Antioxidants Like Melatonin and CoQ10 May Help Mitigate the Impact of Environmental Exposures and Aging on Reproductive Health.
We live in an increasingly toxic world, with literally thousands of different potential toxins being released into our water, air, and soil each day by industry, agricultural practices, and our daily living.[1],[2],[3],[4] These toxins cycle into our food supply, accumulating in animals and plants.[5],[6],[7],[8] Many environmental pollutants do not degrade over time, and thus continue to accumulate; these chemicals are classified as persistent organic pollutants. Pollutants such as these also don’t remain in one place—they are cycled in our environment and distributed globally.[9],[10]
Environmental toxicants impact our longevity, increase our risk for chronic disease, and gravely affect our reproductive health as well.[11],[12],[13],[14] Exposure to toxic pollutants is not only a reproductive factor in our older years – it also has an impact when we are young.[15],[16],[17],[18] Because females have a limited amount of gametes, set from the moment they are born, and their detoxification surfaces and pathways have a lower capacity then men, the long-term impact of toxicants on female fertility may be more dramatic.[19] Other factors such as immune dysfunction and autoimmunity also disproportionately affect females and may be environmentally triggered factors in female infertility.[20]
The two key ways in which environmental toxins adversely affect our health is by their endocrine effects and the oxidative damage they cause. In addition to limiting exposure to toxins, undertaking a comprehensive assessment of exposure and using evidence-based supplements and medications to safely remove them is paramount, particularly if historic exposures are significant.
Herein, we take a look at the different antioxidant therapies that have been clinically studied and shown to be of benefit for reproductive health in both males and females struggling with infertility, highlighting melatonin and coenzyme Q10 (CoQ10).
Melatonin
It may come as a surprise that the hormone/antioxidant best known for the role it plays in our sleep cycle has also been studied for its reproductive impact. Extensive research exists on the anti-inflammatory and immune-regulating properties of melatonin,[21] which may also give rise to its positive impact on both female and male reproductive health.[22],[23]
The study of melatonin’s impact on female fertility largely grew out of research in the late ’80s that found high levels of melatonin in female preovulatory follicular fluid—approximately 3.5 times higher than the corresponding serum concentration.[24] Animal and human studies suggest that the melatonin found in the follicular fluid is taken up the ovaries from systemic circulation, although some may also be produced in the ovaries themselves.[23]In women, daily administration of 3 mg of melatonin in the evening has been shown to increase follicular levels of melatonin more than three-fold.[25] Melatonin has been shown to impact follicular growth, with significantly higher levels of endogenous melatonin being found in the larger, healthier follicles versus the small follicles that were obtained from women for fertilization procedures.[26]
The majority of research concerning melatonin for female fertility is in women undergoing in vitro fertilization (IVF)-embryo transfer (ET) procedures, using their own harvested oocytes. Supplementation with 3 mg of melatonin/day was found to lead to a higher percentage of mature oocytes being retrieved for IVF-ET procedure, with trends to a higher clinical pregnancy rate compared to placebo.[27] In another study, melatonin taken at 3 mg/day was shown to significantly improve fertilization rates in women who failed to become pregnant in their last IVF-ET procedure.[25] In a third clinical study of women undergoing IVF, the addition of 3 mg of melatonin to daily treatment with 200 mg of folic acid [CD1] and 2 g of myo-inositol significantly increased the number of mature oocytes, with trends toward higher implantation and clinical pregnancy rates.[28] Multiple additional human studies also point to similar effects on oocyte quality and fertilization rates.[29],[30],[31],[32]
The effects of melatonin on female reproductive health are not limited to those undergoing IVF treatment, of course—the potential benefits of this antioxidant/hormone also extend to several other conditions that affect the female reproductive system. Numerous cellular and animal studies suggest melatonin may have a positive impact on endometriosis; recurrent spontaneous abortion; PCOS; and immune-, chemotherapy-, or radiation-induced primary ovarian insufficiency;[33] as well as the normal fertility decline with aging.[34],[35]
The data suggests that supplemental melatonin may also have a positive impact on male reproductive health. Men who are fertile tend to have higher blood and semen melatonin levels, on average, than those who are infertile.[36],[37] In men being counseled for infertility, higher (endogenous) urinary melatonin metabolite (6-sulfatoxymelatonin [aMT6s]) levels were significantly and positively associated with sperm concentration, forward motility, and normal morphology range.[38] Significantly lower testicular melatonin levels have also been shown to be associated with testicular histological abnormalities.[39] A comparison of morning urinary aMT6s levels between infertile males and recent fathers showed significantly higher levels in the new fathers, despite both groups being individuals who worked night shifts.38
Although seminal plasma melatonin levels are significantly lower than those of the blood,[40] melatonin administration still dramatically increases both seminal plasma and serum levels,[41] similar to its effects in women. The addition of melatonin to semen in vitro improves sperm viability, motility, penetration ability, and subsequent embryo development.[42],[43],[44] Studies both in vitro and in humans have also shown that melatonin protects sperm from oxidative stress and DNA fragmentation[45],[46]—which is important not only for conception, but also for the growth and development of the fetus into a healthy child.
Oral melatonin supplementation has been shown to increase melatonin levels in human testes, where sperm are produced, and to decrease oxidative stress and inflammation-related markers.[39] In a population of infertile men having idiopathic azoospermia, melatonin, taken at a dose of 3 mg for three months, significantly lowered the number of testicular macrophages and improved histological abnormalities, specifically decreasing testicle tubular wall fibrosis. Initially, testicular macrophage numbers and tubule wall thickness in the men with histological abnormalities were approximately double those of the men without such abnormalities; with melatonin supplementation, the macrophage levels and tubule wall thickness were nearly restored to those of the men with normal histology.
Melatonin also protects sperm against the damage caused by environmental pollutants, including BPA,[47] heavy metals (cadmium, mercury, and lead),[48],[49],[50] and pesticides (diazinon and others).[51],[52] Melatonin receptors exist in numerous cell types associated with male reproductive function—Leydig cells, Sertoli cells, and several different testicular immune cells—shedding light on a wide array of potential reproductive functions.[85]Although further studies are needed, the evidence points to melatonin as a supplement that can ameliorate oxidative stress and perhaps improve male fertility.
CoQ10
In similar ways, CoQ10 also helps protect the gametes. Like melatonin, CoQ10 is a fat-soluble antioxidant and helps protect cellular membranes from oxidative stress. Additionally, CoQ10 is an important nutrient for mitochondrial energy production—a factor for both male and female reproductive health. Because CoQ10 levels decline with aging, it is perhaps not a surprise that a primary focus of research with this nutrient concerns diseases and conditions associated with aging: cardiovascular and metabolic disease,[53] neurodegenerative disorders,[54] sarcopenia and muscle strength,[55] skin changes such as wrinkles,[56] and “reproductive aging,” the term used to describe nonspecific fertility decline with age.
A female factor in reproductive aging is the dwindling supply of viable oocytes. One factor in oocyte viability is its ability to mature, which was touched on lightly in the discussion of melatonin. Prior to its release from the ovary, an oocyte undergoes a complex and energy-intensive process of nuclear, cytoplasmic, and even epigenetic changes that allow it to mature to a “ripe” stage where it is ready to be fertilized.[57] Then, during the process of its release from the ovary, it also is subject to increased oxidative stress, which, in a not-so-healthy oocyte, can lead to membrane and organelle damage, making it not compatible with fertilization.[58]
Clearly, antioxidants are an important tool as they promote healthy oocyte maturation and help protect the oocyte from this oxidative damage. Additionally, alterations in mitochondrial energy production are factors contributing to the decline in maturation of viable oocytes with age.[59] Enter stage left: CoQ10.
The primary energy-generating pathway in the developing oocyte is mitochondrial oxidative phosphorylation, which depends on adequate amounts of CoQ10.[60] The steps involved in energy production also generate substantial oxidative stress and can be very damaging to the mitochondria, giving further rise to this antioxidant’s local importance.
In an aged animal model, dietary supplementation with CoQ10 was shown to significantly increase the number of ovulated eggs, while other mitochondrial nutrients (lipoic acid and resveratrol) were not observed to have such an effect.[61] In further studies of female mice with compromised antioxidant defense pathways, supplementation with CoQ10 was also shown to greatly ameliorate the related decline in fertility.[62] In cellular studies, CoQ10 has also specifically been shown to help protect germ cells (a precursor to gametes) against damage due to exposure to BPA.[63]
Clinical studies with CoQ10 have also shown promising results. In one of these studies, women under the age of 35 shown to have diminished ovarian reserve were randomized to receive placebo or 200 mg of CoQ10 three times daily for 60 days prior to IVF-ET treatment.[64] In women taking CoQ10, significant improvements were seen in the number of retrieved oocytes, the quality of embryos, and the fertilization rate. While the ET procedure was canceled due to poor quality in 22.89% of women receiving the placebo, it was only canceled in 8.33% of those taking CoQ10. Clinical pregnancy and live birth rates after ET both tended to be higher in women given CoQ10, but the difference was not significant.
Lower rates of aneuploidy (an abnormal chromosome number, which may be incompatible with life or lead to genetic disorders) have also been seen with daily supplementation of 600 mg of CoQ10 in women undergoing IVF procedures;[65] however, due to concerns of safety with the evaluation aspect of this study design, it was terminated prior to obtaining adequate data for this improvement to reach statistical significance.
CoQ10 has also been shown to improve multiple aspects of fertility in women with PCOS, a condition associated with anovulation and fertility struggles. Treatment with clomiphene citrate is the first-line therapy to induce ovulation in these women; however, it often remains unsuccessful, leading to studies of numerous nutraceuticals and pharmaceuticals as adjunctive therapies to improve outcomes. With PCOS, N-acetylcysteine may also be of benefit, and it has been the topic of multiple studies for the fertility and metabolic challenges this population faces.[66],[67]
In a study of women with PCOS for whom treatment with clomiphene citrate was unsuccessful for multiple menstrual cycles, CoQ10 was considered as an adjunctive therapy. Women were randomized to receive clomiphene citrate alone, or with the addition of CoQ10 at a dose of only 60 mg three times daily from the beginning of their cycle to ovulation induction.[68] The impact CoQ10 had on fertility was quite profound: there was a significant increase in number of larger mature follicles, endometrial thickness, ovulation rate (65.9 versus 15.5%), and clinical pregnancy rate (37.3 versus only 6%).
Clearly, the positive findings of the clinical and preclinical studies suggest CoQ10 may be of great benefit for women with diminished fertility due to a variety of causes, including the general decline with aging. However, an important point was brought up in a comprehensive review of the studies considering the impact CoQ10 has on reproductive aging.[69] The point made was that many of the anti-aging fertility benefits seen in mouse models are with dietary supplementation of CoQ10 for a period that would be equivalent to a decade in human years, suggesting this antioxidant should be part of the daily protocol for any woman who wishes to consider childbirth in her later years.
In infertile men, CoQ10 has been extensively studied, primarily with regards to sperm counts and motility. CoQ10 also helps protect the cellular lipid membranes of sperm against oxidative stress, keeping them viable through the many stages of their journey to successful fertilization.[70]
Sperm must swim long distances through viscous fluids of the female reproductive tract, and upon reaching the egg, encounter oxidative stress in the transition to a hyperactivated sperm and the process of fusing with the egg.[71] Although the seminal plasma serves as a pH and general buffer for the dissimilar fluids of the vaginal tract,[72] the journey still poses challenges. Excessive lipid peroxidation of spermatozoa cellular membranes can be a factor in infertility and make sperm less likely to achieve the mission at hand, giving rise to the importance of fat-soluble antioxidants like CoQ10.[73]
Although oxidative stress is necessary and important for the final stages of fertilization, when it is out of balance with protective antioxidant factors, infertility can result.[74] Crucially important for sperm motility and successful fertilization is mitochondrial function and energy production.[75] Mitochondrial function also plays a major role in sperm penetration ability,[76] a male fertility factor that will not be identified with standard sperm count assessments.[77]
Semen CoQ10 concentrations have been shown to be significantly correlated with sperm numbers and motility.[78],[79] When lackluster human sperm are bathed in a CoQ10-enriched medium, their swimming ability has been shown to improve.[80],[81] Similar results have also been seen in otherwise healthy men with infertility due to decreased sperm counts and motility.[82] In this population, supplementation of 150 mg of CoQ10 for six months significantly increased total sperm counts by 53%, sperm motility by 26%, and quantity of rapidly motile sperm by 41%. In another study of a similar population of men, CoQ10 supplementation at 200 or 400 mg per day for three months was shown to improve sperm concentration and motility, with slightly greater improvements at the higher dose.[83]
These studies are not the only ones. A 2013 systemic review and meta-analysis of three randomized, double-blind, placebo-controlled trials found that supplementation of 200 to 300 mg of CoQ10/day for 12 to 26 weeks significantly increased sperm concentration and motility, along with an increase in seminal CoQ10 levels. Additional clinical trials subsequent to the 2013 review also found that supplemental CoQ10 (200 to 600 mg daily for three to six months) increased semen CoQ10 levels and improved sperm quality.[84],[85] Perhaps the most important finding from the study in which CoQ10 was taken at 600 mg a day was that 34% of the men (who all previously had a history of two years of failed attempts at conception) achieved successful pregnancy with their partners after a mean of 8.4 months.[85]
While not discussed at length here, vitamins A, C, and E; lycopene; quercetin; and glutathione are additional antioxidants that have data from cellular and animal models showing that they may help protect against the detrimental effects environmental toxins have on reproductive health.[86] Molecular hydrogen[CD2] is at an early stage in its research, and also shows promise for enhancing fertility via reduction of oxidative damage due to a variety of external and internal causes.[87],[88],[89],[90]
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[CD1]Link to article about vitamins/minerals and reproductive health
[CD2]Insert link to Molecular Hydrogen resource center
