Research Focus
My research interest is focussed on how the ovary works in health and disease.
We are investigating how the ovary changes across the menstrual cycle and how this is controlled by hormones released from the brain and compounds produced locally.
We study how this changes in a month when the egg is fertilised to understand how the period is delayed and the factors involved in the helping support the pregnancy.
One condition when the ovary does not work properly is ‘polycystic ovary syndrome’. This is the most common hormone disorder of women and one in five women will have this problem to one degree or another. It is associated with many clinical problems including irregular periods, skin and weight problems, subfertility and miscarriage. We are investigating what causes this syndrome to develop and how the environment inside the womb during pregnancy can perhaps programme this condition to occur.

Background to the Research
1) The molecular regulation of tissue and vascular remodelling.
The molecular regulation of tissue and vascular remodelling, and its manipulation, is of great generic importance in the understanding of how changes in tissue structure are controlled in health and disease. There is nowhere else in the body where tissue and vascular remodelling is as marked, predictable and highly regulated as in the female reproductive tract. We are using the ovary as a model to increase understanding of the molecular regulation of tissue remodelling and identify target molecules for its manipulation. The ovary undergoes intense cyclic remodelling and physiological angiogenesis each month. In the course of a few days the follicle, with its avascular layer of granulosa cells, turns into the highly vascular corpus luteum. The corpus luteum has the highest blood supply per unit mass in the body, eight times that of the kidney. In the absence of pregnancy, the highly vascular, and synthetically active corpus luteum that measures up to two centimetres in diameter, will turn into a small avascular fibrous remnant that is difficult to identify within the ovary. The molecular regulation of this tissue and vascular modelling is not yet fully understood. The laboratory studies the role of matrix metalloproteinases, growth factors, immune cells and their regulatory molecules in luteal formation, luteolysis and luteal rescue.

2) Paracrine signalling molecules in the human ovary
During luteolysis there are marked effects on the survival and function of endothelial cells, fibroblasts and immune cells, that are prevented by exposure to hCG acting through the LH receptor. As LH receptors are only found on the steroidogenic cells, the function of the other cell types must be regulated by paracrine molecules regulated by LH/hCG. The laboratory studies the LH receptor and its activation using steroidogenic cells. The paracrine effects of steroids, cytokines, chemokines, prostaglandins and growth factors are studied using in vitro models of luteal cell function.

3) The molecular regulation and inhibition of LH receptor action
The molecular regulation of progesterone secretion from the human corpus luteum is of fundamental importance to the regulation of the menstrual cycle and the establishment of early pregnancy. It is clear that progesterone secretion from luteal steroidogenic cells falls in the presence of continued LH, LH receptors and all elements of the steroidogenic pathway. This fall is key in the initiation of luteolysis but its molecular regulation is not understood. What is clear is that hCG by acting through LH receptors can prevent the decline in progesterone secretion from the corpus luteum. We are investigating the regulation of LH receptor function, signalling, alternative LH receptor splicing, differential LH/hCG effects and the effects of different splice variants on LH receptor functioning.

4) Development origins of Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women and it presents with infrequent periods, amenorrhoea, hirsuitism, female infertility and recurrent miscarriage. It is also associated with an increased risk of obesity, endometrial carcinoma and type II diabetes mellitus. We do not understand its aetiology or its variable phenotype and current treatment options are limited and largely symptomatic in nature. Twenty percent of women have polycystic ovaries but only some will experience the hyperandrogenism and abnormal gonadotrophins of PCOS, and some of these will be insulin resistant. Studies have suggested that increased exposure in androgens in utero can result in many of the phenotypic manifestations of PCOS. In a new development, the laboratory is starting to study the possible fetal programming of polycystic ovary syndrome. We hypothesised that the PCOS phenotype results from abnormal exposure to androgens during development and a hierarchy of androgen effects results in variable phenotypic penetrance, depending on the level of prenatal androgen exposure. This research programme will afford the scientific opportunities to understand the development of PCOS and the medical opportunities for the development and testing of new treatment strategies.

Top left: Localisation of macrophages (red) and phospho-smad (green) signalling in human luteal cells (blue). Top right: Luteinised granulosa cells in culture. Bottom left: The human corpus luteum showing granulosa-lutein cells (GL), theca-lutein cells (TL), blood vessels (BV), Stroma (St) and the central clot (CC).
Bottom right: In situ hybridisation of LH receptor mRNA in steroidogenic cells of the human corpus luteum.

5) Steroid regulation of the SLIT/ROBO interaction
The SLITs are ligands for the ROBO receptors. They promote apaptosis and inhibit cell migration and have a role in development of disparate organ systems. In adult tissues they function as tumour suppressor genes and expression is lost during development of some cancers. They however have a physiological role in the tissue and vascular remodelling in the reproductive system. They are regulated by endocrine and paracrine molecules including steroids. We are investigating this regulatory system and its manipulation in reporductive cancers.

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Recent Progress

• We have demonstrated that cortisol is a liteotrophic molecule in the human corpus luteum. Ref: Myers M, Lamont MC, van den Driesche S, Mary N, Thong KJ, Hillier SG, Duncan WC (2007) Role of luteal glucocorticoid metabolism during maternal recognition of pregnancy in women. Endocrinology 148: 5769-5779.
  
  
• We have identified Activin A as a potential key factor implicated in the regulation of  human luteolysis.
  Ref: In vitro evidence suggests activin-A may promote tissue remodeling associated with human luteolysis. Myers M., Gay E., McNeilly A.S., Fraser H.M. and Duncan W.C. (2007) Endocrinology 148: 3730-3739.
  
  
• We have shown that the novel splice variants of the human LH receptor we’ve previously identified are developmentally regulated.
  Ref: Dickinson RE, Stewart AJ, Myers M, Millar RP, Duncan WC (2009) Differential expression and functional cross-talk of luteinizing hormone receptor (LHR) splice variants in human luteal cells: implications for luteolysis. Endocrinology 150: 2873-2881
  
  
• We have shown that Hypoxia Induced Factor 1a (HIF-1alpha) is hormonally regulated in human luteal cells and that it is solely not responsible for Vascular Endothelial Growth Factor (VEGF) regulation.
  Ref: van den Driesche S, Myers M, Gay E, Thong KJ, Duncan WC (2008) Human chorionic gonadotrophin up-regulates hypoxia inducible factor-1 alpha in luteinised granulosa cells: implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteum. Mol Hum Reprod 14: 455-464.
  
  
• We have demonstrated a physiological role for the SLIT/NOBO system in the ovary and its regulation by steroids. Ref: Dickinson RE, Myers M, Duncan WC (2008) Novel regulated expression of the SLIT/ROBO pathway in the ovary: possible role during luteolysis in women. Endocrinology 149: 5024-5034.