Antioxidants and Fertility

Antioxidants such as vitamins C and E, Coenzyme Q10, N-acetyl cysteine, melatonin and many others have been shown to enhance fertility by improving egg and sperm quality. They do this by protecting cells, mitochondria and DNA from a process called oxidative stress. Antioxidants are just that – anti-oxidation molecules. They can transform or neutralize potentially damaging compounds, such as free radicals or reactive oxygen species (ROS) in the body, keeping them in check.

What is Oxidative Stress?

The production of ROS in the body is a natural part of our biology. These molecules, which include hydrogen peroxide and superoxide and hydroxyl free radicals are produced as part of normal metabolism. ROS’s are highly reactive and in enough amounts can cause significant cellular damage, but they’re not always detrimental. A small amount of these ROS are actually needed by the body as they play a special role in cell signalling.

In order to keep ROS levels under control, the body uses antioxidants. Some can be made by the body, while others we get from our diet. However, when the body uses them up too quickly or when the production of ROS outpaces the action or concentration of antioxidants, we see oxidative stress as a result. Lifestyle choices and environmental exposures such as nicotine use, alcohol consumption and excessive weight, are all associated with increased ROS in the body.

Oxidative stress contributes to aging, chronic disease and infertility or subfertility. Correct cell division and DNA replication is required for good quality sperm and eggs, and to make an embryo that can properly develop and grow. Oxidative stress can damage cell membranes, DNA and mitochondria (the energy-makers of our cells), leading to cellular dysfunction and accelerated cell death.

Oxidative Stress, Aging and the Ovaries

Aging is strongly linked to ROS accumulation and oxidative stress, and this applies to the ovaries as well. As we age, oxidative stress naturally increases and energy production from the cell’s mitochondria declines. In maternal aging, egg quality decreases while the rate of chromosomal abnormalities, including Down’s Syndrome, increases. Having damaged mitochondria impairs energy production in the ovaries and their follicles, while damaged DNA and poor cell division leads to DNA abnormalities in follicles/eggs.

Many hormonal disorders associated with subfertility and infertility such as Polycystic Ovary Syndrome (PCOS), endometriosis and low ovarian reserve are associated with increased oxidative stress. Every step that leads to the birth of a healthy live baby, including egg development and quality, ovulation, fertilization, embryo development, implantation, placental and fetal growth and development can be affected by oxidative stress. That said, even normal reproductive function requires some ROS to proceed, but it’s the excess and imbalance that can cause major problems. This includes negative pregnancy outcomes such as miscarriage and preeclampsia. Therefore having a poor nutritional antioxidant intake, being overweight, and/or having increased exposure to air pollution, cigarette smoking and alcohol use will all promote the production of excess ROS which can affect fertility.

Understanding these connections has led many researchers to investigate the effects of supplementing with antioxidants to slow or even reverse the cellular aging of the ovaries and eggs, while also using them in men to improve sperm quality.

Antioxidants for Egg Quality

Coenzyme Q10 (CoQ10) is an antioxidant most famous for its role in cellular energy production. As a co-factor for mitochondrial energy production, CoQ10 is a special consideration for women, especially those over the age of 30, since almost all of the mitochondria in the embryo comes from the egg!

Studies have shown that CoQ10 can improve egg and embryo quality, restoring mitochondrial function and reducing chromosomal abnormalities in women over the age of 38.¹ In one study of those undergoing IVF, supplementing with 600mg of CoQ10 daily for two months before egg retrieval led to a greater amount of eggs retrieved, a higher fertilization rate and more high quality embryos compared to those who were not given CoQ10.²

L-carnitine and Acetyl-L-carnitine are two related compounds with antioxidant effects in both male and female fertility. Carnitine works with CoQ10 to shuttle fatty acids into mitochondria to be transformed into cellular ATP energy. Supplementation with carnitine has been shown to improve the growth and maturation of ovarian follicles into eggs.³

N-acetyl cysteine (NAC) is an antioxidant itself, but it also increases the levels of other antioxidants in the body.⁴ Many of those with PCOS don’t ovulate because follicle development in the ovaries is suppressed. NAC supplementation in women with PCOS has been shown to improve insulin sensitivity and improve IVF outcomes, increasing the likelihood of ovulation by three to nine times.⁵

Another study showed that supplementing with 1200mg of NAC daily led to a greater rate of ovulation compared to those who were given placebo (45% vs 28%, respectively) and a higher rate of pregnancy (20.7% vs 9.4%, respectively).⁶

Antioxidants and Sperm Quality

Brand new sperm is continuously produced throughout a man’s lifespan, but this doesn’t mean that men are immune to the effects of ROS on their sperm quality. Oxidative stress can affect the structure of sperm, interfering with their ability to swim (motility) and fertilize an egg. Oxidative stress can also cause breaks and mutations in DNA, resulting in increased sperm DNA fragmentation.⁷

L-carnitine is an antioxidant found in high concentrations in mature sperm and in the epididymis. Known for its role in mitochondrial function and energy production, it helps preserve sperm motility and viability. In one study, supplementing infertile men with 2g of L-carnitine daily, compared to placebo, led to significant improvements in sperm motility (11% vs 8.8%) and concentration (9 million per mL vs 5.3 million per mL).⁸

NAC acts as a super antioxidant in both male and female fertility, as studies have shown that NAC can protect sperm mitochondria and improve their function. In one study, 50 infertile men with poor sperm quality were given 600mg of NAC for three months. This led to significantly improved sperm concentration (increase by about 5 million/mL) and motility (4% increase), increased semen volume and decreased DNA fragmentation.⁴

Vitamins C and E are both well known for their antioxidant actions and they both recycle each other in the body. Vitamin E specifically helps reduce oxidative stress to lipids and cholesterol. As well, direct associations have been made between vitamin E concentrations in semen and sperm motility. Supplementing with 300IU has been shown in one study to increase sperm motility by about 25%.⁹

Is there such a thing as too much antioxidants?

Yes. Remember that ROS are required by the body in small amounts. Reproductively we need them for proper egg maturation and ovulation, as well as for the interaction between the sperm and egg to occur. ROS are needed for sperm to become able to “drill” and fertilize an egg. Some studies are even showing that small amounts of ROS are required for proper development and function of the placenta. That doesn’t mean that we need to completely avoid all antioxidants. There are many benefits to taking antioxidants, but they shouldn’t always be consumed chronically at super high doses (i.e. too much of a good thing).

That said, the role of antioxidant supplementation on fertility is an important consideration which could drastically change the outcome when trying to conceive, especially as we age. There is an important balance between ROS and the antioxidants that control them, but over the age of about 35 to 38 years, we accumulate greater amounts of ROS which affects egg and sperm quality. This highlights the need for antioxidants to preserve reproductive function in those trying to conceive in their 30’s, 40’s and beyond.

References

• Ma L, Cai L, Hu M, et al. (2020). Coenzyme Q10 supplementation of human oocyte in vitro maturation reduces post-meiotic aneuploidies. Fertil Steril. 114: 331-7

• Xu Y, Nisenblat, V, Lu C, et al. (2018). Pretreatment with coenzyme Q10 improves ovarian response and embryo quality in low-prognosis young women with decreased ovarian reserve: a randomized controlled trial. Reprod Biol Endocrinol. 16(1): 29

• Ismail AM, Hamed AH, Saso S, Thabet HH. (2014). Additing L-carnitine to clomiphene resistant PCOS women improves the quality of ovulation and the pregnancy rate. A randomized clinical trial. Eur J Obstet Gynecol Reprod Biol. 180: 148-52

• Jannatifar R, Parivar K, Roodbari NH, Nasr-Esfahani MH. (2019). Effects of N-acetyl cysteine supplementation on sperm quality, chromatin integrity and level of oxidative stress in infertile men. Reprod Biol Endocrinol. 17(1): 24

•  Thakker D, Raval A, Patel I, Walia R. (2015). N-acetylcysteine for polycystic ovary syndrome: A systematic review and meta-analysis of randomized controlled clinical trials. Obstet Gynecol Int. 2015: 817849

•  Salehpour S, Sens AA, Saharkhiz N, et al. (2012). N-acetylcysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome. J Obstet Gyne Res. 38(9): 1182-86

• Steiner AZ, Hansen KR, Barnhart KT, et al. (2020). The effect of antioxidants on male factor infertility: the males, antioxidants, and infertility (MOXI) randomized clinical trial. Fertil Steril. 113(3): 552-60

• Lenzi A, Lombardo F, Sgro P, et al. (2003). Use of carnicine therapy in selected cases of male factor infertility: a double-blind crossover trial. Fertil Steril. 79(2):292-300

• Majzoub A and Agarwal A. (2018) Systematic review of antioxidant types and doses in male infertility: benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate. Arab J Urol. 16(1): 113-124