A Look at the Research Behind Selenium, Zinc, Folate and Vitamin B12 as They Pertain to Reproductive Health.
The age at which we elect to reproduce has been on the rise for some time. Both men and women are putting parenthood secondary to pursuing a variety of things, including one’s career, financial security, travel and global exploration, and, in general, the search for a purposeful mission in life.
Although we often don’t notice particularly gradual shifts with time, when we take a step back and look at what things were like when we were born and compare them to more recent times, the difference is striking. In 1990 there were approximately five births per 1,000 women between the ages of 40 and 44; by 2014, this number had more than doubled.[1] Over the same period, the birth rate also nearly doubled in women age 35 to 39, rising from around 30 to more than 50 per 1,000 women. And the numbers continue to rise: between 2013 and 2014 alone, the birth rate in women age 40 to 44 increased by 2%, while over the same period there was a 3% increase in births to women age 30 to 39.
Similar numbers are seen in men. Between 1980 and 2014, the birth rate in men between ages 25 and 29 declined by 27%, while over the same period, birth rates rose in each older segment of male age groups. In men age 30 to 34, there was a 15% increase, while in the older age groups there was a particularly dramatic rise: in men 35 to 39, 40 to 44, and 45 to 49 years of age, birth rates increased by 61%, 63%, and 52%, respectively.[2]
In females, fertility begins to decline even before 30, and accelerates after 35.[3] This rapid decline is largely due to the lack of viability of a women’s own oocytes, as we still see a fairly high rate of success until the later 40s with implantation of embryos from donor eggs.[4] The increasing age at which women seek to give birth has led to a considerable reliance on medicine for reproductive assistance in developed nations: in 2005, approximately 1% of U.S. births were conceived using assisted reproductive technology, and by 2012, the number had increased to 1.5%.[4],[5]
Up to 50% of the infertility struggles couples face is attributable to male factors,[6] mainly related to spermatogenesis. In men, the impact of age on fertility is not nearly as dramatic, but it still takes its toll. The decline in male fertility is associated with a variety of semen parameters including sperm count, morphology, and motility, with pregnancy outcomes being associated with sperm genetic and epigenetic defects, which are also increasingly prevalent with age.[7],[8] A study comparing men of age 30 with 50-year-old men found that in the older men, there is up to a 22% decrease in semen volume, and up to 37% and 18% decreases in sperm motility and percentage of normal sperm, respectively.[2]
The impact of these male factors on pregnancy rates is a bit more difficult to come by, as with couples, there also is the female age factor. In one retrospective study, the effect of male partner age was shown to be negligible with female partners younger than age 34, but with female partners age 35 to 39, delayed conception was more than twice as likely with men older than 40 compared to the younger men.[9] In a different study, a much more dramatic effect was seen. This study looked at the time to pregnancy in couples, comparing couples with an older male (>40 years of age) and young female (<25 years of age) with a couple having two young partners (<25 years of age).[10] In couples having the older male partner, the time to pregnancy was four-fold greater than in couples in which both partners were young.
Given these figures, and the difficulties that many experience with fertility, there has been substantial clinical research with nutritional therapies for the various subcategories of infertility challenges. Herein, we look at the research behind selenium, zinc, and the B vitamins folate and B12, while in other articles the studies considering the antioxidants CoQ10 and melatonin and the impact of DHEA on female fertility are discussed.
Although all of the essential vitamins and minerals are, by their very essence, necessary for human life and reproduction, particular nutrients rise to the top of the list when we specifically direct our focus at reproductive health.
Selenium and Reproductive Health
In the human body, selenium is necessary for the normal function of 25 different selenium-containing proteins, known as selenoproteins.[11] A large portion of these selenoproteins are enzymes that catalyze redox reactions, helping our bodies to maintain antioxidant/oxidant homeostasis. Selenium is necessary for the body to facilitate the many redox reactions involving glutathione, our main water-soluble antioxidant.[12] Selenium and its redox enzymes have been shown to play an important role in the health and development of both female and male gametes.[13],[14]
Many of the selenium-dependent enzymes have an impact on thyroid function, which is one reason why it is so important for female conception.[15],[16] Selenium also plays an important role in immune function. Where fertility is concerned, the data behind selenium is significant for the role it plays in regulating the immune response; that is, its action of putting a “damper” on autoimmunity.[17] Thyroid autoimmunity is an increasingly common problem and has been shown in numerous studies to increase the likelihood of miscarriage two- to three-fold.[18]
In women suffering from recurrent miscarriages (not known to have thyroid autoimmunity), significantly lower levels of selenium have been shown compared to a population of women who had healthy pregnancies.[19] Lower levels of selenium have also been shown in the follicular fluid obtained from women with idiopathic infertility, as compared to those for whom tubal issues or male factors were deemed to be the cause of infertility.[20] Similarly, selenium levels have also been shown to be lower in infertile women with endometriosis or polycystic ovarian syndrome (PCOS) than control women, both of these being additional female populations in which fertility is known to be compromised.[21],[22]
Multiple clinical studies have shown that selenium supplementation reduces the thyroid autoimmune response.[23],[24] Selenium has been shown clinically to improve thyroid function post-pregnancy in women with thyroid autoimmunity, significantly reducing the occurrence of both hypothyroidism and postpartum thyroiditis.[25],[26] Although there have not been studies looking at selenium as a monotherapy in women as an adjunctive to reproductive assistance, positive outcomes with multinutrient combinations including selenium have been seen.[27],[28] The dose of selenium used in the clinical studies with positive findings varied, but was generally 200 mcg a day or less.
Although we most often see thyroid autoimmunity in women, selenium also has been shown to have a positive impact on male fertility, likely due to its antioxidant effects. That said, excessive amounts of selenium have been shown to have detrimental effects on multiple markers of sperm health in animal studies, pointing toward an important balance between nutritional adequacy and excess that must be maintained.[29]
One multi-arm study considered three different interventions versus placebo for the treatment of male factor infertility due to various spermatogenesis defects. The four different arms were given selenium at 200 mcg/day (form unspecified), N-acetylcysteine (NAC) at 600 mg/day, the combination of selenium and NAC, or placebo.[30] (NAC is another antioxidant that is also important for glutathione formation.) All semen parameters were shown to be significantly improved with the interventions, with the combination having additive effects. A positive correlation was seen between multiple markers of sperm health and seminal plasma concentration of selenium and NAC, with their sum being significantly associated with sperm concentration, motility, and percent normal morphology.
A systemic review and meta-analysis broadly considering single and combination nutrient therapies as well as dietary enhancement found an overall positive association between increased selenium intake and multiple male fertility parameters.[31] Improvements were seen in sperm concentration, motility, and morphology with selenium use. However, the authors caution against the heterogeneity of data in the included trials because doses, intervention periods, and other parameters were quite variable. Similar to the animal models in which adverse effects were seen with higher selenium intake, a human study looking at variable selenium doses for a prolonged period found that at 297 mcg/day (from dietary intake) a decrease in sperm motility was seen.[32] A recent systemic review concludes: “Assessment of serum Se [selenium] levels followed by low-dose replacement therapy when necessary is a reasonable approach to improve male idiopathic infertility and gestational outcome,” appropriately summing up a pragmatic approach to applying the slightly mixed findings as we await more conclusive data.[33]
Zinc and Reproductive Health
Zinc is another mineral worth mention in a discussion of fertility, at least where male health is concerned.[34] Zinc also has antioxidant and immune-modulating effects,[35],[36] much like selenium. Zinc deficiency contributes to lower levels of testosterone and decreased sperm counts.[37],[38] Studies suggest up to 13% of the population of North America and Europe is at risk for low zinc intake, with nearly half of the world’s population being at risk.[39] Deficiency is more likely with digestive disease and increasing age,[40],[41] making it a factor that should be considered with age-related infertility.
Comparisons between fertile and infertile men have shown significantly higher seminal levels of zinc in the fertile men.[42] Additionally, zinc levels significantly correlated with sperm count and normal sperm morphology. A 2016 systemic review and meta-analysis of 20 studies, including 2,600 infertile men and 876 controls, strongly reinforces this relationship, also finding that seminal plasma zinc concentrations were significantly lower in infertile men than in normal controls.[43] Moreover, it was shown from assessment of the six studies that included zinc as a treatment that supplementation significantly increased semen volume, sperm motility, and the percentage of sperm having normal morphology.
Although seminal plasma zinc levels are assessed via a more unique specialty lab test, a blood draw will also give indication of zinc levels. Zinc is highly concentrated in the seminal plasma (about 30 times greater than blood levels[44]); however, seminal plasma zinc concentration is proportionate to that of the blood.[45] With zinc, similar to selenium, a proper balance is important because excess zinc can have oxidative effects.[46]
Folate, B12 and Reproductive Health
Another factor that comes up in discussions of fertility is the folate cycle and factors that affect it. Folate is essential for cellular replication and embryo development, and adequate amounts during pregnancy are necessary to prevent neural tube and other congenital defects.[47],[48] As a nutrient, folate is often found in supplements and used for food fortification in its most economical form: folic acid. In the body, folic acid is converted through a process of reactions to its active form, known as 5-methyltetrahydrofolate (5-MTHF), which is needed for metabolism of homocysteine. Adequate amounts of folic acid and vitamin B12 are necessary for proper homocysteine metabolism, while other nutrients also play a role.[49] Excess homocysteine can be damaging, contributing to inflammation and adversely impacting endothelial vasodilation, predisposing one to numerous diseases.[50]
Altered folate and homocysteine metabolism are factors that may contribute to suboptimal fertility in both females and males.[51] Certain genetic variants of the enzymes involved in these processes may be a contributing factor. In men and women, genes associated with folate, B12, and choline metabolism and methylation may play a role in infertility and abnormal fetal development.[52],[53],[54],[55] When coupled with suboptimal intake of folate and the other B vitamins, the impact is more significant.
In a population of 269 women undergoing in vitro fertilization (IVF) procedures, it was shown that although homocysteine levels were deemed to be appropriate in 69% of the population (<10.43 µmol/L), only 44% of women had adequate levels of B12 (>474 pg/mL) and a mere 12% had adequate red blood cell levels of folate (>400 ng/mL) to prevent neural tube defects.[56] Of the entire group, 125 women reported taking folate as a supplement for an extended period—and of this subpopulation, still, only about 25% of women were found to have adequate levels of folate.
Another study of women undergoing IVF looked a bit more closely at whether supplementation with the recommended amount of folate (400 µg/day) was adequate to achieve folate sufficiency. Although about 75% of the women were taking in the recommended amount of folate for at least three months, only 61% of women were found to have optimal levels.[57]
In male non-supplement users, significantly lower levels of folate have also been shown in infertile men compared to fertile controls.53 As an intervention in men with suboptimal fertility, folate supplementation has been observed to increase sperm concentration, and when given in combination with zinc, additional positive effects have been seen.[58]
A comprehensive 2014 review on the matter suggests increasing the guidelines for folic acid supplementation in pregnancy to 800 µg/day to overcome hindrances in folate metabolism due to genetic variants;[59] supplementation of folate in its active form, 5-MTHF, may also circumvent the issue. Folate inadequacy may be a factor that renders one more susceptible to the adverse effects of bisphenol A exposure,[60] a factor in both male and female fertility.[61]
The stresses of infertility are immense and contribute not only to personal mental health issues surrounding self-worth, but also affect interpersonal relationship issues with partners, family, and even friends. Although our modern era offers numerous medical tools that we can turn to for treatment of infertility, it is important to remember these nutritional basics.
Carrie Decker, ND, graduated with honors from the National University of Natural Medicine in Portland, OR. Prior to becoming a naturopathic physician, Dr. Decker was an engineer and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign, respectively. She continues to enjoy academic research and writing and uses these skills to support integrative medicine education as a writer and contributor to various resources.
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