Basic and Clinical Science Research Programs

Ovarian and Follicular Function

Ovarian research examines the basic physiology and biology of the ovary to improve clinical outcomes, particularly in polycystic ovary syndrome. Research also investigates the cellular biology of the ovarian follicle. Current research programs are directed at -

• The role of leukocytes and in particular macrophages in the ovary and the way that they interact with the theca, granulosa layers and the oocyte.
• The mechanisms whereby polycystic ovary syndrome is expressed and the contribution of androgen receptor action and polymorphisms.
• The interrelationships between diet, nutrition and ovarian function as evidenced by polycystic ovary syndrome.
• The study of the extracellular matrix, including the follicular basal lamina and the genesis of the epithelial membrana granulosa

In 2004, RCRH research in conjunction with Reproductive Medicine Laboratories produced 'The Egg Timer' test, which measures blood hormone levels in conjunction with a pelvic ultrasound to test for the proportion of good quality eggs left within a woman's ovaries at any given time (ovarian reserve). This test helps women to compare their chronologic and biological age and assist family planning.

Key contacts
Prof Robert Norman
Professor David Armstrong
Professor Ray Rodgers
Dr Robert Gilchrist
Dr Darryl Russell
Dr Kelton Tremellen
Dr Rebecca Robker

Oocyte and Early Embryo Development

This Program investigates the important step of oocyte maturation, fertilisation and early embryo development. A significant importance of this resarch is its clinical and veterinary application, especially in assisted reproductive technologies, as well as understanding basic mechanisms involved in development. Current research programs are directed at:

• The influence of the external microevironment surrounding oocytes and early embryos on embryonic programming and fetal development.
• Maternal factors programming oocyte and early embryo development leading to altered fetal and placental development.
• The molecular and biochemical signals regulating early development.
• Novel systems for the automation of embryo production.
• Diagnostic evaluation of sperm, oocytes and early embryos.
• Oocyte and embryo freezing and storage.
• Research on oocyte secreted factrors and GDF-9/9B, their role, production and regulation.
• Studies on the regulation of oocyte maturation and cumulus cell function by paracrine/gap junctional signalling between the 2 cell types, including exchange of small regulatory molecules such as cAMP. These projects include true IVM (ie effects on embryo developmetnal potential).
• Work continues using the marmoset primate model to investigate characterisation of the role of FSH in reproductive cycles.
• In vitro maturation: physiological and molecular mechanisms of oocyte cytoplasmic maturation in animal models and development of methods for clinical application in assisted reproductive technology.
• Investigations of interactions between hormones (steroids, gonadotrophins) and paracrine growth factors in follicle regulation: in vitro studies with pig and human follicle cell models.
• Role of seminal components in regulation of follicle and corpus luteum development and function: in vivo studies with mouse and pig models
• Enhancement of embryo development and survival by immune modulating molecules: role in increased fecundity in pigs

Key Contacts
A/Prof Jeremy Thompson
A/Prof Mark Nottle
A/Prof Bill Breed
Prof David Armstrong
Dr Robert Gilchrist
Dr Michelle Lane
Dr Karen Kind

Embryo Implantation and Placental Development, Endometriosis

Impaired placentral trophoblast invasion of the endometrium has been implicated in a variety of pregnancy complications including implantation failure, recurrent miscarriage, intrauterine growth restriction, pre-term birth and preeclampsia. Together these complications afflict about one third of couples wishing to achieve pregnancy. These may result from deficient endometrial differentiation, deficient pro-invasive factors in trophoblast or an excess of anti-invasive factors in the endometrium or a combination of factors.

We are particularly interested in the molecular mechanisms that control differentiation of the endometrium to create the implantation window and accommodate an invading embryo, placental trophoblast invasion, differentiation and function. This research focuses on the interactions between a variety of growth factors and utilises in vitro and in vivo methods.

Endometriosis is a condition where the lining of the womb grows at sites in the pelvis causing period pain and subfertility for 6-10% of reproductive aged women.  Sufferers of endometriosis require surgery to obtain a diagnosis and then often require repetitive and chronic treatment for this condition.  The aim of the research group is to improve the understanding of the pathophysiology of endometriosis in order to develop better diagnostic and therapeutic tools for this condition.  To explore endometrisois further the research team utilises several in vivo models plus sophisticated molecular and cellular laboratory techniques.

Current research programs are directed at:

• The role of cytokines and immune cells in preparing endometrial receptivity and regulating placental development.
• The role of male seminal factors in conditioning the female reproductive tract for pregnancy.
• The effect of specific growth factors on implantation.
• The interaction between the hormone relaxin and other factors to induce decidualization and differentiation of the endometrium.
• Maternal insulin-like growth factors (IGFs): impact on trophoblast invasion, placental function and fetal growth and survival.
• Developing diagnostic tests to predict risk of pregnancy complications.
• Epigenetic change following perturbations of early pregnancy
• Hormonal control of the myometrium

Key Contacts:
A/Prof Claire Roberts
A/Prof Sarah Robertson
Dr Louise Hull
Dr Wendy Ingman
Prof Richard Ivell
A/Prof Bill Breed

Male Reproduction

Molecular techniques are used to address key issues in the differentiation of the male reproductive system. These include transcriptional analysis of germ cell development and maturation, as well as the differentiation of the somatic components of the testis (Leydig and Sertoli cells) and their perturbation through extrinsic factors. A major recent discovery has been the role of the new Leydig cell hormone Insulin-like factor 3 (INSL3) in male reproductive health. Altered testicular function in the aging male is also a focus of attention.

Damaged sperm DNA will lead to infertility and miscarriage, even if IVF is used to assist conception. RCRH Adnrology research in conjunction with Repromed, is centred on sperm and infertility and how to improve assisted reproductive treatment and pregnancy outcome. Current projects focus on the use of anti-oxidants to improve sperm function, through the Anti-Oxidant Trial for Male Infertility (the Menevit study).

Key Contacts:
Prof Richard Ivell
A/Prof Bill Breed
A/Prof Sarah Robertson
Dr Kelton Tremellen
Dr Ravinder Anand-Ivell

Reproductive Immunology

The reproductive process is a test of the natural immune system of the female, in both the acceptance of foreign-to-the-body sperm and the implantation of the embryo. It is now recognised that much of the "unexplained infertility" and early embryo loss is a result of immunological rejection and understanding of how the body copes with these challenges will help improve reproductive health and outcomes. Current research programs are directed at -

• Immunology of the female immune response to embryo implantation
• The role of semen in maternal immune tolerance for pregnancy
• Cytokine regulation of early embryo development
• Cytokines and leukocytes in ovarian function
• Novel therapeutics for infertility and recurrent miscarriage
• Improved methods for IVF and human embryo culture

Key Contact
A/Prof Sarah Robertson
Dr Wendy Ingman
Dr Melinda Jasper
Dr Rebecca Robker
Dr Louise Hull

Human and Animal Reproductive Biotechnology

This research group has an international reputation in the general areas of reproductive biology and the development of associated technologies such as embryo culture and freezing. In collaboration with a number of University, Institute and Hospital Research groups in Australia as well as overseas, current research is focused on developing organ, tissue and cell replacement therapies. In particular, work is focused on isolating embryonic and adult stem cells in animal models. Our work is funded by various agencies including the Australian Research Council, the Juvenile Diabetes Research Foundation, the National Health and Medical Research Council and industry.

Key Contacts:
A/Prof Mark Nottle
A/Prof Jeremy Thompson

Nutrition, Environment and Reproduction

The Centre's close collaboration with large clinical operations provides an excellent resource for epidemiological studies. Current research programs are directed at -

• Lifestyle and treatment factors that impact on fertility and success from Assisted Reproductive Technology (ART). The projects in this area include the Australian Study of Single Embryo Transfer (ASSET) and studies on obesity, smoking and age.
• Fetal programming of the reproductive axis, and the effects of maternal diet in pregnancy on fetal growth and postnatal development.
• The discovery of the suite of clock gene transcription factors and the recognition that they are rhythmically expressed in a wide range of tissues and organs has led to a broadening of research on the potential roles of circadian rhythms in health and disease. We are actively working in several areas ranging from the control of SCN function to the consequences of rhythm disruption on systems.

Key Contacts:
Prof Robert Norman
A/Prof David Kennaway
A/Prof Michael Davies
A/Prof Claire Roberts
Dr Rebecca Robker
Dr Vivienne Moore

Health and Social Outcomes in Reproduction

Clinical treatment programs for infertility and other reproductive issues are often controversial in the community. The research interests of this group are client-centred and focus on studying the attitudes and experience of women and their partners. Current research is currently directed towards:

• A qualitative study of the experience of deciding an outcome for embryos created in In Vitro Fertilisation (IVF) if they are unused, the meaning of the human embryo - to infertile progenitors and the community, and the issues encountered in making such a decision.
• A 10 year cohort study of the decisions made by clients and clinics in South Australia about the cryostorage of unused embryos.
• A national survey of IVF clinics regarding the outcomes available to and selected by clients for unused embryos.
• A study of factors influencing clients decisions to have one or two embryos transferred during treatment .

Key Contact
A/Prof Michael Davies
Prof Robert Norman
Dr Sheryl de Lacey

Early Life Programming of Fetal Development and Adult Health

This research group has two major streams firstly seeking to increase fundamental knowledge about early growth and development and how it is altered in major disease states, especially fetal growth restriction.

Secondly, the perinatal and postnatal consequences of fetal growth restriction and other perinatal disturbances for cardiovascular and metabolic homeostasis and for neuromotor development and function are being examined.

Finally, this knowledge is being utilised to the design and testing of interventions to prevent or ameliorate the perinatal factors leading to later disease or their adverse consequences:

• What controls fetal growth and functional development, specifically, the roles of the mother, placenta, and the insulin-like growth factors?
• What are the initiating events in utero and in infancy, and the mediating mechanisms involved, whereby the early life environment influences our later metabolic and cardiovascular homeostasis and neuromotor development and function as infants, children and adults?

Current Projects:

• Maternal insulin-like growth factors (IGFs): impact on placental function and fetal growth and survival.
• Insulin-like growth factors: fetal supplementation and impact on prenatal and postnatal growth, survival and function.
• Prenatal programming of adult diabetes: molecular and cellular defects?
• Prenatal programming of adult diabetes: role of stress hormone axes?
• Maternal calcium supplementation and prevention of diabetes in offspring born small.
• Prematurity and fetal growth restriction: impact on neuromotor development and function in children and adults.

Key Contacts:
Prof Julie Owens
Prof Jeffrey Robinson
A/Prof Jeremy Thompson
A/Prof Michael Davies
A/Prof Claire Roberts
A/Prof Sarah Robertson

Menopause Research

This multidisciplinary group is based in the Discipline of Obstetrics and Gynaecology at the Adelaide Women's & Children's Hospital. It conducts epidemiological studies, large clinical trials and educational programmes on the menopause and postmenopausal women's health.

Professor MacLennan is Editor-in-Chief of CLIMACTERIC, The Journal of the International Menopause Society and is a Past President of the Australian Menopause Society. His research team includes Ms Jessica Broadbent, Mrs Anne Chandler, Dr Alice MacLennan, Associate Professor Anne Taylor.

Recent and Current Projects include:

• Epidemiological studies on pelvic floor dysfunction, alternative therapies and hormone therapy use, quality of life in collaboration with the Department of Health. Population Research and Outcome Studies Unit using the S.A Health Omnibus Survey.
• Cochrane Collaboration systematic review on HRT and vasomotor symptoms.
• The Women's International Study of Long Duration Oestrogen after Menopause (WISDOM).
• Research into Memory, Brain function and Oestrogen Replacement (REMEMBER study) and genetic sub study.
• Tibilone after breast cancer four year study (LIBERATE).
• Long-term Intervention on Fractures with Tibilone Trial (LIFT).
• Phase I, II and III studies on new treatments for menopause and osteoporosis.

Key Contacts:
Prof Alastair Maclennan (Chairman)