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The role of selenium in human conception and

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DOI: 10.1016/j.jtemb.2014.07.003

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 Journal of Trace Elements in Medicine and Biology 29 (2015) 3138

Contents lists available at ScienceDirect

Journal of Trace Elements in Medicine and Biology

journal homepage: www.elsevier.de/jtemb

Review

The role of selenium in human conception and pregnancy

Joanna Pieczynska , Halina Grajeta
Department of Food Science and Dietetics, Wroclaw Medical University, Borowska 211, 50-556 Wrocaw, Poland

a r t i c l e i n f o a b s t r a c t

Article history: Selenium (Se) is a trace element essential for the appropriate course of vital processes in the human
Received 11 December 2013 body. It is also a constituent of the active center of glutathione peroxidase that protects cellular mem-
Accepted 11 July 2014 branes against the adverse effects of H2 O2 lipid peroxides. Epidemiological surveys have demonstrated
that selenium deciency in the body may contribute to an increased risk for certain neoplasmic dis-
Keywords: eases (including colonic carcinoma, gastric carcinoma, pulmonary carcinoma and prostate carcinoma),
Selenium
as well as diseases of the cardiovascular, osseous and nervous systems. Apart from its cancer prevention
Antioxidative activity
and antioxidative activities, selenium protects the body against detrimental effects of heavy metals and
Pregnancy
Reproduction
determines the proper functioning of the immunological system.
Furthermore, selenium plays a signicant role in the undisturbed functioning of the reproductive sys-
tem. Many studies have addressed correlations between its intake and fertility as well as disorders of
procreation processes. Selenium deciencies may lead to gestational complications, miscarriages and
the damaging of the nervous and immune systems of the fetus. A low concentration of selenium in blood
serum in the early stage of pregnancy has been proved to be a predictor of low birth weight of a newborn.
A deciency of this element may also cause infertility in men by causing a deterioration in the quality
of semen and in sperm motility. For this reason, supplementation in the case of selenium deciencies in
the procreation period of both women and men is of utmost signicance.
2014 Elsevier GmbH. All rights reserved.

Contents

Biochemical properties of selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Selenium sources in the human diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Human selenium status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Health impact of selenium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Phospholipid peroxide glutathione peroxidase and thioredoxin reductase in spermatogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Selenoprotein P in the testes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Selenium and testosterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Correlations between estrogen and selenium in menstruation cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Selenium in ovulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Selenium and female infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Selenium status in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Implications of selenium deciencies on the fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Selenium status in pregnancy-related complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Pre-term delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Miscarriages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Cholestasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Gestational diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Corresponding author. Tel.: +48 071 7840214l; fax: +48 071 7840206.

E-mail address: joanna.pieczynska@interia.pl (J. Pieczynska).

http://dx.doi.org/10.1016/j.jtemb.2014.07.003
0946-672X/ 2014 Elsevier GmbH. All rights reserved.
32
Thyroid dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Effect of tobacco, alcohol and polycyclic aromatic hydrocarbons on selenium status in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biochemical properties of selenium
Selenium was discovered in the year 1817 by the Swedish
chemist Jns Jacob Berzelius. Initially, it had been perceived as a
toxic element, but after 140 years, a study by Schwarz and Folt [1]
demonstrated that Se is essential for human biology. Today, it is
acknowledged as a trace element fundamental to human health.
Selenium is absorbed from food in the form of inorganic
compounds like selenites (Me2 SeO3 ) and selenates (Me2 SeO4 )
or organic links selenomethionine (SeMet) and selenocysteine
(SeCys). The absorption of selenium from organic compounds
reaches 9095%, whereas from inorganic links, it is lower by ca. 10%
[2]. Its bioavailability increases when a diet is rich in low molecular
weight proteins, vitamins (mainly A, C and E), and it decreases if
a diet contains an increased concentration of heavy metals (cad-
mium, lead, arsenic and mercury) [3].
Selenium sources in the human diet
For humans, a source of this microelement is foodstuff of
both plant and animal origin, and marginally drinking water.
High quantities of selenium are provided by, among others, cereal
products, seafood, haslets, eggs, yeast, tomatoes, asparagus, gar-
lic, broccoli, nuts (especially Brazilian nuts), and turnip cabbage.
Although more selenium is found in products of animal origin, the
best sources of this element are wheat and other plant products
owing to its better bioavailability [3]. The Se content of plant food
depends mainly on the soil-type in which the plant was grown, but
also on the agricultural use of pesticide, manure and phosphate fer-
tilizers [4,5]. The health impacts of Se deciency in human subjects
can be related, however, to the level of Se in the environment if the
local inhabitants are dependent on their direct surroundings for
sustenance. In developed and well urbanized countries in which
populations are less dependent on their proximate environment
for food and drinking water, establishing a link is more difcult
(Table 1).
Human selenium status
The nutritional status of selenium can be assessed by determin-
ing Se levels in blood (whole blood, erythrocyte, serum or plasma),
urine, nails and hair. Serum or plasma selenium reects short-term
status as opposed to erythrocyte selenium which reects long-term
status [9]. There is a marked variation in Se intake and status from
Table 1
Selenium content in food products from different countries (gSe/100 g) [68].
Food product
Wheat bran
Breakfast cereal cornakes
Bread white prepared with bread mixture
Bread brown, wheat
Cabbage white, raw
Egg chicken, whole
Oysters
Herring salted
Salmon smoked
Liver chicken, raw
Kidney pork, raw
J. Pieczy
nska, H. Grajeta / Journal of Trace Elements in Medicine and Biology 29 (2015) 3138
35
36
36
36
one part of the world to another. Furthermore, it is often difcult
to compare results because of variations in methodology in dif-
ferent laboratories. Because of variations in selenium status there
are no accepted normal/optimal reference ranges. Usually, the rec-
ommended reference values are based on the evaluation of data
from the literature in particular countries. An example might be
the German Human Biomonitoring Commission which estimated
reference values for selenium status: serum/plasma 50120 g/L;
whole blood: females 60120 g/L and males 79130 g/L; eryth-
rocytes per g hemoglobin females and males 0.20.6 g (Table 2)
[10].
Health impact of selenium
This element, as a constituent of selenoproteins, activates anti-
carcinogenic factors, prevents diseases of the cardiovascular sys-
tems as well as exhibits anti-proliferative and anti-inammatory
activities [31,32]. Furthermore, it stimulates the immune system
and acts antagonistically to such heavy metals as: arsenic, cad-
mium, lead and mercury [3335]. Selenium deciencies are mainly
developed due to insufcient content in diet, but also as a result of
disorders in its transport in biological uids and in the improper
synthesis of selenoproteins. They may also results from active dis-
ease [32,36].
As a component of enzymes, Se serves many important func-
tions in the human body. The key one is its antioxidative function
it impairs adverse processes of lipids peroxidation and protects
cells against damage to genetic material. The protective role of
selenium results from its presence in glutathione peroxidase (GPx)
and thioredoxin reductase (TrxRs), namely in the active center of
antioxidative enzymes [37].
Phospholipid peroxide glutathione peroxidase and
thioredoxin reductase in spermatogenesis
Proper spermatogenesis requires two selenoproteins: phospho-
lipid peroxide glutathione peroxidase PHGPx and selenoprotein P.
In the testes, selenium occurs mainly in the PHGPx form, namely in
the form of one of the selenium-dependent antioxidative enzymes.
TrxRs was additionally detected in the testes of mature male mice.
Its high quantities may be observed in maturing spermatides,
whereas its reduced expression in mature semen [38]. Scientists
have advanced a hypothesis that both selenoenzymes TrxRs and
PHGPx together constitute a system capable for the formation of
disulde bridges that stabilize the protein ultrastructure of semen
[39]. In turn, spermatic tubules have been shown to contain seleno-
protein V, whose physiological role is still undened, though it is
speculated to play some role in the regulation of redox processes
Denmark Finland Canada [40,41].
The testes are organs which are characterized by the highest
2 9.5 77.6
5 2.9 15 expression of PHGPx in the body of mammals, exceeding even the
4 2.9 17.3 expression of such key organs as the liver and kidneys. The most
4 5.7 28.8 signicant function of this enzyme includes the protection of plas-
1 1.5 0.3 matic membranes of maturing spermatozoa against the attack of
17 24.9 34.2
36 3 33.8
free radicals. Researches have shown, however, that not only the
46 22 36.5 antioxidative properties of PHGPx are utilized in spermatozoa [42].
16 26 22.2 This protein constitutes ca. 50% of the material contained in the
49 - 54.6 mitochondrial membrane of a spermatozoon and is enzymatically-
150 135 190
inactive therein. The structural function of selenoproteins may
 J. Pieczy
nska, H. Grajeta / Journal of Trace Elements in Medicine and Biology 29 (2015) 3138 33

Table 2
Selenium status in healthy adult individuals from different countries.

Country Selenium assessment (technique) Mean selenium concentration (gSe/L) Reference

Men Women Total

Australia Plasma (ICP-OES)a 103.0 (n = 288)b [11]

Belgium Serum (GFAAS) 84.3 (n = 26) [12]
Chile Plasma (AAS) 112.9 (n = 29) [13]
Croatia Serum (AAS) 72.7 (n = 123) [14]
Czech republic Whole blood (HGAAS) 81.4 (n = 1781) 82.0 (n = 633) 81.9 (n = 2414) [15]
Finland Serum (ETAAS) 117.9 (n = 38) 113.1 (n = 70) 115.5 (n = 108) [16]
France Serum (ETAAS) 90.0 (n = 5141) 86.1 (n = 7876) 88.0 (n = 13,017) [17]
Greece Serum (ICP-MS) 90.5 (n = 296) 93.9 (n = 210) 91.8 (n = 406) [18]
Germany Serum (ICP-MS) 87.7 (n = 492) [19]
India Serum (GFAAS) 90.8 (n = 196) [20]
Japan Plasma (uorimetry) 119.8 (n = 7) [21]
Plasma (uorimetry) 119.2 (n = 6) [22]
Korea Serum (ICP-MS) 103.2 (n = 50) 120.8 (n = 50) 112.0 (n = 100) [23]
Pakistan Whole blood (ICP-MS) 92.0 (n = 56) 100.0 (56) 96.0 (112) [24]
Poland Plasma (AAS) 77.6 (65) 70.4 (n = 81) 72.5 (n = 146) [25]
Russia Serum (uorimetry) 96.0 (n = 2462) [26]
Serum (uorimetry) 93.9 (n = 556) [27]
Sweden Serum (ICP-MS) 110.0 (n = 304) 109.0 (n = 362) 109.0 (n = 666) [28]
United Kingdom Plasma (ICP-MS) 66.3 (n = 589) 67.1 (n = 545) 67.0 (n = 1134) [29]
USA Serum (ICP-MS) 136.4 (n = 796) [30]
a
ICP-MS, inductively coupled plasma mass spectrometry; AAS, atomic absorption spectrometry; ETAAS, electrothermal atomic absorption spectrometry; GFAAS, graphite
furnace atomic absorption spectrometry; HGAAS, hydride generation atomic absorption spectrometry.
b
Mean (number of samples).

elucidate the reduced motility of spermatozoa caused by disorders
in morphology of the spermatozoon mid-piece (the area between
the head and the tail that contains multiple mitochondria gen-
erating energy necessary to propel the sperm cell) in the case of
selenium deciencies [38].
In addition, PHGPx may participate in chromatin organiza-
tion. In a study on knockout mouse deprived of testicular PHGPx,
disorders could be observed in chromatin condensation in the
spermatozoa present in the head of the epididymis [43]. In spite
of that, the spermatozoa were viable and capable of fertilization,
whereas the chromatin defect was probably xed in the process
of sperm cell maturation in the epididymises. In other research,
spermatozoa of a mouse fed a selenium-poor diet showed abnor-
mal spermatozoon head morphology [44]. Complete deprivation
of PHGPx synthesis (both mitochondrial, nuclear and cytosolic) in
mice resulted in a signicant increase of fetal mortality rate in
homozygous mice. In addition, target silencing of gene expression
for the mitochondrial isoform has led to severe damages in cerebel-
lum development and has inducted apoptosis in the cerebral tissue,
whereas the silencing of the nuclear form resulted in delayed heart
development [45].
The appropriate supply of selenium and its positive impact on
reproduction have been documented in studies with experimental
animals. Results of surveys with human patients are, however, less
explicit. Many scientists have linked a low concentration of PHGPx
in patients suffering from oligoasthenozoospermis with reduced
motility of spermatozoa and abnormalities in mitochondria mor-
phology [4648]. X-ray uorescence microscopy may conrm their
suspicions. This method can be used to visualize and quantify the
tissue, cellular and subcellular topography of Se. Analyses using
this method showed that PHGPx was present at high levels in the
epididyma sperm [49]. This, however, has not been corroborated
in other studies [50,51]. Differences in results could be due to dif-
ferent research material origin from mice and men. As a result
more exhaustive research is needed regarding male infertility and
its correlation with deciency of selenium or selenoproteins.
Selenoprotein P in the testes
The second signicant component of the selenium pool in
the testes is selenoprotein P. Its deciency in a group of
knockout mice (deprived of this selenoprotein) has induced
numerous disorders of the structure of the spermatozoa tail:
improper mitochondrial membranes, disorders in the morphol-
ogy of axonema microtubules, and improper morphology of the
links of the central and main section of the spermatozoon. Symp-
toms of selenoprotein P deciency were the same as in the second
group in which mice were fed a diet poor in Se. The difference
lay in the fact that selenium supplementation was contributing to
an improvement in the status linked with diet-related deciency,
whereas not in the status caused by the lack of selenoprotein P. This
enabled the conclusion that this protein is essential for selenium
homeostasis and for functional development of spermatozoa [52].
Infertility in selenoprotein P knockout mice can be eliminated by
transgenic expression of human selenoprotein P under the control
of a hepatocyte-specic transthyrein promoter [53]. Most seleno-
protein P is produced and secreted by the liver, although other
tissues produce it as well. In a study conducted by Olson et al. [54]
authors dene the uptake mechanism and trafcking pathway by
which selenoprotein P delivers its selenium to developing germ
cells. They demonstrate that apolipoproteinE receptor 2 (ApoER2)
is a selenoprotein P receptor and a component of the selenium
delivery pathway to spermatogenic cells.
Selenoprotein P is highly concentrated not only in the testes,
but also in seminal uid, likewise important to protection of sperm
during storage, genital tract passage and nal journey [55].
Selenium and testosterone
Tests conducted on rats by Behne and co-workers [56,57]
suggest that selenium may also inuence the biosynthesis and
secretion of testosterone. These authors have demonstrated that in
the case of an insufcient supply of this element with diet, it is rst
delivered to testes and then to other tissues. A reduced level of Se
was noted in the testes of hypophysectomized individuals. How-
ever, its level increased upon the administration of testosterone,
which points to either an indirect or direct dependency of hor-
mones responsible for spermatogenesis on the appropriate level
of selenium in this organ. Furthermore, stimulation with luteiniz-
ing hormone-releasing hormone (LHRH) or chorionic gonadotropin
(hCG) in individuals with selenium deciency elicited a less
34 J. Pieczy
nska, H. Grajeta / Journal of Trace Elements in Medicine and Biology 29 (2015) 3138
Fig. 1. Plasma selenium concentration during menstrual cycle.
signicant increase in the serum concentration of testosterone,
than in Se adequate males. It is also speculated that deciency of
this element causes some changes in the receptors of the luteinizing
hormone (LH) on Leydig cells, thus affecting testosterone secretion
[58].
Correlations between estrogen and selenium in
menstruation cycle
Despite sparse information on the relationship between female
sex hormones and selenium status, research conducted with
healthy women point to a correlation between estrogen content
and selenium content as well as GPx activity depending on the
phase of the menstruation cycle [59,60]. Both selenium concentra-
tion in the serum and GPx activity in the serum and erythrocytes
are at their lowest in the early follicular phase, whereas they are
at their the highest in the pre-ovulation phase, and then decrease
in the middle luteal phase. These changes are concurrent with
jumps in the concentration of 17--estradiol during the menstru-
ation cycle [59,60]. Such correlations were, however, not observed
with respect to selenium concentration in erythrocytes. Likewise,
no correlations were noted between the activity of GPx and concen-
trations of progesterone and androgens during the cycle [59,60].
These results are indicatory of the regulating effect of estradiol
on the activity of GPx in erythrocytes during the menstruation
cycle. These authors emphasize also the necessity of considering
the phase of the menstruation cycle while evaluating the selenium
status in women, though not all studies demonstrated a correlation
between Se concentration in the plasma and the phase of the cycle
[22,60]. This lack of correlation could be a result of not equal num-
ber of subjects in studied groups and different participants country
origin (Japan, USA and Italy) (Fig. 1).
Selenium in ovulation
Although reduced fertility in women is often linked with insuf-
cient body saturation with selenium, its role in this process still
remains unknown. Perhaps it is due to the fact that selenium is
a co-factor of antioxidative enzymes that are responsible for the
neutralization, elimination and prevention of synthesis of reactive
oxygen species (ROS) [61,62]. Through ROS, the oxidative stress
affects oocytes. It has been observed that the rst meiotic division
in these cells is induced by an increase in ROS concentrations, and
that it is inhibited by antioxidants. This allows for the presumption
that ROS secretion, regulated by a pre-ovulation ovarian follicle, is a
signicant promoter in the course of ovulation and requires main-
taining a gentle balance between ROS and antioxidants [63,64].
Investigations on bovine granular cells enveloping the pri-
mordial ovarian follicle have demonstrated that selenium had a
signicant effect on their proliferation and enhanced the stimulat-
ing action of gonadotropins in these cells [65]. This element also
affects the production of nitrogen oxide (NO), which plays a key
role in the activity of ovaries. Selenium reduced NO production
induced by bovine folliculotropic hormone (bFSH), in cells of both
large and small follicles, although the most tangible differences
were observed in the latter [66].
Selenium and female infertility
In one of the sparse human studies, Paszkowskis group [67]
observed a lower selenium concentration in the follicular uid
of women with unexplained infertility, compared to women who
were infertile due to other reasons. Simultaneously, no differences
were demonstrated in either selenium concentration in the serum
or GPx concentration in the serum and the follicular uid between
the analyzed groups of women. According to these authors, the
results obtained suggest that the antioxidative activity of GPx in the
follicular microenvironment may play a certain role in the process
of gametogenesis and fertilization.
Selenium status in pregnancy
Pregnancy is an exceptional condition of enhanced demand for
various nutrients. Physiological changes proceeding in the body
of a pregnant woman caused, for example, by a high concentra-
tion of progesterone, include a reduced bioavailability of some
dietary components and an increased demand for them owing
to a developing fetus. Deciencies of mineral elements and vita-
mins in this period may contribute to the occurrence of perinatal
complications, fetus necrobiosis, congenital organ defects in the
child and impairment of the immune system functioning in a fetus
[6870].
During pregnancy, the concentration of selenium in the blood
decreases signicantly. Wasowicz et al. [71] assayed its level in the
blood of 64 women during delivery and compared it with selenium
concentration in the blood of non-pregnant women. Se concen-
tration was observed to decrease signicantly during pregnancy,
in the pregnant women it accounted for 35 g/L, whereas in the
non-pregnant women, 59 g/L, on average. Similar results were
obtained by Zachara et al. [72], who additionally showed a drop
in GPx activity in mothers plasma.
Mihailovic et al. [73] determined concentrations of selenium
and malondialdehyde (MDA) and the activity of GPx in the blood
of pregnant women in particular trimesters of pregnancy. A signif-
icant decrease in the level of selenium was noted in the second and
the third trimester of pregnancy and during delivery. Concurrently,
a decline was observed in the activity of GPx in the rst trimester.
Throughout the two subsequent trimesters it maintained a similar
level of activity as in the rst trimester, whereas during delivery it
slightly increased.
Furthermore, changes in selenium homeostasis during preg-
nancy are probably, due to an increased demand for oxygen in the
body of mother and a developing fetus. Enhanced production of ROS
and the intensity of lipid oxidation processes are then observed.
The assurance of the appropriate antioxidative protection to the
fetus is indispensable due to enhanced oxygen transformations
taking place during delivery and in the early postnatal period
[73,74]. Another reason behind the boosted demand for selenium
in pregnant women may be an increased mass of erythrocytes in
the fetus [75].
The estimated average requirements (EAR) and recommended
dietary allowances (RDA) for selenium have been stipulated at lev-
els which assure the optimal concentration of GPx in blood serum,
however due to the aforementioned reasons during pregnancy, the
RDA for this element is increased and ranges from 55 g/day to
60 g/day [51].
 J. Pieczy
nska, H. Grajeta / Journal of Trace Elements in Medicine and Biology 29 (2015) 3138
Implications of selenium deciencies on the fetus
Deciency of selenium in pregnant women may lead to dysfunc-
tions in the nervous system of a developing fetus. Cengiz et al. [76]
demonstrated a positive correlation between a low concentration
of this element in the serum of pregnant women and the occurrence
of neural tube defects, especially anencephaly and rachischisis (a
type of birth defect that causes abnormal formation of the spinal
column), in their progeny. It ought to be emphasized, however, that
the development of the nervous system defects is affected by many
factors, with selenium deciency during pregnancy being only one
of them [77,78].
Selenium status in pregnancy-related complications
Preeclampsia
Maternal selenium status may contribute to the incidence of
the preeclamptic state (EPH gestosis). Conicting results have been
found in research examining the serum concentrations of selenium
in preeclamptic women. Some studies have observed a reduction in
concentrations of selenium in plasma or serum [79,80], and others
have reported an increased selenium concentration in preeclamp-
tic woman than in normal pregnant women [81,82]. Gromadzinska
et al. [81] observed higher concentrations of selenium and activity
of GPx in serum of women with preeclampsia and with the risk
of premature delivery. It is speculated to be a consequence of the
action of mechanisms protecting the body against the occurrence of
oxidative stress. Circulating lipid peroxides may lead to damage of
the placenta, which causes retardation of fetus growth. They addi-
tionally lead to an increased content of thromboxane, a reduced
content of prostacyclins, and damage of vascular endothelium cells,
resulting in an improper blood ow in the placenta [80].
Pre-term delivery
Bogden et al. [83] examined 107 women with pre-term deliv-
ery and 126 women with planned delivery. Progeny of the female
patients with extremely low selenium concentration in the serum
was characterized by a signicantly lower birth weight than the
progeny of women with a higher selenium concentration dur-
ing pregnancy. The difference in the birth weight was signicant
and reached 259 g. However, this study did not demonstrate any
correlation between the low concentration of this element and
pre-mature delivery.
Miscarriages
Low concentrations of selenium and antioxidative enzymes may
also elicit recurrent miscarriages [84,85]. Al-Kunani et al. [86]
examined two groups of non-pregnant women. One group included
18 women after one or more normal deliveries, whereas the other
group included 26 women with recurrent pregnancy losses (3).
The study involved a comparison of selenium content in the hair
and serum of women of both groups. Corresponding results were
achieved in Kumar et al. [87] study which demonstrated a signi-
cantly lower concentration of Se in erythrocytes in women with RPL
compared to normal women. However, Zachara et al. [88] deter-
mined the concentration of selenium and activity of GPx in the
blood of 40 women ages 1740, who had miscarried in the rst
or second trimester of pregnancy. In the above study, selenium
concentration in whole blood or plasma was comparable between
women with miscarriage and healthy women. The activity of GPx in
erythrocytes and plasma was signicantly lower, and the concen-
tration of glutathione in erythrocytes was higher in patients after
35
miscarriage than in the women with a normal course of pregnancy
as well as woman in the control group.
A lower concentration of selenium in women with RPL com-
pared to women with miscarriage may be due to a chronic
deciency of this element in their diet.
Cholestasis
Authors of some studies point also to a correlation between
selenium deciency and the incidence of cholestasis in pregnant
women. The pregnant women with cholestasis were characterized
by a lower selenium concentration in the blood and by a lower
activity of GPx in erythrocytes than the healthy pregnant women. In
patients with intrahepatic cholestasis of pregnancy the low concen-
tration of selenium (possibly disturbed function of the microsomal
cytochrome P-450 system, also controlled by selenium) and the
reduced activity of glutathione peroxidase, may lead to the for-
mation of free radicals, which could damage the hepatocytes and
reduce excretion of bile [89,90].
Gestational diabetes mellitus
Diabetes is one of the most common diseases developing in
pregnant women. Due to insulin-resistance and the increased
demand for insulin in the period of pregnancy, some women
suffer from debilitated glucose tolerance, which may transform
into gestational diabetes mellitus (GDM). Selenium is speculated
to be essential for the proper glucose uptake, the regulation of
the cellular absorption of glucose and reduction of insulin resis-
tance. Contrary to those expectations, recent epidemiological and
intervention studies revealed a surprising association between
high plasma selenium levels and type 2 diabetes, hyperglycemia
and dyslipidemia. It is tempting to speculate that selenoprotein
P and/or low-molecular-weight selenium compounds may affect
insulin induced signaling pathways related to carbohydrate and
lipid metabolism. The epidemiological association between high
plasma selenium levels and hyperglycemia might also be explained
by a disturbance of selenium homeostasis as a side-effect of a dys-
regulated carbohydrate metabolism [91]. Tan et al. [92], after the
examination of 234 pregnant women (98 with glucose intolerance,
46 with gestational diabetes, and the remainder with normal preg-
nancy), demonstrated a signicantly lower selenium concentration
in the blood of women with gestational pregnancy, compared to
normal pregnant women. Corresponding results were showed in
Al-Saleh et al. study [93].
Thyroid dysfunction
Selenium, as a component of selenoproteins, plays a signicant
role in the biosynthesis of thyroid hormones.
In women who are at the reproductive age, hypothyroidism has
an indirect or direct impact on their fertility, course of pregnancy
and the development of the child. The development of the cen-
tral nervous system takes place in the rst and second trimester
of pregnancy and is determined most of all by the transport of
the mothers thyroid hormones through the placenta [94]. A hor-
mone essential for the proper development of the organs of the
fetus is triiodothyronine. Klinger et al. [95] assayed concentrations
of selenium, thyroxin, thyreotropic hormone and triiodothyronine
in the blood of 29 newborns born between weeks 26 and 28 of
pregnancy, with a mean birth weight of 809 g. They did not, how-
ever, demonstrate any correlation between the selenium level and
concentrations of the assayed thyroid hormones. Selenium plays
an important role in the thyroid gland under normal physiological
conditions and in the case of disease. In particular, pregnant women
36 J. Pieczy
nska, H. Grajeta / Journal of Trace Elements in Medicine and Biology 29 (2015) 3138

Table 3
Selenium status in pregnancy-related complications.

Selenium assessment Country Case subjects Selenium Noncase subjects Selenium Reference
(technique) concentration concentration
(gSe/L) (gSe/L)

Serum (uorimetry) Indonesia Spontaneous 66.71 (n = 25)a Normal pregnancies 76.36 (n = 46) [97]
miscarriage
Serum (AAS)b South Wales Spontaneous 54.48 (n = 40) Normal pregnancies 65.29 (n = 40) [84]
miscarriage
Red cells (uorimetry) India Non-pregnant women 119.55 (n = 20) Healthy non-pregnant women 150.55 (n = 20) [87]
with recurrent
miscarriage
Whole blood (AAS) Yugoslavia Hypertensive pregnant 54.65 (n = 23) Normotensive pregnant women 57.5 (n = 37) [98]
women
Whole blood (AAS) Kuwait Diabetic pregnant 85.65 (n = 14) Healthy pregnant women 102.65 (n = 17) [93]
women
Plasma (AAS) Chile Intrahepatic 78.43 (n = 21) Healthy pregnant women 92.22 (n = 98) [89]
cholestasis pregnant
women
Serum (AAS) Finland Intrahepatic 27.65 (n = 12) Healthy pregnant women 41.65 (n = 12) [90]
cholestasis pregnant
women
Plasma (GFAAS) Iran Pregnant women with 71.22 (n = 38) Healthy pregnant women 80.27 (n = 38) [79]
preeclampsia
Toenail (INAA) (mg/kg) United Kingdom Pregnant women with 0.56 (n = 53) Healthy pregnant women 0.62 (n = 53) [80]
preeclampsia
Serum (AAS) United Kingdom Pregnant women with 39.7 (n = 25) Healthy pregnant women 58.4 (n = 25) [99]
preeclampsia
Whole blood (AAS) Italy Euthyroid pregnant 75.7 (n = 74) Healthy pregnant women 76.8 (n = 81) [96]
women
a
Mean (number of samples).
b
AAS, atomic absorption spectrometry; GFAAS, graphite furnace atomic absorption spectrometry; INAA, instrumental neutron activation analysis.

with autoimmune thyroiditis (thyroid-peroxidase-antibody posi-
tive) are prone to develop hypothyroxinemia during pregnancy and
thyroid dysfunction after delivery. In a study conducted by Negro
et al. [96] after selenomethionine supplementation of pregnant
woman (200 g per day), thyroid inammatory activity fell, and
post-partum thyroid disease and permanent hypothyroidism were
signicantly reduced (Table 3).
Effect of tobacco, alcohol and polycyclic aromatic
hydrocarbons on selenium status in pregnancy
The course of pregnancy is also negatively affected by tobacco
smoking. Toxic substances present in tobacco smoke intensify
oxidative transformations and exert adverse effects on fetus devel-
opment. Frequent smoking and exposure to environmental tobacco
smoke during pregnancy may cause reduced availability of sele-
nium to fetus tissues, preterm delivery, preterm rupture of fetal
membranes, reduced birth weight of the child, hypotrophy, and
many other severe disorders in the period of intrauterine devel-
opment [100,101]. A low concentration of selenium lowers the
effectiveness of defense against detrimental factors and of the
antioxidative defense of the body. Kantola et al. [102] demonstrated
that the level of this element in the blood plasma of women in
delivery and in the plasma of cord blood was signicantly lower
in women who smoke than in non-smokers. No effect was, how-
ever, noted of tobacco smoking on selenium concentration in the
placenta.
Another addiction implicated in the suppression of selenium
transport to the fetus is alcohol consumption during pregnancy.
Alcohol may cause damage to and reduce the weight of the placenta,
through which selenium is transported to a developing child [103].
The proper amount of selenium in the bodies of a mother and
a fetus may protect them against the carcinogenic and muta-
genic activity of polycyclic aromatic hydrocarbons (PAH) present
in tobacco smoke and exhaust fumes, as well as in smoked foods
and those fried at high temperatures. Most PAHs induce the activ-
ity of P450-1A1 cytochrome (CYP1A1), which is responsible for the
formation of their toxic metabolites. This induction may also occur
in the placenta, and the PAHs may inactivate enzymes present
therein. This process is especially enhanced during pregnancy
[104,105]. Other studies have demonstrated that selenates might
inhibit the activity of CYP1A1. Huel et al. [106] examined 178
pregnant women and observed a lower concentration of selenium
in the plasma of women at risk of preterm delivery than in women
with a normal course of pregnancy. The patients at risk of preterm
delivery were also noted to have a higher activity of CYP1A1
cytochrome. The results of this study suggest that the antioxidative
activity of selenium may prevent preterm deliveries, affect the nal
outcome of cyclic compounds metabolism and protect the bodies
of fetus and mother against their adverse effects.
This review presents the potential inuence of selenium status
on many disorders relating to human reproduction and pregnancy.
The limitation of many previous studies is the lack of correction
for potential confounding factors such as include other nutritional
deciencies, dietary habits, general health of the participants, etc.
Obtaining detailed and accurate dietary and medical data is essen-
tial in the designing of any future studies. In conclusion, though
reliable evidence already exists to suggest that additional selenium
intake would be benecial in some of the aforementioned disor-
ders in selenium-decient women and men, results from future
intervention trials can provide us with arguments for or against
increasing selenium intake.
Conict of interest
The authors declare that there are no conicts of interest.
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