Andrology Projects

Androgens, Ageing and Female Reproductive Physiology

• Androgens and the Ovary
• FSH and Female Reproductive Ageing - for details link here

• Androgens and the Ovary

K Walters, CM Allan, DJ Handelsman in collaboration with L Salamonsen (Prince Henry’s Institute of Medical Research, Monash University)

Enhanced understanding of ovarian and uterine physiology and function is of great importance as infertility occurs in 1 in 6 Australian couples, with 50% attributable to female factors. Androgens are essential for male reproduction and traditionally are regarded as a defining characteristic of masculinity. However, in recent years, studies have shown that androgens can influence female reproduction. We and others have shown experimentally in mouse models, that androgen actions mediated by the androgen receptor (AR) have a previously unrecognized influence on female fertility. These may provide long overdue new insights into the basis of the timing of menopause and androgen associated female reproductive disorders such as polycystic ovary syndrome (PCOS), premature ovarian failure (POF), endometriosis, and uterine hyperplasia, a precursor of endometrial carcinoma.

Currently we are identifying the precise mechanism how the AR influences female reproductive physiology, notably in the ovary, brain and female reproductive tissues (ovary, breast, uterus). We have created a unique transgenic model whereby the AR gene has been selectively inactivated (ARKO), resulting in female mice functionally unable to respond to any androgens. Using this novel model Dr Walters has revealed defects in ovulation (Fig. 1) and late-stage follicle growth as the major contributors to the observed reduced fertility. Furthermore, more recent work provides strong direct evidence that as well as intra-ovarian AR-mediated actions, extra-ovarian AR-mediated functions also play a central role via neuroendocrine signalling in maintaining female fertility. In addition, we have shown a role for AR-mediated actions in the regulation of uterine growth and development, which may have important long-term functional consequences for hormone dependent uterine disorders such as endometrial hyperplasia and cancer. This work aims to further enhance our understanding of how androgens regulate female reproductive function, and unravel disruptions in androgenic mechanisms which may be involved in the establishment of androgenassociated reproductive disorders.
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• FSH and Female Reproductive Ageing

K McTavish, K Walters, DJ Handelsman, CM Allan Collaborations: R Kalak, H Zhou, M Seibel, C Dunstan (Bone Biology, ANZAC)

In women, reproductive ageing (declining fertility) coincides with an accelerated decline in ovarian follicles (cells that contain the developing eggs). An early sign of reproductive ageing is increasing levels of serum FSH, which may occur several years prior to cessation of menstrual cycling (menopause). High FSH levels are associated with premature ovarian failure or onset of menopause, reduced ovarian reserve and reduced success of assisted reproduction. We established a unique transgenic mouse model with increasing levels of FSH and premature infertility. Current research (via NHRMC funding) employs this model to determine whether or not high FSH is a passive marker or actively contributes to reproductive ageing. Kirsten McTavish successfully completed her PhD investigating this high FSH expressing model, and is now a postdoctoral fellow with Prof Shunichi Shimasaki at UCSD (San Diego). This research showed that premature infertility due to elevated FSH occurs despite estrous cycling, follicle development and ovulation (similar to reproductive ageing in women), but appears not to be linked to early depletion of the non-renewable ovarian follicle pool. Ongoing research is investigating the effects of high FSH on the ovarian follicle reserve. Premature infertility in transgenic FSH females was due to reduced embryo-fetal survival, which can be rescued using pharmacological (antiprogesterone) or genetic (AR-deficiency) approaches showing elevated FSH disrupted progesterone-androgen signalling pathways. Higher levels of transgenic FSH in another line produced earlier infertility as well as ovarian cysts. Thus, our transgenic FSH model provides a valuable opportunity to study female reproductive ageing, gonadotrophin-induced hyper-stimulation and ovarian dysfunction.

Recent research has also focussed on the role of FSH in bone loss, after the recent but controversial proposal that elevated levels of FSH can induce bone loss in ageing hypogonadal women, a major problem in our ageing population. Our recent work has studied age-related changes to bone structure and dynamics in our transgenic FSH female mouse models. This work suggests that increased FSH alone does not directly stimulate overall bone gain or loss but depends on complex ovariandependent mechanisms to influence overall bone dynamics. Continued analysis of these models has major clinical relevance to the onset of age-related diseases (eg. osteoporosis) associated with loss of ovarian function (eg. estradiol deficiency) due to menopause.
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