The Janus Face of Stress on Reproduction: From Health to Disease

Abstract

Parenthood is a fundamental feature of all known life. However, infertility has been recognized as a public health issue worldwide. But even when the offspring are conceived, in utero problems can lead to immediate (abortion), early (birth), and late (adulthood) consequences. One of the most studied factors is stress. However, stress response is, per se, of adaptive nature allowing the organism to cope with challenges. Stressors lead to deterioration if one is faced with too long lasting, too many, and seemingly unsolvable situations. In stress adaptation the hypothalamus-pituitary-adrenocortical axis and the resulting glucocorticoid elevation are one of the most important mechanisms. At cellular level stress can be defined as an unbalance between production of free radicals and antioxidant defenses. Oxidative stress is widely accepted as an important pathogenic mechanism in different diseases including infertility. On the other hand, the goal of free radical production is to protect the cells from infectious entities. This review aims to summarize the negative and positive influence of stress on reproduction as a process leading to healthy progeny. Special emphasis was given to the balance at the level of the organism and cells.

Full text

Review Article
The Janus Face of Stress on Reproduction:
From Health to Disease
Dóra Zelena
Hungarian Academy of Sciences, Institute of Experimental Medicine, Szigony 43, Budapest 1083, Hungary
Correspondence should be addressed to D´
ora Zelena; zelena.dora@koki.mta.hu
Received  December ; Revised  March ; Accepted  March 
Academic Editor: Sabrina Corbetta
Copyright ©  D´
ora Zelena. is is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Parenthood is a fundamental feature of all known life. However, infertility has been recognized as a public health issue worldwide.
But even when the ospring are conceived, in utero problems can lead to immediate (abortion), early (birth), and late (adulthood)
consequences. One of the most studied factors is stress. However, stress response is, per se, of adaptive nature allowing the organism
to cope with challenges. Stressors lead to deterioration if one is faced with too long lasting, too many, and seemingly unsolvable
situations. In stress adaptation the hypothalamus-pituitary-adrenocortical axis and the resulting glucocorticoid elevation are one
of the most important mechanisms. At cellular level stress can be dened as an unbalance between production of free radicals and
antioxidant defenses. Oxidative stress is widely accepted as an important pathogenic mechanism in dierent diseases including
infertility. On the other hand, the goal of free radical production is to protect the cells from infectious entities. is review aims to
summarize the negative and positive inuence of stress on reproduction as a process leading to healthy progeny. Special emphasis
was given to the balance at the level of the organism and cells.
1. Introduction
Parenthood is one of the most universally desired goals of
adulthood in all species []. However, among humans not all
coupleswhodesireachildwillachieveonespontaneously.
Although global infertility prevalence rates are dicult to
determine due to the presence of both male and female factors
[], infertility has been recognized as a public health issue
worldwide by the World Health Organization []. One in
every four couples in developing countries had been found to
be aected by infertility. Around % of these cases are due
to males, while the other half is due to female factors [,].
us, the burden remains high. For better understanding of
thebiologicalprocessesandfordevelopingnewtreatment
strategies animal models are indispensable. Moreover, there
is an economic interest due to livestock and plant infertility.
Reproduction. Reproduction is a fundamental feature of all
known life; each individual organism exists as the result
of reproduction and its main goal is to reproduce its gens
[]. In asexual reproduction an individual can reproduce
without involvement of another individual of that species
[]. Sexual reproduction typically requires the involvement
of two individuals or gametes. ere is a wide range of
reproductive strategies []. Some animals such as the human
do not reach sexual maturity for many years aer birth and
even then produce few ospring (k-strategy). For example,
elephantshaveonebabyaboutthreeyearsapart,andthe
whole group looks aer the youngsters. Because they ensure
the survival of a good percentage of their young, elephants do
not need to produce many ospring to hold their numbers
close to constant. Other species reproduce quickly; however,
under normal circumstances, most ospring do not survive
to adulthood (r-strategy). Frogs are a good example as they lay
many eggs and leave them in the water to hatch into tadpoles.
Some of the eggs and many of the little tadpoles as well as
developed frogs get eaten; thus, if one frog from a hundred
eggs lives to be a parent, his/her survival is really outstanding.
However frogs survive because of the many eggs.
Hindawi Publishing Corporation
International Journal of Endocrinology
Volume 2015, Article ID 458129, 10 pages
http://dx.doi.org/10.1155/2015/458129

International Journal of Endocrinology
In a wider view reproduction is a process leading to
healthy progeny. is process can be inuenced by internal
and external factors. First of all several factors have an
impact on fertility and mating ability of the individuals. But
even when the ospring are conceived, in utero problems
canleadtoimmediate(abortion),early(detectableatbirth,
e.g., preterm birth, low birth weight, and malformations),
and late consequences (detectable later in life and might
be only changes in vulnerability) []. e “developmental
origins of health and disease” concept says that the risk of
developing some chronic diseases in adulthood is inuenced
by environmental factors acting during the periconceptual,
fetal, and infant phases of early life [].
Nowadays human beings are challenged by changing in
mother-child relationship and social models of the extended
family []. e accelerated pace of life and unpredictable
environmental changes are added to the above factors. All of
these factors are, actually, chronic stressors, which we have to
deal with and they inuence the reproduction.
Stress
In the Body. Numerous health experts say that the number
one killer on the planet is stress. On the other hand the
father of stress concept, Hans Selye, considered stress the
“spice of life” [ ]. As such, he felt it was neither advantageous
nor even possible to eliminate it from life. Instead, the
challengeistocontainanystressandchannelitintofeelingsof
mastery.
We have to take into consideration a number of factors
contributing to the qualitative nature of the stress response
such as the intensity (high or low) and duration (acute or
chronic) of stressors, the individual’s ability to initiate an
adaptive response, and the phase of the life when the stressor
event occurs []. When we can cope with the challenges, then
we can become stronger (Figure ). us, stress response is,
per se, of adaptive nature as it allows the organism to cope
with stressful challenges, no matter of what nature, and to
maintain or restore body homeostasis. is is considered to
be eustress, which has also been positively correlated with life
satisfaction and well-being. On the contrary, when a person is
unable to adapt to the stressors, they will induce maladaptive
behaviors. We can call this state distress.Wehavetobealso
aware that the complete lack of stimuli is also harmful. us,
although it is important to minimize your distress, yet at the
same time you have to maximize your eustress by optimizing
the amount of stimuli.
During stress several systems are activated in the body;
however, according to Selye, the hypothalamus-pituitary-
adrenocortical (HPA) axis, as well as the resulting glucocor-
ticoid (GC) elevation, is the most important one (Figure ).
As a nal common pathway to dierent kind of stimuli
corticotropin-releasing hormone (CRH) and arginine vaso-
pressin (AVP) are released from the parvocellular cells of
the nucleus paraventricularis hypothalami (PVN) to the long
portal vessels of the median eminence []. ey reach the
anterior lobe of the pituitary through these vessels and stimu-
late the synthesis and release of adrenocorticotropin (ACTH)
from the adenohypophysis. ACTH reaches the adrenal gland
Optimum
(eustress)
Overload
(distress)
Boring
(lack of stress)
High
Performance
Low
Stress
F : Stress in the body: an optimal level of stress (called
eustress) is required for the best performance. Not only too much,
but also too little stimuli are harmful.
PVN
Hypothalamus
Pituitary
Adrenal gland
ACTH
GC
ox
CRH,
AVP
e eect of chronically enhanced GC on reproduction is as follows:
epigenetic changes, reduced weight of reproductive organs, shi in
puberty onset, gonad hormone dysfunction, miscarriage, preterm
labour, and poor immediate and late outcomes in ospring
F : e stress axis: the activation of the hypothalamo-
pituitary-adrenocortical axis is fundamental for adaptation. PVN:
nucleus paraventricularis hypothalami, ox: optic chiasm, CRH:
corticotropin-releasing hormone, AVP: arginine vasopressin,
ACTH: adrenocorticotropin, and GC: glucocorticoids, in rodents
corticosterone.
through the general circulation and releases GCs (mainly
cortisol in human and corticosterone in rodents) from the
zona fasciculata of the adrenal cortex. e release of GCs
is an adaptive response with an ultimate goal to maintain
homeostasis. HPA axis activation favors energy mobilization,
cardiac output, and sharpened cognition over growth, cellular
immunity, and reproduction. us, at high circulating levels

International Journal of Endocrinology 
Free
radicals
Antioxidants
Oxidative
stress
Well-being
Problems in reproduction:
follicle apoptosis
Estrogens are antioxidants!
↓Semen number and qualit
y
↑Sperm DNA damage
♀
♂
F : Stress at cellular level: an unbalance between production
of free radicals (e.g., reactive oxygen species (ROS)) and antioxidant
defenses inducing oxidative stress in the cells. Although oxidative
stress is widely accepted as an important pathogenic mechanism in
dierent diseases, yet ROS are physiological mediators of transcrip-
tion control and in many cells (e.g., leukocytes) ROS are protection
factors against infectious stimuli. e complete elimination of
free radicals would thus disrupt, rather than extend, the normal
functioning of the body.
of GCs survival occurs at the expense of reproduction.
erefore we can conclude that the division of resources
in the trade-o between survival and reproduction is likely
mediated, in part, through regulation of the stress response
by the HPA axis [].
At Cellular Level. Beyond the general beliefs stress can
be dened also at cellular level as an oxidative stimulus.
Oxidative stress (OS) is an unbalance between production
of free radicals, molecules characterized by high reactivity
(like reactive oxygen species (ROS) such as superoxide anion,
hydrogen peroxide, and the hydroxyl radical) and antiox-
idant (such as glutathione, vitamins, catalase, superoxide
dismutase, and various peroxidases) defenses in biological
systems (Figure )[]. Enhancement in ROS and their
metabolites can attack the cell membrane, and they can
result in modication of the DNA, lipids, and proteins
(such as tyrosine nitration and S-glutathionylation), altering
enzymatic systems. e imbalance of ROS can eventually lead
to epigenetic dierences, changes in cellular pathways and
transcription factors, produce irreparable alterations, and
cause cell death []. OS is widely accepted as an important
pathogenic mechanism in dierent diseases like rheumatoid
arthritis, myocardial infarction, diabetes mellitus, and so
forth []. According to the free radical theory (also known
as the OS theory) of aging the progressive decline in physio-
logical functions with age is also a result of the accumulation
of ROS-induced damage []. Among others OS has been
identiedasoneofthemanymediatorsofinfertility[].
On the other hand, in leukocytes and many other cells
(endothelial cells, mesangial cells, broblasts, thyrocytes,
oocytes, Leydig cells, adipocytes, etc.) ROS generation has
been assessed to have a positive physiological role protecting
the cells from pathological stimuli [].
2. Janus Face of Stress
2.1. Negative Eects. Individuals have limited resources that
they can either devote to reproduction or devote to somatic
maintenance (e.g., protection against ROS) []. erefore
it is not surprising that the general view is that stress,
which requires eorts to maintain homeostasis, negatively
inuences reproduction.
2.1.1. Fertility. Stress-induced trade-os to reproductive out-
put are evident across species. Animals (mammals, birds, and
reptiles), but even plants, all respond to physical stress by
decreasing male and female reproductive function [,].
From economical point of view, summer heat stress is a main
factorrelatedtolowfertilityinhigh-producingdairyherds
living in warm areas worldwide []. Costs of reproductive
eort are also evident: adult female rodents and primates
have higher GC levels during lactation [], which may lead
to the development of stress-related disorders like anxiety
and depression []. Negative consequences of stress are also
present in human and are not only an acute, short lasting
eect on fertility or mating abilities; but psychological or
physical stress experienced by adolescents can alter the onset
of puberty, shiing the clock of fertility [](Figure ).
Considering the mechanism of stress-induced infertil-
ity, expression of glucocorticoid receptors (GRs) has been
described in multiple cell types of the testis and expression is
conserved across species. e male gonads are direct targets
of GC action controlling testosterone biosynthesis in Leydig
cells []. Additionally, exogenous and stress-induced GCs
cause Leydig cell death [,], thereby providing contribut-
ing mechanisms to stress-derived androgen dysfunction in
males. e role of GCs in the female reproductive tract is
realized in the hypothalamus, where it is well established
that the stress-activated HPA axis suppresses hypothalamic-
pituitary-gonadal (HPG) function through inuencing the
gonadotropin releasing hormone secretion. In addition to
direct HPG axis regulation, GCs may regulate novel medi-
ators of the axis like gonadotropin-inhibitory hormone and
kisspeptin. Moreover, GRs have also been demonstrated in
the ovary, where GCs directly regulate steroid biosynthesis.
Another possible contribution of stress to fertility is
at cellular level. Human-made chemicals (among other air
pollutants) as well as unhealthy lifestyle behaviours, mainly
obesity, tobacco smoking, alcohol consumption, and medical
drug abuse, involve the generation of ROS and cellular oxida-
tivedamage.Moredataareavailableonmalereproduction
as both spermatogenesis and Leydig cell steroidogenesis are
very vulnerable to OS []. e impairments in male infer-
tility have resulted via mechanisms involving the induction
of peroxidative damage in the sperm plasma membrane,
DNA damage, and apoptosis [,] leading to metabolic
and functional disorders of male germ cells and may be a
primary cause of some types of infertility []. Motor vehicle
exhaust contains variety of toxic components and contributes

International Journal of Endocrinology
to a large proportion of the air pollution []. Its inhalation
can cause harmful eects on male reproductive functions by
altering organ weights, reducing the spermatozoa qualities,
and inducing OS. On the other hand, suboptimal maternal
nutrition (both low-protein diet and maternal obesity) is
accompanied by enhanced OS in ospring leading to altered
sperm function too [,]. Not only in rodents, but also
in humans, paternal obesity is associated with increased
OS in sperm, reduction in semen quality, and decreased
fertility. Beside direct oxidative damage the OS-induced
decrease in fetal lutein hormone concentration has negative
consequences on gonadal development leading to decreased
testosterone serum levels and sperm concentration [].
Although females are not that well studied, yet there is
strong evidence that ROS are involved in ovarian toxicity as
well [,]. More specically, several chemical and physical
agents induced ROS production, which initiates apoptosis in
antral follicles and also in primordial and primary follicle
[]. We have to add, however, that ovarian steroid might have
protective role by upregulating the expression of antioxidants
[]. Indeed, many preclinical reports indicated an enhance-
ment in OS aer ovariectomy [] and in postmenopausal
women estradiol therapy might decrease the ROS production
[].
Another side of the coin is that free radicals and ROS are
produced in direct proportion to metabolic rate as an
inevitable consequence of the molecular functioning of mito-
chondria and the electron transport chain. (is notion was
subsequently encapsulated in the “rate of living” theory [],
the idea that living fast is inevitably linked to dying young.)
Higher rates of metabolism that accompany reproduction
lead to greater free radical production and hence act as a
potential mediator of the trade-o between reproduction
and survival []. is cost of reproduction was conrmed
in many dierent species. For example, an increase in
Drosophila melanogaster female reproduction increased the
susceptibility to OS [].
2.1.2. In Utero Stress. Spontaneous miscarriage is the most
common adverse pregnancy outcome in humans and occurs
in –% of all recognized pregnancies [](Figure ).
e causes for a spontaneous miscarriage are diverse and
comprise genetic, endocrinologic, anatomic, immunologic,
or microbiologic aspects. Among others, environmental
factors such as psychosocial stress have been identied to
account for infertility and unexplained reproductive failure in
humans and other mammalian species such as baboons, elks,
and rodents. Stress has been shown to challenge pregnancy
maintenance by initiating an inammatory response at the
fetomaternal interface.
High perceived stress during pregnancy is a risk factor
for preterm labor and poor outcomes in ospring [].
Moreover, a higher frequency of growth-restricted fetuses
is a well-documented side eect of GC treatment during
pregnancy []. Although some form of stress per se might
not be harmful (e.g., work-related occupational stress), the
presence of other risk factors may result in a synergistic
eect which strengthened the odds of an adverse outcome
[]. It was also established that, for example, disasters as
perinatal stressors themselves are not that inuential on child
development, but the mental health of the mother (disturbed
bythedisaster)maystronglyinuencethelaterdevelopment
[].
e consequences of intrauterine stress extend beyond
the immediate perinatal period. Epidemiologic studies sug-
gest that elevations in GC exposure during fetal life may
result in fetal programming of cardiovascular, metabolic,
and neuroendocrine disorders in adult life. In the placenta,
conversion of maternal GCs into their inactive metabolites
provides a protective barrier. However, following GC excess,
this may be ineective in protecting the fetus from overex-
posure. In the rat, maternal exposure to dexamethasone (a
synthetic GC) during gestation results not only in reduced
birthweight,butalsoinhypertensionoftheadultospring
[,]. A nonhuman primate model of intrauterine dexam-
ethasone treatment revealed a dose-dependent reduction in
postnatal growth together with impaired glucose tolerance
andhyperinsulinemiainospring[]. Similarly, antenatal
GCs treatment in human ospring also induced insulin
resistance []. Furthermore, fetal exposure to synthetic GCs
is associated with persistent neurological consequences in
humans, including cortical thinning []. Excessive endoge-
nous GC levels have similar consequences (reduced birth
weight and programming eects, e.g., emotional problems)
[,]. One of the underlying mechanisms could be a
change in hippocampal GR expression, an important com-
ponentofthenegativefeedbackloopoftheHPAaxis
[].
As late, transgenerational consequences, ospring of
female rats subjected to restraint or environment stress (e.g.,
nutrient restriction) during pregnancy experienced fewer and
longer pregnancies, with less viable young, as adults [–].
Male rats from stressed or GC treated dams also demon-
strated reduced sexual behavior and fertility [,]. An
indirect connection between in utero stress and reproduction
wasthatstress,ACTH,orGCtreatmentofthemicemother
during pregnancy induced a subsequent delay in the onset
of puberty []. Persistent changes in gene expression that
remain aer the inciting event are thought to be mediated by
epigenetic mechanisms []. Intrauterine growth restriction
intheratcausedchangesinepigeneticproleofGRin
the hippocampus []. Moreover, fetal GC exposure caused
signicant variations in genome-wide promoter methylation,
ultimately leading to profound changes to the epigenetic
landscape.
Additionally, not only perinatal stress of the pups []
but also maternal stress during lactation may alter the
development of the ospring [].
2.2. Positive Eects
2.2.1. Fertility. GCs mediate the release of sex steroids thereby
regulating the timing of puberty onset. However, an optimum
level is needed, as both in the case of hypocortisolism (Addi-
son’s disease) and in the case of hypercorticism (Cushing’s
syndrome) the onset of puberty is altered.

International Journal of Endocrinology 
It is known that preconceptional eects can profoundly
alter later pregnancy and the fetus []. Despite this fact, in
humans, the pregnancy rate is not inuenced by injection
drug (such as heroin) use [], known to stimulate the HPA
axis []. We must mention, however, that low uptake of
reliable contraception can confound these results. Neverthe-
less, appropriate usage of morphine can be even benecial in
enhancing the pregnancy rate, based on a study using embryo
transfer in rats [].
Moreover, physical exercise, which stimulates the HPA
axis as well [], may prevent reproductive complications
associated with maternal obesity. e reduction in obesity
lowerstheriskofinfertilityandmiscarriage,anditmay
also reduce the probability of obesity-related complications
during later pregnancy [].
A possible mechanism of the enhanced pregnancy rate
can be the apoptosis inhibiting eect of GCs on luteal cells,
as the maintained luteal function contributes to the survival
of the fetus [].
As a further positive eect at homeostatic levels GCs
regulate many key aspects of early pregnancy, including the
eects of the maternal immune system, embryo attachment,
and invasion, along with the growth and development of
the fetus [,]. Despite the previously mentioned negative
consequences, the pregnancy-promoting potential of GCs
was also conrmed []. It is well established that uterine
receptivity and embryo implantation are determined by
uterine natural killer (NK) and other cells regulated by the
immune system []. Daily GC administration suppressed
thelevelsofuterineNKcellsinapatientwithahistory
of recurrent miscarriages []. ese immune modulatory
eects of GCs provide a link between stress and reproductive
function through improvement of the intrauterine environ-
ment. Although some further human cases also suggest
positive pregnancy rates and outcomes aer preconceptional
GC treatment [,], yet the association is not that unequiv-
ocal []. Nevertheless, there are GRs in the uterus and
GCs regulate estrogen eect through an interaction with
estrogen receptors. Moreover, in relation with reproduction
GCs primarily induce an antiapoptotic eect in cells of the
mammary gland [].
With respect to the cellular level, some carefully con-
trolled laboratory work has repeatedly concluded that OS is
unchanged or is lower in those individuals that reproduce
compared to those that do not despite the reproduction-
survival trade-o (see earlier) []. Females have extremely
high energetic demands during reproduction, particularly
through lactation. However, there was no evidence of
increased OS in mice. Instead, in the liver, markers of
oxidative damage (malondialdehyde, protein thiols, and the
proportion of glutathione in the oxidized form) indicated
lower OS in reproducing females when compared with
nonreproductive controls. Even during peak lactation, none
of the markers of oxidative damage indicated higher OS
than among nonreproductive females. Another example is
the breeding canaries, which showed decrease in plasma
oxidative damage (reactive oxygen metabolites and protein
carbonyls) compared both with nonbreeding canaries and
premanipulation values irrespective of sex and brood size
[].
ereasonmightbethat,forseveraltranscriptionfactors,
ROS are physiological mediators of transcription control.
e well-known examples of redox-sensitive transcription
factors are nuclear factor-𝜅B(NF-𝜅B) and activator protein-
(AP-). Studies have also demonstrated that low and con-
trolled concentrations of ROS play an important role in
normal sperm physiological processes such as capacitation,
hyperactivation, acrosome reactions, and signaling processes
to ensure appropriate fertilization []. e complete elimi-
nation of free radicals would thus disrupt, rather than extend,
the normal functioning of the body.
Another explanation is that reproduction activates
behavioural or physiological mechanisms that protect against
OS in order to improve immediate reproductive success and,
possibly, not to compromise future reproduction. is may
be especially important in species with multiple reproductive
cycles over the course of a lifetime.
Moreover, oxidative damage is not necessarily an evolu-
tionary mistake but may be benecial for evolution [].
2.2.2. In Utero. GCs are essential in mammals toprepare for
life aer birth. eir blood levels rise dramatically shortly
before birth. GCs trigger parturition not only in animals,
but also in humans []. However, for labour simultaneously
high estrogen levels are also required, but GCs may inhibit
the synthesis of the precursors both in fetus and mothers,
thereby reducing the placental estrogen synthesis. us, the
exogenously given GC may not be benecial; however, the
estrogen inhibiting eect of endogenous GC might be coun-
teracted by its degradative enzymes (-beta-hydroxysteroid
dehydrogenase) in the placenta.
If there is any sign of preterm birth, it has become
common practice to treat either antenatally the mother or
postnatally the infant with GCs to accelerate tissue develop-
ment, particularly of the lung [].isisaratherbenecial
eect; however, in the long run it can increase the risk of
adverse outcome in later life or even shorter lifespan (see
earlier). e perinatal action of the GCs depends on the
context and the timing as well as the type of administered
steroid. e optimal amount of GCs is very important as
either insucient or excessive GC exposure before birth may
alter the normal GC-regulated trajectory of maturation with
potential life-long consequences [].
Controversially, enriched environmental model, where
the animals show all endocrine signs of a chronic stress state
[], was benecial in many preclinical disease models [,
]. However, prenatal enriched environment (through the
entire pregnancy) per se induced anxiety and depressive-like
behaviors with poor attentional performance in male adult
ospring []. On the other hand it prevented the harmful
eect of adult acute stress. Moreover, juvenile enrichment
could transgenerationally rescue a genetic defect in long-term
potentiationandmemoryinaknockoutmousestrain[].
us, prenatal enriched environment may be also benecial
leading to resilience to adulthood.

International Journal of Endocrinology
Another model leading to chronic stress is the voluntary
wheel running [,]. e benecial eect of physical activ-
ity in many disease states is well-documented. In rodents,
wheel running during pregnancy transiently enhanced mem-
ory and hippocampal neurogenesis in the ospring until
preadolescence [,]. Exercise during pregnancy pro-
vided long lasting protection from neurodegeneration and
improved brain plasticity in the otherwise unstimulated
progeny []. Moreover, maternal voluntary wheel run-
ning signicantly oset morphological impairments due to
prenatal stress (maternal restraint) in the ospring []. In
humans, maternal exercise during pregnancy positively inu-
enced fetal health and ospring’s cognitive performance until
childhood []. Women who are the most physically active
had the lowest prevalence of gestational diabetes with
decreased incidence of obesity and type  diabetes in both
mother and ospring []. Exercise during pregnancy and
lactation prevented maternal obesity-induced elevation in
corticosterone in rat ospring as well []. us, in addition
to maintaining physical tness in the pregnant women, exer-
cise may be benecial in preventing or treating maternal-fetal
diseases.
Although in utero stress mostly results in low birth
weight, yet some authors reported even increased birth
weight aer intrauterine protein restriction []. We have to
add, however, that even in this case the pups had proportion-
ally smaller brains and at weaning rats exposed to low-protein
diets in utero had signicantly higher systolic blood pressure
relative to control animals.
e long-term consequences of in utero stimuli might be
dependent on the later environment. For example, the
ospring of protein restricted mothers lived longer than
absolute controls if they were to grow up on protein restricted
diet; however, a normal diet shortened their life [].
is eect might be induced by predictive adaptive
response (a kind of preconditioning) []. It means that
the organism adapts to a certain environment in utero and
in case aer birth the eventually experienced environment
matches the predicted environment, the organism’s pheno-
type proves to be adapted and life span is extended.
Positive eect of stress was detected also in the case
when repeated maternal stress was applied during the lacta-
tion period []. Male ospring of these mothers favoured
goal-directed behaviours and showed enhanced behavioural
exibility in their adulthood. Additionally, when the moth-
ers’ drinking water was supplemented with a low dose
corticosterone (. mg/mL) during the lactation (reecting
a form of mild environmental stimulation), the ospring
develop the ability to cope better with dierent situations
during life []. e progeny of these mothers, once adults,
showed improved learning capabilities, reduced fearfulness
in anxiogenic situations and resistance to ischemic neuronal
damage, and adapted better to colonic inammatory stress.
is protective eect is linked to hyporeactive HPA axis due
to epigenetically transmitted enhanced negative feedback in
the hippocampus.
3. Intervention Options
Taking into consideration thegrowing infertility public health
issue worldwide it is important to prevent the negative
consequences of stress on reproduction.
3.1. Body Stress. Because stress is considered to be number
one killer, several methods (many belonging to alternative
medicine) have been developed for stress relief. It is clear
that the mental status of the parents can profoundly alter the
fertility [,] and stress has a great impact on the psyche
[]. erefore mental well-being is an important factor [],
which can be reached by dierent relaxations techniques
(mental or physical), nutritional interventions, and pharma-
cological treatments. Psychological interventions were found
to improve some patients’ chances of becoming pregnant []
and relaxation may prevent preterm labour []. Massage
therapy may be also relaxing []. Physical activity is a good
example of eustress []. e benecial eect of exercise []
may be due—at least partly—to its trophic eect through,
for example, an enhanced brain derived growth factor level
in the hippocampus []. Pharmacological intervention is
focused mainly on the treatment of stress-related disorders,
thereby preventing secondary diseases. For example, pain
killers [], anxiolytics [], and antidepressant are all good
for stress relief, thereby enhancing the spirit for reproduction,
but their potential for enhancing, for example, the pregnancy
rate is not known, yet.
3.2. Oxidative Stress. Already plants have evolved a plethora
of mechanisms to circumvent the potential damaging eects
of OS. ese mechanisms include dierent levels of organi-
zation, from root-shoot signalling at the whole-plant level to
specic biochemical responses at the subcellular level, such
as reductions in photosynthesis and the consequent activa-
tion of photo- and antioxidant mechanisms in chloroplasts
[].
In mammals dierent antioxidant systems help to protect
the body against OS. For example, the MRE complex is an
important source of stress relief, being a key component of
DNA repair []. e most studied antioxidants are ascorbic
acid (Vitamin C), tocopherols (Vitamin E), and carotenoids
(Vitamin A), but enzymes, as well as Vitamin B complex,
glutathione, pantothenic acid, coenzyme Q, and carnitine,
and micronutrients such as zinc, selenium, and copper seem
to be also important [,,]. However, only low
quality evidence suggests that antioxidant supplementation
in subfertile males may improve clinical pregnancy rates
[] and in pregnant women there were no changes in
smoking induced OS in relation to vitamin supplement intake
[].
Because of high incidence obesity is one of the most
prevalent sources of OS []. Weight loss inducing lifestyle
changes such as dietary and exercise interventions has
benecial eects on metabolism both in rodents and in
humans []. In obese men weight loss can improve semen
parameters and therefore fertility.

International Journal of Endocrinology 
4. Conclusion
As many other processes, stress has also two faces; it is at the
sametimethegoodandthebadguy.Wehavetobeaware
that the most important thing is the balance, not too much,
butalsonottoolittle(Figure ).
A stress situation in itself does not aect health harmfully
when it is accompanied by the feeling that one is able to
overcome diculties successfully, which is actually the basis
of physical and mental development []. Challenges and new
situations lead to deterioration if one does not know the
solutions, if one is faced with too long lasting, too many,
and seemingly unsolvable situations, and if society seems
unpredictable, chaotic, and uncontrollable. e distress is
the hotbed of reproductive disabilities as well. However,
eustress, a certain level of HPA axis activation, is important
for normal fertility and pregnancy as well as intrauterine and
later development. An optimal level of stress is required for
resilience to bigger, harmful challenges.
At cellular level, when the natural balance between ROS
and antioxidants is disturbed, the rst restorative measure to
be taken should be changes in lifestyle, such as cessation of
smoking, limiting substance use, and maintaining a healthy
and balanced diet, which all may increase the reproduc-
tional capacity. Antioxidant supplementation may be taken
to improve the patient’s health outcomes including fertility,
pregnancy rate, and normal pregnancy []. We have to be
aware that males are more vulnerable to OS than females
because of the protective role of estrogens. On the other hand,
it appears that threshold levels for the benet or harm of OS
exist. erefore care must be given to acknowledge potential
undesirable eects of excessive vitamin supplementation
[].
Abbreviations
ACTH: Adrenocorticotropin
AP-: Activator protein-
AVP: v a s opr e ssi n
CRH: Corticotropin-releasing hormone
GC: Glucocorticoid
GR: Glucocorticoid receptors
HPA: Hypothalamic-pituitary-adrenocortical axis
HPG: Hypothalamic-pituitary-gonadal
NF-𝜅B: Nuclear factor-𝜅B
NK: Natural killer
OS: Oxidative stress
PVN: Nucleus paraventricularis hypothalamic
ROS: Reactive oxygen species.
Conflict of Interests
e author declares that there is no conict of interests
regarding the publication of this paper.
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