Androgen receptor (AR) physiological roles in male and female reproductive systems: lessons learned from AR-knockout mice lacking AR in selective cells

Abstract

Androgens/androgen receptor (AR) signaling is involved primarily in the development of male-specific phenotypes during embryogenesis, spermatogenesis, sexual behavior, and fertility during adult life. However, this signaling has also been shown to play an important role in development of female reproductive organs and their functions, such as ovarian folliculogenesis, embryonic implantation, and uterine and breast development. The establishment of the testicular feminization (Tfm) mouse model exploiting the X-linked Tfm mutation in mice has been a good in vivo tool for studying the human complete androgen insensitivity syndrome, but this mouse may not be the perfect in vivo model. Mouse models with various cell-specific AR knockout (ARKO) might allow us to study AR roles in individual types of cells in these male and female reproductive systems, although discrepancies are found in results between labs, probably due to using various Cre mice and/or knocking out AR in different AR domains. Nevertheless, no doubt exists that the continuous development of these ARKO mouse models and careful studies will provide information useful for understanding AR roles in reproductive systems of humans and may help us to develop more effective and more specific therapeutic approaches for reproductive system-related diseases.

Keywords: ARKO mice; androgen receptor; androgens; fertility; male sexual function; reproductive system; sex differentiation; spermatogenesis.

FIG. 1

Effect of various tissue-specific ARKO on female and male reproductive systems in mice. In the male reproductive system (top), loss of the AR in specific types of cells can impair the fertility function, the spermatogenesis process, and the development of sex accessory organs, such as the epididymides, SV, and prostate. In the female reproductive system (bottom). the AR can play essential roles. ARKO in certain types of cells can cause abnormal development of the ovary and mammary gland, subfertility, and premature ovarian failure. T-ARKO is ARKO(ACTB-Cre), Multi-ARKO is ARKO(CMV-Cre), and Multi-AR^Ex3 is AR^-EX3(CMV-Cre) denoting total ARKO, multiple ARKO, and multiple AR^EX3 mice, respectively. The remaining abbreviations are as described in the text.