Oxidative Stress, Nutritional Antioxidants, and Testosterone Secretion in Men

Review Article

Ann Nutr Disord & Ther. 2015;2(1): 1019.

Oxidative Stress, Nutritional Antioxidants, and Testosterone Secretion in Men

Glade MJ1* and Smith K2

1The Nutrition Doctor, Kailuα-Kona, USA

2Progressive Laboratories Inc, USA

*Corresponding author: Glade MJ, The Nutrition Doctor, Suite 406, 78-7100 Kamehameha III Road, Kailuα-Kona, HI 9674, USA

Received: December 02, 2014; Accepted: February 23, 2015; Published: February 25, 2015


The biochemistry of testosterone synthesis within the Leydig cells of the human testes is well characterized. Reliance on the mitochondrial electron transfer system for the energy to drive testosterone synthesis exposes Leydig cell mitochondria to oxidative stress. Leydig cells experiencing oxidative stress exhibit reduced activities of antioxidant enzymes, increased lipid peroxidation, reductions in mitochondrial membrane potential required for testosterone synthesis, and reduced expression of the StAR steroidogenic acute regulatory (StAR) protein, culminating in inhibition of the synthesis and secretion of testosterone.

Evidence obtained from in vitro, laboratory, and animal experiments, and from human trials, provides strong support for the hypothesis that reducing oxidative stress releases Leydig cells from oxidative inhibition of testosterone synthesis and can improve testosterone status. Selected dietary antioxidants (e.g., the phytonutrients in pomegranates, phosphatidylserine, vitamin C, vitamin E, α-lipoic acid, zinc, and selenium) can contribute safely to oxidative stress reduction and enhanced androgenic status in otherwise healthy adult males. In this era of science-based medical decision-making, addressing oxidative stress and its potential role in undermining testosterone status deserves closer scrutiny.

Keywords: Low testosterone; Leydig cells; Oxidative stress; Antioxidants; Phosphatidylserine; Pomegranates


SHBG: Steroid Hormone Binding Globulin; DHT: Dihydrotestosterone; the STAR protein: The Steroidogenic Acute Regulatory Protein; ERK1/2: Extracellular Signal-Regulated Kinase 1/2; LH: Luteinizing Hormone; AMP: Adenosine Monophosphate; 5’-Adenylic Acid; cAMP: Cyclic AMP; P450scc, CYP11A1: Cytochrome P450cholesterol side-chain cleavage enzyme; NADPH: Reduced Nicotine Adenine Diphosphonucleotide; Cytochrome P450 17α-hydroxylase/17, 20-lyase: CYP17A1 hydroxylase and CYP17A1 lyase; 3β-HSD, HSD3B2: 3β-hydroxysteroid dehydrogenase/Δ5→Δ4 isomerase; 17β-HSD, HSD17B3: 17β-hydroxysteroid dehydrogenase; DHEA: Dehydroepiandrosterone; SRD5A1, SRD5A2, SRD5A3: Short-Chain Dehydrogenase/Reductases; GnRH: Gonadotropin- Releasing Hormone; MrOS: The Osteoporotic Fractures in Men Study; BACH: The Boston Area Community Health Survey; CRP: C-Reactive Protein; TNF-α: Tumor Necrosis Factor-α; MIP1α: Macrophage Inflammatory Protein 1α; MIP1β: Macrophage Inflammatory Protein 1β; ROS: Reactive Oxygen Species; SO: ·O2 -, Superoxide; H2O2: Hydrogen Peroxide; ·OH-: Hydroxy Radical; ·NO: Nitric Oxide; ·ROO-: Peroxyl Radical; ·ONOO-, Peroxynitrite; ·1O2: Singlet Oxygen; HOCl: Hypochlorous Acid; SOD: Superoxide Dismutase; GPx: Glutathione Peroxidase; MDA: Malondialdehyde; PON1: Paraoxonase 1; PON2: Paraoxonase 2; CCl4: Carbon Tetrachloride; CYP1A2: Cytochrome P450 Isozyme CYP1A2; CYP3A: Cytochrome P450 Isozyme CYP3A:GR; Glutathione Reductase; MAM: Mitochondriα-Associated Membrane; DHA: Docosahexaenoic Acid; Akt: Protein Kinase B; mTOR2: Mammalian Target of Rapamycin-2; HDL: High-Density Lipoprotein; LDL: Low-Density Lipoprotein; DHA: Dehydroascorbate; HO-1: Heme Oxygenase-1; Nrf2: Nuclear Factor-Erythroid 2-Related Factor 2

Testosterone Synthesis and Metabolism

Testosterone appears in the human circulation either free from binding to any carrier molecules, bound to albumin, or bound to steroid hormone binding globulin (SHBG). Bound and unbound forms can be measured and serum testosterone concentrations are expressed as either free testosterone, biologically active testosterone (unbound testosterone plus testosterone bound to albumin), or total testosterone (unbound testosterone plus testosterone bound to SHBG plus testosterone bound to albumin) [1,2]. Circulating testosterone concentrations, which determine the availability of testosterone to the tissues, reflect the net balance between testicular synthesis and secretion of testosterone and the conversion of circulating testosterone into 17β-estradiol, dihydrotestosterone (DHT), and excretory metabolites.

Testosterone Synthesis

The biochemistry of testosterone synthesis within the Leydig cells of the human testes is well characterized [3,4]. Testosterone anabolism in men is proportional to the plasma concentration of pituitary-derived luteinizing hormone (LH) [5] and is triggered by binding of LH to its plasma membrane receptors on Leydig cells of the testes [6] and subsequent activation of intracellular signaling cascades that increase the conversion of adenosine monophosphate (AMP) to cyclic AMP (cAMP) and initiate the de novo synthesis of testosterone [7]. Testosterone biosynthesis begins with the activation of the steroidogenic acute regulatory protein (the StAR protein) by extracellular signal-regulated kinase 1/2 (ERK1/2) in response to the LH-induced increase in intracellular cAMP concentration (Figure 1) [8]. The StAR protein is a component of a transmembrane multiprotein complex (the transduceosome) that catalyzes the rate-limiting step in steroid biosynthesis [9], the translocation of cholesterol from the cytoplasm to cytochrome P450cholesterol side-chain cleavage enzyme (P450scc; CYP11A1) embedded within the inner mitochondrial membrane [9- 13].