Reproductive Health for Women

Reproductive Medicine Unit scientists awarded $8.3 million grant to improve reproductive health for women

The Australian National Health and Medical Research Council (NHMRC) awarded a highly prestigious Program Grant to 5 senior scientists in The Reproductive Medicine Unit, Discipline of Obstetrics and Gynaecology, University of Adelaide. The Grant, worth $8.3 million and to be administered over a 5-year period (2003-2008), is entitled Reproductive Health for Women: From Egg to Embryo and reflects the outstanding research record and continuing success of awardees Professor Robert Norman, Associate Professor Raymond Rodgers, Professor David Armstrong, Dr Jeremy Thompson and Dr Sarah Robertson.

What is an NHMRC Program Grant?

The federal government of Australia's NHMRC Program Funding Scheme aims to provide support for high achieving teams of Australian researchers to pursue broadly based collaborative research activity that contributes new knowledge at a leading international level in important areas of health and medical research. The provision of funding over a 5-year period allows stable and continuous research to be implemented.

Reproductive Health for Women: From Egg to Embryo

Sub-optimal reproductive health can have a critical impact on the wellbeing of women at puberty, through the menstrual years, during the establishment and maintenance of pregnancy, in parturition and lactation and at menopause. The broad aim of this project is to improve basic knowledge of the cellular and molecular mechanisms governing female reproductive processes, and to integrate that knowledge into improved therapeutic strategies and health outcomes for women.

Specifically, the following areas will be addressed:

• Optimisation of ovarian follicle development
  Folliculogenesis is the process by which the somatic cells surrounding dormant oocytes begin to grow and differentiate. The oocyte is essential for initiation of follicle growth, and conversely follicle growth and maturation is important in determining the quality of the oocyte. In addition, the follicle produces hormones such as progesterone, androgen and oestrogen. When follicle growth or development is not optimal, poor quality oocytes are generated and/or imbalances in ovarian hormone synthesis occurs with resultant impact on physical and psychological health.
  We aim to discover and characterise the factors that contribute to follicle development, to examine the role of extracellular matrix in follicular development, to determine which factors are critical for granulosa cell maturation, to characterise processes of cellular atresia that occur in follicles, to identify the key components of the aetiology of polycystic ovary syndrome and to expand our knowledge regarding the role of diet and exercise in optimal ovarian health.
• Optimisation of oocyte quality
  Failure of normal oocyte maturation represents the most devastating failure in gametogenesis in humans hoping to conceive a child, since an incompetent oocyte compromises embryo development and thus pregnancy. In women undergoing stimulated ovulation cycles, up to 30% of oocytes may exhibit subtle maturational anomalies which compromise assisted reproductive technologies such as IVF.
  We aim to improve clinical outcomes in terms of ovulation induction, to improve oocyte maturation in vitro and to predict optimal outcome from follicles. In particular, this will involve the development of unique culture systems to improve the quality of oocytes matured in vitro , better characterisation of the roles of ovarian macrophages in oocyte maturation and hormone secretion and identification of new genes involved in human ovulation.
• Maximisation of early embryo viability and potential
  The challenge for human assisted reproductive technology is to enable women to successfully give birth to a single healthy infant, using as minimally invasive technology as practicable, and without the need for fetal reduction. However, to maximise the chances of success, most IVF programs transfer at least two embryos into the reproductive tract of women hoping to conceive. A risk associated with this practice is multiple pregnancy, a phenomenon which is increasingly viewed as medically and ethically unacceptable. Furthermore, there is an urgent need to improve assisted reproductive technology in order that children born by use of these techniques are at no greater risk of growth retardation, post-natal complications or adult disease than other children.
  We hope to deliver a cost-effective, successful embryo transfer program that meets patient and clinical expectations, and results in infants with health outcomes comparable to those of naturally conceived children. To achieve this important goal, we aim to identify markers of follicles that bear oocytes with maximal potential to result in high-quality embryos, to discover the molecular and biochemical linkage between ex vivo culture environment and fetal and post-natal development and to investigate the mechanisms by which the molecular environment to which an embryo is exposed contribute to its quality, growth and mRNA expression.
• Promoting uterine receptivity
  The success of pregnancy is largely determined by pre- and peri-implantation events. Implantation failure occurs in 40% of pregnancies in fertile women, and accounts for the majority of unsuccessful IVF cycles. Moreover, pathologies of pregnancy, including pre-eclampsia and recurrent miscarriage, as well as fetal growth retardation and placental insufficiency (both causally linked to adult metabolic disorders) are all now recognised to stem from sub-optimal embryo implantation. A key determinant of the quality of embryo implantation, and thus the development of these and other pathologies, is the receptivity of the endometrium. We have previously determined that paternal factors ( i.e. factors in semen) play a pivotal role in generating the receptivity of the endometrium by initiating a precisely orchestrated cascade of cytokine and leukocyte activity in the uterus, which leads to the generation of an appropriate tissue and immunological environment for implantation.
  We aim to elucidate the molecular and cellular events linking insemination with immune tolerance of the conceptus, to characterise the cellular and molecular consequences of uterine exposure to seminal fluid in women, to determine the role of seminal fluid and in particular seminal TGF b in generation of a uterine environment conducive to implantation and to investigate the role of semen in promoting optimal development of the corpus luteum. We hope to utilise our findings in these areas to develop novel assays for male infertility, and to investigate the potential of supplementing women with exogenous TGF b to improve reproductive outcomes.

Program Grant Awardees

Robert Norman is a Professor in the Discipline of Obstetrics and Gynaecology, University of Adelaide, and Head of the Reproductive Medicine Unit, The Queen Elizabeth Hospital, Adelaide. He is a specialist in Obstetrics and Gynaecology, with subspecialties in endocrinology and infertility. With a strong research focus in reproductive endocrinology and clinical medicine, particularly in uterine biology and ovarian physiology coupled to clinical reproductive outcomes, he has over 200 refereed publications. He combines clinical and basic research with extensive laboratory experience, having worked in diagnostic and research laboratories for the past 20 years.

Raymond Rodgers , a Principal Research Fellow of the NHMRC and an Associate Professor, University of Adelaide, undertakes novel and internationally competitive research in the area of female ovarian and reproductive function. Having published over 70 papers in peer-reviewed scientific journals, his career has featured numerous novel discoveries many of which are now well engrained in the common literature regarding female reproductive function. In particular, since the early 1980's Associate Professor Rodgers has made a substantial contribution to the understanding of the unique cellular and molecular strategies by which ovaries produce hormones. Such achievements were reached by way of diverse experimental approaches including physiology, histology, electron microscopy, morphometry, cell isolation, cell culture and molecular biology.

An eminent member of the international reproductive biology community, David Armstrong is an Emeritus Professor of The University of Western Ontario, Canada and a Professor of the University of Adelaide. He has been active in reproduction research over a 45-year period during which time he has contributed to some of the most significant developments and breakthroughs leading to our current understanding of ovarian regulation. His career has seen remarkable technical and conceptual advances in research, and he has used a multifaceted strategy from the classical approach of endocrine gland ablation and hormone replacement therapy to modern cell culture, immunoassay and molecular biological approaches to study basic reproductive mechanisms. Professor Armstrong has published regularly and consistently over his impressive research career in top-ranking specialist journals of reproduction, endocrinology and applied animal sciences. His list of over 300 publications includes seminal contributions to high impact journals Nature and Proceedings of the National Academy of Science, USA.

Jeremy Thompson is a Senior Lecturer and Head of the Clinical and Research Embryology Laboratories, Reproductive Medicine Unit, Discipline of Obstetrics and Gynaecology, University of Adelaide. Dr Thompson has published around 60 research papers in his chosen field: the biology of the pre-implantation embryo, specifically its interaction with environmental signals and how these affect metabolic processes and developmental potential. He uses a variety of microscopic (especially fluorescent and confocal) and molecular biology techniques to examine the cell biology of the early embryo. Because of the extremely limited material that an embryo provides for analysis of cellular functions, he has had a long-term interest in microassays to study cell biology. This has lead to the development of several novel techniques, including a real-time fluorescence assay for the determination of very low-level oxygen consumption and the adaptation of a commercial assay for the determination of protein content of individual embryos.

Sarah Robertson is an NHMRC Senior Research Fellow, a scientific advisor to the Scandinavian Fertility Centre Pty Ltd and an Associate Scientist at the Pest Animal CRC, Canberra, Australia. With nearly 20 years experience in basic immunology and cell biology research, since 1988 she has established herself as a leading figure in the quest to identity the immunological processes involved in reproduction. Over the past 13 years she has explored the events of early pregnancy, in particular the role of the maternal immune system in nurturing the embryo as it traverses the tract prior to and during implantation. Specifically, Dr Robertson's work focuses on the cellular and molecular biology of the female immune response to semen and its consequences for embryo and placental development. She has discovered that exposure to semen has a ‘priming' role in promoting successful pregnancy, through preparing the uterus to accommodate the embryo and inducing maternal immune ‘tolerance' to the father's transplantation antigens. Dr Robertson has published more than 30 refereed articles.