Improvement of Testicular Steroidogenesis Using Flavonoids and Isoflavonoids for Prevention of Late-Onset Male Hypogonadism

Abstract

Androgen production, being important for male fertility, is mainly accomplished by the Leydig cells from the interstitial compartment of the testis. Testosterone plays a critical role in testis development, normal masculinization, and the maintenance of spermatogenesis. Within seminiferous tubules, appropriate Sertoli cell function is highly dependent on testicular androgen levels and is essential to initiate and maintain spermatogenesis. During aging, testosterone production by the testicular Leydig cells declines from the 30s in humans at a rate of 1% per year. This review outlines the recent findings regarding the use of flavonoids and isoflavonoids to improve testosterone production, contributing to normal spermatogenesis and preventing age-related degenerative diseases associated with testosterone deficiency. With the cumulation of information on the actions of different flavonoids and isoflavonoids on steroidogenesis in Leydig cells, we can now draw conclusions regarding the structure-activity relationship on androgen production. Indeed, flavonoids having a 5,7-dihydroxychromen-4-one backbone tend to increase the expression of the steroidogenic acute regulatory protein (StAR), being critical for the entry of cholesterol into the mitochondria, leading to increased testosterone production from testis Leydig cells. Therefore, flavonoids and isoflavonoids such as chrysin, apigenin, luteolin, quercetin, and daidzein may be effective in delaying the initiation of late-onset hypogonadism associated with aging in males.

Keywords: Leydig cells; androgen; flavonoids; polyphenols; testis; testosterone.

Figure 1

Common pathways for steroid synthesis within Leydig cells. Abbreviations for enzymes: Cyp11a1, P450 side-chain cleavage; Hsd3b1, 3β-hydroxysteroid dehydrogenase; Cyp17a1, P450 17α-hydroxylase/20-lyase; Hsd17b3, 17β-hydroxysteroid dehydrogenase; Srd5a1, 5α-reductase; Cyp19a1, P450 aromatase. Abbreviations for steroids: DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone.

Figure 2

Classification of major groups of flavonoids (a) and isoflavonoids (b).

Figure 3

Structures of chrysin (1), apigenin (2), luteolin (3), and baicalein (4).

Figure 4

Structures of daidzein (5) and genistein (6).

Figure 5

Structures of quercetin (7), myricetin (8), and pentaacetylquercetin (9).

Figure 6

Structures of kaempferol (10), icariin (11), rutin (12), and taxifolin (13).

Figure 7

Structures of naringenin (14), hesperetin (15), and hesperidin (16).

Figure 8

Structures of catechin (17), epicatechin (18), and epigallocatechin gallate (19).

Figure 9

Structure of cyanidin-3-glucoside (20).

Figure 10

Summary of the mechanism of action of flavonoids and isoflavonoids on testosterone production from testicular Leydig cells. Flavonoids and isoflavonoids mainly regulate steroidogenesis through the modulation of StAR gene expression. Dotted lines represent the unknown regulatory mechanisms of flavonoids and isoflavonoids.