Nutritional Factors in Female Fertility, Part 2 of 2

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Antioxidants and 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]} They 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 (POPs). Pollutants such as these also don’t remain in one place – they are cycled in our environment and distribute globally.^[9],[10]

The best way to address extensive exposure to environmental toxins is to work with a healthcare practitioner who is familiar with protocols to facilitate their removal prior to attempts at conception.

Environmental toxicants not only impact our longevity and risk for chronic disease,^{[11],[12],[13]} they also gravely affect reproductive health.^[14] Our exposure to toxic pollutants is not only a reproductive factor in our older years, it has an impact when we are young as well.^[15],[16] Because females have a limited number 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.^[17]

The two key ways in which environmental toxins adversely affect our health is by their endocrine effects and the oxidative damage they cause. Although the best way to address extensive exposure to toxins such as these is to work with a healthcare practitioner who is familiar with protocols to facilitate their removal prior to attempts at conception, support with antioxidant therapies also can be of help for many. Herein, we take a look at the evidence behind melatonin and CoQ10 as antioxidants that support female reproductive health.

Melatonin

Multiple studies suggest melatonin has positive effects on oocyte quality and fertilization rates, as well as the common female conditions of endometriosis and polycystic ovarian syndrome.

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 effects of melatonin,^[18] which also may give rise to its positive effects on both female and male fertility.^[19],[20]

The study of melatonin’s impact on female fertility largely grew out of research in the late 80’s which found that high levels of melatonin exist in female preovulatory follicular fluid – approximately 3.5 times higher than the corresponding serum concentration.^[21] 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.^[20] 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.^[22]

The majority of research concerning melatonin for female fertility is in women undergoing 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.^[23] 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.^[24] Multiple additional human studies also point to positive effects on oocyte quality and fertilization rates.^{[25],[26],[27],[28]}

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, polycystic ovarian syndrome, and immune, chemotherapy, or radiation-induced primary ovarian insufficiency,^[29] as well as the normal fertility decline with aging.^[30],[31]

Evidence also points to melatonin as a supplement that can ameliorate oxidative stress and perhaps improve male fertility in the setting of natural conception as well as IVF procedures.^[32],[33]

CoQ10

Human studies suggest CoQ10 may positively impact outcomes in women with diminished ovarian reserve or polycystic ovarian syndrome who were going through fertility treatments.

In similar ways, CoQ10 also helps protect the gametes of both men and women. Like melatonin, CoQ10 is a fat-soluble antioxidant, and helps protect cellular membranes from oxidative stress. Additionally, CoQ10 is an essential nutrient for mitochondrial energy production – which is important for both male and female reproductive health. Because CoQ10 levels decline with aging, it perhaps is not a surprise that a primary focus of research with this nutrient concerns diseases and conditions associated with aging: cardiovascular and metabolic disease,^[34] neurodegenerative disorders,^[35] sarcopenia and muscle strength,^[36] skin changes such as wrinkles,^[37] and “reproductive aging”, the term used to describe non-specific fertility decline with age.

Alterations in mitochondrial energy production are one factor that contributes to reproductive aging and the decline of viable oocytes with age.^[38] The primary energy-generating pathway in the developing oocyte takes place in the mitochondria and depends on adequate amounts of CoQ10.^[39] 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.^[40]

In studies of female mice with compromised antioxidant defense pathways, supplementation with CoQ10 also helped prevent the related decline in fertility.^[41] In cell studies, CoQ10 has additionally been shown to help protect germ cells (a precursor to gametes) against oxidative damage due to exposure to BPA.^[42]

In women taking CoQ10, significant improvements were seen in the number of retrieved oocytes, the quality of embryos, and the fertilization rate.

Clinical studies with CoQ10 have shown promising results. In one of these studies, women (< 35 years of age) who had diminished ovarian reserve were randomized to receive placebo or 200 mg of CoQ10 three times daily for 60 days prior to IVF-ET treatment.^[43] 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 those given CoQ10, but the difference was not significant compared to placebo.

CoQ10 also has been shown to improve multiple aspects of fertility in women with polycystic ovarian syndrome (PCOS), a condition commonly associated with fertility struggles. Treatment with clomiphene citrate is the first-line therapy to induce ovulation in females with PCOS who are attempting to become pregnant, however, oftentimes, it is unsuccessful.

In women with PCOS for whom treatment with clomiphene citrate was unsuccessful for multiple menstrual cycles, the addition of 60 mg of CoQ10 three times daily (from the beginning of their cycle to ovulation induction) had a significant positive impact on multiple markers of fertility as well as conception.^[44] The women receiving the combination (as compared to clomiphene citrate alone) experienced a significant increase in number of larger mature follicles and endometrial thickness, while 65.9% of them ovulated, compared to only 15.5% taking the medication as a monotherapy. Most remarkable was the increase in clinical pregnancy rate – 37.3% of those receiving both treatments became pregnant while only 6% of those taking clomiphene did.

Clearly, the positive findings of the clinical and preclinical studies suggest CoQ10 may be of great benefit for women with a 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.^[45] 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 later in life.

Fertility challenges can be very difficult for all involved parties. Although our modern era offers numerous medical tools that we can turn to, it is important to remember the nutritional basics. The antioxidant supplements discussed herein, the nutrients discussed in Part 1, and additional supplements that have been researched in the setting of male reproductive health, should offer further hope to the individuals dealing with these challenges.

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