1. Effects of Folic Acid and Zinc Supplementation on Semen Quality
and Conception
Fredrick Blaisdell1, Denise Lamb, R.N.2, Erica B. Johnstone, M.D.2, C. Matthew Peterson, M.D.2
1Biological Sciences, Cornell University, Ithaca, NY, United States
2Division of Reproductive Endocrinology and Fertility, University of Utah, Salt Lake City, UT
Contact information: Fredrick Blaisdell Email: fbb27@cornell.edu
This research experience was funded and supported by the Native American
Research Internship, University of Utah Department of Pediatrics, and the
Obstetrics and Gynecology Research Network. Thank you to the FAZST staff for a
fantastic summer and for your mentorship, kindness, and patience.
#lifeintheFAZSTlane
ACKNOWLEDGMENTS
INTRODUCTION
The objective of this study is to evaluate the effects of folic acid and zinc directly
on male sperm parameters, and indirectly on fertility and pregnancy outcomes in
couples actively trying to conceive.
• Approximately 10-15% of couples of childbearing age in the United States are
considered infertile, defined as experiencing one year of unprotected intercourse
without conception (Evenson et al1).
• As many as 20-25% of couples attempting pregnancy are successful per cycle
while infertile couples are much lower at a rate of < 6% per cycle
• Many studies focus on female components of fertilization, but few have
investigated male components
• Many factors affect male fertility including sperm motility, morphology
concentration and DNA integrity
• Assisted Reproductive Technology may be effective, however it is expensive:
• Folate supplies essential methyl groups for DNA methylation (Wagner3, 1995) and
pyrimidine production (Brody4, 1999).
• Zinc is an essential co-factor for DNA maintaining enzymes (Hamdi et al 5) and
proper folate utilization (Tamura et al 6)
• Recent studies suggest folic acid and zinc as an effective, inexpensive intervention
to improve sperm concentration and count in sub-fertile men2
Figure 1. Wang et al 2 demonstrated significantly improved sperm concentrations from 7.5
to 12 million cells per mL in sub-fertile Netherlandish men.
• The Folic Acid and Zinc Supplementation Trial (FAZST) is the largest study of male
fertility to date
REFERENCES
1) Evenson, DP. et al. (2002). Sperm chromatin structure assay: it's clinical use for detecting sperm DNA
fragmentation in male infertility and comparisons with other techniques. Journal of Andrology, 23(1), 25-43.
2) Wu, AK., et al. (2014). Out-of-pocket fertility patient expense: Data from a multicenter prospective infertility
cohort. Journal of Andrology, 191, 427-432.
3) Wagner, C. (1995). Biochemical role of folate in cellular metabolism. . In L. B. Bailey (Ed.), Folate in Health and
Disease (pp. 23-42). New York: Marcel Dekker
4) Brody, T. (1999). Folate in Nutritional Biochemistry. San Diego: Academic Press
5) Hamdi, SA., et al. (1997). Effect of marginal or severe dietary zinc deficiency on testicular development and
functions of the rat. Archives of Andrology, 38(3), 243-253.
6) Tamura, T., et al. (1987). Increased methionine synthase activity in zinc-deficient rat liver. Archives of
Biochemistry and Biophysics, 256(1), 311-316.
Overview of visit procedures: Male participants are followed for 6 months
where samples are taken and questionnaires given every 2 months in addition to
daily questionnaires.
• Semen samples will be analyzed using World Health Organization semen
analysis procedures 5th edition guidelines for volume, concentration,
total sperm count, total motile count, percent motility, percent forward
motility, percent normal morphology, and sperm DNA integrity
• To date, 1600 couples are enrolled
• Anticipated completion date: April 2018
STUDY DESIGN
BL
•Male and Female in clinic, Male randomized to treatment
•Blood, Urine, Saliva, Semen analysis (SA), Pregnancy test, questionnaires
V2
•Male in clinic,
•Blood, urine, saliva, SA, questionnaires
V3
•Male in clinic, Blood, urine, saliva, SA, questionnaires, toenails
V4
•Male in clinic
•Blood, urine, saliva, SA, safety questionnaire
OBJECTIVE
Mean $ Out of Pocket Price (IQR) Over 18 Month Observation
Non-cycle Based Treatment
Medication
Only IUI IVF
Costs:
Office based∗ 381 (191–864) 616 (343–2,276) 1,683 (735–3,474) 13,502 (3,675–20,318)
Medication† 12 (0–64) 94 (25–242) 141 (45–1,021) 2,136 (329–4939)
Miscellaneous‡ 73 (0–247) 55 (21–315) 263 (60–624) 412 (55–1,290)
Overall couple expense 595 (306–1,573) 912 (394–3,124) 2623 (1,373–5,107) 19,234 (7,134–29,308)
∗ Includes copayments, laboratory tests, procedures, radiology fees, etc.
† Including ovulation induction for female partner.
‡ Including travel expenses, parking, food, etc.
• Double blind, randomized clinical trial
• N= 2400 couples
• Enrollment Locations:
• Male participants are randomized to take 5 mg folic acid and 30 mg elemental
zinc or matching placebo daily for 6 months
 Salt Lake City, UT
 South Jordan, UT
 Orem, UT
 Iowa City, IA
 Chicago, IL
 Minneapolis, MN*
*No longer enrolling
ELIGIBILITY CRITERIA
Males Females
 Age ≥18 years
 No history of poorly controlled chronic diseases, or
genetic cause of infertility
 No history of, anemia, B12 deficiency or vasectomy
without reversal, or obstructive azoospermia
 Consume non-vegan diet
 Abstaining from use of testosterone, or supplements
containing folic acid or zinc
 Age 18-45 years
• Heterosexual couples in committed relationships attempting to conceive:
Table 1. Patient ART Out of Pocket Costs from an 18 Month Study (Wu et al 2).