Micronutrient (Zinc and Selenium) supplements and subfertility

THE FERTILITY SOCIETY OF AUSTRALIA - Pre-Conception Health Special Interest Group

Micronutrient (Zinc and Selenium)
supplements and subfertility
Recent systematic reviews of the effects of micronutrients on male fertility have identified clear positive effects on basic sperm characteristics [1-3]. The vast majority of studies
reviewed found that micronutrients, particularly those that are antioxidants or aid their
function, significantly reduce sperm oxidative stress or DNA damage in subfertile males
but greater evidence is required to clearly state whether these improvements translate
to improved fertility [1-3]. Despite clinical trials and systematic reviews having been
undertaken in males, very few, if any, clinical studies have thoroughly investigated the
effects of micronutrient supplementation on female fertility. There is also a paucity of
research investigating the role of micronutrients in women who are undergoing infertility
treatment. Several recent reviews, based mainly on observational studies, have however
identified that micronutrient concentrations in the peri-conception period influence female
fertility and embryogenesis, and may prevent adverse pregnancy outcomes [4-6]. The possible
effects on subfertility of two micronutrients (Zinc and Selenium), components of antioxidant
enzymes which are commonly included in oral supplements, are discussed here.

Zinc (Zn) - The recommended daily intake of Zn for an average weight
female (61kg) and male (76kg) living in Australia and New Zealand is
8mg/day and 14mg/day respectively, with a recommended maximum
intake for both sexes of 40mg/day [7]. These recommendations account
for losses through menstruation in women and ejaculation in males;
especially as semen has a high Zn concentration.
Effects on male subfertility - Zn concentration in seminal plasma is known
to correlate with sperm count, motility and viability, although studies report
conflicting findings about the magnitude of these correlations [8-10] and
whether concentrations are higher or lower in subfertile compared to fertile
men; probably explained by between-study differences in inclusion criteria.
Although the underlying mechanisms by which Zn affects spermatogenesis
remain unknown, the positive effects of Zn on sperm count and
parameters (morphology and motility) are documented [11-16]. Recently,
the ability of Zn to reduce oxidative stress in sperm was also identified
[16], although this was negatively associated with sperm decondensation
[17]. Even when Zn supplementation far exceeds the recommended daily
intake, a concurrent increase in circulating or local concentrations of Zn
or FSH and testosterone are not always evident; possibly explained by the
absence of Zn deficiency or high excretion by the prostate [14]. Unfortunately
to date, no studies have measured secondary outcomes, so the effect of Zn
on fertility remains unknown in both fertile and subfertile populations.
Effects on female subfertility - Serum Zn concentrations are almost twice
as high as follicular concentrations, although the high expression of Zn
transport genes in the oocyte suggests active Zn transport during the first
stages of pre-implantation development [18]. Similar to studies on males,
studies report conflicting findings as to whether differences exist in serum
Zn concentrations between infertile and fertile women [19, 20]. Lower
follicular fluid and serum Zn and selenium levels were found in IVF
patients than in fertile women [19], with normalisation to those of fertile
women following multivitamin supplementation [19], although the effect
on pregnancy rate was not investigated.
Selenium (Se) - The recommended daily intake of Se for an average
weight female (61kg) and male (76kg) living in Australia and New
Zealand is 60μg/day and 70μg/day respectively, with a recommended
maximum intake for both sexes of 400μg/day [7].
Effects on male subfertility - Only one double-blind, placebo controlled,
randomised clinical trial has investigated the effects of Se supplementation
(200μg/day orally) on sperm characteristics of subfertile men [21]. None
of these men were deficient in Se but after 26 weeks of Se supplementation
the mean total sperm count, concentration, normal morphology percentage
and motility increased from baseline relative to placebo treatment [21].
These improvements were coupled with changes in hormone concentrations,
although all parameters returned to baseline after supplementation ceased.
What is not known is whether the beneficial effects on semen parameters
were accompanied by improved fertility, as pregnancy rates were not
determined. In a contrasting study, higher Se supplementation (300μg/
day orally) increased serum and seminal plasma Se concentrations but did
not affect sperm Se, serum androgen concentrations or sperm parameters
[22]. The lack of an increase in sperm Se suggests that testicular Se stores
are unresponsive to dietary Se concentrations [22]. In fact, excessive
(>400μg/day) dietary Se can reduce motile spermatozoa in fertile men
[23]. Thus, oral Se supplementation appears to be beneficial at 200μg/
day [21] but not at 300μg/day [22] or above [23] in improving sperm
characteristics in subfertile males.

Data are available from several studies on the supplementation of Se in
combination with other antioxidants [21,24-27]. Improvements were
evident in sperm motility [21,24,25,27], concentration [21], morphology
[21,27] and pregnancy rate [26,27]. When Se was taken for three months
as part of a combined antioxidant treatment (MenevitTM one daily
dose) no differences were identified in basic sperm parameters (count,
motility, morphology, semen volume) or hormone concentrations relative
to baseline [28], though MenevitTM only contains 26μg of Se per dose;
far below the recommended daily intake. Decreased DNA fragmentation,
apoptosis and reactive oxygen species (ROS) production were however
observed in subfertile men [28], potentially due to other micronutrients
included in the supplement.
Effects on female subfertility - Nearly all published studies in both humans
and animals have focussed only on the potential effects of Se concentrations
during pregnancy and lactation. No studies were found on the effects of
Se, endogenous or supplemented, around the peri-conception period in
fertile or subfertile females. This statement also generally applies to animals
studies, with a few exceptions in sheep, in which Se supplemented females
had higher conception rates than non-treated females [29].
Aside from a few studies, the effects of oral Zn or Se supplementation on
male subfertility has only been investigated in combination with other
micronutrients, making it impossible to delineate the specific effects of Zn
or Se. To date, no clinical studies have thoroughly investigated the effects
of Zn or Se supplementation on female fertility. Furthermore, no studies
have investigated the effects of Zn or Se supplement on pregnancy rate, in
either fertile or subfertile populations. The majority of studies to date
involved small, heterogeneous cohorts, and interestingly, the administration
of supplements comprising several micronutrients matched results for
single micronutrients, with no apparent synergistic effects on the outcome
variables. Many reviews highlight that when taking combinations of
micronutrients it is vital to pay attention to the doses and number of
ingredients used.
Despite the growing number of studies on the effects of micronutrient
supplementation on subfertility, inconsistencies in the literature relating to
males and the lack of studies on females, preclude firm recommendations
relating to their prescription and the specific dose or the optimum
duration of treatment. In addition, no information is available on whether
cohorts with specific subfertility issues will benefit more than others from
supplementation. Importantly however, none of the studies identified any
detrimental effects of Zn or Se on male or female fertility when administered
below the recommended daily intake. There may well be some benefit
in Zn and Se supplementation, although data is currently unavailable to
substantiate this claim. Thus, it is recommended that large randomised
clinical trials, with appropriate controls, be undertaken in which Zn or Se
supplementation alone is administered to investigate their potential effects
on pregnancy rate in both fertile and especially subfertile populations.

For more information about pre-conception health visit www.yourfertility.org.au

1. Gharagozloo P, Aitken RJ 2011 “The role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy.” Human Reproduction 26: 1628-1640.
2. Ross C, Morriss A, Khairy M, Khalaf Y, Braude P, et al. 2010 “A systematic review of the effect of oral antioxidants on male infertility.” Reproductive Biomedicine
Online 20: 711-723.
3. Showell MG, Brown J, Yazdani A, Stankiewicz MT, Hart RJ 2011 “Antioxidants for male subfertility.” Cochrane Database of Systematic Reviews.
4. Cetin I, Berti C, Calabrese S 2010 “Role of micronutrients in the periconceptional period.” Human Reproduction Update 16: 80-95.
5. Ebisch IMW, Thomas CMG, Peters WHM, Braat DDM, Steegers-Theunissen RPM 2007 “The importance of folate, zinc and antioxidants in the pathogenesis and
prevention of subfertility.” Human Reproduction Update 13: 163-174.
6. Ruder EH, Hartman TJ, Blumberg J, Goldman MB 2008 “Oxidative stress and antioxidants: exposure and impact on female fertility.” Human Reproduction Update 14: 345-357.
7. National Health and Medical Research Council 2006 “Nutrient reference values for Australia and New Zealand: Including recommended daily intakes.” In: Australian
Government Department of Health and Ageing, editor. Canberra, Australia: NHMRC pp. 1-319.
8. Chia SE, Ong CN, Chua LH, Ho LM, Tay SK 2000 “Comparison of zinc concentrations in blood and seminal plasma and the various sperm parameters between
fertile and infertile men.” Journal of Andrology 21: 53-57.
9. Akinloye O, Abbiyesuku FM, Oguntibeju OO, Arowojolu AO, Truter EJ 2011 “The impact of blood and seminal plasma zinc and copper concentrations on
spermogram and hormonal changes in infertile Nigerian men.” Reproductive Biology 11: 83-98.
10. Colagar AH, Marzony ET, Chalchi MJ 2009 “Zinc levels in seminal plasma are associated with sperm quality in fertile and infertile men.” Nutrition Research 29: 82-88.
11. Kynaston HG, Lewisjones DI, Lynch RV, Desmond AD 1988 “Changes in seminal quality following oral zinc therapy.” Andrologia 20: 21-22.
12. Omu AE, Dashti H, Al-Othman S 1998 “Treatment of asthenozoospermia with zinc sulphate: andrological, immunological and obstetric outcome.” European
Journal of Obstetrics Gynecology and Reproductive Biology 79: 179-184.
13. Tikkiwal M, Ajmera RL, Mathur NK 1987 “Effect of zinc administration on seminal zinc and fertility of oligospermic males.” Indian journal of physiology and
pharmacology 31: 30-34.
14. Wong WY, Merkus H, Thomas CMG, Menkveld R, Zielhuis GA, et al. 2002 “Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind,
randomized, placebo-controlled trial.” Fertility and Sterility 77: 491-498.
15. Agarwal A, Sekhon LH 2010 “The role of antioxidant therapy in the treatment of male infertility.” Human Fertility 13: 217-225.
16. Omu AE, Al-Azemi MK, Kehinde EO, Anim JT, Oriowo MA, et al. 2008 “Indications of the mechanisms involved in improved sperm parameters by zinc therapy.”
Medical Principles and Practice 17: 108-116.
17. Menezo YJR, Hazout A, Panteix G, Robert F, Rollet J, et al. 2007 “Antioxidants to reduce sperm DNA fragmentation: an unexpected adverse effect.” Reproductive
Biomedicine Online 14: 418-421.
18. Menezo Y, Pluntz L, Chouteau J, Gurgan T, Demirol A, et al. 2011 “Zinc concentrations in serum and follicular fluid during ovarian stimulation and expression of
Zn2+ transporters in human oocytes and cumulus cells.” Reproductive Biomedicine Online 22: 647-652
19. Ozkaya MO, Naziroglu M, Barak C, Berkkanoglu M 2011 “Effects of multivitamin/mineral supplementation on trace element levels in serum and follicular fluid of
women undergoing in vitro fertilization (IVF).” Biological Trace Element Research 139: 1-9.
20. Soltan MH, Jenkins DM 1983 “Plasma and copper and zinc concentrations and infertility.” British Journal of Obstetrics and Gynaecology 90: 457-459.
21. Safarinejad MR, Safarinejad S 2009 “Efficacy of selenium and/or n-acetyl-cysteine for improving semen parameters in infertile men: A double-blind, placebo
controlled, randomized study.” Journal of Urology 181: 741-751.
22. Hawkes WC, Alkan Z, Wong K 2009 “Selenium supplementation does not affect testicular selenium status or semen quality in North American men.” Journal of
Andrology 30: 525-533.
23. Hawkes WC, Turek PJ 2001 “Effects of dietary selenium on sperm motility in healthy men.” Journal of Andrology 22: 764-772.
24. Keskes-Ammar L, Feki-Chakroun N, Rebai T, Sahnoun Z, Ghozzi H, et al. 2003 “Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement
on semen quality in infertile men.” Archives of Andrology 49: 83-94.
25. Scott R, Macpherson A, Yates RWS, Hussain B, Dixon J 1998 “The effect of oral selenium supplementation on human sperm motility.” British Journal of Urology 82: 76-80.
26. Tremellen K, Miari G, Froiland D, Thompson J 2007 “A randomised control trial examining the effect of an antioxidant (Menevit) on pregnancy outcome during
IVF-ICSI treatment.” Australian & New Zealand Journal of Obstetrics & Gynaecology 47: 216-221.
27. Moslemi MK, Tavanbakhsh S 2011 “Selenium-vitamin E supplementation in infertile men: Effects on semen parameters and pregnancy rate.” International Journal of
General Medicine 4: 99-104.
28. Tunc O, Thompson J, Tremellen K2009 “Improvement in sperm DNA quality using an oral antioxidant therapy.” Reproductive Biomedicine Online 18: 761-768.
29. Munoz C, Carson AF, McCoy MA, Dawson LER, Irwin D, et al. 2009 “Effect of supplementation with barium selenate on the fertility, prolificacy and lambing
performance of hill sheep.” Veterinary Record 164: 265-272.