- In this podcast episode I am going to go through some very important information for those of you faced with fertility challenges. What will be presented may outline a potential causative factor contributing to your infertility, and clearly explain what can be done to rectify these circumstances. This includes the following topics;
- What is oxidative stress – (00:00)
- How oxidative stress impacts male and female fertility – (00:00)
- What is glutathione (GSH) – (00:00)
- How glutathione (GSH) supports male and female fertility – (00:00)
- How to ensure your glutathione (GSH) levels are optimized – (00:00)
- Before we start I want to thank Adeoye Oyewopo and his team of scientists for their review published in 2018 on the role of glutathione (GSH) on oxidative stress and infertility. Their article comprises the backbone of the references and inspiration for this piece.
WHAT IS OXIDATIVE STRESS?
- Oxidative stress (inflammation) arises from an imbalance between reactive oxygen species (ROS) and protective antioxidants. This affects the entire physiology of a human, but for our purposes, can impose negative influences on the entire reproductive systems of men and women.
- Reactive Oxygen Species (ROS), sometimes referred to as ‘free radicals’ or collectively ‘oxidative stress’, are unstable molecules produced by normal body functions and exposure to external stressors and toxins. More technically, examples of ROS in the body are hydrogen peroxide (H2O2), superoxide (O2•-), and the hydroxyl radical (•OH). These little critters, in excess, can cause disruption to normal cellular function and can damage various parts of our cells (for our purposes cell membranes, mitochondria, & DNA of the sperm, egg, and other reproductive organ tissues). Additionally, this becomes very problematic in regards to our health and fertility when levels of ROS are continually increased and compounded by;
- overconsumption of sugar
- use of oxidized vegetable oils (i.e. industrially produced vegetable oils)
- smoking, anything.
- exposure to environmental toxins (pollution, pesticides, plastics)
- high or chronic emotional stress
- circadian rhythm dysregulation (poor sleep)
- lack of exercise
- lack of antioxidant intake
- Important note; antioxidants are substances that can prevent or minimize ‘oxidative stress’ and reduce damage to cells.
HOW DOES OXIDATIVE STRESS IMPACT FERTILITY?
- Oxidative stress (inflammation) influences oocytes (eggs), spermatozoa (sperm), embryos and their environments. More specifically, the reactive oxidative species (ROS) affect microenvironments associated with the fluid surrounding the egg, fallopian tube fluid, and abdominal fluid and have a direct bearing on egg quality (cell membranes, mitochondria & DNA), sperm-egg interaction (fertilization), sperm-mediated egg activation, implantation, and early embryo development.
- WHEREAS low levels of ROS (homologous to exercise or other necessary stress which makes us stronger) exert critical function in normal sperm physiology, such as fertilizing ability (acrosome reaction, hyperactivation, capacitation, and chemotaxis) and sperm motility; RESEARCH on male factor infertility demonstrates that sperm are vulnerable to higher levels of reactive oxidative species (ROS)
- More specifically, sperm are particularly vulnerable to ROS because their plasma membrane (cell wall) and cytoplasm (fluid inside the cell) contain large amounts of polyunsaturated fatty acids (i.e. omega 3 & 6 ALA DHA & EPA), and lipid (fatty acid) peroxidation (damage) of the sperm membrane is the key mechanism of this ROS-induced sperm damage, leading to infertility.
- This ROS sperm damage manifests in the following ways;
- a decrease in sperm motility (due to mitochondria damage resulting in reduction in ATP [energy], and damage to the tail
- a decrease in sperm viability (how long they remain alive)
- an increase in mid-piece morphology defects (comprised of mostly mitochondria)
- deleterious effects on sperm capacitation and acrosome reaction (aka sperms ability to fertilize the egg)
- increased sperm DNA damage and apoptosis (cell death)
- And could contribute to possible birth defects
- It should be noted that almost all human ejaculate contains reactive oxygen species (ROS), primarily produced from the above mentioned lifestyle and environmental factors (consumption of sugars and oxidized vegetable oils, smoking, alcohol, exposure to environmental toxins, high or chronic emotional stress, circadian rhythm dysregulation (poor sleep), lack of exercise, infections, and a lack of antioxidant intake), as well as from abnormally shaped sperm present (meaning, if there is a high % of abnormally shaped sperm, or poor morphology, more reactive oxygen species (ROS) will be present, and these days, most sperm samples contain a large % of abnormally shaped sperm). Therefore the overall impact on fertility that ROS has is not a matter of if it is there or not (as mentioned earlier, some oxidative stress is required for various reproductive physiological functions), but when levels of ROS are too high (or antioxidant levels are too low) it becomes pathological to sperm and the ability to get pregnant.
- This is highlighted and will be discussed more later by research that has shown that levels of antioxidants (including Glutathione) in seminal plasma from infertile men is significantly lower than levels in fertile men.
As with male fertility, oxidative stress or reactive oxygen species (ROS) in the female reproductive system, at low levels, is important in the mediation of processes such as hormone signaling, egg maturation, folliculogenesis (follicle growth cycle), fallopian tube function, proper production of hormones from the ovaries, changes in the uterine lining throughout the cycle, various functions throughout pregnancy, and initiation of labour.
BUT, again, when ROS reaches higher pathological levels (so common), many problems arise, including (but not limited to);
- Lipid (cell membrane) damage
- inhibition of protein synthesis
- Mitochondria & ATP (cellular energy) depletion
- hydatidiform mole (molar pregnancy)
- Fallopian tube issues
- unexplained infertility
- Pre-eclampsia (high blood pressure during pregnancy)
- birth defects
In addition, and more specifically;
- Excess reactive oxidative species (ROS) in the follicular fluid can directly damage the egg. The DNA of eggs may be damaged, resulting in fertilization issues.
- Even when fertilization is achieved, oxidative stress (inflammation)-induced apoptosis (cell death) may result in
- embryo fragmentation
- implantation failure
- insufficient luteal hormonal levels
- impaired placenta development
- inadequate growth of the uterine lining (necessary for embryo development
- congenital abnormalities
More reproductive condition specific;
In Polycystic Ovary Syndrome (PCOS) oxidative stress (inflammation) has been shown to be involved in mediating insulin resistance and androgen hormone increases.
It is also important to note that research on the abdominal fluid (which surrounds the ovaries) of both fertile and infertile women demonstrated that higher levels of reactive oxidative species (ROS) were present in the fluid taken from patients with unexplained infertility.
With Endometriosis, the inflammation involved compounds the production of reactive oxidative species (ROS). Oxidative stress (inflammation) increases lesions and adhesions via the production of endothelial growth factor which promotes angiogenesis (blood vessel formation) to the Endometriosis.
- One study even showed a difference in how the gene expression of Endometriosis tissue metabolizes glutathione (GSH).
WHAT IS GLUTATHIONE?
- Glutathione is the mother of all antioxidants, the master detoxifier and maestro of the immune system
- Glutathione is a tripeptide made up of 3 amino acids; glutamic acid, cysteine, and glycine
- The synthesis of glutathione in the body involves two enzymes, the first of which binds L-cysteine and glutamic acid to one another in a gamma configuration (producing γ-glutamylcysteine), and the second enzyme adds a glycine molecule onto it to ultimately form glutathione.
- Glutathione (GSH) is an antioxidant in plants, animals, fungi, and some bacteria.
- It is found in the cytosol (fluid) and organelles (ER, Mitochondria, nucleus) of the cell
WHAT DOES GLUTATHIONE DO?
Glutathione has many important functions in our body, but most importantly, it is the king (or queen) of antioxidants, which essentially means that it protects cells (egg/sperm) from damage due to ROS such as lipid hydroperoxides (turning them into alcohols) and hydrogen peroxide (turning it into water). Glutathione also plays a vital role in the recycling of other important antioxidants such as vitamin C and E, so their net protective effects are increased.
Obviously, consequently, if we are not taking good care of ourselves, glutathione (GSH) levels can be deficient, and with this, no doubt, comes consequences.
Let’s unpack that – more specifically, Glutathione is a part of the ‘glutathione system’. The ‘glutathione system‘ comprises the enzymes that synthesize glutathione within a cell as well as dedicated enzymes that use glutathione (GSH) as the means to exert antioxidant effects.
Within its role as the body’s most important antioxidant, Glutathione is capable of preventing damage to important cellular components caused by reactive oxygen species (such as free radicals, peroxides, lipid peroxides), xenobiotics, and heavy metals
Glutathione also plays important roles in nutrient metabolism, and regulation of cellular events including;
- Proper gene methylation (expression of genes)
- DNA and protein synthesis
- cell proliferation (growth)
- cellular apoptosis (regulated cell death)
- cellular communications
- immune response
…as well as a being important in a process called protein glutathionylation, which has several biological functions such as;
- regulation of metabolic pathways
- calcium homeostasis
- remodeling of cytoskeleton
- protein folding
Other Vital Roles of glutathione (GSH) include;
Many of these detailed functions are beyond the scope of this post but are worth mentioning here so that the true importance and impact of glutathione (GSH) is realized. Glutathione is essential in;
- The delivery of B12 to cells
- Dopamine and serotonin production (in conjunction with methionine)
- Heart & blood vessel (endothelial) health in conjunction with nitric oxide (NO)
Another important function of glutathione (GSH) is its role in the immune response and the potential positive impact on autoimmune issues. Glutathione is involved in immune function via regulation of;
- cytokine production (cell mediated immunity)
- genes that cause chronic inflammation
Glutathione is our primary protector, and a large part of this job is defending us from environmental toxins, many of which can disrupt hormone levels, reproductive potential, and pregnancy. We are exposed to these toxins through contact with radiation, plastics, chemicals, pollution, molds, heavy metals, and pesticides.
If glutathione (GSH) levels are low, these toxins are not efficiently removed from the body and can cause damage to cellular DNA, cell membranes, and mitochondria, which can result in an array of symptoms and disease, contribute to existing medical conditions (such as infertility), and cause problems with pregnancy and the future health of the offspring.
Glutathione IN GENERAL appears to be reduced in the elderly when compared to youthful controls, even if there are no apparent disease states. Fortunately, literature shows that proper supplementation can increase GSH levels to those seen in youthful controls fairly rapidly.
As mentioned earlier, if we are not taking good care of ourselves glutathione (GSH) levels can be deficient, and with this comes consequences. Glutathione deficiency contributes to oxidative stress (inflammation), which plays a key role in aging and the pathogenesis of many diseases including (but not limited to);
- Alzheimer’s disease
- Parkinson’s disease
- liver disease
- cystic fibrosis
- sickle cell anemia
- HIV, AIDS
- heart attack
Glutathione is important in almost every biological cellular function – so running a deficiency is obviously not favorable to overall human health.
GLUTATHIONE & FERTILITY
- With everything mentioned so far, in a nutshell, glutathione (GSH) can improve fertility by reducing the damage oxidative stress (inflammation) in the reproductive system.
- The body produces its own glutathione (GSH) but it is depleted by poor diet, pollution, toxins, medications, stress, trauma, aging, infections, and radiation.
- A deficiency of glutathione (GSH) leads to increased oxidative stress (inflammation) resulting in issues with sperm and egg quality, fertilization, implantation, and embryo development.
GLUTATHIONE & MALE INFERTILITY
Remember, it is well understood that oxidative stress (inflammation) interferes with normal sperm function via membrane lipid peroxidation (cell membrane fatty acid damage) and fragmentation or damage of nucleic acids (DNA). Due to sperm’s abundance of membrane polyunsaturated fatty acids (PUFAs) and their own innate capacity to generate reactive oxygen species (ROS) (via abnormally shaped sperm morphology), human sperm are highly susceptible to oxidative stress (inflammation).
- Therefore, if glutathione (GSH) reduces oxidative stress (inflammation) and resultant reactive oxygen species (ROS) damage, glutathione (GSH) protects sperm.
I like it best, the way Lenzi A et al said it in their paper ‘Rationale for Glutathione Therapy’ published in the Oxford journal Human Reproduction;
- Sperm cell homeostasis (aka healthy function) could be summed up as the balance between the sperm membrane levels of peroxidable substances (i.e. PUFA – polyunsaturated fatty acids, the primary component of the cell membranes) and the effectiveness of the battle between oxidative stress (inflammation) and antioxidants. If the oxidative stress wins this battle, sperm quality is affected.
- Main sources of reactive oxygen species (ROS) in the genital tract are;
- Sperm themselves (especially abnormally shaped sperm, typically measured in semen analysis and referred to as morphology)
- Leukocytes (white blood cells) during inflammatory processes
- Ischemia/hypoxia (lack of oxygen) during vascular(blood vessel) issues (i.e. varicocele)
- Glutathione is in significant quantity in the seminal plasma. Levels can be increased by systemic administration, and concentrates in the seminal plasma, where it can produce its physiologic and therapeutic roles.
- Increased Epididymal levels of glutathione (GSH) (part of the male reproductive tract, where sperm final maturation occurs) can protect the sperm membrane PUFA, playing a protective role in sperm maturation.
Research on Glutathione and Male Infertility
This section may be a little dry for some and essential for others, but I feel it important to quickly go through some of the available research proving the connections between sperm quality, reactive oxygen species (ROS), and glutathione.
Research published in BioMedical Central Urology journal [a part of Springer Nature] by Atig et al that compared a group of 190 men with abnormal sperm parameters against a control group of fertile men with normal sperm parameters and revealed that decreased seminal GSH is implicated in low sperm quality.
- It should be noted that men with known conditions that would cause inflammation (such as genital tract infections, varicocele) or that used alcohol, smoked, or were currently taking antioxidants were all excluded from the study to create a more consistent base-line of existing oxidative stress (inflammation) between the groups
- This study also showed that the higher the measured levels of ROS, the more damage there was to sperm function.
- Lower GSH in semen & higher ROS affecting sperm further substantiated by;
- A. Bhardwaj et al, Asian Journal of Andrology
- Hesham Nabil, et al, Australian Journal of Basic and Applied Sciences
- Agarwal A, et al, Fertility Sterility
- And many of the studies I am about to discuss also corroborate these findings but report of other aspects of the relationship to glutathione (GSH) and sperm…
- Lower GSH in semen & higher ROS affecting sperm further substantiated by;
- This study also showed that the higher the measured levels of ROS, the more damage there was to sperm function.
Garrido N et al published research in Fertility Sterility showed that intracellular (inside the cell) Glutathione concentrations are lower when severe sperm morphology is present, establishing the connections between high sperm morphology rates and high ROS, and the need for glutathione (GSH) supplementation.
Multiple studies done by Lenzi A et al (a research group in Italy) which were published in The Oxford Journal of Human Reproduction, Frontiers in BioScience, Archives of Andrology, and Contraception, came to the following conclusions in regards to sperm, oxidative stress (inflammation), and glutathione;
- Glutathione injections significantly improved forward motility and morphology due to its protective effect against ROS on the PUFA that largely comprise sperm cell membranes.
Crisol L et al published a study in Fertility Sterility confirmed studies regarding ROS damage to sperm membranes resulting in a negative impact on fertilization. They also found that ROS damage affected the nucleus of the sperm causing DNA damage which could be transmitted to the next generation and be responsible for increased disease susceptibility in offspring.
- Kodama H et al also published in Fertility Sterility states very similar findings;
- DNA – Deoxyribonucleic acid bases and phosphodiester backbones are susceptible to oxidative stress (inflammation), and peroxidation of these structures can cause strand breaks and cross-linking of the DNA and result in disrupted transcription, translation, and DNA replication
- It has been suggested that damaged genomic DNA of the spermatozoa can be transmitted to the offspring and lead to increased incidences of miscarriage, fetal anomalies, and birth defects
- They went on to show that treatment with Vitamin C and Glutathione reduced the level of hydroxy-2’-deoxyguanosine which is a measure of DNA oxidative damage.
Scientific reviews by Hemachand & Shaha. published in the Federation of European Biochemical Societies Letters (a division of Wiley) and Hansen & Degushi, Acta veterinaria Scandinavica concluded that a glutathione deficiency can lead to instability of the sperm’s midpiece (which contains the mitochondria and ATP necessary for swimming) resulting in defective motility. This conclusion is verified by research published by;
- Ursini, F et al, Science
Research done by Sorenson MB et al published in the journal Molecular Human Reproduction (a part of Oxford Academics) showed that when glutathione is present in extracellular space (outside the cell) it is able to react directly with cytotoxic aldehydes produced during lipid peroxidation (ROS) and thus protects the sperm plasma membrane. In other words, glutathione also protects the cell from the outside, not simply from ROS forming on the inside of the cell.
This was confirmed and elaborated on by Fafula, Roman V et al who published research in the Journal of Human Reproductive Sciences that shows glutathione not only important in protecting the sperm and improving motility and viability, but that the female reproductive tract contains extracellular glutathione, and if levels are adequate, would give sperm a survival advantage.
…and this is a good segway into our next section.
GLUTATHIONE & FEMALE INFERTILITY
Again, diving into some of the available research…
First of all, an amazing scientific review on glutathione (GSH) and fertility by Adeoye O et al published in the Journal of Brazilian Assisted Reproduction concluded that glutathione (GSH) protects the egg in the same way it protects the sperm by shielding the eggs from damage caused by oxidative stress (inflammation) during folliculogenesis (maturation and growth of an egg), and therefore, egg quality is dependent on it. Research done by Mukherjee et al published in the Journal of assisted reproduction and genetics concluded that eggs with higher levels of intracellular glutathione (GSH) produce healthier and stronger embryos. They went on to state that glutathione (GSH) can reduce oxidative stress (inflammation) by fighting the formation of damaging free radicals in the reproductive system. Similar findings were reported by Gardiner et al in Biology of Reproduction.
Glutathione (GSH) is the cell’s primary antioxidant. Across the board, to put it bluntly, low levels of glutathione (GSH) are a marker for disease and premature death.
Another study done by Kankofer et al published in the journal Aging clinical and experimental research that in younger years, ovaries have higher intracellular glutathione (GSH) levels.
It has also been reported by Lim et al published in Cancer research, that glutathione (GSH) deficiency is related to premature ovarian aging and even ovarian cancer.
Research by Tola et al published in the journal Reproduction, fertility, and development found that for women undergoing IVF, higher levels of glutathione (GSH) in a woman’s follicle translated into increased fertilization rates.
The journal of Reproductive biology and endocrinology published a scientific review by Fujii et al which determined that glutathione (GSH) is shown to be a powerful anti aging antioxidant which could have a possible impact on egg health, one of the cells most affected by the aging process.
Tsai-Turton & Lauderer in their publication in the journal Endocrinology reported that evidence proves oxidative stress (inflammation) induces apoptosis (cell death) in preovulatory follicles and that the antiapoptotic (preventing cell death) effect of FSH is mediated in part by stimulation of follicular glutathione (GSH) and suppression of ROS production.
Finally, the authors of the previously mentioned review, Adeoye O et al, went on to state that glutathione (GSH) may have an important impact on is autoimmune issues. Glutathione is involved in regulating the genes and the production of cytokines that cause chronic inflammation. This may be helpful for those who are experiencing immunological miscarriages or if the body is rejecting one’s mate’s sperm.
Supplementation of glutathione (GSH) will support the pool of glutathione (GSH) in a cell and thus maintain the efficacy of the entire glutathione (GSH) system. Due to it being broken down in the digestive tract into its base amino acids, oral supplementation is not effective, this is why we provide glutathione (GSH) injection therapy at Yinstill.
Glutathione administration can be a stand-alone IV or subcutaneous/intramuscular injection (10 min appointments) that can be added to the end of an IV drip or acupuncture appointment. Generally, injections / IV’s are recommended once a week for 8 weeks to start. Afterwards, patients may either continue with weekly treatments or move to a maintenance schedule based on their unique clinical needs.
It should be mentioned that better versions of liposomal (surrounded by fat) oral glutathione (GSH) are being developed to improve absorption, and lipodermal (through the skin) gels are also an option. Although, neither of these administration routes are as reliable as injections.
We also recommend that people ensure vitamin C intake is adequate, as glutathione (GSH) and vitamin C work synergistically to help protect our body from oxidative stress (inflammation).
Finally, we also suggest that clients concurrently stack N-acetylcysteine (NAC) supplementation when working to increase their glutathione (GSH) and overall antioxidant levels. Research has demonstrated that NAC is able to reliably increase glutathione (GSH) concentrations in cells.
- High degrees of oxidative stress (inflammation) and low antioxidant status are implicated in conditions contributing to infertility
- Deficiencies of glutathione (GSH) have been shown to negatively impact both sperm and egg quality, the fertilization process, and embryo development.
- Glutathione is the body’s most powerful antioxidant which also helps in preserving and recycling other antioxidants.
- Glutathione injection treatment strategies to boost the exhausted antioxidant defense of the reproductive microenvironment is intuitive.
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- A. Lenzi, F. Culasso, L. Gandini, F. Lombardo, F. Dondero, Andrology: Placebo-controlled, double-blind, cross-over trial of glutathione (GSH) therapy in male infertility, Human Reproduction, Volume 8, Issue 10, October 1993, Pages 1657–1662
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