**5. Summary**

194 Basic and Clinical Endocrinology Up-to-Date

**4.5 Potential application of natural flavonoids in delaying the declines in StAR gene** 

StAR gene expression and testosterone biosynthesis through different mechanisms.

The potential for application of natural flavonoids in delaying the decline in testosterone is supported by the animal studies on the flavonoid-enhanced testosterone production and reproductive function. A study with 2-year-old male rats reported that supplementation with chrysin improved their reproductive functions, with their sperm count, fertilization potential and litter size being increased when they were allowed to interact with female rats (Dhawan et al., 2002). It was also observed that lifetime exposure to the flavonoids, including daidzein, glycitein and genistein, increased serum and testicular testosterone concentrations of rats (McVey et al., 2004). The observation was enhanced by the study on the effects of catechins on testosterone biosynthesis in rats, in which injection with catechins or its derivatives increased testosterone in blood (Yu et al., 2010). A recent study reported the beneficial effects of quercetin in diabetic rats, with their sperm viability and motility being improved by the flavonoid. These effects of quercetin are associated with an increase in serum total testosterone (Khaki et al., 2010). In addition, some flavonoids in herbal medicine are able to enhance testosterone production in rats. For example, icariin, a flavonoid in the plants in *Epimedium* family, has been extracted from traditional Chinese medicine (Du et al., 2002). It was observed that supplementation of icariin to 15-month-old male rats significantly increased their blood testosterone levels (Zhang & Yang, 2006). For application of natural flavonoids to improve the health of aging males, further studies, especially long-term animal studies and clinical studies, are needed. Two of the important considerations in the studies are mechanism and efficacy of the flavonoid-enhanced testosterone biosynthesis. The mechanisms reported for the inhibitory effects of flavonoids on COX2-dependent signaling are mostly based on the studies with the cells from various tissues. These mechanisms need to be verified with Leydig cells. In addition to the COX2 dependent signaling, other mechanisms might be involved in the flavonoid-enhanced StAR gene expression and testosterone production. Further studies on the mechanisms may improve the understanding of the steroidogenic effects of flavonoids. Regarding the efficacy, bioavailability is an important factor being discussed in the studies on flavonoids

The studies reviewed above suggest that flavonoids are potential resources for alternative medicine to delay the decline in StAR gene expression. Among the various compounds of natural flavonoids, many of them are able to reduce COX2 expression, such as Kaempferol (Garcia-Mediavilla et al., 2007), tectorigenin, tectoridin (Kim et al., 1999), wogonin (Chen et al., 2008) and Silibinin (Kim et al., 2009). Some of the flavonoids reduce the inflammatory factors that induce COX2 expression (Garcia-Lafuente et al., 2009; Khanna et al., 2007; Kim et al., 2004). Another group of flavonoids was reported as receptor antagonists that inhibit the COX2-dependent signaling by blocking the TBX A2-binding to the receptors (Navarro-Nunez et al., 2009). In addition to the COX2-dependent signaling, StAR gene expression is affected by the signaling through different pathways. For example, calcium influx through L-type calcium channels regulates the threshold of cAMP-induced StAR gene expression, so that blocking the L-type calcium channels reduced the threshold and enhanced StAR gene expression in Leydig cells (Pandey et al., 2010). There is a group of natural flavonoids that are able to block the L-type calcium channels, such as genistein (Belevych et al., 2002), daidzein (Yokoshiki et al., 1996), equol (Liew et al., 2003) and epigallocatechin-3-gallate (EGCG) (Kang et al., 2010). The steroidogenic effects of the flavonoids in this group were described (Yu et al., 2010). It is possible to identify different flavonoids that might enhance

**expression and testosterone biosynthesis** 

In summary, LH-stimulation of Leydig cells induces both positive and negative signals in the regulation of StAR gene expression and testosterone biosynthesis. In the aging process, the increase in COX2 enhances the negative signaling, resulting in the declines in StAR gene expression and testosterone biosynthesis in Leydig cells. It was found that some of the flavonoids are able to block the COX2-dependent signaling and enhance StAR gene expression. While further investigations are needed, the studies suggest a potential for application of the natural flavonoids in delaying the age-related declines in StAR gene expression and testosterone biosynthesis.
