise the treatments if it has occurred.

Technical Summary

This research is focussed on understanding the molecular aetiology and developing new treatments for polycystic ovary syndrome (PCOS). We are utilising a prenatal androgenisation ovine model that develops hormonal, ovarian and metabolic phenotypes reminiscent of PCOS. We have developed a strategy for direct fetal manipulation using ultrasound guided fetal injection. Exposure of the fetus to androgens using a fetal route as well as the maternal route of exposure produces the disparate PCOS phenotype. However fetal testosterone exposure, by either route, is associated with increased fetal estradiol and cortisol. In addition nutritional stress during pregnancy has parallel ovarian and metabolic changes. This research builds on our recent experience and our novel fetal injection model to address three important areas: 1) The first area deconstructs possible mediators of testosterone action in the fetus by their direct manipulation. We will study the direct effects of adrenal manipulation, cortisol, estradiol and nutritional stress in utero on fetal and adult hormonal, ovarian and metabolic phenotypes. 2) The second area uses the established androgenisation model to investigate therapeutic strategies. We will study the molecular and phenotypic effects of novel and conventional direct ovarian, hormonal and metabolic manipulation. 3) The third area is the development of novel strategies to dissect the direct effects on the ovary from the effects on the hormonal and metabolic environment. We will utilise our direct fetal intervention model to facilitate the development of ovarian transplantation models. Together these research areas: dissect out fetal changes as antecedents to increase our understanding of mechanisms and therapeutic targets, assess interventions focussing on different phenotypic targets and develop manipulative strategies to investigate the direct ovarian phenotype. This research involves a partnership between a clinician scientist and basic scientists, all of whom have experience in ovine large animal modelling, in an ideal environment and collaborative framework. They are particularly well placed to dissect out the antecedents and focussed manipulative strategies to help women blighted with the reproductive and lifelong metabolic consequences of PCOS.

Publications

10 25 50
 
Description Academic Scholarship
Amount £10,000 (GBP)
Organisation Society for Reproduction and Fertility 
Sector Charity/Non Profit
Country Global
Start 07/2013 
End 06/2014
 
Description Barbour Watson Trust
Amount £2,500 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 01/2018 
End 01/2019
 
Description Barbour Watson Trust
Amount £4,700 (GBP)
Organisation Barbour Watson Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2014 
End 09/2015
 
Description Industrial partnership
Amount £554,183 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 08/2015 
End 07/2018
 
Description MRC Centre for Reproductive Health at the University of Edinburgh
Amount £1,444,459 (GBP)
Funding ID MR/N022556/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2016 
End 09/2021
 
Description PhD Studentship
Amount £45,000 (GBP)
Organisation Edinburgh Napier University 
Sector Academic/University
Country United Kingdom
Start 09/2011 
End 08/2014
 
Description Project Grant
Amount £144,337 (GBP)
Organisation Wellbeing of Women 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2012 
End 06/2014
 
Description Studentship
Amount £2,700 (GBP)
Organisation Society for Reproduction and Fertility 
Sector Charity/Non Profit
Country Global
Start 06/2014 
End 07/2014
 
Description Testing The Health And Therapeutic Potential Of In Vitro Derived Oocytes For The Restoration Of Female Fertility And The Treatment of Infertility
Amount £1,474,143 (GBP)
Funding ID MR/T025654/1 
Organisation MRC Biomedical Catalyst Developmental Pathway Funding Scheme (DPFS) 
Sector Academic/University
Country United Kingdom
Start 04/2020 
End 04/2023
 
Description University of Edinburgh PhD Studentship
Amount £60,000 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 09/2013 
End 08/2016
 
Description University of Edinburgh PhD Studentship
Amount £56,000 (GBP)
Organisation University of Edinburgh 
Sector Academic/University
Country United Kingdom
Start 10/2010 
End 09/2013
 
Description Visiting Fellowship
Amount £75,000 (GBP)
Organisation Japan Society for the Promotion of Science (JSPS) 
Sector Public
Country Japan
Start 01/2011 
End 12/2012
 
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). 
 
Title Ovine tissue exposed to steroids in vivo 
Description Fetal and lamb tissue directly exposed to steroids by fetal injection in vivo in paradigm known to programme adult disease. 
Type Of Material Biological samples 
Year Produced 2011 
Provided To Others? Yes  
Impact New collaborations UK wide. 
 
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 Gene Methylation 
Organisation University College London
Department Department of Obstetrics and Gynaecology
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of samples for assessment of liver IGF-1 and pancreatic Insulin gene methylation status
Collaborator Contribution Combination of expertise in ovine programming
Impact Data generated for funding application
Start Year 2013
 
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 Proteomics of Liver 
Organisation University of Aberdeen
Department Institute of Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Formal collaboration utilising cross institute expertise
Collaborator Contribution Sample provision and Analysis
Impact Co-Application to MRC for Funding
Start Year 2013
 
Description Steroids and autism related genes in the brain 
Organisation Edinburgh Napier University
Department Life, Sport and Social Sciences Napier
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of tissues and expertise.
Collaborator Contribution Generation of funding, analysis of samples and provision of a PhD studentship.
Impact LInk to Neuroscientists. Edinburgh Napier University Funding provided.
Start Year 2011
 
Description Steroids and infection defence during pregnancy 
Organisation Edinburgh Napier University
Department Life, Sport and Social Sciences Napier
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of samples and expertise
Collaborator Contribution Analysis of samples. Pilot data for full grant applications
Impact Edinburgh Napier University funding provided
Start Year 2012
 
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 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 - 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 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 Public Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Public lecture as part of annual programe attended 200 members of public. Half of which were school pupils. Excellent discussion afterwards

Excellent formal feedback that increased attendance at subsequent lectures. Asked to talk at 2012 Edinburgh Science Festival.
Year(s) Of Engagement Activity 2010
 
Description School Research 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Hands on laboratory experience

University Applications
Year(s) Of Engagement Activity 2013
 
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
 
Description School presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Lecture in research outcomes to schools in Edinburgh
Year(s) Of Engagement Activity 2018