In a recent review published in the Nutrients, a group of authors reviewed the use of natural polyphenolic compounds to enhance testosterone production and prevent age-related hypogonadism in aging males.

Study: Prevention of Male Late-Onset Hypogonadism by Natural Polyphenolic Antioxidants. Image Credit: marilyn barbone/Shutterstock.com

Background 

Androgens are primarily produced by Leydig cells in the testes and are vital for the development and maintenance of male sex organs and secondary sexual characteristics.

Testosterone stimulates the development of male reproductive structures in the embryo and plays key roles at puberty, including spermatogenesis and regulation of gonadotropins.

Testosterone production declines by about 1% per year starting in the thirties, leading to late-onset hypogonadism, characterized by reduced libido, muscle mass, and bone density, among other symptoms.

Further research is needed to fully understand the mechanisms by which polyphenolic compounds enhance testosterone production and to establish their efficacy and safety as therapeutic agents for preventing late-onset hypogonadism in aging males.

Testosterone biosynthesis in leydig cells

Leydig cells are responsible for the biosynthesis of testosterone in the testis. They also produce androstenedione and dehydroepiandrosterone (DHEA), though these hormones are less effective at activating the androgen receptor than testosterone.

Leydig cells contain the aromatase enzyme (CYP19A1), which converts androgens into estrogens, though this conversion is minimal, and estrogens generally moderate steroid production in Leydig cells.

The biosynthesis of testosterone relies on several steroidogenic enzymes, including cholesterol side-chain cleavage enzyme (CYP11A1), cytochrome P450 17α-hydroxylase/20-lyase (CYP17A1), 3β-hydroxysteroid dehydrogenase (HSD3B), and 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3), with cholesterol as the initial substrate.

Cholesterol can be produced from Acetyl Coenzyme A (acetyl-CoA) or obtained from plasma via receptor-mediated endocytosis of Low-Density Lipoprotein (LDL) particles. Under normal conditions, Leydig cells store cholesterol as esters in lipid droplets and depend primarily on endogenous cholesterol synthesis for testosterone biosynthesis.

The initial step in steroid production involves the translocation of cholesterol into mitochondria, which is facilitated by a protein complex that includes the steroidogenic acute regulatory protein (STAR) and the translocator protein (TSPO).

Inside mitochondria, cholesterol is converted to pregnenolone by CYP11A1 with the help of ferredoxin and Nicotinamide Adenine Dinucleotide Phosphate (NADPH): ferredoxin reductase. Pregnenolone then moves to the smooth endoplasmic reticulum (SER) for further conversion to testosterone by HSD3B, CYP17A1, and HSD17B3.

Regulation of steroidogenesis

Steroidogenesis in Leydig cells is primarily regulated by luteinizing hormone (LH), which activates the Cyclic Adenosine Monophosphate (cAMP)/protein kinase A (PKA) signaling pathway, influencing the expression of steroidogenic enzymes. PKA substrates include STAR, which is critical for cholesterol transport within mitochondria, and several transcription factors that regulate steroidogenic gene expression.

Other signaling pathways, such as mitogen-activated protein kinases (MAPK), protein kinase C (PKC), Ca2+-calmodulin-dependent protein kinases (CAMK), and Janus kinases/signal transducer and activator of transcription proteins (JAK/STAT), also play roles in this regulation.

Development of late-onset male hypogonadism

Late-onset male hypogonadism is characterized by a decline in testosterone production due to aging. This condition is typically treated with testosterone replacement therapy, which can have side effects such as reduced spermatogenesis and decreased fertility due to negative feedback on the hypothalamus and pituitary.

Testosterone is crucial for maintaining muscle mass, bone density, sexual function, energy levels, metabolic health, cognitive function, and overall well-being.

As men age and testosterone levels decline, they may experience sarcopenia, decreased bone mineral density, reduced libido, erectile dysfunction, fatigue, and cognitive decline. Maintaining adequate testosterone levels is essential for health and well-being in aging males.

Natural antioxidants and androgen production

Flavonoids

Flavonoids are important plant compounds found in various parts of the plant. They play significant roles in plant development and defense against pathogens. Flavonoids can be divided into flavanones, flavones, flavonols, and anthocyanidins.

They have been associated with numerous health benefits, including cancer prevention and reducing the risk of cardiovascular and neurodegenerative diseases. Flavones such as luteolin and apigenin, found in celery, thyme, and parsley, can stimulate the expression of steroidogenic genes and enhance androgen production in Leydig cells.

Isoflavones

Isoflavones like genistein and daidzein, found in soybeans and chickpeas, can disrupt estrogen signaling in the testis.

High concentrations of isoflavones may reduce steroidogenesis in Leydig cells. While some studies suggest isoflavones lower testosterone levels, others indicate no significant effects on testosterone.

Flavonols

Flavonols like quercetin and myricetin, found in berries, apples, and tea, enhance steroidogenesis and testicular function. Quercetin improves testosterone levels in male mice exposed to endocrine disruptors. However, its effects on testosterone synthesis may vary between species.

Flavanones

Flavanones such as naringenin, found in grapefruits, can increase serum testosterone levels and prevent decreases in testosterone caused by endocrine disruptors.

Catechins

Catechins in apples, red wine, and tea can increase plasma testosterone levels in male rats. However, some studies have reported green tea polyphenols inhibit androgen synthesis.

Anthocyanidins

Anthocyanidins in berries and grapes are known for their antioxidant and antimicrobial properties. They may improve steroidogenesis by inhibiting Cyclooxygenase-2 (COX2) and modulating MAPK signaling.

Hydroxycinnamic acid phenethyl ester derivatives

Hydroxycinnamic acids, such as ferulic acid phenethyl ester, can enhance androgen production by improving the expression of steroidogenesis-related genes in Leydig cells.

Resveratrol and gigantol

Resveratrol in grapes and red wine enhances spermatogenesis and testosterone production but may inhibit androgen production in some conditions. Gigantol, isolated from orchids, can improve progesterone production and steroidogenesis in Leydig cells.

Conclusions 

To summarize, plasma levels of natural polyphenolic compounds in the low micromolar range can be achieved with a diet rich in fruits and vegetables, supporting optimal Leydig cell function.

Flavonoids with a 5,7-dihydroxychromen-4-one backbone enhance Star expression and androgen synthesis, indicating potential synergistic effects on steroidogenesis.