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"Low normal testosterone status" ("Leydig cell impairment"), with midmorning serum total testosterone concentrations between 7 nmol/L and 14 nmol/L), is affecting an increasingly large proportion of men who are middle-aged and older.1 A relatively recently recognized clinical condition, low normal testosterone status is associated with lack of energy, motivation, initiative, self-confidence, concentration, and memory; poor sleep quality; replacement of muscle bulk and strength and skeletal structure with body fat; impaired work performance; depressed outlook; and increased systemic inflammation and oxidative stress. These overt signs and symptoms are accompanied by reduced life expectancy that is associated primarily with increased risks for developing any form of cardiovascular disease, especially fatal or nonfatal cardiovascular events.1
It is becoming increasingly evident that chronically elevated systemic oxidative stress is a "root cause" of low normal testosterone status, exposing the primary testosterone-producing Leydig cells of the testes to oxidative damage that inhibits the synthesis and secretion of testosterone. Equally convincing evidence demonstrates that reducing oxidative stress releases Leydig cells from oxidative inhibition, allowing testosterone synthesis in response to luteinizing hormone (LH) to recover and reestablish normal-for-age circulating testosterone concentrations. The available reliable data obtained from well-designed studies show that otherwise healthy men who consume dietary nutrients and phytonutrients with antioxidant properties can enjoy the combined and mutually beneficial health advantages of oxidative stress reduction and enhanced androgenic status. In a society embracing the attitude that "60 is the new 40," maintaining healthy testosterone status through dietary oxidative stress reduction is eminently sensible.1
Oxidative Stress Impairs Leydig Cell Testosterone Secretion
Leydig cells experience increased levels of oxidative stress during aging, after exposure to environmental prooxidants, and when testosterone synthesis is stimulated.2-9 Because the mitochondrial electron transfer system supplies the energy that drives testosterone synthesis in response to LH, producing a surge of oxidizing free radicals that themselves can overwhelm an underprepared antioxidant defense system, additional chronic endogenous factors (such as aging) and environmental stressors act in concert to suppress testosterone status.
The aging-associated decline in testosterone status is a consequence of cumulative oxidative stress within Leydig cells.2,3,9-11 Oxidatively damaged Leydig cells and Leydig cells in aged testes exhibit suppression of antioxidant enzyme activities, reduced intracellular glutathione content, accelerated lipid peroxidation and oxidative modification of DNA, and loss of the mitochondrial membrane potential required for testosterone synthesis.2,3,9-17 In addition, they become less sensitive to LH, with fewer LH receptors per cell and impaired ability of LH to activate steroidogenic acute regulatory (StAR) protein-catalyzed transport of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane, a rate-limiting step in testosterone synthesis.16,18-22 Furthermore, the activities of several enzymes of the testosterone biosynthetic pathway are reduced and testosterone synthesis is inhibited in oxidatively stressed adult human testes.23 In contrast, a reduction in systemic oxidative stress in mice reduces oxidative stress within Leydig cells and increases the rate of testosterone secretion.24
Nutritional Support for Healthy Testosterone Synthesis
The body of scientific evidence indicates that oxidative stress reduction sustains and restores testosterone production. Consistent with this hypothesis, several nutritional antioxidants (e.g., the phytonutrients in pomegranates, vitamin C, vitamin E, a-lipoic acid, zinc, selenium, and phosphatidylserine) contribute to a reduction in systemic and local oxidative stress, stimulation or reversal of inhibition of testosterone synthesis, and enhancement of androgenic status.
Pomegranates. In adult rats, intraperitoneal injection of pomegranate polyphenols prevented carbon tetrachloride (CCl4) inhibition of testicular antioxidant enzyme activities and promoted LH-stimulated testosterone synthesis.25 The consumption of the pomegranate polyphenol, ellagic acid, blocked adriamycin-induced testicular lipid peroxidation and inhibition of testosterone synthesis in young male rats.26
Vitamin C. Vitamin C directly stimulates LH secretion by the pituitary, testosterone synthesis by Leydig cells, and increased serum total testosterone concentrations in healthy male rats.27-29 Vitamin C supplementation prevents oxidative suppression of testosterone synthesis in animals exposed to cadmium, lead, cyclophosphamide, or arsenic trioxide, and upregulates testicular testosterone synthesis.30-35
Vitamin E. Vitamin E (a-tocopherol), a powerful chain-breaking lipid-soluble dietary antioxidant, attenuates oxidant-induced lipid peroxidation in adult male rat testes in vivo.36,37 Dietary vitamin E prevents the oxidative inhibition of testicular testosterone synthesis induced by exhaustive exercise, cadmium, chromium VI, and sodium azide.30,38-42 Combined dietary supplementation with vitamin E and vitamin C prevents oxidative inhibition of testosterone synthesis by arsenic trioxide.43 Leydig cell responsiveness to LH is proportional to the amount of vitamin E that is present.37 Supplemental vitamin E (483 mg daily for 8 weeks) increased testosterone synthesis an average of 20% in healthy men.44
α-Lipoic Acid. Exposure to bisphenol A (BPA) inhibits the activities of antioxidant enzymes in Leydig cells, increases intracellular lipid peroxidation, and attenuates testosterone synthesis in adult rats and in cultured rat Leydig cells.45,46 In contrast, dietary supplementation with α-lipoic acid has prevented or attenuated these detrimental effects on testosterone status.45
Zinc. Chronic zinc deficiency produces testosterone deficiency and, in healthy men, the serum total testosterone concentration is directly correlated with dietary zinc intake. Increased dietary zinc intake can stimulate testosterone synthesis in men and improve testosterone status.48,47
Selenium. Dietary selenium deficiency impairs testosterone synthesis in response to LH.49 However, supplemental selenium attenuates or prevents the inhibition of testosterone synthesis caused by exposure to several oxidants, including cadmium, sodium azide, or di(2-ethylhexyl) phthalate.42,50-52
Phosphatidylserine. Testicular cells are enriched in phosphatidylserine and require phosphatidylserine for full activation of testosterone synthesis.53-55 By initiating androgenic signaling cascades and through direct stimulation of testosterone synthesizing enzymes, dietary phosphatidylserine directly enhances testosterone status.54-56 For example, in a double-blind, randomized, placebo-controlled study, healthy men with initially "desirable" resting plasma free testosterone concentrations and participating in a prescribed exercise regimen supplemented their diets with 600 mg of phosphatidylserine daily for 10 days.57 Supplemental phosphatidylserine produced a 60% greater increase in resting plasma free testosterone concentration than was produced by placebo.
Human aging often is accompanied by excessive endogenous and exogenous oxidative stress. Oxidatively damaged Leydig cells exhibit decreased responsiveness to LH and impaired testosterone synthesis. On the other hand, antioxidant defenses that can be augmented by dietary supplementation with specific antioxidant nutrients can reduce oxidative damage to Leydig cells, removing oxidative inhibition of testosterone synthesis, increasing testosterone secretion, and safely improving testosterone status with beneficial effects on human male health.
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