Sex Differences in Selenium Metabolism and Selenoproteins

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Males and females are different in ways that go beyond the morphology of their sex organs. This sexual dimorphism affects critical aspects of the selenium metabolism in animals and humans. Here Seale et al. review the available information on the influence of biological sex parameters on selenium metabolism and the effect of selenium and selenoproteins on sex hormones.

One thing that the Covid-19 infections have taught us is that biological sex differences affect the way we respond to the virus. The Johns Hopkins University biologist Dr. Sabra Klein says that men are more likely to die from Covid-19 and more likely to be hospitalized with severe cases of the disease.

This seems to hold true even though women are just as likely to be infected and even when researchers control for the effect of factors such as age and region.

Women seem to have a stronger immune response to pathogens – bacteria, viruses, parasites – and to have a higher antibody production after vaccination. On the other hand, women are at greater risk for the development of auto-immune diseases.

Why men’s and women’s immune systems seem to respond differently to an infectious disease is not known. The explanation may well come from sex-related differences in gene expression and hormone activity.

Sex Differences in the Effect of Selenium on All-Cause and CVD Mortality Risk

Li et al. [2020] examined how sex differences might affect the relationship between serum selenium concentrations and all-cause mortality and cardiovascular disease (CVD) mortality.

The researchers used data from the 1999–2006 US National Health and Nutrition Examination Survey data set.

  • In their study, they had 2,903 subjects (50.7% female) with a mean age of 61.9 ± 13.7 years and a mean serum selenium concentration of 136.4 ± 19.6 mcg/L.
  • There were 858 (29.6%) cases of all-cause mortality and 126 (4.3%) cases of CVD mortality during the median follow-up period of 10.2 years.
  • On average, deceased participants had lower serum selenium levels, (135.1 ± 22.3 vs. 137.0 ± 18.4 mcg/L; P = 0.02).
  • Serum selenium was also lower in female than male (134.7 ± 19.7 vs. 138.2 ± 19.4 mcg/L; P < 0.01).

Comparing with the lowest quartile, participants with the highest serum selenium concentration had a lower risk for all-cause (HR: 0.60, 95%CI: 0.45, 0.78; P < 0.01, P for trend<0.01) and CVD mortality (HR: 0.73, 95%CI: 0.37, 1.43; P = 0.36, P for trend = 0.90).

In the Li study [2020], participants (male and female combined) with higher serum selenium levels had lower rates of all-cause mortality and cardiovascular mortality.

Higher serum selenium level was significantly associated with lower all-cause mortality in both females and males, separately.

The relationship of higher serum selenium level with lower cardiovascular disease mortality was statistically significant only among females, not among males.

Sex Differences/Sex Hormones and Selenium Metabolism and Selenoprotein Formation

Seale et al [2018] have done a review of sexual dimorphism in selenium metabolism and selenoproteins. There follows a short summary of their findings:

Selenium absorption

Intestinal absorption of selenomethionine has been shown to be approximately 96% in healthy women and approximately 76% in healthy men. The molecular explanation for this sex-related difference is not known.

Selenium in the blood circulation

With respect to the influence of sex on circulating selenocompounds in humans, women have been seen to have higher glutathione peroxidase activity in the blood circulation than men but not higher selenium levels overall.

In humans, sex differences seem to play a role in the selenium distribution in the plasma in people with the same total selenium levels. Research has shown sex-related differences in the ratios of selenium bound to albumin and in selenium incorporated into the selenoproteins Selenoprotein P or GPX3. The biological consequences of these differences are not yet known.

Selenium supplementation

  • When they are selenium deficient, female rats take up selenium more efficiently than male rats.
  • Supplemented female rats increase plasma levels of GPX activity more than male rats.
  • Female rats have a lower selenium requirement than males.
  • In the reproductive organs, selenium is taken up and retained very efficiently in the testes; the female reproductive organs do not take up or retain significant levels of selenium.

Selenomethionine conversion to selenocysteine

The available evidence shows that sex hormones regulate the trans-selenation process by which ingested selenomethionine is converted into selenocysteine and circulated in the blood in selenoprotein P.

Seale et al [2018] suggest that selenomethionine metabolism and subsequent selenocysteine formation and selenocysteine availability for selenoprotein synthesis are not the same in females and males.

Selenoprotein expression

  • There are numerous examples, mostly in animal studies, of sex-specific differences in selenoprotein expression and function.
  • Dietary selenite affects glutathione peroxidase 1 in the liver of rats in a sex-dependent fashion; GPx1 activity is enhanced twice as much in females as in males.
  • In rodent studies, males prioritized selenium distribution to the testis at the expense of selenium for the brain to maintain neurological function.
  • A differential sex-related pattern of the down-regulation of selenoproteins has been seen, taking into account age and the levels of dietary selenium.
  • Studies suggest that sex affects the aging-related fragility of the selenocysteine incorporation mechanisms.

Selenium and energy metabolism

Enzymes involved in selenium metabolism have been shown to act on glucose pathways.

Selenocysteine lyase is an enzyme involved in selenium metabolism; it catalyzes the decomposition of selenocysteine to alanine and selenide.

Selenocysteine lyase depleted mice develop a metabolic syndrome. If they are males, they develop obesity, glucose intolerance, hyperinsulinemia, and hypercholesterolemia. If they are females, they gain weight but do not exhibit the other symptoms. The regulation of selenium seems to be sex specific, with differences in the development of metabolic syndrome in male and female mice.

Sex differences in selenocysteine lyase activity in metabolic tissues suggests distinct roles for selenocysteine lyase in males and females.

The researchers note that selenoproteins have also been shown to act on glucose metabolism; however, a sex difference has yet to be found.

Selenium and the effect on sex hormones

Selenium supports testosterone production; selenium deficient rats exhibit defective testosterone secretion.

Selenium plays a direct role in spermatogenesis; normal GPX4 expression is necessary to maintain the structural integrity of spermatozoa.

The effects of selenium on estrogen are not clear. More studies are needed to clarify the relationship between selenium and the female sex hormones.

Effect of sex hormones on selenium distribution and selenoprotein expression

Seale et al use the following reasoning to conclude that sex hormones account, to some unknown extent, for sex differences in selenoprotein regulation.

  1. None of the genes encoding for selenoproteins or selenocysteine incorporation factors are found in the sex chromosomes of humans or mice.
  2. Sex differences in selenoprotein expression or selenocysteine incorporation factors must then be regulated by other factors, e.g. sex hormones.
  3. Sex-related differences in selenium distribution and selenoprotein expression are well-documented.
  4. Sex hormones seem to play a direct role in selenium distribution and metabolism.
Conclusion – Sex a Factor in Selenium Metabolism

Selenium researchers need to account for the influence of sex differences on study outcomes.

For example, results from a nested case-control study that used data from the Women’s Health Initiative observational study (804 colorectal cancer cases and 805 matched controls) showed no protective effect of selenium on colorectal cancer among women. Similarly, a meta-analysis of 12 observational studies and two clinical trials on selenium showed no association between selenium and colorectal tumor risk in women.

However, the meta-analysis did show a significant inverse association between selenium status and colorectal tumor risk in men [Takata 2011].

Not analyzing the study outcomes by sex could skew the evidence in a misleading direction for one of the sexes.

Another example: 

In the French SU.VI.MAX study, a randomized, double-blind, placebo-controlled primary prevention trial enrolling 13,017 French adults (7876 women aged 35-60 years and 5141 men aged 45-60 years), study participants took 100 mcg of selenium together with other antioxidants or placebos.

The median follow-up time was 7.5 years.

Analyzing the data, the researchers saw no major differences between the two groups in total cancer incidence. However, further analysis showed a significant interaction between sex and group effects on cancer incidence. Sex-stratified analysis showed a protective effect of selenium and antioxidants in men but not in women. A similar trend was observed for all-cause mortality in men but not in women [Hercberg 2004].


Hercberg S, Galan P, Preziosi P, Bertrais S, Mennen L, Malvy D, Roussel AM, Favier A, Briançon S. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004 Nov 22;164(21):2335-42.

Li J, Lo K, Shen G, Feng YQ, Huang YQ. Gender difference in the association of serum selenium with all-cause and cardiovascular mortality. Postgraduate Medicine. 2020 Mar;132(2):148-155.

Seale LA, Ogawa-Wong AN, Berry MJ. Sexual Dimorphism in Selenium Metabolism and Selenoproteins. Free Radic Biol Med. 2018 Nov 1;127:198-205.

Takata, Y., Kristal, A. R., King, I. B., Song, X., Diamond, A. M., Foster, C. B., Hutter, C. M., Hsu, L., Duggan, D. J., Langer, R. D., Petrovitch, H., Shikany, J. M., Vaughan, T. L., Lampe, J. W., Prentice, R. L., & Peters, U. Serum selenium, genetic variation in selenoenzymes, and risk of colorectal cancer: primary analysis from the Women’s Health Initiative Observational Study and meta-analysis. Cancer epidemiology, biomarkers & prevention. 2011;20(9), 1822–1830.

The information presented in this review article is not intended as medical advice and should not be construed as such.

15 March 2021

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