IMPORTANCE Dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality. However, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth.OBJECTIVE To determine the effect of daily folic acid and zinc supplementation on semen quality and live birth. DESIGN, SETTING, AND PARTICIPANTSThe Folic Acid and Zinc Supplementation Trial was a multicenter randomized clinical trial. Couples (n = 2370; men aged Ն18 years and women aged 18-45 years) planning infertility treatment were enrolled at 4 US reproductive endocrinology and infertility care study centers between June 2013 and December 2017. The last 6-month study visit for semen collection occurred during August 2018, with chart abstraction of live birth and pregnancy information completed during April 2019.INTERVENTIONS Men were block randomized by study center and planned infertility treatment (in vitro fertilization, other treatment at a study site, and other treatment at an outside clinic) to receive either 5 mg of folic acid and 30 mg of elemental zinc (n = 1185) or placebo (n = 1185) daily for 6 months. MAIN OUTCOMES AND MEASURESThe co-primary outcomes were live birth (resulting from pregnancies occurring within 9 months of randomization) and semen quality parameters (sperm concentration, motility, morphology, volume, DNA fragmentation, and total motile sperm count) at 6 months after randomization. RESULTS Among 2370 men who were randomized (mean age, 33 years), 1773 (75%) attended the final 6-month study visit. Live birth outcomes were available for all couples, and 1629 men (69%) had semen available for analysis at 6 months after randomization. Live birth was not significantly different between treatment groups (404 [34%] in the folic acid and zinc group and 416 [35%] in the placebo group; risk difference, −0.9% [95% CI, −4.7% to 2.8%]). Most of the semen quality parameters (sperm concentration, motility, morphology, volume, and total motile sperm count) were not significantly different between treatment groups at 6 months after randomization. A statistically significant increase in DNA fragmentation was observed with folic acid and zinc supplementation (mean of 29.7% for percentage of DNA fragmentation in the folic acid and zinc group and 27.2% in the placebo group; mean difference, 2.4% [95% CI, 0.5% to 4.4%]). Gastrointestinal symptoms were more common with folic acid and zinc supplementation compared with placebo (abdominal discomfort or pain: 66 [6%] vs 40 [3%], respectively; nausea: 50 [4%] vs 24 [2%]; and vomiting: 32 [3%] vs 17 [1%]).CONCLUSIONS AND RELEVANCE Among a general population of couples seeking infertility treatment, the use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve semen quality or couples' live birth rates. These findings do not support the use of folic acid and zinc supplementation by male partners in the treatment of infertility.

These findings demonstrate the importance of taking menstrual cycle phase into account when measuring uric acid in premenopausal women, and confirm the hypothesized beneficial lowering effects of endogenous E2 on uric acid levels. These findings suggest that there could be an underlying association affecting both sporadic anovulation and high uric acid levels among young, regularly menstruating women. Further studies are needed to confirm these findings and elucidate the connection between uric acid and reproductive and later cardiovascular health.

Endogenous reproductive hormones and oxidative stress have been independently linked to risk of chronic disease but mostly in postmenopausal women. The interplay between endogenous reproductive hormones and oxidative stress among premenopausal women, however, has yet to be clearly elucidated. The objective of this study was to investigate the association between endogenous reproductive hormones and F(2)-isoprostanes in the BioCycle Study. Women aged 18-44 years from western New York State were followed prospectively for up to 2 menstrual cycles (n = 259) during 2005-2007. Estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, sex hormone-binding globulin, F(2)-isoprostanes, and thiobarbituric acid-reactive substances were measured up to 8 times per cycle at clinic visits timed by using fertility monitors. F(2)-Isoprostane levels had an independent positive association with estradiol (beta = 0.02, 95% confidence interval: 0.01, 0.03) and inverse associations with sex hormone-binding globulin and follicle-stimulating hormone (beta = -0.04, 95% confidence interval: -0.07, -0.003; beta = -0.02, 95% confidence interval: -0.03, -0.002, respectively) after adjustment for age, race, age at menarche, gamma-tocopherol, beta-carotene, total cholesterol, and homocysteine by inverse probability weighting. Thiobarbituric acid-reactive substances, a less specific marker of oxidative stress, had similar associations. If F(2)-isoprostanes are specific markers of oxidative stress, these results call into question the commonly held hypothesis that endogenous estradiol reduces oxidative stress.

An evolving body of evidence supports that cadmium, a non-essential heavy metal, may be associated with multiple adverse women’s reproductive health outcomes. Our objective was to conduct a systematic review of epidemiologic studies that evaluated cadmium exposure and the following reproductive health outcomes: puberty/menarche, fertility, time to pregnancy, pregnancy loss, preeclampsia, endometriosis, uterine leiomyoma, and menopause. Twenty-two studies were identified based upon our search criteria. Available evidence was inadequate to draw meaningful conclusions for most of the reproductive outcomes studied. The strongest evidence was for a possible association between cadmium and preeclampsia, which was limited to cross-sectional studies. Some evidence, although conflicting, was also observed for fertility related outcomes. This lack of evidence underscores the need for additional research on cadmium and women’s reproductive health outcomes.

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