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Subfertile Female Androgen Receptor Knockout Mice Exhibit Defects in Neuroendocrine Signaling, Intraovarian Function, and Uterine Development But Not Uterine Function

Andrology Laboratory (K.A.W., K.J.M., M.G.S., M.J., C.M.A., D.J.H.) and Vascular Biology Laboratory (A.C.M.), ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia; and Prince Henry’s Institute of Medical Research (L.A.S.), Clayton, Victoria 3168, Australia

Address all correspondence and requests for reprints to: Professor David J. Handelsman, ANZAC Research Institute, Sydney, New South Wales 2139, Australia. E-mail: djh{at}anzac.edu.au.

Female androgen receptor (AR) knockout mice (AR^–/–) generated by an in-frame Ar exon 3 deletion are subfertile, but the mechanism is not clearly defined. To distinguish between extra- and intraovarian defects, reciprocal ovarian transplants were undertaken. Ovariectomized AR^–/– hosts with wild-type (AR^+/+) ovary transplants displayed abnormal estrus cycles, with longer cycles (50%, P < 0.05), and 66% were infertile (P < 0.05), whereas AR^+/+ hosts with either AR^–/– or surgical control AR^+/+ ovary transplants displayed normal estrus cycles and fertility. These data imply a neuroendocrine defect, which is further supported by increased FSH (P <0.05) and estradiol (P <0.05), and greater LH suppressibility by estradiol in AR^–/– females at estrus (P <0.05). Additional intraovarian defects were observed by the finding that both experimental transplant groups exhibited significantly reduced pups per litter (P < 0.05) and corpora lutea numbers (P < 0.05) compared with surgical controls. All groups exhibited normal uterine and lactation functions. AR^–/– uteri were morphologically different from AR^+/+ with an increase in horn length (P < 0.01) but a reduction in uterine diameter (P < 0.05), total uterine area (P < 0.05), endometrial area (P < 0.05), and myometrial area (P < 0.01) at diestrus, indicating a role for AR in uterine growth and development. Both experimental transplant groups displayed a significant reduction in uterine diameter (P < 0.01) compared with transplanted wild-type controls, indicating a role for both AR-mediated intraovarian and intrauterine influences on uterine physiology. In conclusion, these data provide direct evidence that extraovarian neuroendocrine, but not uterine effects, as well as local intraovarian AR-mediated actions are important in maintaining female fertility, and a disruption of AR signaling leads to altered uterine development.

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