Glutathione Genes Predict Treatment Outcome in Male Infertility
Infertility affects approximately one out of six couples, with male factor infertility representing on average 30% of cases. Several genetic and environmental factors contribute to male factor infertility.
Sperm are particularly susceptible to oxidative stress (OS). Oxidative stress arises from an imbalance between reactive oxygen species (ROS)(oxidants) and protective antioxidants. These ROS have the capacity to alter cell function and lead to a decrease in the ability of the cell to produce energy, in the form of intracellular ATP. This is thought to cause a decrease in sperm viability and motility, mid-piece morphology defects, and reduce the ability of the sperm to fertilize an egg (decrease in sperm capacitation and acrosome reaction). In semen samples from men with infertility, high levels of biomarkers of ROS are seen in 25-40% of cases.1
The glutathione system, which includes glutathione, and the glutathione-based enzymes glutathione-S- transferase (GST) and glutathione peroxidase (GPx), is one of the main chemical defence mechanisms in the testes that protect spermatozoa cells and DNA from oxidative damage. Studies show that the intracellular glutathione system in spermatozoa is lower in those with infertility.2 The body’s glutathione stores can be depleted by several factors, including diet, pollution, toxins, medications, stress, trauma, aging, infections and radiation. In addition, individuals with certain genetic variations in the GST enzymes are more prone to glutathione depletion and oxidative stress from these external factors.
Several epidemiological studies have reported that the GSTM1 and GSTT1 null genotypes are correlated with an increased susceptibility to male infertility. In a meta-analysis of males with idiopathic infertility (n=1,845), those with the GSTM1 null genotype and GSTM1-GSTT1 dual null genotype had an increased risk of male idiopathic infertility (OR = 1.40, 95% CI 1.07-1.84) and (OR = 1.85, 95 % CI 1.07-3.21), respectively, which were most pronounced in Caucasian populations.3
Predict Therapeutic effect of antioxidants on Male Factor Infertility
One difficulty that arises in male factor infertility is determining which antioxidants to give, how much and for how long, to reduce the oxidative stress enough to see effective results. If an individual is missing the GST enzyme(s), do they require more or less?
In a case–control study of 310 men with idiopathic infertility and 170 healthy controls, the response to antioxidant therapy was analyzed according to GST genotypes. The treatment group received vitamin C (0.1 g), vitamin E (0.1 g), and Co Q10 (10 mg) three times a day for 3 months and were followed for 6 months.4
At baseline, the sperm concentration, motility, viability, mitochondrial membrane potential (MMP), and seminal plasma total antioxidant capacity (T-AOC) level in patients missing genes in GSTT1 or GSTM1 (null genotypes) were lower, and the sperm DNA fragmentation index (DFI), 8-hydroxy-2’-deoxyguanosine (8-OH-dG), and malondialdehyde (MDA) and nitric oxide (NO) levels were higher than those who were carriers of the GSTT1 or GSTM1 gene. In addition, the study found that the frequency of the GSTM1 null and GSTT1 null was higher in the group with idiopathic infertility than the controls, (59.4%, vs. 35.9%) and (61.9%, vs. 45.9%), with the highest odds ratio in those missing both the GSTM1 and GSTT1 genes, 37.7% vs. 12.4% in the control group (OR = 5.681; P < 0.001). 4
After 3- and 6– months of treatment, sperm concentration, sperm motility, sperm viability, MMP, and seminal plasma T-AOC increased, while DFI, 8-OH-dG, MDA, and NO levels in seminal plasma decreased significantly (all P < 0.001). However, the reductions in those missing the GSTT1 or GSTM1 genes were lower than the average levels, while those in the GSTM1(+), GSTT1(+), and GSTM1/T1(+/+) subgroups had a greater improvement in sperm concentration, sperm motility, sperm viability, and DNA fragmentation. 4
This highlights a potential need for an increase in dose of antioxidants for GST null genotypes. The dose of CoQ10 was modest at 30mg daily; however, much higher doses may be necessary and perhaps an increase in treatment time. Multiple studies show the successful use of 200mg up to 600mg of CoQ10 daily for 3 months effectively improves sperm concentration and motility in infertile men with oligoasthenozoospermia (OAT).5 CoQ10 has also been used successfully in combination with glutathione (100mg) to improve semen parameters (concentration, motility and morphology) and pregnancy rate after 4 months of use.6 While these studies show an improvement, they do not isolate the response according to genotype.
Indirect and Direct Lab markers for oxidative stress
Semen analysis – low concentration, motility and morphology, high DNA fragmentation
- Uric acid – marker for pyrimidine (DNA) destruction
- GGT – gamma glutamyl transferase, facilitates glutathione transport (run with AST, ALT to differentiate high GGT as a result from gallbladder issues vs oxidative stress)
- 8-OHdG – marker for DNA damage
- MDA – marker for lipid peroxidation
How to Improve Glutathione Levels and Enzyme Function
In those with a history of male infertility and the null genotypes of GSTM1 and GSTT1, it is particularly important to optimize antioxidant and glutathione status, through diet, supplementation and avoiding environmental factors that deplete glutathione.
- Diet: consume sulphur-rich foods such as garlic, onions, cabbage, cauliflower, broccoli, whey protein.
- Supplements: NAC, selenium, glutathione, lipoic acid, vitamin C and E (mixed tocopherols)
- Avoid environmental factors: Refrain from smoking; Reduce sugar, fat and alcohol consumption; Avoid using charcoal or wood for cooking and heating; Limit exposure to paint strippers, spray paint, aerosol products, pesticides and fumigants..
For more ideas to improve glutathione status see the Male Infertility (glutathione) card in the LoveMyHealth PRO Fertility panel.
- Agarwal, A. & Allamaneni, S. S. Role of free radicals in female reproductive diseases and assisted reproduction. Reprod. Biomed. Online 9, 338–347 (2004).
- Adeoye, O., Olawumi, J., Opeyemi, A. & Christiania, O. Review on the role of glutathione on oxidative stress and infertility. JBRA Assist. Reprod. 22, 61–66 (2018).
- Kan, H.-P. et al. Null genotypes of GSTM1 and GSTT1 contribute to male factor infertility risk: a meta-analysis. Fertil. Steril. 99, 690–696 (2013).
- Zhang, H. et al. Effect of glutathione S-transferase gene polymorphisms on semen quality in patients with idiopathic male infertility. J. Int. Med. Res. 49, 3000605211061045 (2021).
- Alahmar, A. T., Calogero, A. E., Sengupta, P. & Dutta, S. Coenzyme Q10 Improves Sperm Parameters, Oxidative Stress Markers and Sperm DNA Fragmentation in Infertile Patients with Idiopathic Oligoasthenozoospermia. World J. Mens Health 39, 346–351 (2021).
- Gianmaria. Coenzyme Q10 and Male Infertility: A Systematic Review. (2020).
By Dr. Robyn Murphy, ND
Scientific Advisory Board Member