**4. Flavonoid intervention in the COX2-dependent inhibition of StAR gene expression and testosterone biosynthesis**

To study the possibility of delaying the decline in blood testosterone by intervention in the mechanism, aged rats were fed with increasing concentrations of a selective COX2 inhibitor mixed in their diet. After 30 days, StAR protein in their Leydig cells increased in a concentration-dependent manner. The blood testosterone concentrations increased up to 120% over control (Wang et al., 2005). The studies suggest a possibility of delaying the agerelated declines in StAR protein and testosterone using COX2 inhibitors. However, longterm application of the COX2 inhibitors currently used in the clinical practice is limited by their side effects. Therefore, alternative approaches are needed for the health of aging males. In the recent years, steroidogenic effects of natural flavonoids have been studied with Leydig cells. Flavonoids are a group of the polyphenolic compounds that are widely distributed in various food and food supplements, especially in fruits and vegetables. Previous studies have reported the activities of flavonoids in anti-inflammation, anti-cancer, and anti-oxidation (Cardenas et al., 2006; Chen et al., 1990; Ferrandiz & Alcaraz, 1991). One of the important mechanisms for these activities is the inhibition of COX2 expression and blocking the COX2-dependent signaling by flavonoids, which enables flavonoids to enhance StAR gene expression and testosterone biosynthesis in Leydig cells. A group of flavonoids has been identified, including chrysin, apigenin, luteolin, and quercetin (Fig. 1), to be able to enhance StAR gene expression and steroidogenesis in Leydig cells by blocking the COX2 dependent signaling.

Fig. 1. Chemical structures of the flavonoids used in the experiments to enhance StAR gene expression and steroidogenesis in Leydig cells
