Evidence That Granulosa Cell Aromatase Induction/Activation by Follicle-Stimulating Hormone Is an Androgen Receptor-Regulated Process in-Vitro

Abstract

The role of androgen in aromatase induction/activation by follicle-stimulating hormone (FSH) was studied in cultured granulosa cells from estrogen-pretreated, immature rat ovaries. Aromatase activity was measured in washed cell monolayers after a 48-h culture in medium containing hFSH and/or various sex steroids or their analogues. Culture with hFSH (100 ng/ml) plus 10(-7) M testosterone (T) stimulated aromatase activity to a level similar to that of granulosa cells from preovulatory follicles in the cyclic adult on the morning of proestrus. But if T was omitted, or replaced by estrogen (DES) or progesterone (P), the response to hFSH was at least 90% lower. The abilities of T, androstenedione, five nonaromatizable 5 alpha-reduced androgens, an aromatase reaction intermediate (19-hydroxyandrostenedione), and a pharmacological competitive aromatase inhibitor (delta 1-testoloalactone) to stimulate the aromatase response to hFSH were proportionate to their stimulatory effects on P production during the culture. By both criteria T was the most potent androgen while 19-hydroxyandrostenedione and delta 1-testololactone were completely inactive. The stimulatory effect of 10(-7) M T on the aromatase response to FSH was inhibited by the nonsteroidal antiandrogen SCH 16423 (ID50 = 3.6 x 10(-6) M). These results indicate that granulosa cell aromatase induction/activation by hFSH is an androgen receptor-regulated process in vitro.

Androgen actions in the ovary: balance is key

“…In mice GCs, FSH alone promoted follicular growth; however, addition of androgens significantly increased FSH-mediated follicular diameter (Wang et al 2001, Sen et al 2014). In addition, synergistic actions of testosterone and FSH increased P450arom expression and conversion of androgens to estrogens in the rat (Hillier & De Zwart 1981, Fitzpatrick & Richards 1991, Tetsuka et al 1995, bovine (Luo & Wiltbank 2006), and primate GCs (Weil et al 1999) as well as in porcine (Slomczynska et al 2003) and mice small follicles (Wang et al 2001). In primate GCs, P450arom mRNA was selectively expressed in AR and FSHR positive follicles (Weil et al 1999); and in rat GCs, the stimulatory effect of testosterone on P450arom in response to FSH was inhibited by thenon-steroidal anti-androgen SCH16423 (Hillier & De Zwart 1981).…”

Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression

“…Furthermore, to avoid unwanted effects caused by pretreatment with pharmacologic gonadotropin concentrations, we used freshly isolated primary GCs from unprimed mice. Although androgen-induced increases in FSHR levels may be one mechanism by which androgens facilitate follicular growth, it is likely that androgens also modulate post-FSHR signaling, such as FSH-induced induction of cAMP (25,48,49).…”

Mechanisms of phthalate ester toxicity in the female reproductive system.

“…Finally, testosterone diffuses into the granulosa cell, where it is converted to estradiol by the aromatase enzyme (Richards 1980). Aromatase is stimulated both by FSH action on granulosa cells and by thecal androgens, the substrates for aromatase (Daniel and Armstrong 1980;Hillier and De Zwart 1981).…”