Ovarian anti-Mullerian hormone: what does it do in the normal ovary and why is it so high in polycystic ovary syndrome?

Lead Research Organisation: St George's University of London
Department Name: Basic Medical Sciences

Abstract

In the womb, boy babies develop part of their reproductive system because of the actions of a hormone called anti-Mullerian hormone (AMH). Interestingly, this hormone has now been shown to play a part in adult women in that it is involved in the working of the ovary. In the ovary each month an egg is grown and released. We have found that only those eggs which have got rid of AMH manage to grow. This is important because we have also found that the levels of this hormone are very high in a common condition which causes infertility. We now need to find out why the levels are high in these women and what exactly AMH does in the ovary. We hope that this will allow us to help these women to have better fertility in the future.

Technical Summary

The male fetal sexual differentiative factor anti-Mullerian hormone is a potentially important signalling molecule in the adult ovary. Although much of this information was derived from knock-out mice, AMH is increasingly being heralded as a clinical marker of ?fertility?. Very little is known about its production or action in human ovary. We have discovered that, although AMH is high in human follicles of 2-6 mm, it is absent from follicles progressing beyond selection. Preliminary results indicate that this is because it inhibits FSH-stimulated aromatase, an inhibition which would limit continued folliculogenesis. We now wish to elucidate the mechanism of this inhibition. This work will be carried out in human granulosa cells and we will focus on the function of specific SMADs using siRNAs, dominant negatives and overexpression. We will then determine which aromatase promoter II-associated transcription factors are altered by AMH treatment and gel shift assay. In parallel with this candidate approach we will screen for other differentially expressed genes in granulosa and theca cells from normal ovaries exposed to AMH using microarray.
Our observation that AMH levels in cells from polycystic ovaries are 75 times higher than those from normal has important implications for fertility in these women. Our second aim therefore is to elucidate the molecular basis for the upregulated AMH expression. We will investigate alterations in transcriptional regulation of the gene by investigating promoter activity in granulosa cells from PCO and normal ovaries. In this way we will distinguish between the failure to repress versus the acquisition of promiscuous activation in PCOS. It is also conceivable that the upregulation reflects alterations in AMH protein turnover which we will investigate by measuring the half-life of tagged versions of AMH in the two types of granulosa cells. This will also permit us to understand the normal mechanism of the control of AMH production in the developing follicle.
If AMH is to be used as an important clinical marker then we need to understand its production and actions. Determining how and why AMH levels are tightly controlled in the follicle at the critical time of selection will add fundamental knowledge to this key process. Anovulation is an important consequence of PCOS for many women and yet the cause remains unknown and treatments are far from perfect. As AMH is only made by granulosa cells, elucidating its role in inhibition of follicle progression may make it an ideal target for treatment.

Publications

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Dewailly D (2014) The physiology and clinical utility of anti-Mullerian hormone in women. in Human reproduction update

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Hatzirodos N (2011) Linkage of regulators of TGF-ß activity in the fetal ovary to polycystic ovary syndrome. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

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Irving-Rodgers HF (2009) Phenotypes of the ovarian follicular basal lamina predict developmental competence of oocytes. in Human reproduction (Oxford, England)

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Pellatt L (2010) Anti-Müllerian hormone and polycystic ovary syndrome: a mountain too high? in Reproduction (Cambridge, England)

 
Description Best Poster Prize
Amount £500 (GBP)
Organisation International Society of Gynecological Endocrinology (ISGE) 
Sector Charity/Non Profit
Country Global
Start 03/2009 
End 03/2011
 
Description St. George's, University of London Research priming funds
Amount £5,058 (GBP)
Organisation St George's University of London 
Sector Academic/University
Country United Kingdom
Start 11/2009 
End 10/2010
 
Description Thomas Addison PhD studentship
Amount £87,000 (GBP)
Organisation St George's University of London 
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 12/2014
 
Description Travel Award
Amount £600 (GBP)
Organisation Endocrine Society (USA) 
Sector Learned Society
Country United States
Start 06/2010 
End 07/2010
 
Description Travel Award
Amount £600 (GBP)
Organisation Endocrine Society (USA) 
Sector Learned Society
Country United States
Start 06/2009 
End 07/2009
 
Description University of London Central research fund
Amount £6,000 (GBP)
Organisation St George's University of London 
Sector Academic/University
Country United Kingdom
Start 06/2008 
End 08/2011
 
Description Ovarian fibrillin-3 
Organisation University of Adelaide
Department Discipline of Obstetrics and Gynaecology
Country Australia 
Sector Academic/University 
PI Contribution discussion of protocol and provision of human ovarian tissue samples for investigation
Impact 2 publications
Start Year 2009
 
Description control of aromatase 
Organisation Prince Henry's Institute (PHI)
Country Australia 
Sector Academic/University 
PI Contribution we have invesigated the effect of metformin on aromatase in ovrian cells
Collaborator Contribution Following a one-month visit to Melbourne the funded postdoc developed a new technique which was used in our subsequent publications. We have had continual discussions regarding ovarian aromatase and contunue to do so.
Impact publication conference presentations
Start Year 2008
 
Description ovarian tissue 
Organisation University of Malta
Department Department of Obstetrics and Gynaecology
Country Malta 
Sector Academic/University 
PI Contribution we carry out the research
Collaborator Contribution the team in Malta work hard to sourse suitable material for our studies from their surgical patients. they also make available laboratory facilities for conducting experiments in Malta
Impact publications conference presentations
 
Description Interviews for magazines and newspapers 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact regularly give interviews over phone to journalists regarding PCOS and always try to include research findings. Most want to know them anyway!

Causes a cascade..ie increases contacts from other journalists, especially freelance
resulted in a number of invitations to speak at healthcare professionals meetings
2 page spread in Times
Interest from TV producer who is in talks to raise fundes for programme
Year(s) Of Engagement Activity 2007,2008,2009,2010
 
Description Talk to GPs 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact 100+ GPs attended talk which generated many questions about AMH

Resulted in invitations elsewhere
Year(s) Of Engagement Activity 2007,2008,2009,2010
 
Description Talk to healthcare professionals London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Health professionals
Results and Impact Research included in a talk on PCOS

Increased activity on the PCOS-uk website (but this was from the whole day)
Year(s) Of Engagement Activity 2008,2009,2010
 
Description Talk to patients- London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Included research findings in talk on PCOS to patient self-help group Verity.

Interviews for magazines. Full page on work in medical school journal
2009 talk attended by journalist from Times who subsequently produced 2 page spread mentioning the MRC and their funding of our work
Year(s) Of Engagement Activity 2008,2009,2012,2013
 
Description patient charity meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact 102 patients attended a day on PCOS in which i spoke for 1 hr and then had 1hr questions

good patient feedback. 'the first time i have understood it', 'makes me feel better to know that research is being done'
Year(s) Of Engagement Activity 2011