Genistein exposure inhibits growth and alters steroidogenesis in adult mouse antral follicles

Abstract

Genistein is a naturally occurring isoflavone phytoestrogen commonly found in plant products such as soybeans, lentils, and chickpeas. Genistein, like other phytoestrogens, has the potential to mimic, enhance, or impair the estradiol biosynthesis pathway, thereby potentially altering ovarian follicle growth. Previous studies have inconsistently indicated that genistein exposure may alter granulosa cell proliferation and hormone production, but no studies have examined the effects of genistein on intact antral follicles. Thus, this study was designed to test the hypothesis that genistein exposure inhibits follicle growth and steroidogenesis in intact antral follicles. To test this hypothesis, antral follicles isolated from CD-1 mice were cultured with vehicle (dimethyl sulfoxide; DMSO) or genistein (6.0 and 36 μM) for 18 – 96 hours (h). Every 24 h, follicle diameters were measured to assess growth. At the end of each culture period, the media were pooled to measure hormone levels, and the cultured follicles were collected to measure expression of cell cycle regulators and steroidogenic enzymes. The results indicate that genistein (36 μM) inhibits growth of mouse antral follicles. Additionally, genistein (6.0 and 36 μM) increases progesterone, testosterone, and dehydroepiandrosterone (DHEA) levels, but decreases estrone and estradiol levels. The results also indicate that genistein alters the expression of steroidogenic enzymes at 24, 72 and 96 h, and the expression of cell cycle regulators at 18 h. These data indicate that genistein exposure inhibits antral follicle growth by inhibiting the cell cycle, alters sex steroid hormone levels, and dysregulates steroidogenic enzymes in cultured mouse antral follicles.

Preconception exposure to dietary levels of genistein affects female reproductive outcomes

“…We found that genistein exposure did not affect estradiol and progesterone levels at any time points (Figure 6). Contrary to our results, numerous in vitro studies conducted on adult ovarian cells show that exposure to genistein reduces estradiol biosynthesis and alters progesterone production [19, 27, 28, 38, 39]. One major difference between our study and the previous in vitro studies is the dose selection.…”

“…Specifically, genistein inhibits steroidogenesis or steroidogenic enzymes in cultured rat pre-antral follicles [22], rat granulosa-luteal cells [23], porcine granulosa, theca, or luteal cells [24–27], and mouse antral follicles [28]. Additionally, studies have shown that genistein exposure alters follicle growth [17], induces follicular atresia [29], inhibits oocyte maturation [30], and inhibits antral follicle growth [28] in rodents. Collectively, these studies show that genistein exposure can affect hormone levels and follicle growth, both of which are necessary for normal female fertility [31].…”

Effects of isoliquiritigenin on ovarian antral follicle growth and steroidogenesis

“…This is the first time, to our knowledge, that the effects of isoliquiritigenin on ovarian sex steroid hormone levels have been investigated. However, our findings are consistent with a few studies examining the effects of other phytoestrogens on the levels of steroid hormones [35, 42–44]. For instance, genistein was found to reduce estradiol and increase progesterone synthesis of cultured mouse antral follicles [35].…”

“…However, our findings are consistent with a few studies examining the effects of other phytoestrogens on the levels of steroid hormones [35, 42–44]. For instance, genistein was found to reduce estradiol and increase progesterone synthesis of cultured mouse antral follicles [35]. It was also found to decrease estradiol levels in porcine granulosa cells [44].…”

“…Another study found that licorice root extract caused apoptosis of MCF-7 breast cancer cells partly through induction of the pro-apoptotic factor Bax , inhibition of Cdk 2 and cyclin E, and induction of G1 cell cycle arrest [32]. Previous studies with genistein, a commonly used phytoestrogen found in soy, showed that it could induce atresia of rat follicles [34] and inhibit growth of mouse antral follicles via Cdkn1a upregulation [35]. Equol, a metabolite of the soy phytoestrogen daidzein, was found to inhibit mouse antral follicle growth and increase follicle atresia [36].…”