Hormonal regulation of folliculogenesis

Summary

Our current work is determining the detailed mechanisms of how hormones and local ovarian factors interact to regulate ovulation. Our goal is to elucidate the local control of ovarian follicular development in order to obtain a better understanding of, and treatments for, infertility, premature menopause and ovarian cancer.

Description

To better understand infertility in women, we are investigating the ovary and the impact of hormones and other secreted factors on ovarian function. The primary functions of the ovary are to produce eggs (housed within structures called follicles) and hormones, predominantly the sex steroids oestrogen and progesterone and the protein hormone inhibin. Factors produced by the pituitary gland and the ovary are necessary to trigger the growth and development of follicles that culminate in ovulation.

Folliculogenesis, which is the series of stages a follicle undergoes in the adult ovary in order to produce a mature egg, fails in 10-20% of all women, disrupting the generation of viable oocytes. Given the importance of ovarian development and folliculogenesis to ovarian health and function, the focus of our laboratory is to determine the factors which govern these processes.

Hormones produced by the pituitary play important roles in regulating the growth of ovarian follicles and the release of oocytes from the follicles at ovulation. Despite this knowledge, little is known about the factors and mechanisms operating within the ovary that determine the size of the follicle pool, which follicles will be recruited into the growth phase, or selects those follicles which will ovulate and those which will die. An understanding of how follicles initially form and grow and what it is about a select few follicles that ensures they go on to ovulate while the rest die is key to identifying new targets for contraceptive development. It may also provide insights into premature menopause. Only by understanding how normal ovary growth occurs and is regulated can we begin to address and treat ovarian disorders.

Funding

National Health and Medical Research Council

Outcomes

Described for the first time the expression and localisation of activin receptors, Smads and betaglycan in the ovary, which with earlier papers establishes a role and mechanism of action of activin in ovarian folliculogenesis.
Defined the ovarian phenotype of the aromatase deficient mouse and identified a novel role of oestrogen in the differentiation of the ovarian somatic cells.
Identified fibroblast growth factor-9, a male sex determining factor, in the ovary and established a role for it in the regulation of progesterone production.
Determined that betaglycan is required for inhibin action in target tissues.

Selected Publications

Escalona RM, Stenvers KL, Farnworth PG, Findlay JK, and Ooi GT Reducing Betaglycan Expression by RNA interference (RNAi) Attenuates Inhibin Bio-Activity in LβT2 Gonadotropes Mol Cell Endocrinol. In press. 2009

Bowden MA, Li Y, Liu YX, Findlay JK, Salamonsen LA, Nie G. HTRA3 expression in non-pregnant rhesus monkey ovary and endometrium, and at the maternal-fetal interface during early pregnancy. Reprod Biol Endocrinol 6:22. 2008

Rosairo D, Kuyznierewicz I, Findlay J, Drummond A. TGF-beta: its role in ovarian follicle development. Reproduction. 136(6): 799-809, 2008

Drummond AE, Tellbach, M., Dyson, M. Findlay JK, Fibroblast growth factor 9, a male sex determining factor identified in the ovary. Endocrinology, 148, 3711-3721, 2007

Kerr JB, Duckett R, Britt KL, Mladenovska T, Myers M and Findlay JK. Quantification of healthy follicles in the neonatal and adult mouse ovary. Reproduction 132, 95-109, 2006

Findlay JK, Gear ML, Illingworth PJ, Junk SM, Kay G, Mackerras AH, Pope A, Rothenfluh HS and Wilton L. Human embryo - a biological definition. Human Reproduction 10, 1093, 2006

Britt KL, Simpson ER and Findlay JK. Effects of phytoestrogens on the ovarian and pituitary phenotypes of estrogen deficient female Aromatase knockout mice. Menopause, 12, 174-185, 2005

Britt KL, Stanton PG, Misso M, Simpson ER and Findlay JK. The effects of estrogen on the expression of genes underlying the differentiation of somatic cells in the murine gonad. Endocrinology, 145, 3950-2960, 2004

Britt KL, Saunders PK, McPherson SJ, Misso ML, Simpson ER and Findlay JK. Estrogen actions on follicle formation and early follicle development. Biology of Reproduction 71, 1712-1723, 2004

PHI Research Team