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Characterizing the Neuroendocrine and Ovarian Defects of Androgen Receptor Knockout Female Mice

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AJP Endocrinology and Metabolism

Published online on

Abstract

Homozygous AR knockout female mice (ARKO) are sub-fertile due to both intra- and extra-ovarian (neuroendocrine) defects as defined by ovary transplantation. However the precise molecular and cellular pathways required for optimal androgen-regulated ovulation and fertility remain to be defined. Deficient neuroendocrine negative feedback is evident in ARKO females with a reduced serum luteinizing hormone (LH) response to ovariectomy (OVX) (P<0.01). At late proestrus, ARKO females exhibit an often mistimed endogenous ovulatory LH surge. Furthermore, ARKO females display diminished pre-ovulatory serum estradiol (E2) (P<0.01) and LH (P<0.05) surge levels, and Kiss1 mRNA expression in the anteroventral periventricular nucleus (P<0.01) at late proestrus, indicating reduced positive neuroendocrine 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 intrahypothalamic control of the kisspeptin-GnRH-LH cascade. Adult ARKO ovaries collected at proestrus have small antral follicles with reduced oocyte:follicle diameter ratios (P<0.01) and increased proportions of 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 blastocyst stage is 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 neuroendocrine regulation and timing of the ovulatory LH surge as well as antral/preovulatory follicle development.