Professor Stephen Franks
Ovarian function and polycystic ovary syndrome
Previous and Current Research
The focus of my research has been on physiology and disorders of ovarian function, with a special interest in the commonest endocrinopathy in women, namely polycystic ovary syndrome (PCOS). PCOS is not only the commonest cause of anovulatory infertility, but it is also a major risk factor for development of type 2 diabetes mellitus (T2D) (Franks, 1995). Our work has involved clinical and laboratory based studies, has been supported by grants from (amongst others) The Wellcome Trust, the MRC (Programme Grant) and Wellbeing of Women, and has resulted in over 100 publications. In early clinical studies, we highlighted the fact that the spectrum of presentation of PCOS included women with hyperandrogenism and regular cycles; we described a disorder of energy balance (associated with insulin resistance) in women with PCOS and demonstrated that metabolic abnormalities in PCOS were linked to menstrual dysfunction (Robinson et al., 1992; Robinson et al., 1993). In laboratory based studies we found evidence for an intrinsic abnormality of steroidogenesis (Gilling-Smith et al., 1994) and demonstrated abnormal granulosa cell responses to gonadotrophins in PCO follicles (Willis et al., 1998). We were able to show that insulin resistance in granulosa cells from PCOS was confined to insulin mediated uptake and metabolism of glucose and had no impact on steroidogenesis (Rice et al., 2005). Working with Dr Kate Hardy and Professor Jaroslav Stark (Mathematics) we developed a mathematical model of gonadotrophin-dependent follicle development in human ovary which helps to explain the mechanism of anovulation in PCOS (Chavez-Ross et al., 1997).
Another important aspect of our work on PCOS (in collaboration with, first, Bob Williamson and more recently Mark McCarthy (Oxford)) has been the search for the genetic basis of the PCOS. This too has resulted in a number of key publications and is ongoing (Franks et al., 1997; Haddad et al., 2002; Gaasenbeek et al., 2004; Powell et al., 2005; Barber et al., 2007, Barber et al., 2008a)
In recent years, in collaboration with Dr Kate Hardy, the work on ovarian function has concentrated on investigation of the earliest stages of ovarian follicle growth in normal and polycystic ovaries, and elucidating factors involved in this. In 2003 we described abnormalities in early folliculogenesis - and, in particular, an increased proportion of follicles that had initiated growth from the primordial pool (Webber et al., 2003) - and more recently we have shown that this is associated with abnormal granulosa cell proliferation and aberrant expression of growth factors implicated in follicle development, including anti-Mullerian hormone (AMH) (Stubbs et al., 2005; Stubbs et al., 2007). In work funded by Wellcome, and in collaboration with Professor Ilpo Huhtaniemi we are currently examining the role of insulin-like growth factors in normal and aberrant folliculogenesis.
Future Research
Future studies will capitalise on progress made in understanding the underlying ovarian abnormality in PCOS, the genetic basis of the syndrome and the effects of PCOS of reproductive and metabolic function. With Professor Jaroslav Stark, we will employ a Systems Biology approach to understanding interactions between environmental and genetic factors in the aetiology of the syndrome. The major areas of planned research are:
Ovarian abnormalities in PCOS
We plan to extend these studies to examine the molecular and cellular processes that underlie aberrant granulosa cell proliferation and abnormal preantral folliculogenesis in PCOS. These studies will include investigation of the potential role of androgens, of growth factors of the transforming growth factor beta (TGFb) superfamily and (in parallel with studies in mouse ovary with Dr Kate Hardy) examination of the role of cell adhesion molecules and associated cell signalling pathways in normal and abnormal early follicle development in the human ovary.
Genetic basis of PCOS
In a very recent case-control association study, we (ie the group led by Professor Mark McCarthy and I) have identified a potential susceptibility locus for PCOS, which implicates the recently identified FTO (fat mass and obesity-related) gene (Barber et al., 2008a). Future work will include further examination of this and other candidate loci using case-control cohorts but the major focus of our work will be participating in and co-ordinating large genome-wide association studies (GWAS) to identify new loci, together with collaborators in Europe (UK, Netherlands, Iceland, Sweden, Greece) and the USA (Northwestern University Chicago and University of Chicago).
Developmental origin of PCOS: role of early life events
We have hypothesised that early life events, including exposure to excess androgen in utero, have a significant effect on the phenotype of PCOS (Abbott et al., 2002). In collaboration with Professor Marjo-Riitta Jarvelin (Imperial) and Finnish colleagues we have access to a cohort of more than 3000 girls born in 1986 in the north of Finland (the Northern Finland Birth Cohort (NFBC) 1986) for whom we have data on maternal and early life events, endocrine and metabolic indices, together with recent clinical data including menstrual cycle history. We will also have access to data from a similar UK-based (1990) birth cohort - the Avon Longitudinal Study of Parents and Children (ALSPAC) and are in the process of applying for funding from the Wellcome Trust to investigate the effects of early life events on development of markers of PCOS and associated cardiovascular risk factors in adolescents within these cohorts.
Metabolic abnormalities in PCOS
PCOS is clearly a prediabetic state and identification of young women with PCOS who are at particular risk of developing T2D is important so that appropriate interventions can be undertaken. Metabolic abnormalities (particularly insulin resistance and dyslipidaemia) in PCOS are associated with fat distribution and androgen levels. Our recent studies have confirmed that visceral adiposity is a predictor of metabolic abnormalities (Barber et al., 2008c) but surprisingly little is known about visceral fat deposition in women with PCOS. Together with Dr Tony Goldstone and Professor Jimmy Bell (Imaging, Imperial) we plan to study the relationship of metabolic indices to body fat distribution as determined by whole-body MRI and 3-D reconstruction. Regarding intervention and prevention of the sequelae of metabolic dysfunction in PCOS, we know that calorie restriction is effective in obese women with PCOS but the role of exercise is poorly understood. Together with Professor Desmond Johnston (Metabolic Medicine, St Mary's) we plan to study the effect of an exercise programme on glucose-insulin homeostasis in women at risk of diabetes ie those with PCOS and/or gestational diabetes.
Teaching
We (Kate Hardy and Stephen Franks) encourage medical students undertaking the BSc modules in Reproductive Medicine or in Endocrinology to take an active part in laboratory-based projects in our group. BSc students spend 6-8 weeks in the lab and are given projects (usually related to lab-based studies of ovarian folliculogenesis in mouse or human ovary). Students have the opportunity to present their research at internal or external scientific meetings and many are co-authors on publications arising from the work.
Laboratory-based projects form an important part of the well-established MSc course in Reproductive and Developmental Biology, based in the IRDB. Lab projects are undertaken over 5-6 months which provides the opportunity for the student to make a substantial contribution to the work of the lab.
Research Opportunities
There are opportunities for undergraduate and postgraduate students from either clinical or non-clinical background to undertake lab studies (in the key areas outlined above) towards a further degree (MSc, MD or PhD). We also have opportunities for research assistants at post-doctoral level. Funding of current and research students and post-doctoral fellows have come from a variety of sources including MRC, BBSRC, Wellcome Trust, Wellbeing of Women and the local Institute Trust Fund.
Selected Publications
Abbott DH, Dumesic DA & Franks S. (2002). Developmental origin of polycystic ovary syndrome - a hypothesis. J Endocrinol 174, 1-5.
Barber TM, Bennett AJ, Gloyn AL, Groves CJ, Sovio U, Ruokonen A, Martikainen H, Pouta A, Taponen S, Weedon MN, Hartikainen AL, Wass JA, Jarvelin MR, Zeggini E, Franks S & McCarthy MI. (2007). Relationship between E23K (an established type II diabetes-susceptibility variant within KCNJ11), polycystic ovary syndrome and androgen levels. Eur J Hum Genet 15, 679-684.
Barber TM, Bennett AJ, Groves CJ, Sovio U, Ruokonen A, Martikainen H, Pouta A, Hartikainen AL, Elliott P, Lindgren CM, Freathy RM, Koch K, Ouwehand WH, Karpe F, Conway GS, Wass JA, Jarvelin MR, Franks S & McCarthy MI. (2008a). Association of variants in the fat mass and obesity associated (FTO) gene with polycystic ovary syndrome. Diabetologia 51, 1153-1158.
Barber TM, Casanueva FF, Karpe F, Lage M, Franks S, McCarthy MI & Wass JA. (2008b). Ghrelin levels are suppressed and show a blunted response to oral glucose in women with polycystic ovary syndrome. Eur J Endocrinol 158, 511-516.
Barber TM, Golding SJ, Alvey C, Wass JA, Karpe F, Franks S & McCarthy MI. (2008c). Global adiposity rather than abnormal regional fat distribution characterizes women with polycystic ovary syndrome. J Clin Endocrinol Metab 93, 999-1004.
Chavez-Ross A, Franks S, Mason HD, Hardy K & Stark J. (1997). Modelling the control of ovulation and polycystic ovary syndrome. J Math Biol 36, 95-118.
Franks S. (1995). Polycystic ovary syndrome. N Engl J Med 333, 853-861.
Franks S. (2008). Polycystic ovary syndrome in adolescents. Int J Obes (Lond) 32, 1035-1041.
Franks S, Gharani N, Waterworth D, Batty S, White D, Williamson R & McCarthy M. (1997). The genetic basis of polycystic ovary syndrome. Hum Reprod 12, 2641-2648.
Franks S, Stark J & Hardy K. (2008a). Follicle dynamics and anovulation in polycystic ovary syndrome. Hum Reprod Update 14, 367-378.
Franks S, Webber LJ, Goh M, Valentine A, White DM, Conway GS, Wiltshire S & McCarthy MI. (2008b). Ovarian morphology is a marker of heritable biochemical traits in sisters with polycystic ovaries. J Clin Endocrinol Metab 93, 3396-3402.
Gaasenbeek M, Powell BL, Sovio U, Haddad L, Gharani N, Bennett A, Groves CJ, Rush K, Goh MJ, Conway GS, Ruokonen A, Martikainen H, Pouta A, Taponen S, Hartikainen AL, Halford S, Jarvelin MR, Franks S & McCarthy MI. (2004). Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone. J Clin Endocrinol Metab 89, 2408-2413.
Gilling-Smith C, Willis DS, Beard RW & Franks S. (1994). Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries. J Clin Endocrinol Metab 79, 1158-1165.
Haddad L, Evans JC, Gharani N, Robertson C, Rush K, Wiltshire S, Frayling TM, Wilkin TJ, Demaine A, Millward A, Hattersley AT, Conway G, Cox NJ, Bell GI, Franks S & McCarthy MI. (2002). Variation within the type 2 diabetes susceptibility gene calpain-10 and polycystic ovary syndrome. J Clin Endocrinol Metab 87, 2606-2610.
Powell BL, Haddad L, Bennett A, Gharani N, Sovio U, Groves CJ, Rush K, Goh MJ, Conway GS, Ruokonen A, Martikainen H, Pouta A, Taponen S, Hartikainen AL, Halford S, Zeggini E, Jarvelin MR, Franks S & McCarthy MI. (2005). Analysis of Multiple Data Sets Reveals No Association between the Insulin Gene Variable Number Tandem Repeat Element and Polycystic Ovary Syndrome or Related Traits. J Clin Endocrinol Metab 90, 2988-2993.
Rice S, Christoforidis N, Gadd C, Nikolaou D, Seyani L, Donaldson A, Margara R, Hardy K & Franks S. (2005). Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from anovulatory women with polycystic ovaries. Hum Reprod 20, 373-381.
Robinson S, Chan SP, Spacey S, Anyaoku V, Johnston DG & Franks S. (1992). Postprandial thermogenesis is reduced in polycystic ovary syndrome and is associated with increased insulin resistance. Clin Endocrinol (Oxf) 36, 537-543.
Robinson S, Kiddy D, Gelding SV, Willis D, Niththyananthan R, Bush A, Johnston DG & Franks S. (1993). The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clin Endocrinol (Oxf) 39, 351-355.
Stubbs SA, Hardy K, Da Silva-Buttkus P, Stark J, Webber LJ, Flanagan AM, Themmen AP, Visser JA, Groome NP & Franks S. (2005). Anti-mullerian hormone protein expression is reduced during the initial stages of follicle development in human polycystic ovaries. J Clin Endocrinol Metab 90, 5536-5543.
Stubbs SA, Stark J, Dilworth SM, Franks S & Hardy K. (2007). Abnormal preantral folliculogenesis in polycystic ovaries is associated with increased granulosa cell division. J Clin Endocrinol Metab 92, 4418-4426.
Webber LJ, Stubbs S, Stark J, Trew GH, Margara R, Hardy K & Franks S. (2003). Formation and early development of follicles in the polycystic ovary. Lancet 362, 1017-1021.
Willis DS, Watson H, Mason HD, Galea R, Brincat M & Franks S. (1998). Premature response to luteinizing hormone of granulosa cells from anovulatory women with polycystic ovary syndrome: relevance to mechanism of anovulation. J Clin Endocrinol Metab 83, 3984-3991.
