Subfertile female androgen receptor knockout mice exhibit defects in neuroendocrine signaling, intraovarian function, and uterine development but not uterine function.
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.
Walters
K A
KA
Andrology Laboratory, ANZAC Research Institute, Sydney, New South Wales 2139, Australia.
McTavish
K J
KJ
Seneviratne
M G
MG
Jimenez
M
M
McMahon
A C
AC
Allan
C M
CM
Salamonsen
L A
LA
Handelsman
D J
DJ
D000818:Animals; D004958:Estradiol / Q000097:blood / Q000494:pharmacology; D030762:Estrous Cycle; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics; D007247:Infertility, Female / Q000235:genetics*; D037101:Luteinizing Hormone, beta Subunit / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology* / Q000637:transplantation; D010902:Pituitary Gland / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics*; D011966:Receptors, LHRH / Q000235:genetics; D014599:Uterus / Q000502:physiology* / Q000503:physiopathology
D037201:Follicle Stimulating Hormone, beta Subunit; D037101:Luteinizing Hormone, beta Subunit; D011944:Receptors, Androgen; D011966:Receptors, LHRH; D004958:Estradiol; D005640:Follicle Stimulating Hormone