Characterizing androgen receptor-mediated androgen action in female fertility — ASN Events
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Characterizing androgen receptor-mediated androgen action in female fertility (#180)

Kirsty A Walters 1 , Mark Jimenez 1 , Reena Desai 1 , Linda J Middleton 1 , Charles M Allan 1 , David J Handelsman 1
  1. ANZAC Research Institute, CONCORD, NSW, Australia

Homozygous AR knockout (ARKO) female mice were generated using Cre/LoxP recombination for an in-frame excision of exon 3, encoding the second zinc finger essential for DNA-binding. Resulting ARKO females were sub-fertile producing fewer pups/litter (P<0.01)1  with impaired ovulation being the main mechanism, as ARKO females exhibited a reduction in corpora lutea numbers (P<0.01)1 . Reduced ovulation rates were overcome by gonadotrophin hyperstimulation, suggesting an extra-ovarian neuroendocrine defect in the hypothalamic-pituitary regulation of gonadotrophin secretion1 . Reciprocal ovarian transplantation studies revealed thatARKO females are sub-fertile due to both intra- and extra-ovarian defects2 . Recent work has now revealed impaired negative feedback in ARKO females which exhibit a reduced serum luteinizing hormone (LH) response to ovariectomy (OVX) (P<0.01). Furthermore, ARKO females often exhibit a mistimed endogenous ovulatory LH surge as well as diminished pre-ovulatory serum estradiol (E2) (P<0.01) and LH (P<0.05) surge levels during late proestrus, consistent with impaired positive and negative steroidal feedback. However, this reduced LH response in ARKO females can be rescued by OVX and E2 priming or treatment with endogenous GnRH. These findings reveal that AR-regulated negative and positive steroidal feedback pathways impact on hypothalamic control of the GnRH-LH cascade. In addition, an ovarian defect was evident as ARKO ovaries collected at proestrus have small antral follicles with reduced oocyte:follicle diameter ratios (P<0.01) and more unhealthy large antral follicles (P<0.05) compared to controls. Furthermore, as a consequence of aberrant follicular growth patterns, proestrus ARKO ovaries also exhibit fewer preovulatory follicle (P<0.05) and corpora lutea numbers (P<0.01). Embryo development to the 2-cell1 and blastocyst stages are unchanged in ARKO females, hence the sub-fertility is a consequence of reduced ovulations and not altered embryo quality. These findings reveal that the AR has a functional role in maintaining normal ovarian function and female fertility by influencing neuroendocrine regulation as well as antral/preovulatory follicle development.

  1. Walters KA, Allan CM, Jimenez M, Lim PR, Davey RA, Zajac JD, Illingworth P and Handelsman DJ. Female mice haploinsufficient for an inactivated androgen receptor (AR) exhibit age-dependent defects that resemble the AR null phenotype of dysfunctional late follicle development, ovulation, and fertility. Endocrinology 148: 3674-3684, 2007.
  2. Walters KA, McTavish KJ, Seneviratne MG, Jimenez M, McMahon AC, Allan CM, Salamonsen LA and Handelsman DJ. Subfertile female androgen receptor knockout mice exhibit defects in neuroendocrine signaling, intraovarian function, and uterine development but not uterine function. Endocrinology 150: 3274-3282, 2009.
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