Gonadotropin action in the polycystic ovary

Polycystic ovary syndrome (PCOS) is the commonest hormone disorder in women, affecting between 5-10% of women of reproductive age, and typically first manifests itself during adolescence. It is a major cause of infertility and causes distressing skin problems (acne and unwanted body hair) that contribute to a negative impact on quality of life and often, overt depression. PCOS is also associated with risks to long-term health, and, in particular there is a 3-fold increase in the risk of developing type 2 diabetes (late onset, or non insulin-dependent diabetes) in later life. Infertility in women with PCOS is due to infrequent or absent ovulation (monthly release of an egg) and can usually be corrected by appropriate choice of treatment but many women remain involuntarily infertile and/or have persistent skin problems.
Genetic factors play a major role in the development of PCOS but we still do not fully understand the cause or causes of the syndrome. Nevertheless, recent data from the genetic studies have provided some new clues about the key factors that might be involved in abnormal function of the ovaries and those data complement previous work in our lab that has demonstrated the importance of disordered hormone signals that control the ovary. The two most important reproductive hormones that control the ovary are luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are produced by the pituitary gland in the brain. These hormones bind to specific proteins (receptors) on the surface of cells that nurture the growing eggs, ensuring that they behave in a way that supports healthy egg growth and ovulation. In PCOS, it is thought that these receptors might behave abnormally, resulting in the egg stopping growing and failing to ovulate.
The purpose of the proposed research project is to study in detail how LH and FSH act on these cells from normal and polycystic ovaries. We shall focus, in particular, on the function of the receptors in the ovary that recognize LH and FSH and the way in which these hormones, once bound to their receptors, signal within the cell both in normal women and those with PCOS. We will use granulosa-lutein (GL) cells that are obtained at the time of egg collection for IVF and are normally discarded because they are not needed otherwise. GL cells will be collected from individual patients and transported to the lab for our research protocol. We have ethical approval for these studies and the patients each give informed consent. Once in the laboratory we shall prepare the cells in various ways, including culturing them for up to 72h. Using techniques including analysis of hormones produced by the cells (and the genes and proteins that are involved in regulation of hormone production) as well as high-resolution microscopy, we will examine the key steps involved in the action of LH and FSH on GL cells and how these differ between normal and PCOS ovaries.
We anticipate that in future the information generated can be directly applied to improve the quality of life of women with PCOS. We expect to uncover specific biochemical "fingerprints" of PCOS that will be applicable to making an early diagnosis (e.g. in adolescent girls with early signs of PCOS but who do not have a firm diagnosis) and, in particular, to identify those most at risk of problems with fertility or long-term complications. Importantly, once we have identified the biochemical pathways that are dysfunctional in PCOS, it will be possible, in future, to design and test drugs with potential to target key points in these pathways to improve function. Our results will be presented at scientific meetings and prepared for publication in the leading scientific journals in the field. The applicants have extensive experience in talking about their research to fund-raising bodies, to patient groups and to broadcast and written media.

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women, affecting between 5-10% of women of reproductive age. It is a major cause of infertility, acne and hirsutism that all contribute to a negative impact on quality of life. PCOS is also associated with risks to long-term health, including a 3-fold increase in the risk of developing type 2 diabetes. The major biochemical hallmark of PCOS is hypersecretion of androgen which, in turn, impacts on reproductive and metabolic abnormalities. Genetic factors play a major role in development of PCOS but the aetiology remains unclear. Recent data from the genetic (GWAS) studies, together with our own studies of ovarian tissue, suggest that abnormalities of gonadotropin action play a key role in pathogenesis of PCOS. Gonadotropin action is mediated by the G-protein-coupled receptors (GPCRs) LHR and FSHR. Our recent studies have highlighted the functional importance of distinct signalling pathways associated with GPCRs and focused on novel aspects of LH/FSH receptor function, particularly intracellular trafficking of the receptor and endomembrane signalling.
Our hypothesis is that there are intrinsic differences between normal and polycystic ovaries in gonadotropin receptor function, affecting the mechanism of anovulation, glucose metabolism and steroidogenesis. Using granulosa and theca cells from women with and without PCOS, our primary aims are to investigate 1) the mechanisms underlying enhanced LH activity in PCOS at the level of LH receptor (LHR), including the role of endomembrane receptor signalling; 2) cross-talk between LHR and the FSHR in human ovarian cells; 3) differences in LH/FSH-mediated effects on metabolism and steroidogenesis between PCOS and control subjects; 4) the impact of androgens on gonadotropin receptor function. Our findings will inform development of specific biomarkers for PCOS and to help identify pathways susceptible to novel targeted pharmaceutical intervention.

Despite the profound effects of polycystic ovary syndrome (PCOS) on ovarian and metabolic function, little is known about the underlying pathogenic mechanisms. Increased understanding of the processes by which gonadotropins affect granulosa cell function in the ovary provides a basis for better-targeted therapies for both reproductive and metabolic effects of PCOS.
ACADEMIC IMPACT
Our principal aim is to investigate the mechanisms underlying aberrant gonadotropin activity in PCOS. With an established track record in top-ranking research in ovarian physiology, we are now in a position to make significant advances in understanding aberrant ovarian function in PCOS.
The potential impact on women's health includes (1) Improving understanding and treatment of infertility, menstrual disturbances and effects of androgen excess (hirsutism, acne, alopecia) in PCOS: The mechanism of ovulatory dysfunction in PCOS remains unclear and current methods of induction of ovulation are empirical and symptomatic and have remained essentially unchanged for decades. There is a clear need for more specific modes of management. It is therefore important to understand how gonadotropin action influences the abnormalities of follicle development that underlie anovulation in PCOS. (2) Improving understanding of G-protein-coupled receptors (GPCRs) in health and disease: GPCRs are not only important in gonadotropin action but are ubiquitous receptors which mediate a large and varied range of cellular functions. They are amongst the most common drug targets. The work proposed here will add to our understanding of both cell membrane mediated GPCR signalling and - a particular novelty in this application - the functional role of GPCR trafficking and internalised endomembrane signalling.
ECONOMIC AND SOCIETAL IMPACT
Charities: The outcome of the work proposed is relevant to human fertility in general and to PCOS in particular. SF is a member of the Medical Advisory Board of Infertility Network UK and is medical advisor to Verity, the PCOS patient support group. He contributes to the quarterly magazine of both charities and speaks at their regular meetings.
Education: An important aim is to motivate young people by providing information about, and promoting interest in biomedical research. Links with local schools have already been established; KH has spoken at Latymer Upper School in Hammersmith and has been involved in a number of its science activities. KH and SF have held informal discussion groups with local 6th form students.
General Public: We wish to promote public engagement in science. SF has provided information to media about reproductive science and its impact on society, both directly to journalists and via the Imperial College Press Office or the Society for Endocrinology.
Planned activities that will contribute to realising these aims.
Charities: The Genesis Research Trust (of which SF is a trustee and vice-chair and both SF, KH and AH are members of the scientific advisory committee) relies on a committed team of fund-raisers. KH and SF will continue to inform participants about Trust-funded research. SF will make regular contributions to the publications and meetings of Verity and The Infertility Network.
Education & General Public: KH, SF and AH will identify and establish links with Biology Departments in local state schools in West London, with activities ranging from giving motivational talks on careers in science to seminars on specific research topics. SF has recently given an extensive interview about PCOS for a BBC science programme. The involvement as CYA as Co-I emphasises that our reach will be international as well as national.