Androgens in the regulation of ovarian function before reproductive life

In females, androgens contribute to ovarian diseases such as polycystic ovarian syndrome (PCOS), but they are key for ovarian physiology, i.e., follicular growth and sex steroid synthesis during reproductive life in interaction with LH and FSH. However, it is unclear whether androgens play a role in the ovary before reproductive life. Indeed, follicular growth and sex steroid synthesis begin well before reproductive life and are particularly active after birth, during a transient phase called minipuberty characterized by high levels of gonadotropins. Therefore, we analyzed the intra-ovarian actions of androgens and their possible interaction with gonadotropins during minipuberty, using the mouse as an experimental model. We used biochemical- and molecular-based studies and pharmacological approaches in vivo and on cultured ovaries. Minipubertal ovaries produce significant amounts of testosterone and display androgen receptor (AR) expression in growing follicles, both under the control of LH. By blocking androgen signaling either in vivo or in ovarian cultures, we found that this pathway may participate in the regulation of estradiol synthesis and follicular growth by mediating the expression of a number of key intra-ovarian regulators, including FSH receptor, the aromatase enzyme converting androgens into estrogens ( Cyp19a1 ) and the cell cycle inhibitor p27KIP1. This work suggests that androgens signaling is already activated in mini-pubertal ovaries to regulate key ovarian processes, at the interplay with gonadotropin signaling. We propose that mini-pubertal androgens play an important physiological role in the ovary, and by extension, in future reproductive function.