Key Vitamins and Minerals for Reproductive Health

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.

Key Vitamins and Minerals

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.

[1] Hamilton BE, et al. Births: Final Data for 2014. National Vital Statistics Reports. 2015 Dec 23;64(12):1-64. Available from:

[2] Eisenberg ML, Meldrum D. Effects of age on fertility and sexual function. Fertil Steril. 2017 Feb;107(2):301-4.

[3] O’Connor KA, et al. Declining fecundity and ovarian ageing in natural fertility populations. Maturitas. 1998 Oct 12;30(2):127-36.

[4] Wright VC, et al. Assisted reproductive technology surveillance–United States, 2005. MMWR Surveill Summ. 2008 Jun 20;57(5):1-23.

[5] Sunderam S, et al. Assisted Reproductive Technology Surveillance — United States, 2012. MMWR Surveill Summ. 2015 Aug 14;64(6):1-29.

[6] Jung JH, Seo JT. Empirical medical therapy in idiopathic male infertility: promise or panacea? Clin Exp Reprod Med. 2014 Sep; 41(3):108-14.

[7] Belloc S, et al. How to overcome male infertility after 40: Influence of paternal age on fertility. Maturitas. 2014 May;78(1):22-9.

[8] Sharma R, et al. Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring. Reprod Biol Endocrinol. 2015 Apr 19;13:35.

[9] de La Rochebrochard E, Thonneau P. Paternal age >or=40 years: an important risk factor for infertility. Am J Obstet Gynecol. 2003 Oct;189(4):901-5.

[10] Hassan MA, Killick SR. Effect of male age on fertility: evidence for the decline in male fertility with increasing age. Fertil Steril. 2003 Jun;79 Suppl 3:1520-7.

[11] Schweizer U, Fradejas-Villar N. Why 21? The significance of selenoproteins for human health revealed by inborn errors of metabolism. FASEB J. 2016 Nov;30(11):3669-81.

[12] Cohen G, et al. Glutathione peroxidase: the primary agent for the elimination of hydrogen peroxide in erythrocytes. Biochemistry. 1963 Nov-Dec;2:1420-8.

[13] Qazi IH, et al. Selenium, Selenoproteins, and Female Reproduction: A Review. Molecules. 2018 Nov 22;23(12):3053.

[14] Mintziori G, et al. Evidence for a manifold role of selenium in infertility. Hormones (Athens). 2020 Mar;19(1):55-9.

[15] Köhrle J, et al. Selenium and thyroid. Best Pract Res Clin Endocrinol Metab. 2009 Dec;23(6):815-27.

[16] Ruz M, et al. Single and multiple selenium-zinc-iodine deficiencies affect rat thyroid metabolism and ultrastructure. J Nutr. 1999 Jan;129(1):174-80.

[17] Schomburg L. Selenium, selenoproteins and the thyroid gland: interactions in health and disease. Nat Rev Endocrinol. 2012;8(3):160-71.

[18] Prummel MF, Wiersinga WM. Thyroid autoimmunity and miscarriage. Euro J Endocrinology. 2004 Jun 1;150(6):751-6.

[19] Tyagi P, et al. Evaluation of Total Oxidative Stress, Total Antioxidant Capacity Along with Selenium and Vitamin E Level among Saudi Women Experiencing Unexplained Recurrent Miscarriage and Intrauterine Foetal Death. Int J Med Res Prof. 2018 Sept;4(5):148-53. 

[20] Paszkowski T, et al. Selenium dependent glutathione peroxidase activity in human follicular fluid. Clin Chim Acta. 1995 May 15;236(2):173-80.

[21] Singh AK, et al. Markers of oxidative stress in follicular fluid of women with endometriosis and tubal infertility undergoing IVF. Reprod Toxicol. 2013 Dec;42:116-24.

[22] Coskun A, et al. Plasma selenium levels in Turkish women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2013 Jun;168(2):183-6.

[23] Zhu L, et al. [Effects of selenium supplementation on antibodies of autoimmune thyroiditis]. Zhonghua Yi Xue Za Zhi. 2012 Aug 28;92(32):2256-60.

[24] Gärtner R, et al. Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations. J Clin Endocrinol Metab. 2002 Apr;87(4):1687-91.

[25] Negro R, et al. The influence of selenium supplementation on postpartum thyroid status in pregnant women with thyroid peroxidase autoantibodies. J Clin Endocrinol Metab. 2007 Apr;92(4):1263-8.

[26] Mantovani G, et al. Selenium supplementation in the management of thyroid autoimmunity during pregnancy: results of the “SERENA study”, a randomized, double-blind, placebo-controlled trial. Endocrine. 2019 Dec;66(3):542-50.

[27] Luddi A, et al. Antioxidants reduce oxidative stress in follicular fluid of aged women undergoing IVF. Reprod Biol Endocrinol. 2016 Sep 7;14(1):57.

[28] Jiménez Tuñón JM, et al. A Double-blind, randomized prospective study to evaluate the efficacy of previous therapy with melatonin, myo-inositol, folic acid, and selenium in improving the results of an assisted reproductive treatment. Clin Med Insights: Therapeutics. 2017 Nov 24;9:1179559X17742902.

[29] Shalini S, Bansal MP. Dietary selenium deficiency as well as excess supplementation induces multiple defects in mouse epididymal spermatozoa: understanding the role of selenium in male fertility. Int J Androl. 2008 Aug;31(4):438-49.

[30] Safarinejad MR, Safarinejad S. Efficacy of selenium and/or N-acetyl-cysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study. J Urology. 2009 Feb;181(2):741-51.

[31] Salas-Huetos A, et al. The Effect of Nutrients and Dietary Supplements on Sperm Quality Parameters: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Adv Nutr. 2018 Nov 1;9(6):833-48.

[32] Hawkes WC, Turek PJ. Effects of dietary selenium on sperm motility in healthy men. J Androl. 2001 Sep-Oct;22(5):764-72.

[33] Mirone M, et al. Selenium and reproductive function. A systematic review. J Endocrinol Invest. 2013 Nov;36(10 Suppl):28-36.

[34] Fallah A, et al. Zinc is an Essential Element for Male Fertility: A Review of Zn Roles in Men’s Health, Germination, Sperm Quality, and Fertilization. J Reprod Infertil. 2018 Apr-Jun;19(2):69-81.

[35] Powell SR. The antioxidant properties of zinc. J Nutr. 2000 May;130(5S Suppl):1447S-54S.

[36] Bonaventura P, et al. Zinc and its role in immunity and inflammation. Autoimmun Rev. 2015 Apr;14(4):277-85.

[37] Prasad AS, et al. Zinc status and serum testosterone levels of healthy adults. Nutrition. 1996 May;12(5):344-8.

[38] Abbasi AA, et al. Experimental zinc deficiency in man: effect on spermatogenesis. Trans Assoc Am Physicians. 1979;92:292-302.

[39] Brown KH, et al. The importance of zinc in human nutrition and estimation of the global prevalence of zinc deficiency. Food Nutri Bulletin. 2001;22(2):113-25.

[40] El-Tawil AM. Zinc deficiency in men with Crohn’s disease may contribute to poor sperm function and male infertility. Andrologia. 2003 Dec;35(6):337-41.

[41] Blumberg JB, et al. Contribution of dietary supplements to nutritional adequacy in various adult age groups. Nutrients. 2017 Dec 6;9(12):1325.

[42] Colagar AH, et al. Zinc levels in seminal plasma are associated with sperm quality in fertile and infertile men. Nutr Res. 2009 Feb;29(2):82-8.

[43] Zhao J, et al. Zinc levels in seminal plasma and their correlation with male infertility: A systematic review and meta-analysis. Sci Rep. 2016 Mar 2;6:22386.

[44] Xu B, et al. Trace elements in blood and seminal plasma and their relationship to sperm quality. Reprod Toxicol. 1993 Nov-Dec;7(6):613-8.

[45] Ali H, et al. Relationship of zinc concentrations in blood and seminal plasma with various semen parameters in infertile subjects. Pakistan J Med Sci. 2007 Jan 1;23(1):111.

[46] Allouche-Fitoussi D, Breitbart H. The Role of Zinc in Male Fertility. Int J Molec Sci. 2020 Jan;21(20):7796.

[47] Laurence KM, et al. Double-blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural-tube defects. Br Med J (Clin Res Ed). 1981 May 9;282(6275):1509-11.

[48] Christensen B, Rosenblatt DS. Effects of folate deficiency on embryonic development. Baillieres Clin Haematol. 1995 Sep;8(3):617-37.

[49] Allergy Research Group. Homocysteine-Reducing Therapies. FOCUS Newsletter. Spring 2019:4-6.

[50] Allergy Research Group. Homocysteine: Smoke or Fire of Disease Processes? FOCUS Newsletter. Spring 2019:2-3.

[51] Forges T, et al. Impact of folate and homocysteine metabolism on human reproductive health. Hum Reprod Update. 2007 May-Jun;13(3):225-38.

[52] Altmäe S, et al. Variations in folate pathway genes are associated with unexplained female infertility. Fertil Steril. 2010 Jun;94(1):130-7.

[53] Murphy LE, et al. Folate and vitamin B12 in idiopathic male infertility. Asian J Androl. 2011 Nov;13(6):856-61.

[54] Safarinejad MR, et al. Relationship between genetic polymorphisms of methylenetetrahydrofolate reductase (C677T, A1298C, and G1793A) as risk factors for idiopathic male infertility. Reprod Sci. 2011 Mar;18(3):304-15.

[55] Laanpere M, et al. Folate-mediated one-carbon metabolism and its effect on female fertility and pregnancy viability. Nutr Rev. 2010 Feb;68(2):99-113.

[56] La Vecchia I, et al. Folate, homocysteine and selected vitamins and minerals status in infertile women. Eur J Contracept Reprod Health Care. 2017 Feb;22(1):70-5.

[57] Ponzano A, Tiboni GM. Folate serum levels in Italian women entering an in vitro fertilization program. Gynecol Endocrinol. 2017 Nov;33(11):861-3.

[58] Irani M, et al. The Effect of Folate and Folate Plus Zinc Supplementation on Endocrine Parameters and Sperm Characteristics in Sub-Fertile Men: A Systematic Review and Meta-Analysis. Urol J. 2017 Aug 29;14(5):4069-78.

[59] Thaler CJ. Folate Metabolism and Human Reproduction. Geburtshilfe Frauenheilkd. 2014 Sep;74(9):845-51.

[60] Mínguez-Alarcón L, et al. Dietary folate intake and modification of the association of urinary bisphenol A concentrations with in vitro fertilization outcomes among women from a fertility clinic. Reprod Toxicol. 2016 Oct;65:104-12.

[61] Meli R, et al. Oxidative Stress and BPA Toxicity: An Antioxidant Approach for Male and Female Reproductive Dysfunction. Antioxidants (Basel). 2020 May 10;9(5):405.