The role of DHEA and androgens in the regulation of ovarian follicular development

In the United Kingdom, 1 in 6 couples have fertility problems. Around a third of infertility in women is due to problems with ovulation (the monthly release of the egg). Before the egg is ready to be released, it develops inside a tiny fluid-filled space (called a follicle) on the ovary.

Polycystic ovary syndrome (PCOS) is a condition in which women typically have an increased number of small follicles that do not develop properly; meaning ovulation does not take place. This is due to high levels of male hormones that cause a hormone imbalance. PCOS affects millions of women in the UK (5-10% of the women).
Infertility in women is also linked to age, as the reserve of eggs in the ovaries gradually decreases. Elderly women typically have fewer follicles that develop poorly and ovulation does not occur. However, several studies have shown that treatment with male hormone increases fertility in women with low ovarian reserve. The biggest decrease in fertility begins during the mid thirties, when the male hormone production in the adrenal gland and the ovary decreases.

Taken together, male hormones seem to play an important role in the development of the follicle and the egg, and thus potentially also in fertility.

In my project I will study in detail the exact role of male hormones throughout the development of the follicle. Therefore I will culture mouse follicles and eggs. I will train to learn this technique from its developer, Professor Teresa Woodruff, in her laboratory in Chicago. I will carry out experiments exposing follicles to male hormones, in the laboratory of Professor Wiebke Arlt, who is a leading specialist on sex hormones at the University of Birmingham. Finally, I will correlate my findings in mouse follicles to human follicles. Through collaboration with the Birmingham Women's Hospital Fertility Centre, I will analyse follicular fluid from women undergoing in vitro fertilisation (IVF).

I am convinced that my research will help to understand the mechanisms of infertility in women with PCOS and low ovarian reserve. I hope it will also lead to new fertility treatment options.

AIMS:
To study the role of DHEA and androgens in follicular development
OBJECTIVES:
Follicular androgen levels appear to be crucial for follicular development, oocyte release and fertility. I hypothesize that increased androgen levels promote early stage folliculogenesis, but result in follicular arrest at the antral stage. I plan to test this hypothesis, which may help to elucidate mechanisms underlying impaired follicular development in prevalent conditions such as polycystic ovary syndrome (PCOS) and low ovarian reserve.
METHODOLOGY:
In vitro studies
I will employ a unique murine in vitro follicular maturation model (collaboration Professor Teresa Woodruff, Chicago). This model allows detailed examination of all stages of folliculogenesis after alginate encapsulation of immature follicles harvested from prepubertal mice. I will expose the follicles to the universal androgen precursor DHEA and to the most potent androgen, dihydrotestosterone, with additional manipulation by inhibitors that block androgen synthesis or action. I will assess follicular development and oocyte quality by microscopy. I will analyse mRNA expression of genes involved in follicular development and steroidogenesis employing microfluidic card realtime PCR. Finally, I will assess steroidogenic capacity of the follicles by mass spectrometry based steroid assays in follicular fluid and cell culture supernatant samples.
Ex vivo studies
I will have access to human biomaterial including follicular fluid and cumulus granulosa cells from women with PCOS, normal and low ovarian reserve and also to clinical data on androgen status and fertility outcome. This will allow me to test results from my mouse based studies in the human situation.
SCIENTIFIC /MEDICAL OPPORTUNITIES:
PCOS and low ovarian reserve are the leading causes of anovulatory infertility and enhancing our understanding of underlying mechanisms may identify novel diagnostic markers or even targets for therapeutic interventions.

This project represents a unique collaboration between endocrine and reproductive research, as well as basic laboratory science paired with translational clinical investigation and objectives. There is huge potential for applying its outcomes in the field of reproductive health, where polycystic ovary syndrome (PCOS) and low ovarian reserve are the leading causes of anovulation and female infertility. Both conditions are related to default androgen action at the level of the follicle. With that in mind, it is crucial to determine the exact role of androgens in follicular development. This research has the potential to provide novel insights into the mechanisms regulating androgen synthesis and action in the ovary. This knowledge is an essential step to gain new insight in the pathophysiology of PCOS and low ovarian reserve. It is likely to provide clues for discovering novel treatment options for these conditions.

To maximise the translational potential of this project, we will make sure that results are highlighted to academic researchers, clinicians, industry representatives where relevant, and also to the general public. To reach academics we will publish and present the results of this proposal at local, national and international meetings, and data will be published in high impact factor journals. To reach clinicians, we will build on the collaborations we have here with the Birmingham Women's Hospital to engage other local potential clinical collaborators and service providers, highlighting the clinical relevance of our investigations and outcomes.

In terms of industrial links, both the College and the University have very active and effective groups which oversee the commercialisation of research, and whom will be evolved in the ongoing evaluation of this project - within the College, the dedicated Technology Transfer Team regularly meet Professor Wiebke Arlt (who already has several patents and industrial support for her research) to assess IP and potential commercial development strategies. The College also has its own External Commercialisation Board (http://www.mds.bham.ac.uk/commercial/business/ECB/index.shtml) made up of top industry experts to advise on and support this process. This is then linked to the University's own dedicated commercialisation company, Alta Innovations (www.alta.bham.ac.uk), who support the patent process and drive licensing and spin-out opportunities. In addition, strategic and senior academic links with surrounding NHS Trusts, particularly Birmingham Women's Hospital and Queen Elizabeth Hospital Birmingham, ensure that clinical benefit and health service support is at the heart of innovation and subsequent development. Together, these groups provide a seamless support service from academic innovation through commercial output and into clinical practice.

Finally, in terms of public engagement, as described previously we will use our links with patient groups to disseminate information and involve service users in development of subsequent projects, particularly through the Birmingham Women's Hospital. We will also use our website (http://www.birmingham.ac.uk/research/activity/mds/centres/cedam/index.aspx) and University Press Office, as well as the MRC Press Office, to publicise our results to the general public.