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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

Department of Andrology (K.A.W., C.M.A., M.J., P.R.L., D.J.H.), ANZAC Research Institute, Concord Hospital, University of Sydney, New South Wales 2139, Australia; Department of Medicine (R.A.D., J.D.Z.), University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia; and Department of Reproductive Medicine (P.I.), Westmead Hospital, New South Wales 2145, Australia

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

The role of classical genomic androgen receptor (AR) mediated actions in female reproductive physiology remains unclear. Female mice homozygous for an in-frame deletion of exon 3 of the Ar (AR^–/–) were subfertile, exhibiting delayed production of their first litter (AR^+/+ = 22 d vs. AR^–/– = 61 d, P < 0.05) and producing 60% fewer pups/litter (AR^+/+: 8.1 ± 0.4 vs. AR^–/–: 3.2 ± 0.9, P < 0.01). Heterozygous females (AR^+/–) exhibited an age-dependent 55% reduction (P < 0.01) in pups per litter, evident from 6 months of age (P < 0.05), compared with AR^+/+, indicating a significant gene dosage effect on female fertility. Ovulation was defective with a significant reduction in corpora lutea numbers (48–79%, P < 0.01) in 10- to 12- and 26-wk-old AR^+/– and AR^–/– females and a 57% reduction in oocytes recovered from naturally mated AR^–/– females (AR^+/+: 9.8 ± 1.0 vs. AR^–/–: 4.2 ± 1.2, P < 0.01); however, early embryo development to the two-cell stage was unaltered. The delay in first litter, reduction in natural ovulation rate, and aromatase expression in AR^+/– and AR^–/– ovaries, coupled with the restored ovulation rate by gonadotropin hyperstimulation in AR^–/– females, suggest aberrant gonadotropin regulation. A 2.7-fold increase (AR^+/+: 35.4 ± 13.4 vs. AR^–/–: 93.9 ± 6.1, P < 0.01) in morphologically unhealthy antral follicles demonstrated deficiencies in late follicular development, although growing follicle populations and growth rates were unaltered. This novel model reveals that classical genomic AR action is critical for normal ovarian function, although not for follicle depletion and that haploinsufficiency for an inactivated AR may contribute to a premature reduction in female fecundity.

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