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Developmental origins of infertility disorders and ovarian disease
Summary
The focus of this project is determining the regulatory factors that control the development of immature oocytes and the establishment of the primordial folliclular pool, both of which impact upon adult reproductive capacity.
Description
There are a number of processes that impact on fertility in women. For example, the extent to which the ovary successfully develops during the foetal and neonatal time periods is a major determinant of the capacity for reproduction in adulthood.
Reduced reproductive lifespan (‘premature ovarian failure’) occurs in 1 in 100 women under the age of 40 and is thought to be due in part to the poor proliferation or survival of immature eggs during ovarian development.
We are researching the regulatory processes which control of the establishment of the ‘primordial follicular reserve’, i.e. the first population of developing follicles from which all growing follicles (maturing eggs) will be derived.
Current dogma says that the neonatal mammalian ovary contains a finite number of non-growing primordial follicles. During adult life this supply progressively declines to the point where the menopause occurs. Menopause and its hormonal consequences such as osteoporosis are the natural consequences of exhaustion of the pool, whereas premature menopause has a number of aetiologies, including genetic or unknown causes and cancer therapy.
Our research seeks to understand the mechanisms regulating the turnover of the primordial follicle pool.
Our recent work has mapped the dynamics of the follicle population across various ages in mice utilising sophisticated stereological methods and further studies are planned to analyse postnatal ovarian development in normal vs transgenic mice.
An understanding of the dynamics of the primordial pool of follicles and an ability to manipulate its size may result in the development of methods to maintain fertility and avoid hormone replacement therapy in women.
Funding
National Health and Medical Research Council
Outcomes
Described for the first time the absolute numbers of healthy follicles, and therefore oocytes, in the ovaries of mice from birth to 200 days of age, using unbiased stereological methods. The results open up the possibility that there is a variable rate of exit of follicles from the primordial pool and of the development and death of follicles in the growth path.
Demonstrated that the betaglycan gene is expressed differentially in the foetal, neonatal, and adult ovary and testis, suggesting multiple sex-specific roles for betaglycan in gonadal differentiation and maturation.
Selected Publications
Rosairo D, Kuyznierewicz I, Findlay J, Drummond A. Transforming growth factor-beta: its role in ovarian follicle development. Reproduction. 2008 Dec;136(6):799-809.
Drummond AE, Tellbach M, Dyson M, Findlay JK. Fibroblast growth factor-9, a local regulator of ovarian function. Endocrinology. 2007 Aug;148(8):3711-21.
Sarraj MA, Chua HK, Umbers A, Loveland KL, Findlay JK, Stenvers KL. Differential expression of TGFBR3 (betaglycan) in mouse ovary and testis during gonadogenesis. Growth Factors. 2007 Oct;25(5):334-45.
Kerr JB, Duckett R, Myers M, Britt KL, Mladenovska T, Findlay JK. Quantification of healthy follicles in the neonatal and adult mouse ovary: Evidence for maintenance of primordial follicle supply. Reproduction. 2006;132(1):95-109.
Findlay JK, Gear ML, Illingworth PJ, Junk SM, Kay G, Mackerras AH, et al. Human embryo: a biological definition. Human Reproduction. 2007 Apr;22(4):905-11.