Research Trial:
Researchers at Monash Medical Centre, Clayton in collaboration with the World Health Organisation are trialing a new male contraceptive method. We need healthy couples living in a stable relationship and not planning pregnancy for two years.
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Hormonal regulation of folliculogenesis

Folliculogenesis is the process by which oocytes [eggs] enclosed in follicles mature in the ovary and ovulate each cycle. Our studies are based on the premise that locally-produced estrogen and transforming growth factor b [TGFb] superfamily members, especially activin, bone morphogenetic proteins [BMP-4/7], growth differentiation factor 9 [GDF-9] and TGFb, contribute in a coordinated manner to the intra-ovarian regulation of follicle development. The actions of these factors within a follicle are determined by ligand availability, receptor expression and induction or repression of alternative signal transduction pathways. We hypothesise that combinations of these components change with follicular development and determine the biological effect of the ligand. Our research investigates the respective roles that estrogen and TGFb superfamily members play in a) recruiting primordial follicles into the growth phase, b) determining whether granulosa cells proliferate or differentiate, and c) mediating cell-cell, including cell-oocyte, interactions in growing follicles.

To address these fundamental issues, we use human ovarian tissues and 3 types of rodent models, (1) developmental models: postnatal, immature and cycling rats, and ovarian grafts in rats and mice, (2) hormone-treated models: estrogen (DES) or equine chorionic gonadotrophin (eCG), (3) estrogen insufficient model: aromatase knockout (ArKO) mouse, as well as tumour cell lines.

(a) The roles of estrogens in folliculogenesis

Estradiol-17b (E2), a product of aromatase conversion of androgen substrate, is the major biologically-active estrogen in the ovary. It acts via two subtypes of estrogen receptor, a and b, that dimerise and act as nuclear transcription factors. We are investigating when and how E2 affects folliculogenesis.

(b) The roles of TGFb superfamily members in folliculogenesis

We are investigating how activin, TGFb, GDF-9 and BMP-4 and -7 are implicated in the regulation of ovarian function. Most of these factors act via transmembrane serine and threonine kinase receptors that activate Smad proteins, complexes of which translocate to the nucleus to mediate transcriptional events. Activin binding and signalling is inhibited by the betaglycan/inhibin complex, which confers an increased affinity of inhibin for activin type II receptors. These components are being analysed in relation to follicular development using the models described above.

Expected outcomes and significance: Our studies will elucidate the local control of ovarian follicular development which will lead to the development of new contraceptives and a better understanding of, and treatments for, infertility, premature menopause and ovarian cancer.