FACTS Series: Male Fertility
June 7, 2021
Folic Acid, Zinc, and Male Fertility: A Research Review
By Victoria Anderson
Editor’s Note: In 2021, the third week of June is set aside to celebrate Men’s Health Week. Beyond that week, FACTS will raise awareness all month about the importance of male fertility. The series begins with a review of research[i] published in JAMA in 2020 by Schisterman et al titled, “Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial.” Although zinc and folate are used commonly as supplements in the setting of male infertility, this research analyzes the data to determine whether science supports their use.
The use of supplemental vitamins is common among men trying to conceive. Most of the supplements marketed for this purpose contain folic acid and zinc based on limited evidence suggesting they may improve sperm quality. Zinc is essential for the function of receptors and enzymes involved in the process of spermatogenesis. It is found in high concentrations in seminal fluid, where it is thought to protect sperm from oxidative damage. Zinc is also necessary for the bioavailability of folate, which also plays a role in spermatogenesis by supporting processes such as DNA synthesis and methylation.
A meta-analysis[ii] of the available evidence published in 2017 showed some improvement in sperm concentration, morphology, and motility with folic acid and zinc supplementation, but concluded that large-scale trials would be necessary to confirm these findings. Furthermore, the more relevant question of whether this supplementation could have any meaningful impact on live-birth rates had yet to be answered. The 2020 randomized clinical trial by Schisterman et al summarized below—the “Folic Acid and Zinc Supplementation Trial” (FAZST)—sought to determine the effect of folic acid and zinc supplementation in men on semen quality and live birth among couples undergoing treatment for infertility.
FAZST was a multicenter trial that was double-blinded, block-randomized, and placebo-controlled. Participants in the study were the male partners in couples planning infertility treatment, and were enrolled at four reproductive endocrinology and infertility care centers located in the United States. Participants were recruited between June 2013 and December 2017. Eligible participants were randomized by study center and planned infertility treatment strategy in a 1:1 ratio to receive folic acid and zinc supplementation or placebo. There were 1,185 men assigned to each group—the experimental and control groups—and all were included in the primary analysis (live birth). For sperm analysis, 793 men were in the experimental group and 834 in the control group, with the rest having insufficient or no samples collected.
Men included in the study received 5mg of folic acid and 30mg of elemental zinc or placebo for 6 months. They received the intervention for a minimum of 4.5-6 weeks before the ovulatory phase of the first infertility treatment cycle. They completed in-person study visits including semen collection at baseline and at 2, 4, and 6 months. Female partners of participants were followed through medical record review and monthly questionnaires about infertility treatment, pregnancy status, and pregnancy outcomes. Live births were determined by abstraction from the medical record.
Semen quality parameters assessed included quantification of sperm concentration, motility, morphology, volume, DNA fragmentation index, and total motile sperm count. The study was powered to detect a 7% difference in live births, which is consistent with other trials assessing pharmacological agents in couples undergoing infertility treatment.
Male participants had a mean age of 32.5 in the folic acid and zinc supplementation group and 32.7 in the control group. Participants were 82% white in both groups and 73% were employed full time, with no noticeable differences in race/ethnicity, education or employment status between the two groups. Twenty-one percent of men in both groups had a male factor infertility diagnosis.
The primary outcome of live birth did not differ significantly between the zinc and folic acid group and the control group, and did not vary by infertility treatment approach (in vitro fertilization or other treatment, onsite or offsite). There was no significant difference between the two groups in terms of semen quality parameters, including sperm concentration, motility, morphology, volume, and total motile sperm count.
The folic acid and zinc supplementation group had a statistically significant increase in preterm birth (6% vs. 4% in the control group), but no other pregnancy complications or outcomes differed between the two groups. In the supplementation group, 32% of patients had adverse events, compared to 27% in the placebo group, mostly relating to gastrointestinal complaints and erythema. There were 12 serious adverse events among both groups, all of them determined to be unrelated to the interventions.
This large prospective trial was the first to assess whether folic acid and zinc supplementation in men improves sperm quality or live-birth rates, and the strong study design is more promising than previous retrospective studies to provide an answer to this question. In this study, the use of folic acid and zinc supplementation in men did not improve sperm quality or live-birth rates among couples undergoing treatment for infertility.
Additionally, supplementation resulted in mild adverse effects in some patients. The trial also found a statistically significant 1.9% greater risk of preterm birth in the supplementation group, but mean gestational ages and birth weights were not significantly different. While this finding could indicate a difference in placental function based on paternal factors, it could also be a chance finding, and verification is needed. The study authors caution that due to the potential for type I statistical error, these positive findings should be interpreted as exploratory rather than definitive.
Given that specific subgroups were not analyzed in this clinical trial, it is possible that certain men may benefit from folic acid and zinc supplementation. One small study[iii] showed that men with a certain polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene were unable to experience improvement in sperm concentration with folic acid and zinc supplementation, while men without said polymorphism did show significant improvement in sperm concentration. Additionally, while this study is generalizable to the general infertility clinic population, it is likely not representative of all couples struggling with infertility. Most patients were white, non-Hispanic, and of high socioeconomic status. Further study will be necessary to be able to generalize the results to a more racially, ethnically, and socioeconomically diverse population, and to clarify whether any specific groups may benefit from folic acid and zinc supplementation.
In conclusion, the study findings do not support the use of folic acid and zinc supplementation in men to increase sperm quality or live-birth rates in couples seeking treatment for infertility.
[i] Schisterman EF, Sjaarda LA, Clemons T, et al. Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial. JAMA. 2020;323(1):35–48. doi:10.1001/jama.2019.18714.
[ii] Irani M, Amirian M, Sadeghi R, Lez JL, Latifnejad Roudsari R. 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; 14(5):4069-4078.
[iii] Ebisch IM, van Heerde WL, Thomas CM, van der Put N, Wong WY, Steegers-Theunissen RP. C677Tmethylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration. Fertil Steril. 2003;80(5):1190-1194. doi:10.1016/S0015-0282(03)02157-5.
About the Author
Victoria Anderson is a fourth-year medical student at Vanderbilt University School of Medicine in Nashville, TN. She plans to pursue a career in family medicine. In her future practice, she hopes to help women and couples to understand their bodies and achieve their reproductive goals with fertility awareness. She is a FACTS Student Ambassador and is grateful for the opportunity to learn more about fertility during the FACTS elective.
The FACTS CME Course
The FACTS 4-part CME Course – Fertility Awareness Based Methods (FABMs) for Family Planning and Restorative Reproductive Women’s Healthcare prepares you as a medical professional to present more comprehensive options for family planning and women’s health monitoring and management of a range of reproductive health concerns. Through online lectures, live case study discussions, and readings, this course will explore the broad applications of modern Fertility Awareness-Based Methods (FABMs) and their role in pregnancy prevention, infertility, and women’s health.
The course is divided into four parts; you may elect to do any or all of them and they may be completed in any order. Each part is worth up to 14 AAFP-approved CME credits.
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