Selenium (Se) is an essential trace element with a number of biological functions. Se occurs in organic and inorganic forms. The organic form is found predominantly in grains, fish, meat, poultry, eggs, and dairy products and enters the food chain via plant consumption.

Male infertility

Infertility is a major clinical concern, affecting 15% of all reproductive age couples. Male factors, including decreased semen quality, are responsible for 25% of these cases.[1,2] Currently, the etiology of suboptimal semen quality is poorly understood, and many physiological, environmental, and genetic factors, including oxidative stress, have been implicated.[3] Selenium (Se) is important for reproductive functions such as testosterone metabolism and is a constituent of sperm capsule selenoprotein. The administration of Se to subfertile patients induced a statistically significant rise in sperm motility.[4] Selenoproteins participate in sperm structure integrity maintenance. Sperm capsular selenoprotein has an important structural role in spermatozoa in the form of glutathione peroxidase (GSH-Px).[5] Increased reactive oxygen species (ROS) decreases fertility because ROS attacks the membrane of the spermatozoa, decreasing their viability. Increasing Se encourages antioxidant GSH-Px activity, thus decreasing ROS and leading to increased male fertility.[6,7] Another study included 690 infertile men with idiopathic asthenoteratospermia. They received supplemental daily Se (200 µg) in combination with vitamin E (400 units) for at least 100 days. There was 52.6% (362 cases) total improvement in sperm motility, morphology, or both, and 10.8% (75 cases) spontaneous pregnancy in comparison with no treatment (95% confidence interval: 3.08 to 5.52). No response to treatment occurred in 253 cases (36.6%) after 14 weeks of combination therapy. Therefore combination therapy with oral Se and vitamin E was effective for treatment of asthenospermia, asthenoteratospermia and induction of spontaneous pregnancy.[8]

Cancer

Because of its effects on DNA repair, apoptosis, and the endocrine and immune systems as well as other mechanisms, including its antioxidant properties, selenium might play a role in the prevention of cancer.[9-12]

Epidemiological studies have suggested an inverse association between selenium status and the risk of colorectal, prostate, lung, bladder, skin, esophageal, and gastric cancers.[13] In a Cochrane review of selenium and cancer prevention studies, compared with the lowest category of selenium intake, the highest intake category had a 31% lower cancer risk and 45% lower cancer mortality risk as well as a 33% lower risk of bladder cancer and, in men, 22% lower risk of prostate cancer.[13] The authors found no association between selenium intake and risk of breast cancer. A meta-analysis of 20 epidemiologic studies showed a potential inverse association between toenail, serum, and plasma selenium levels and prostate cancer risk.[14]

Randomized controlled trials of selenium supplementation for cancer prevention have yielded conflicting results. The authors of a Cochrane review concluded, based on nine randomized clinical trials, that selenium might help prevent gastrointestinal cancers but noted that these results need to be confirmed in more appropriately designed randomized clinical trials.[15] A secondary analysis of the double-blind, randomized, controlled Nutritional Prevention of Cancer Trial in 1,312 U.S. adults with a history of basal cell or squamous cell carcinomas of the skin found that 200 mcg/day selenium as high-selenium baker’s yeast for 6 years was associated with a 52% to 65% lower risk of prostate cancer.[16] This effect was strongest in men in the lowest tertile of selenium concentrations who had a baseline prostate-specific antigen (PSA) level of 4 ng/mL or lower. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized, controlled trial in 35,533 men aged 50 years or older from the United States, Canada, and Puerto Rico, was discontinued after 5.5 years when analyses showed no association between supplementation with 200 mcg/day selenium with or without 400 international units (IU)/day vitamin E and prostate cancer risk.[17] An additional 1.5 years of follow-up data on participants after they stopped taking the study supplements confirmed the lack of a significant association between selenium supplementation and prostate cancer risk.[18]

The recent Vitamins and Lifestyle (VITAL) study looked at the association between some known antioxidant agents (selenium β-carotene, lutein plus zeaxanthine, lycopene, vitamin C, vitamin E and zinc) and the risk of pancreatic cancer. There was no strong evidence of a link with the intake of antioxidants other than with selenium.[19]

A UK study of the EPIC cohort indicated that high intake of selenium was associated with a reduced risk of pancreatic cancer.[20]

The same conclusion has been confirmed by two other studies, which have stated that higher blood markers of selenium are connected with a lower risk of pancreatic cancer.[21,22]

Apart from those at risk of prostate cancer, selenium could be taken as a way of reducing pancreatic cancer risk, but it is important to note that only people with low levels of selenium in their blood should take selenium supplements or it may do more harm than good.[23]

Selenium may improve glucose metabolism, but supplementation could increase the risk of diabetes if a person already has normal levels of selenium in their blood.[23-25] It is therefore important that only patients with proven selenium deficiency take high dose selenium supplements.

Two Se-containing compounds, methylseleninic acid (MSA) and selenodiglutathione (SDG) induce cell death in lymphoma cell lines and primary lymphoma cultures, which with SDG may be partly attributable to the generation of ROS.[26] A study of EG-Se/Pt in T-LBL/ALL lymphoma cells demonstrated efficacy by inducing cell cycle arrest and ROS-mediated apoptosis through the mitochondrial signaling pathway.[27] Dalton’s lymphoma (DL) cells treated with selenium nanoparticles (SeNPs) showed reduced cell viability, altered nuclear morphology, typical apoptotic DNA ladder and apoptosis.[28]

Some studies have suggested that selenium deficiency may be a risk factor for developing lymphomas [29,30] and clinical trials have used selenium in cancer therapy. Forty patients with newly diagnosed NHL were randomly divided into two groups. Group I received standard chemotherapy, whereas group II received adjuvant sodium selenite 0.2 mg kg(-1) day(-1) for 7 days in addition to chemotherapy. Sodium selenite administration resulted in significant increase in percentage of apoptotic lymphoma cells and statistically significant increase in percentage of reduction of cervical and axillary lymphadenopathy, decrease in splenic size, and decreased percentage of bone marrow infiltration.[31]

Oral mucositis (OM) is a complication of high-dose chemotherapy (HDC) followed by hematopoietic SCT (HSCT) with few effective treatments. As selenium has a cytoprotective role via the glutathione peroxidase (Glu.Px) enzyme, preventing chemotherapy-induced toxicities it was used in a clinical trial. Selenium reduced the duration and severity of OM after HDC in 77 mixed leukaemia patients but it has not yet been studied in lymphoma.[32] Other results show that in patients with CLL the mean serum selenium levels are lower than normal controls .[33,34] When sodium selenite was tested on a variety of leukaemia cells several years ago, CLL cells were least sensitive to selenium’s anti-proliferative effects.[35]

Cardiovascular disease

Selenoproteins help prevent the oxidative modification of lipids, reducing inflammation and preventing platelets from aggregating.[23] For these reasons, experts have suggested that selenium supplements could reduce the risk of cardiovascular disease or deaths associated with cardiovascular disease.

The epidemiological data on the role of selenium in cardiovascular disease have yielded conflicting conclusions. Some observational studies have found an inverse association between serum selenium concentrations and risk of hypertension or coronary heart disease. A meta-analysis of 25 observational studies found that people with lower selenium concentrations had a higher risk of coronary heart disease.[36] However, other observational studies failed to find statistically significant links between selenium concentrations and risk of heart disease or cardiac death, or they found that higher selenium concentrations are associated with an increased risk of cardiovascular disease.[37-39]

Several clinical trials have examined whether selenium supplementation reduces the risk of cardiovascular disease. In one randomized, placebo-controlled study, for example, 474 healthy adults aged 60 to 74 years with a mean baseline plasma selenium concentration of 9.12 mcg/dL were supplemented with 100, 200, or 300 mcg selenium per day or placebo for 6 months.[40] The supplements lowered levels of total plasma cholesterol and non–high-density-lipoprotein (HDL) plasma cholesterol (total cholesterol levels minus HDL levels) compared with the placebo group, whereas the 300 mcg/day dose significantly increased HDL levels. Other trials have provided evidence that selenium supplementation (200 mcg/day) or supplementation with a multivitamin/multimineral pill containing selenium (100 mcg/day) does not reduce the risk of cardiovascular disease or cardiac death.[41-43] A review of trials of selenium-only supplementation for the primary prevention of cardiovascular disease found no statistically significant effects of selenium on fatal and nonfatal cardiovascular events.[44] Almost all of the subjects in these clinical trials were well-nourished male adults in the United States.

The limited clinical-trial evidence to date does not support the use of selenium supplements for preventing heart disease, particularly in healthy people who already obtain sufficient selenium from food. Additional clinical trials are needed to better understand the contributions of selenium from food and dietary supplements to cardiovascular health.

Cognitive decline

Serum selenium concentrations decline with age. Marginal or deficient selenium concentrations might be associated with age-related declines in brain function, possibly due to decreases in selenium’s antioxidant activity.[45,46]

The results of observational studies are mixed.[57] In two large studies, participants with lower plasma selenium levels at baseline were more likely to experience cognitive decline over time, although whether the participants in these studies were selenium deficient is not clear.[45,48,49] An analysis of NHANES data on 4,809 elderly people in the United States found no association between serum selenium levels (which ranged from lower than 11.3 to higher than 13.5 mcg/dL) and memory test scores.[50]

Researchers have evaluated whether taking an antioxidant supplement containing selenium reduces the risk of cognitive impairment in elderly people. An analysis of data from the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) study on 4,447 participants aged 45 to 60 years in France found that, compared with placebo, daily supplementation with 120 mg ascorbic acid, 30 mg vitamin E, 6 mg beta-carotene, 100 mcg selenium, and 20 mg zinc for 8 years was associated with higher episodic memory and semantic fluency test scores 6 years after the study ended.[51] However, selenium’s independent contribution to the observed effects in this study cannot be determined. The authors of a systematic review that included nine placebo-controlled studies concluded that the available clinical evidence is insufficient to determine whether selenium supplements can prevent Alzheimer’s disease.[47]

More evidence is required to determine whether selenium supplements might help prevent or treat cognitive decline in elderly people.

Thyroid disease

Selenium concentration is higher in the thyroid gland than in any other organ in the body, and, like iodine, selenium has important functions in thyroid hormone synthesis and metabolism.

Epidemiological evidence supporting a relationship between selenium levels and thyroid gland function includes an analysis of data on 1,900 participants in the SU.VI.MAX study indicating an inverse relationship between serum selenium concentrations and thyroid volume, risk of goiter, and risk of thyroid tissue damage in people with mild iodine deficiency.[52] However, these results were statistically significant only in women. A cross-sectional study in 805 adults with mild iodine deficiency in Denmark also found a significant inverse association between serum selenium concentration and thyroid volume in women.[53]

Randomized, controlled trials of selenium supplementation in patients with thyroid disease have had varied results. In one randomised, double-blind, placebo-controlled trial, 100, 200, or 300 mcg/day selenium for 6 months in 368 healthy adults aged 60 to 74 years had no effect on thyroid function, even though plasma selenium levels increased significantly.[54] Another randomised, double-blind, placebo-controlled trial compared the effects of 200 mcg/day selenium (as sodium selenite), 1,200 mg/day pentoxifylline (an antiinflammatory agent), or placebo for 6 months in 159 patients with mild Graves’ orbitopathy.[55] Compared with patients treated with placebo, those treated with selenium but not pentoxifylline reported a higher quality of life. Furthermore, ophthalmic outcomes improved in 61% of patients in the selenium group compared with 36% of those in the placebo group, and only 7% of the selenium group had mild progression of the disease, compared with 26% of those in the placebo group.

Women with thyroid peroxidase antibodies tend to develop hypothyroxinemia while they are pregnant and thyroid dysfunction and hypothyroidism after giving birth.[9] The authors of a Cochrane review of hypothyroidism interventions during pregnancy concluded, based on a trial that administered supplements containing 200 mcg selenium as selenomethionine daily to 151 pregnant women with thyroid peroxidase antibodies[56], that selenomethionine supplementation in this population is a promising strategy, especially for reducing postpartum thyroiditis.[57] However, the authors called for large randomised clinical trials to provide high-quality evidence of this effect.

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