Subfertility and defective folliculogenesis in female mice lacking androgen receptor

Abstract

The roles of the androgen receptor (AR) in female fertility and ovarian function remain largely unknown. Here we report on the generation of female mice lacking AR (AR ؊/؊ ) and the resulting influences on the reproductive system. Female AR ؊/؊ mice appear normal but show longer estrous cycles and reduced fertility. The ovaries from sexually mature AR ؊/؊ females exhibited a marked reduction in the number of corpora lutea. After superovulation treatment, the AR ؊/؊ ovaries produced fewer oocytes and also showed fewer corpora lutea. During the periovulatory period, an intensive granulosa apoptosis event occurs in the AR ؊/؊ preovulatory follicles, concurrent with the down-regulation of p21 and progesterone receptor expression. Furthermore, the defective conformation of the cumulus cell-oocyte complex from the AR ؊/؊ females implies a lower fertilization capability of the AR ؊/؊ oocytes. In addition to insufficient progesterone production, the diminished endometrial growth in uteri in response to exogenous gonadotropins indicates that AR ؊/؊ females exhibit a luteal phase defect. Taken together, these data provide in vivo evidence showing that AR plays an important role in female reproduction.

Premature ovarian failure in androgen receptor-deficient mice

“…Although follicles and corpora lutea at all developmental stages were still present, corpora lutea numbers were clearly reduced in 8-week-old AR Ϫ/Ϫ mutants ( Fig. 2 b and f ), similar to that observed in another mouse line (20). Expected apoptosis was seen in atretic follicles by activated caspase-3 immunohistochemistry assays (Fig.…”

Low testosterone levels in women with diminished ovarian reserve impair embryo implantation rate: a retrospective case-control study

“…Considering the results of the present study in this context, we can infer that T has a dual function of modulating folliculogenesis and regulating embryo implantation in female reproduction. This hypothesis is supported by the observations of reduced fertility in homozygous female AR knockout mice, which is not only associated with fewer oocytes after super-ovulation and follicular atresia but also with impaired uterine hypertrophy and endometrial growth, which are required for implantation [19,20]. However, in the present study, basal T levels showed no correlation with ovarian stimulus metrics, such as the E 2 levels on the HCG day, number of oocytes retrieved, and the total dose of gonadotropins.…”

Androgen actions in the ovary: balance is key

“…The promoter region of p21 contains an ARE and, therefore, the AR likely regulates its expression. The marked reduction in p21 expression in the Ar-null ovary during the peri-ovulatory stage may disturb the process of terminating proliferation and explain the increased cell apoptosis and follicular atresia in these Ar 2 K/K mice (Hu et al 2004, Walters et al 2010.…”

“…Cyclin-dependent kinase inhibitor-1/p21 p21 is known to play a role in GC luteinization (Robker & Richards 1998), and is downregulated in Ar 2 K/K mice ovaries (Hu et al 2004). The promoter region of p21 contains an ARE and, therefore, the AR likely regulates its expression.…”