Determination of the functional life span of the ovary

Lead Research Organisation: MRC Human Reproductive Sciences Unit

Abstract

All a womans eggs are formed before she is born. The egg cells replicate during the early months of pregnancy and form structures called primordial follicles. These may then wait decades before starting to grow in the lead-up to a small number of them releasing mature eggs at the time of ovulation. The number of eggs in the ovary steadily falls throughout life until the menopause, and they cannot be replaced. While this normally occurs at around the age of 50, a premature menopause can occur at any age, even before puberty.||This programme aims to increase our understanding of how the number of eggs is regulated, to shed light on why it can go wrong. We will also study the maturation of eggs later in life, as some of the factors essential for egg survival in early life are also important in optimising the ability of eggs to develop into early embryos.||A further aspect of this work is improving our ability to assess how many eggs a woman may have, to be able to provide more accurate advice, for example, to young women who have had chemotherapy for cancer whose ovaries may contain a reduced number of eggs as a result.

Technical Summary

Women are born with a finite number of germ cells, which cannot be replaced. Primordial follicles are formed in the human during the 5th month of pregnancy. However the majority of germ cells are lost by apoptosis which can occur during mitosis, entry into and arrest of meiosis and association with somatic cells. The regulation of these processes and primordial follicle formation are thus central to reproductive lifespan, yet little is known about the growth and survival factors involved.||We have demonstrated the expression of the neurotrophin NT4 in pregranulosa cells and its cognate receptor TrkB in oocytes in the human fetal ovary. In collaboration with Dr N Spears (University of Edinburgh) we demonstrated that blockade of neurotrophin signalling in both mouse and human ovarian cultures results in substantial loss of germ cells. Analysis of a TrkB neurotrophin receptor knock-out mouse model showed near complete loss of oocytes at the time of primordial follicle formation.||We have further characterised changing expression of activin, the anti-apoptotic regulator MCL1 and the transcription factor FIGLA, all specifically expressed by oocytes, immediately preceding primordial follicle formation. Activin was shown to stimulate germ cell proliferation in vitro. These data have thus demonstrated germ-cell specific factors in the developing human ovary, whose function and interactions will be explored in future studies.||We will perform functional analyses using the tissue culture methodologies we have established in both human and mouse using specific neurotrophin receptor blockers, RNAi and investigation of neurotrophin and activin signalling pathways to characterise function and interaction at different stages of ovarian development. MCL1 is a candidate target for regulation by FIGLA: this will be explored using transient transfection experiments and electrophoretic mobility shift assays. We will extend these studies to incorporate novel candidates as information becomes available.||Optimisation of final oocyte maturation is of importance for both animal and human assisted reproduction. We have established a role for neurotrophins in this process in collaboration with Dr PA de Sousa (Roslin Institute). Bovine, ovine and human oocytes and cumulus cells were demonstrated to show a cell-specific pattern of expression of neurotrophins and their receptors. Treatment of immature bovine oocytes with the neurotrophin BDNF demonstrated improved developmental potential without advancing nuclear maturation. This will be further explored in both the bovine and human, investigating cell-cell interactions in primordial follicle formation, the neurotrophin ligands and receptors involved, its mediation by cumulus vs direct oocyte effects and identification of the pathways involved.

Publications

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Anderson R (2007) Predicting the menopause: the role of inhibin B in Trends in Urology, Gynaecology & Sexual Health

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Anderson RA (2008) Do doctors discuss fertility issues before they treat young patients with cancer? in Human reproduction (Oxford, England)

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Anderson RA (2008) Uncertainties in preserving fertility in cancer treatment. in BMJ (Clinical research ed.)

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Anderson RA (2008) Ovarian cryopreservation for fertility preservation: indications and outcomes. in Reproduction (Cambridge, England)

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Anderson RA (2008) Fertility preservation techniques: laboratory and clinical progress and current issues. in Reproduction (Cambridge, England)

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Anderson RA (2007) Assessment of the effect of chemotherapy on ovarian function in women with breast cancer. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology

 
Description BFS obesity P&P
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact British Fertility Society policy document
 
Description Cancer and repro function
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact Widely read by those in the field; invited speaker at intl meetings subsequently
 
Description Member of NIH scientific advisory cttee on contraceptive development
Geographic Reach North America 
Policy Influence Type Participation in advisory committee
Impact Review of scientific goals and of clinical trials.; Chair, data monitoring cttee
 
Description RCOG Guidelines and Audit cttee, RCOG Scientific Advisory Cttee and British Fertility Soc Policy and Practice cttee
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact Author and contributor to many national documents; lead author on BFS docs on Preimplantation genetic screening, and obesity and reproduction
 
Description RCOG fetal awareness
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact Main impact: advisory to Parliamentary Scientific cttee
 
Description CSO funding Pilot biomarkers
Amount £58,000 (GBP)
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 03/2007 
End 03/2008
 
Description MRC Experimental Medicine Research Grant
Amount £541,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2008 
End 03/2011
 
Description MRC project grant G0901839
Amount £610,375 (GBP)
Funding ID G0901839 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2010 
End 03/2013
 
Description Medical Research Scotland Fellowship
Amount £115,000 (GBP)
Organisation Medical Research Scotland 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2010 
End 03/2012
 
Description Medical Research foundation
Amount £200,000 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 03/2010 
End 03/2014
 
Description Public engagement activity awards
Amount £210,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2007 
End 03/2009
 
Description Wyeth TMRI
Amount £921,000 (GBP)
Organisation Pfizer Ltd 
Department Wyeth Pharmaceuticals
Sector Private
Country United States
Start 03/2008 
End 03/2010
 
Title FIGLA construct 
Description expression vector for human gene expressed only in oocytes 
Type Of Material Technology assay or reagent 
Year Produced 2007 
Provided To Others? Yes  
Impact Contribution to publication by other research group. 
 
Description Human hepatic and haematopoietic development 
Organisation University of Edinburgh
Department MRC Centre for Regenerative Medicine
Country United Kingdom 
Sector Public 
PI Contribution Provision of human fetal tissues
Impact Publications:
 
Description BBC Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact BBC TV interview regarding in vitro follicle maturation

None
Year(s) Of Engagement Activity 2008
 
Description BBC Interview 
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 Public/other audiences
Results and Impact Interview BBC 'Today' programme following publication of BFS Policy document on Preimplantation Genetic Screening.

encouragement of better clinical trials in the field
Year(s) Of Engagement Activity 2008
 
Description Christie pt support group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Workshop on survival issues to young cancer survivors

part of a series: v highly rated by patients
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013
 
Description Edin Sci Fest 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Speaker at a symposium at Edin Intl Science Festival, audience about 200

positive feedback to BES (organisers)
Year(s) Of Engagement Activity 2010
 
Description Royal College of Physicians of Edinburgh annual symposium 
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 Royal College of Physicians of Edinburgh annual symposium, 'Ethics for Young people" Panel member

Good informal feedback from teachers
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013
 
Description Speaker to patient support group Care Leukaemia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Speaker to patient support group Care Leukaemia, including contributing to their magazine

None
Year(s) Of Engagement Activity 2006
 
Description public lecture 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact part of MRC HRSU public lecture series

increasing attendance at subsequent lectures
Year(s) Of Engagement Activity 2007