Hormones and ovaries: a lifelong journey
Birth of a single baby gives that infant the best possible start to life. In mono-ovular species like man there is a tight control over the hypothalamicpituitaryovarian axis to try to ensure that there is also sufficient time between births to allow the infant to develop to its full potential. Breastfeeding suppresses fertility by modulating pulsatile LH but not FSH secretion delaying the final stages of ovarian follicle maturation and the return of fertility in breastfeeding women, highlighting the fundamental importance of pulsatile LH secretion in regulating fertility. We showed that differential secretion results from different packaging and release pathways for FSH and LH affecting the final stages of follicle development. Collaborative studies on local factors that regulate oocyte activation and follicle development before gonadotrophin dependency concentrated on effects of BMPs, inhibin and activin, the identification of a BMPRIB receptor mutation as the Booroola fecundity gene, and effects of BMPs on pituitary gonadotrophin and secretion. These studies on fecundity genes led us to investigate the role of DAZL, an oocyte RNA binding protein. Heterozygous knockout mice have increased litter sizes while the homozygous null mice lose all oocytes after birth. Surprisingly these oocyte-free ovaries become steroidogenically active, and develop tumour-like phenotypes similar to both types of human ovarian cancer. These studies have highlighted the fact that the oocyte, by determining the fate of the follicle, ultimately regulates the orderly removal of tissue from the ovary that potentially could form tumours. Both small and large animal models have played a vital part in these research endeavours, and we are developing potentially novel techniques, particularly with contrast-enhanced ultrasound, to allow us to exploit our work through to the clinic. I have been fortunate to work and collaborate with many excellent people over the years and I thank them all for their trust.