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Objective: To examine the potential effects of lifestyle factors on male reproductive health. Evidence of a global decline in human sperm quality over recent decades has been accumulating. Environmental, occupational, and modifiable lifestyle factors may contribute to this decline. This review focuses on key lifestyle factors that are associated with male infertility such as smoking cigarettes, alcohol intake, use of illicit drugs, obesity, psychological stress, advanced paternal age, dietary practices, and coffee consumption. Other factors such as testicular heat stress, intense cycling training, lack of sleep and exposure to electromagnetic radiation from mobile phone use are briefly discussed. Materials and method: A comprehensive literature search was performed to identify and synthesise all relevant information, mainly from within the last decade, on the major lifestyle factors associated with male infertility and semen quality. Database searches were limited to reports published in English only. A manual search of bibliographies of the reports retrieved was conducted to identify additional relevant articles. Results: In all, 1012 articles were identified from the database search and after reviewing the titles and abstract of the reports, 104 articles met the inclusion criteria. Of these, 30 reports were excluded as the full-text could not be retrieved and the abstract did not have relevant data. The remaining 74 reports were reviewed for data on association between a particular lifestyle factor and male infertility and were included in the present review. Conclusion: The major lifestyle factors discussed in the present review are amongst the multiple potential risk factors that could impair male fertility. However, their negative impact may well be mostly overcome by behaviour modification and better lifestyle choices. Greater awareness and recognition of the possible impact of these lifestyle factors are important amongst couples seeking conception.
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ORIGINAL ARTICLE
Lifestyle causes of male infertility
Damayanthi Durairajanayagam
*
Discipline of Physiology, Faculty of Medicine, Sungai Buloh Campus, Universiti Teknologi MARA, Selangor, Malaysia
Received 12 November 2017, Received in revised form 5 December 2017, Accepted 12 December 2017
KEYWORDS
Male infertility;
Lifestyle;
Risk factors;
Semen quality;
Sperm DNA fragmen-
tation
ABBREVIATIONS
AAS, anabolic–
androgenic steroids;
APA, advanced pater-
nal age;
ASIH, anabolic
steroid-induced
hypogonadism;
ART, assisted
reproductive technol-
ogy;
BMI, body mass index;
Chk1, checkpoint
kinase 1;
Abstract Objective: To examine the potential effects of lifestyle factors on male
reproductive health. Evidence of a global decline in human sperm quality over recent
decades has been accumulating. Environmental, occupational, and modifiable life-
style factors may contribute to this decline. This review focuses on key lifestyle fac-
tors that are associated with male infertility such as smoking cigarettes, alcohol
intake, use of illicit drugs, obesity, psychological stress, advanced paternal age, diet-
ary practices, and coffee consumption. Other factors such as testicular heat stress,
intense cycling training, lack of sleep and exposure to electromagnetic radiation
from mobile phone use are briefly discussed.
Materials and method: A comprehensive literature search was performed to iden-
tify and synthesise all relevant information, mainly from within the last decade, on
the major lifestyle factors associated with male infertility and semen quality. Data-
base searches were limited to reports published in English only. A manual search of
bibliographies of the reports retrieved was conducted to identify additional relevant
articles.
Results: In all, 1012 articles were identified from the database search and after
reviewing the titles and abstract of the reports, 104 articles met the inclusion criteria.
Of these, 30 reports were excluded as the full-text could not be retrieved and the
abstract did not have relevant data. The remaining 74 reports were reviewed for data
on association between a particular lifestyle factor and male infertility and were
included in the present review.
Conclusion: The major lifestyle factors discussed in the present review are
amongst the multiple potential risk factors that could impair male fertility. However,
*Address: Discipline of Physiology, Faculty of Medicine, Sungai Buloh Campus, Universiti Teknologi MARA, Jalan Hospital, 47000 Sungai
Buloh, Selangor, Malaysia. Fax: +60 3 6126 5224.
E-mail addresses: damayanthi@salam.uitm.edu.my,damayanthi.d@gmail.com.
Peer review under responsibility of Arab Association of Urology.
Production and hosting by Elsevier
Arab Journal of Urology (2018) xxx, xxxxxx
Arab Journal of Urology
(Official Journal of the Arab Association of Urology)
www.sciencedirect.com
https://doi.org/10.1016/j.aju.2017.12.004
2090-598X Ó2018 Production and hosting by Elsevier B.V. on behalf of Arab Association of Urology.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Durairajanayagam D. Lifestyle causes of male infertility, Ar ab J Urol (2018), https://doi.org/10.1016/j.aju.2017.12.004
ECS, endogenous can-
nabinoid system;
GnIH, gonadotropin-
inhibitory hormone;
HADS, Hospital
Anxiety and Depres-
sion Score;
HPA, hypothalamus–
pituitary–adrenal;
HPG, hypothalamus–
pituitary–gonadal;
IVF, in vitro fertilisa-
tion;
ICSI, intracytoplasmic
sperm injection;
IUI, intrauterine
insemination;
MMP, mitochondrial
membrane potential;
ROS, reactive oxygen
species;
SOD, superoxide
dismutase
their negative impact may well be mostly overcome by behaviour modification and
better lifestyle choices. Greater awareness and recognition of the possible impact of
these lifestyle factors are important amongst couples seeking conception.
Ó2018 Production and hosting by Elsevier B.V. on behalf of Arab Association of
Urology. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
There has been increasing evidence on the global decline
in human sperm quality over the past few decades [1–4].
In the most recent report, Levine’s group performed a
systematic review and meta-regression analysis of the
current trends in sperm counts. The comprehensive
study involved 42 935 men with samples spanning over
40 years. They reported a significant decline of 50–
60% in sperm counts amongst men from North Amer-
ica, Europe, Australia and New Zealand [5]. This latest
finding has sparked even greater concern over the rea-
sons behind the apparent decline in the sperm count of
Western men.
As male fertility can be influenced by a variety of fac-
tors, one possible explanation for the declining trend
would be that there are environmental and/or occupa-
tional factors along with lifestyle practices that con-
tribute to the deterioration of semen quality [6–9].
The present article reviews the available evidence
examining the potential effects of lifestyle factors on
male reproductive health. It focuses on the following
lifestyle factors that are associated with male infertility:
smoking cigarettes, alcohol intake, use of illicit drugs,
obesity, psychological stress, advanced paternal age,
dietary practices, and coffee consumption. Other fac-
tors such as testicular heat stress, intense cycling train-
ing, lack of sleep, and exposure to electromagnetic
radiation from mobile phone use are also briefly
touched upon.
Materials and methods
A systematic review of literature was conducted using
PubMed over the last 10 years (from December 2008
to November 2017) for all published reports on the
major lifestyle factors associated with male infertility
(Fig. 1). The inclusion criterion was English language
studies reporting on the lifestyle factors associated with
male infertility such as ‘smoking’, ‘alcohol’, ‘marijuana’,
‘cocaine’, ‘anabolic steroids’, ‘diet’, ‘obesity’, ‘BMI’,
‘psychological stress, ‘advanced paternal age’, and ‘caf-
feine’. The keyword search terms for each of these fac-
tors were used in combination with the following
search terms: ‘male infertility’, ‘male fertility’, ‘sperm
quality’, ‘semen parameters’, ‘DNA fragmentation’, ‘pa-
ternal’, ‘maternal’, ‘ART’, and ‘IVF’. Pertinent studies
that were published prior to the 10-year timeframe were
included at the discretion of the author, as were some
studies on testicular heat stress, intense cycling training,
lack of sleep, and exposure to electromagnetic radiation
from mobile phone use. Reference lists of the reports
were searched for further relevant citations, which were
subject to the inclusion criteria. All non-English lan-
guage studies and those without a published abstract
were not included.
Results
In all, 1012 articles were identified from the database
search and after reviewing the titles and abstract of the
2 Durairajanayagam
Please cite this article in press as: Durairajanayagam D. Lifestyle causes of male infertility, Arab J Urol (2018), https://doi.org/10.1016/j.aju.2017.12.004
reports, 104 articles met the inclusion criteria. Of these,
30 reports were excluded as the full-text could not be
retrieved and the abstract did not have data on the asso-
ciation between the lifestyle factor of interest and male
infertility. The remaining 74 reports were reviewed for
data on the association between a particular lifestyle fac-
tor and male infertility. Available evidence pertaining to
the potential adverse effects of these lifestyle factors on
male fertility vary in strength. Certain factors, such as
cigarette smoking and alcohol intake are likely to exert
an additive effect, whilst other factors may pose a threat
when exposed along with other environmental and occu-
pational factors.
Smoking
Cigarette smoke contains >7000 chemicals, including
highly carcinogenic tobacco-specific nitrosamines, [e.g.
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N-
nitrosonornicotine], polycyclic aromatic hydrocarbons
(e.g. benzo[a]pyrene), and volatile organic compounds
(e.g. benzene) [10]. Cigarette smokers have increased
exposure to hazardous substances such as tar, nicotine
(which is highly addictive), carbon monoxide, and heavy
metals (e.g. cadmium and lead) [11].
Cigarette smoking is a known potential risk factor for
decreased male fertility. Smoking is associated with leu-
cocytospermia, a major endogenous source of reactive
oxygen species (ROS). Moreover, tobacco smoke con-
tains ROS at levels that can overwhelm the endogenous
antioxidant defences. Increased seminal levels of ROS in
smokers expose spermatozoa to oxidative stress, conse-
quently impairing sperm function and ultimately com-
promising male fertility (reviewed in [12]). However,
the mechanisms underlying the effects of smoking on
sperm quality have not been fully clarified.
A large meta-analysis involving males from 26 coun-
tries/regions concluded that smoking causes a decline in
sperm quality in both fertile and infertile men [13].
Sperm concentration in male smokers was reported to
be typically 13–17% lower than that of non-smokers
[14]. Moreover, cigarette smoking has been negatively
associated with sperm count, motility, and morphology.
The decline in semen quality was found to be more
marked in heavy (>20 cigarettes/day) and moderate
(10–20 cigarettes/day) smokers compared to mild smok-
ers (1–10 cigarettes/day). The effect size was higher in
infertile males than in the general population [15].
Besides its association with impaired male fertility,
tobacco smoking is also responsible for increases in
DNA damage, aneuploidies, and mutations in sperm
[16]. One study suggested that the deterioration of
semen quality amongst male smokers was correlated
with increased DNA fragmentation rates and decreased
expression of checkpoint kinase 1 (Chk1). Without the
activation of Chk1 in response to DNA damage, there
would be a decline in sperm repair leading to increased
sperm apoptosis, which could lower semen quality [17].
Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart outlining the process of database
search for study identification, screening, eligibility, and inclusion.
Lifestyle causes of male infertility 3
Please cite this article in press as: Durairajanayagam D. Lifestyle causes of male infertility, Ar ab J Urol (2018), https://doi.org/10.1016/j.aju.2017.12.004
Thus, the general effect of cigarette smoking on male
fertility may result from the combined roles of elevated
oxidative stress, DNA damage, and cell apoptosis,
which could explain not only the reduction in semen
quality, but also impaired spermatogenesis, sperm mat-
uration, and sperm function reported to be present in
smokers compared to non-smokers. Contributing fac-
tors leading to these effects in male smokers include
the presence of nicotine and its metabolite, cotinine,
benzo(a)pyrene, as well as cadmium levels [11]. For
example, a meta-analysis of 13 317 men found that
smoking was associated with higher mean testosterone
levels, which could be attributed to the inhibition of
testosterone breakdown by cotinine [18].
Pre-conception paternal smoking presents an
increased risk of several morbidities in the offspring,
which could perhaps be mediated via epigenetic modifi-
cations transmitted through spermatozoa. Male smok-
ers showed a tendency towards increased alterations in
methylation patterns genome-wide in their sperm
DNA compared with never-smokers [19]. Maternal
smoking during pregnancy and lactation could poten-
tially cause harmful effects on male offspring fertility.
Maternal cigarette smoke exposure during the gestation
and weaning period was shown to cause diminished
germ cell population, germ cell DNA damage, and
defective sperm in the male offspring [20].
With paternal smoking being a significant risk factor
for in vitro fertilisation (IVF) and intracytoplasmic sperm
injection (ICSI) failure, paternal smoking could perhaps
contribute to decreased assisted reproductive technology
(ART) success rates as much as maternal smoking (a risk
factor only for IVF failure) does or more [21]. Moreover,
male smoking could even influence the clinical pregnancy
rate per intrauterine insemination (IUI) cycle [22].
Amongst former smokers, every additional year follow-
ing the male partner’s smoking cessation reduced the risk
of ART failure by 4%, particularly between clinical preg-
nancy and live birth [23].
Despite there being no concrete potential relationship
between smoking and male infertility as of yet, available
evidence on cigarette smoking and male fertility support
the recommendation of smoking cessation and minimis-
ing exposure to tobacco smoke amongst couples who
are trying to conceive.
Alcohol
A meta-analysis involving 29 914 men reported a signif-
icant association between alcohol intake and lower
semen volume, but not sperm parameters [13]. However,
a recent meta-analysis involving 16 395 men reported
that alcohol intake has a detrimental effect on semen
volume and sperm morphology [24]. Direct exposure
of spermatozoa to alcohol (at concentrations corre-
sponding to that of serum after moderate and heavy
drinking) was found to be harmful to sperm motility
and morphology in a dose-dependent manner [25].
The actions of alcohol on the male reproductive sys-
tem seem to occur at all levels of the hypothalamus–pi
tuitary–gonadal (HPG) axis. Alcohol appears to inter-
fere with the production of GnRH, FSH, LH, and
testosterone, as well as impair the functions of Leydig
and Sertoli cells. As a result, the production, morpho-
logical development and maturation of spermatozoa
could be impaired [26]. Spermatogenesis appears to
gradually decline with increasing levels of alcohol intake
[27]. Partial or complete spermatogenic arrest and Ser-
toli cell-only syndrome were more commonly present
amongst heavy drinkers compared to non-drinkers [28].
Chronic alcohol intake was found to have a detri-
mental effect on both semen quality and the levels of
male reproductive hormones [29]. Conversely, a study
comprising 8344 healthy male volunteers found that
moderate alcohol intake was associated with higher
testosterone levels but not with semen quality [30].
Chronic ethanol administration has been shown to
decrease testicular steroidogenic and antioxidant
enzyme activities resulting in increased oxidative stress
[31], which could disrupt testosterone synthesis and
compromise fertility.
A study on the male partners of couples facing pri-
mary infertility found that teratozoospermia was present
in 63% and 72% of males who drank alcohol moder-
ately (40–80 g/day) and heavily (>80 g/day), respec-
tively. None of the heavy alcohol drinkers were
normozoospermic and most were oligozoospermic
(64%), which is suggestive of progressive testicular dam-
age in relation to increasing daily alcohol intake [32].
Similarly, another study found alcohol consumption
rates to be significantly higher in men with severe oligo-
zoospermia and with non-obstructive azoospermia com-
pared to fertile controls [33].
Although the effects of alcohol on male reproductive
function are dependent on the intake amount, a thresh-
old amount of alcohol beyond which the risk of male
infertility increases has not yet been determined. More-
over, it must be kept in mind that whilst alcohol intake
and cigarette smoking alone did not affect sperm param-
eters, both habits together appear to exert an additive
effect that could adversely alter sperm parameters [34].
Recreational drugs
Marijuana, cocaine, anabolic–androgenic steroids
(AAS), opiates (narcotics), and methamphetamines are
examples of illicit drugs that exert a negative impact
on male fertility. The adverse effects of these drugs
could impair the HPG axis, testicular architecture, and
sperm function [35].
Cannabis or commonly referred to as marijuana, is
the most abused illicit drug globally and has
4 Durairajanayagam
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predominantly male users. Regular marijuana smoking
(more than once weekly within the last 3 months) was
found to lower sperm concentration and total sperm
count amongst young men, and this effect was further
exacerbated when marijuana was used in combination
with other recreational drugs [36]. Deregulation of the
endogenous cannabinoid system (ECS) was shown to
significantly impair spermatogenesis resulting in lower
total sperm count and motility [37]. Competition
between the phytocannabinoids in marijuana and endo-
cannabinoids for binding to the cannabinoid and vanil-
loid receptors leads to disruption of the homoeostasis of
the ECS, which could consequently impair male fertility
[38]. Sperm from infertile men have a marked modula-
tion of endocannabinoid metabolism and reduction in
endocannabinoid biosynthesis compared to sperm from
fertile men [39].
Cocaine is a highly addictive, strong stimulant drug.
Male rats given high doses of cocaine chronically before
mating had lower pregnancy rates and offspring birth
weights [40]. Both acute and chronic exposure to cocaine
disrupted spermatogenesis and damaged the testicular
ultrastructure [40,41]. These changes could have been
brought about by cocaine-induced apoptosis [42].
Long-term (5 years) cocaine users were associated with
lower sperm concentration and motility, and a higher
fraction of sperm with abnormal morphology [43].
Compared to other infertile men, infertile cocaine users
are more likely to have other concurrent risk factors of
male infertility such as smoking, (other) substance
abuse, as well as a prior history of sexually transmitted
infections [44].
Testosterone and its derivatives comprise a family of
hormones called AAS. AAS are used primarily by males
to enhance their athletic performance and/or personal
appearance [45]. The use of AAS has expanded beyond
that of professional athletes and the prevalence of ana-
bolic steroid-induced hypogonadism (ASIH) amongst
young men and teenagers is on the rise [46]. A retrospec-
tive study found that ASIH was the most common cause
of profound hypogonadism (50 ng/dL testosterone)
amongst men who sought treatment for hypogonadism
[47]. Increased levels of exogenous testosterone, result-
ing from AAS use, exert a negative feedback on the
HPG axis causing reversible suppression of spermatoge-
nesis, testicular atrophy, and infertility. This may result
in transient azoospermia with a recovery period of pos-
sibly even up to 2 years. Additionally, ASIH induced by
AAS abuse can also result in loss of libido and erectile
dysfunction [48]. Consequences from AAS use and sub-
sequently treatment of the resulting hypogonadotrophic
hypogonadism depend on the dose, duration, and type
of AAS used [49]. Some studies have pointed towards
a more permanent repercussion of steroid use on male
fertility and as such, AAS use should be highly discour-
aged [50].
Obesity
Overweight and obesity are associated with excessive fat
accumulation, which can be evaluated using the body
mass index (BMI). Overweight (BMI 25–<30 kg/m
2
)
and obese (BMI 30 kg/m
2
) males are associated with
a decrease in sperm quality and a greater risk of infertil-
ity. A systematic review of 30 studies comprising 115 158
males found that paternal obesity was associated with
lowered male reproductive potential. Men who were
obese had a higher percentage of sperm with DNA frag-
mentation, abnormal morphology, and low mitochon-
drial membrane potential (MMP), and were more
likely to be infertile [51]. Sperm with high DNA frag-
mentation and low MMP are associated with high levels
of ROS [52].
A meta-analysis involving 13 077 men reported that
obese men were more likely to be oligozoospermic or
azoospermic compared to men within a normal weight
range [53]. A population-based study found that as
BMI and waist circumference increased, the prevalence
of low ejaculate volume, sperm concentration, and total
sperm count were also greater in overweight and obese
men of unknown fertility. However, they did not find
an association between body size and sperm motility,
morphology or DNA damage [54]. A smaller study com-
prising 23.3% obese men showed that males who were
overweight and obese had no increased relative risk of
abnormal semen parameters, although their testosterone
and sex hormone-binding globulin levels decreased with
increasing BMI [55]. Additionally, inhibin B levels are
decreased, whilst oestradiol levels are increased in over-
weight or obese men [56].
The presence of excess white adipose tissue in obese
individuals causes increased conversion of testosterone
to oestrogen, and affects the HPG axis leading to a
reduction in gonadotrophin release. These effects result
in secondary hypogonadism and impaired spermatogen-
esis [57]. Increased production of leptin by the white adi-
pose tissue decreases testosterone production.
Adipokines stimulate the production of ROS by leuco-
cytes. Insulin resistance and dyslipidaemia can induce
systemic inflammation, leading to oxidative stress [58].
Increased scrotal adiposity leads to testicular heat stress
and causes oxidative stress. Increased scrotal tempera-
ture along with lack of activity impairs spermatogenesis.
Increased oxidative stress impairs sperm motility, DNA
integrity, and sperm–oocyte interaction [59].
Obese men who attempt ART have reduced rates of
live birth per ART cycle [51]. Increased paternal BMI
is associated with decreased blastocyst development,
pregnancy, and live-birth rates, but not early embryo
development [60].
One pilot study investigated if maternal obesity could
influence the semen quality of her male offspring.
Increasing maternal BMI had a negative relationship
Lifestyle causes of male infertility 5
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with the offspring’s inhibin B levels. Although the study
found a suggestive trend of impaired fertility status in
the offspring of overweight mothers, it was not statisti-
cally significant [61].
The severity of the consequences of obesity on the
hormonal profile, sperm parameters, and DNA damage,
as well as pregnancy outcomes may be varied due to the
presence of other co-morbidities. Weight loss and lower-
ing of BMI have helped improve sperm quality in some,
but not all men [62].
Psychological stress
Stress, in its many forms, may be detrimental to male
reproductive potential. The classical stress response acti-
vates the sympathetic nervous system and involves the
hypothalamus–pituitary–adrenal (HPA) axis [63]. Both
the HPA axis and gonadotrophin-inhibitory hormone
(GnIH) exert an inhibitory effect on the HPG axis and
testicular Leydig cells. The resulting inhibition of the
HPG axis reduces testosterone levels. This leads to
changes in Sertoli cells and the blood–testis barrier,
which ultimately causes spermatogenesis to be sup-
pressed. Impairment of testosterone secretion forms
the main basis underlying the detrimental effects of psy-
chological stress on spermatogenesis [64]. Raised corti-
costerone levels in stressed rats were found to suppress
both testosterone and inhibin levels [65].
One study evaluated the effects of psychological
stress on reproductive hormones and sperm quality in
the male partner of infertile couples. The level of psy-
chological stress was assessed using the Hospital Anxi-
ety and Depression Score (HADS) questionnaire and
27% of the study population was found to have signifi-
cant psychological stress. Men who were significantly
stressed (HADS 8) had lower levels of testosterone,
and higher levels of FSH and LH than men with normal
HADS (HADS <8). However, GnRH levels were
unchanged. Testosterone was negatively correlated,
whilst FSH and LH were positively correlated with their
HADS. Men with HADS 8 had a lower sperm count,
motility, and normal morphology compared to those
with normal HADS. Serum testosterone levels were pos-
itively correlated, whilst LH and FSH were negatively
correlated with sperm count and motility [66].
Similarly, in an animal model study, acute restraint
stress was shown to suppress sperm motility from 30
min of restraint onwards. Plasma levels of ACTH and
corticosterone were elevated, whilst FSH, LH, and testos-
terone were decreased. It appears that the increased HPA
axis activity had inhibited HPG activity [67].
A meta-analysis of 57 cross-sectional studies involv-
ing 29 914 participants reported that psychological
stress could lower sperm concentration and progressive
motility, and increase the fraction of sperm with abnor-
mal morphology [13].
One study investigated the association between psy-
chological stress in the form of occupational, life stress,
family functioning, and semen quality. They found that
occupational stress was negatively associated with
semen quality, with a positive association between stress
and percentage of sperm with DNA damage. Satisfac-
tion with family functioning was negatively associated
with the percentage of motile sperm cells. However, life
stress did not correlate with semen quality [68]. Another
study evaluated the associations between work-related
stress, stressful life events, and perceived stress on semen
quality. Of these, perceived stress and stressful life
events were negatively associated with semen quality,
particularly sperm motility and percentage normal mor-
phology. However, work-related stress was not associ-
ated with semen parameters [69].
In another study amongst healthy volunteers, the
effect of examination stress was investigated on seminal
antioxidant content and sperm quality. During the
stressful period just before examination, seminal glu-
tathione and free sulphydryl content, as well as sperm
motility was reduced, whilst the percentage of sperm
with abnormal morphology was higher compared to a
non-stress period 3 months after examination [70].Sem-
inal antioxidant enzymes, superoxide dismutase (SOD)
and catalase were also measured. During the stressful
pre-examination period, stress scores and SOD activity
was increased, whilst sperm concentration and motility
were decreased compared to the post-examination
non-stress period. However, catalase activity remained
unchanged [71].
Psychological stress is associated with reduced pater-
nity and abnormal semen parameters, and thus could be
a causative factor in affecting male infertility.
Advanced paternal age (APA)
Advanced maternal age is defined as the age of 35 years,
beyond which there is significantly increased risks of
adverse reproductive outcome for women [72]. How-
ever, APA has not been as well-defined, with studies
commonly defining it to be between 35 and 50 years of
age or categorising it into age ranges of 5 years [73].A
meta-analysis of 90 studies involving 93 839 participants
reported an age-associated decline in semen volume,
sperm total, and progressive motility, normal sperm
morphology along with an increase in DNA fragmenta-
tion. However, despite its decline over time, sperm con-
centration did not decline with increasing male age [74].
Analysis of semen parameters of healthy men over a
wide age range (22–80 years) showed that semen volume
and sperm motility declined gradually and continuously
with age without a specific age threshold [75]. However,
a retrospective study involving 5081 men (aged 16.5–72.
3 years) suggested that the decline in sperm parameters
and its corresponding age threshold were as follows:
6 Durairajanayagam
Please cite this article in press as: Durairajanayagam D. Lifestyle causes of male infertility, Arab J Urol (2018), https://doi.org/10.1016/j.aju.2017.12.004
total sperm count and total motile sperm - after 34 years
of age; sperm concentration and fraction of sperm with
normal morphology - after 40 years of age; sperm motil-
ity and progressive parameters of motile sperm - after
43 years of age; ejaculate volume - after 45 years of
age; ratio of Y:X-bearing sperm in ejaculates - after
55 years of age. Thus, the authors proposed that inde-
pendent of the woman’s age, the likelihood of pregnancy
declines after intercourse with men aged >34 years [76].
The exact mechanisms underlying the age-associated
decline in male fertility have not been determined [77].
These age-dependent changes in semen quality could
probably be attributed to normal physiological changes
in the reproductive tract that occur with ageing,
decreased capacity for cellular and tissue repair of dam-
age induced by exposure to toxicants or diseases, and
increased chances with age of having reproductive dam-
age resulting from exogenous exposures such as smoking
or infections [75]. The fact that both normal physiolog-
ical processes and environmental factors could be held
responsible for the effects of ageing on the male repro-
ductive system adds to its complexity [78].
As men grow older, testicular function and metabo-
lism deteriorates as the testis undergoes age-related mor-
phological changes such as decrease in the number of
germ cells, Leydig and Sertoli cells, as well as structural
changes, including the narrowing of seminiferous
tubules (reviewed in [78]). Concentrations of free and
total testosterone steadily decline with increasing male
age, leading to primary hypogonadism. Regulation of
the HPG axis is also altered as men age. Accumulation
of ROS in male germ cells throughout the course of age-
ing leads to oxidative stress and damage to sperm DNA.
Apoptosis is also increased in the ageing testes (reviewed
in [78]). These age-related changes inevitably lead to
deterioration of sperm quality and quantity.
APA-induced increase in sperm DNA fragmentation
adversely affects the success rates of ART outcomes, as
well as early embryo development [79]. A study of donor
ovum cycles indicated a 26% lower odds of live birth
with each 5-year increase in paternal age [80]. In couples
undergoing IVF, implantation and pregnancy rates
decreased with increasing paternal age when the mater-
nal age was between 30–34 years [81]. However, paternal
age did not seem to affect ART outcomes when ICSI
and good quality oocytes were used [82]. APA nega-
tively influenced the number of high-quality embryos
but did not affect pregnancy outcomes in couples under-
going ICSI cycles [83].
Independent of maternal age, APA is associated with
increased rates of spontaneous abortion and lower preg-
nancy rates amongst couples attempting to conceive
either naturally or using IUI [77]. The association
between APA and foetal loss suggests that DNA muta-
tions originating from the ageing male are detrimental
to the offspring’s health [72]. Paternal ageing causes
genetic and epigenetic changes in spermatozoa, which
could proceed through fertilisation into the offspring,
causing a variety of diseases in the resulting offspring
[78].
Therefore, couples must be counselled with equal
emphasis on the contribution of APA and advanced
maternal age as being potential risk factors of negative
pregnancy outcomes and impaired offspring health.
Diet
Diet and nutrition plays an important role in semen
quality. A recent exhaustive systematic review of obser-
vational studies concluded that intake of a healthy, bal-
anced diet could improve semen quality and fecundity
rates amongst males [84]. For example, the Mediter-
ranean diet, which is enriched with omega-3 fatty acids,
antioxidants, and vitamins, and low in saturated and
trans-fatty acids, were found to be inversely associated
with low semen quality parameters [84]. Thus, greater
compliance to the Mediterranean diet may aid in
improving semen quality [85].
Another study defined a typical ‘Western’-style diet
as one that was high in red and processed meat, refined
grains, and high-energy drinks, whilst a more ‘Prudent’
diet comprised mainly of white meat, fruit, vegetables,
and whole grains. The healthier ‘Prudent’ diet was pos-
itively associated with sperm progressive motility, but
not sperm concentration and morphology [86]. In fact,
a healthy dietary intake was reported to improve at min-
imum one measure of semen quality [87]. To begin with,
the practice of substituting processed red meats with fish
may have a positive impact on sperm counts and mor-
phology [88].
Vegetables and fruits, fish and poultry, cereals and
low-fat dairy products were amongst the foods posi-
tively associated with sperm quality. However, diets
consisting of processed meat, full-fat dairy products,
alcohol, coffee, and sugar-sweetened beverages were
associated with poor semen quality and lower fecundity
rates [84].
Caffeine
Most studies have not found an association between
moderate caffeine intake and male fertility. A large
meta-analysis with 29 914 participants found no signifi-
cant effects of coffee consumption on semen quality [13].
Another study involving 2554 young Danish men also
found no association between moderate caffeine
(800 mg/day) or cola (1 L/day) intake and reduction
in semen quality [89].
However, Belloc et al. [90] found that nearly 76% of
caffeine consumers (3.0 ± 1.8 cups of coffee/day) had a
Lifestyle causes of male infertility 7
Please cite this article in press as: Durairajanayagam D. Lifestyle causes of male infertility, Ar ab J Urol (2018), https://doi.org/10.1016/j.aju.2017.12.004
slight increase in semen volume, whereas fertile vasec-
tomy patients who drank 6 cups of coffee/day pre-
sented with higher sperm motility [91]. A recent
systematic review involving 19 967 men found that in
most of the studies, semen parameters were affected by
cola-containing beverages and caffeine-containing soft
drinks, but not by caffeine intake from mainly coffee,
tea, and cocoa drinks [92].
Caffeine intake may impair male reproductive func-
tion possibly through sperm DNA damage. The Ricci
et al. [92] meta-analysis suggests that caffeine intake
could be associated with double-strand DNA breaks
and sperm aneuploidy, but not DNA adducts. Indepen-
dent of age, healthy non-smoking men whose daily cof-
fee intake amounted to >308 mg (2.9 cups) have
shown increased double-strand sperm DNA damage
[93]. By contrast, the Belloc et al. [90] study found that
caffeine intake was associated with a lower risk of ele-
vated DNA fragmentation (odds ratio 0.92, 95% CI
0.92–0.99).
Some studies have even reported that coffee con-
sumption in males was associated with prolonged time
to pregnancy [92]. Amongst couples undergoing IVF,
male caffeine consumption was not significantly associ-
ated with live-birth, fertilisation and implantation rates
[94]. Male caffeine intake was associated with a lower
probability of achieving a clinical pregnancy and live
birth per ART cycle, particularly in men consuming
272 mg caffeine/day [95]. Male consumption of coffee
had a negative relationship with ICSI fertilisation rate,
but did not seem to affect implantation, pregnancy,
and miscarriage rates [96]. Amongst couples with suc-
cessful IVF/gamete intra-fallopian transfer (GIFT) out-
comes, male caffeine consumption had no effect on
fertilisation, pregnancy or live-birth rates. However,
the odds of multiple gestations increased by 3.0 (95%
CI 1.2–7.4) for men who consumed an additional 100
mg caffeine daily during the week of the initial clinic
visit [97].
The potential developmental toxicity of caffeine in
the reproductive function of the male progeny has also
been examined. Men exposed in utero to increasing
maternal coffee consumption displayed a tendency
toward decreasing semen volume and testosterone
levels. Whilst current caffeine consumption in adult
males was not associated with semen quality, males with
high caffeine intake had increased serum testosterone
levels compared to those with low intake [98]. Maternal
coffee consumption during gestation and lactation
impaired gonadal development and seemed to exert per-
manent detrimental effects on the reproductive potential
of male offspring rats [99].
In summary, based on the current available data,
there is no firm potential relationship between caffeine
intake and male infertility.
Other lifestyle risk factors
Genital heat stress resulting from scrotal hyperthermia
is a substantial risk factor for male infertility. Prolonged
hours of sitting or exposure to radiant heat, varicocele,
and cryptorchidism can all lead to testicular heat stress
[100]. Elevated scrotal temperatures lead to spermato-
genic arrest, germ cell apoptosis, oxidative stress, and
sperm DNA damage [59]. Cycling as a sport is associ-
ated with increased generation of testicular heat. Intense
cycling training for 16 weeks in young healthy male road
cyclists was found to induce an increase in seminal ROS
and malondialdehyde levels, along with a decrease in
enzymatic antioxidants and total antioxidant capacity.
These changes were maintained even after 4 weeks of
recovery [101]. Furthermore, seminal interleukin levels
were raised in these non-professional cyclists and sperm
parameters were suppressed despite the 4 weeks of
recovery [102].
Sleep disturbances may possibly have adverse effects
on male fertility, as semen volume was lower in patients
with difficulty in initiating sleep, including those who
smoked or were overweight [103]. Sleep loss was found
to affect sperm function in an animal study [104]. Con-
stant use of electronic devices also contributes to poor
sleep hygiene. Exposure to radiofrequency electromag-
netic waves radiation emitted by mobile phone use could
potentially exert harmful effects on the testis [105]. One
meta-analysis found that mobile phone exposure is asso-
ciated with reduced sperm motility and viability [106],
whilst another study found this adverse effect on sperm
motility and viability occurs only in vitro [107].
Conclusion
There are a wide variety of risk factors that could poten-
tially influence sperm quality. These include lifestyle fac-
tors such as cigarette smoking, alcohol intake, use of
illicit drugs, obesity, psychological stress, APA, diet,
and caffeine intake. The adverse effects of these factors
could even become intensified from one generation to
the next, and then passed on to the resulting offspring.
However, their negative effects can be overcome to a
large extent by behaviour modification and better life-
style choices. In this manner, the harmful impact of
these factors on the male reproductive potential could
also be alleviated and thus result in a more favourable
outcome.
The evidence supporting the adverse effect of each
risk factor on male fertility, as discussed in the present
review, are of varying strength. Almost all the studies
focus on the specific effects of one or at most two risk
factors that were under evaluation. However, in reality,
exposure to these risk factors does not occur individu-
ally but rather simultaneously, with each one being at
8 Durairajanayagam
Please cite this article in press as: Durairajanayagam D. Lifestyle causes of male infertility, Arab J Urol (2018), https://doi.org/10.1016/j.aju.2017.12.004
a varying duration and severity of exposure. It could
then be said that without insight into the broader picture
of these complex exposures, we may already be underes-
timating the consequences of each exposure.
The additive effects from the risk factors of male
infertility such as smoking and alcohol intake on sperm
parameters have been recognised. Moreover, the other
groups of risk factors of male fertility, such as environ-
mental and occupational factors, may also pose a simul-
taneous underlying threat to male fertility. Exposure to
the confounding factor(s) should also be taken into con-
sideration when planning the study design.
Perhaps by maintaining an overall positive lifestyle,
the burden of the multiple factors that could influence
sperm quality and male fecundity, may begin to slowly
improve. In that respect, awareness and recognition of
the possible impact of risk factors present in daily life
is crucial amongst couples seeking conception. As the
influence of several of these factors governing male
infertility may be reversible, therefore the couple may
benefit from early counselling and clinical intervention.
Conflict of interest
None.
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Lifestyle causes of male infertility 11
Please cite this article in press as: Durairajanayagam D. Lifestyle causes of male infertility, Ar ab J Urol (2018), https://doi.org/10.1016/j.aju.2017.12.004
... The sources of this difference are the methodological differences or the use of different definitions of infertility. It is expected that the rate of infertility would increase in future years by considering the development of human societies, changes in people's lifestyles, and personal habits (19). Since the rate of infertility is one of the appropriate indicators to plan for family health, and because of the need and importance of studies in this field, herein, we have reviewed the prevalence of male PI in Iran. ...
... First, not considering some potential confounders which may influence the quality of semen and sperm and subsequently the fertility potential together with virus infection is another major weakness in studies thus far. For example, sociodemographic factors like drug use and tobacco and alcohol consumption, that might be risk factors for decreased semen quality, were not reported in these studies [28,29]. ...
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Aim The rapid outbreak of the coronavirus disease 2019 (COVID-19) pandemic posed challenges across different medical fields, especially reproductive health, and gave rise to concerns regarding the effects of SARS-CoV-2 on male infertility, owing to the fact that the male reproductive system indicated to be extremely vulnerable to SARS-CoV-2 infection. Only a small number of studies have investigated the effects of SARS-CoV-2 on male reproduction, but the results are not consistent. So, we performed this meta-analysis to draw a clearer picture and evaluate the impacts of COVID-19 on male reproductive system. Method We searched Embase, Web of Science, PubMed, and Google Scholar databases to identify the potentially relevant studies. Standardized mean difference (SMD) with 95% confidence interval (CI) was applied to assess the relationship. Heterogeneity testing, sensitivity analysis, and publication bias testing were also performed. Results A total of twelve studies including 7 case control investigations and 5 retrospective cohort studies were found relevant and chosen for our research. Our result showed that different sperm parameters including semen volume [SMD = − 0.27 (− 0.46, − 1.48) (p = 0.00)], sperm concentration [SMD = − 0.41 (− 0.67, − 0.15) (p = 0.002)], sperm count [SMD = − 0.30 (− 0.44, − 0.17) (p = 0.00)], sperm motility [SMD = − 0.66 (− 0.98, − 0.33) (p = 0.00)], and progressive motility [SMD = − 0.35 (− 0.61, − 0.08) (p = 0.01)] were negatively influenced by SARS-CoV-2 infection. However, sperm concentration (p = 0.07) and progressive motility (p = 0.61) were not found to be significantly associated with SARS-CoV-2 infection in case control studies. No publication bias was detected. Conclusion The present study revealed the vulnerability of semen quality to SARS-CoV-2 infection. Our data showed a strong association of different sperm parameters with SARS-CoV-2 infection. The results suggested that SARS-CoV-2 infection in patients may negatively influence their fertility potential in a short-term period, but more studies are needed to decide about the long-term effects.
... These, small amounts of ROS have been shown to trigger essential physiological functions such as capacitation [17]. On the other hand, excessive production or exposure of cells to excessive amounts of ROS caused by adverse lifestyle [22,26,47] and related conditions such as obesity [42], diabetes mellitus [1,24], or poor nutrition negatively [54,62] affect fertility in men and women and modification of the lifestyle conditions can have positive effects on fertility [62]. In addition, genital tract infections/inflammations [33,35], scrotal hyperthermia due to tight underwear [38,48], sedentary position [25,55], varicocele [37] or cancer [57] and its treatment with radiation [8,15] and chemotherapy [20,36] all have significant negative effects on fertility. ...
Chapter
Since the discovery by John MacLeod in 1943 that spermatozoa produce small amounts of hydrogen peroxide, a member of the so-called reactive oxygen species (ROS), the importance and functions of these highly reactive oxygen derivatives in physiology and pathology are a subject of numerous studies. It has been shown that they play essential roles, not only in causing oxidative stress if their concentration is excessively high, but also in triggering crucial cellular functions if their concentration is low. On the other hand, antioxidants counterbalance the action of ROS to maintain a fine balance between oxidation and reduction as an excessive amount of antioxidants leads to a condition called reductive stress and is as harmful as oxidative stress. This book “Oxidative Stress and Toxicity in Reproductive Biology and Medicine – A Comprehensive Update on Male Infertility” authoritatively summarizes the current knowledge of various causes of oxidative stress including various andrological conditions and environmental pollution as well as the physiological effects of ROS. Moreover, this book expands into the treatment of oxidative stress with antioxidants and phytomedicine, a rapidly developing area. As a first of its kind, this book also sheds light on the effects of the redox potential during the fertilization process and thus highlights the importance of the correct balance of oxidants and antioxidants, even in the culture medium in assisted reproduction. The editors have brought together an impressive group of renowned experts to share their knowledge on the topic of oxidative stress and its clinical management in andrology and assisted reproduction.
... Several lifestyle risk factors, such as smoking, alcohol consumption, obesity, and psychological stress, can influence male fertility (Durairajanayagam, 2018). Ethanol consumption is one of the lifestyle habits that have become very common in the world even though there are many studies have demonstrated the deleterious effects of alcohol on reproductive systems in both humans and animals. ...
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This study investigates the toxic effects of ethanol (Eth) on the reproductive system of male rats and the possible protective role of Silybum marianum seeds-infused solution (SMI) over six consecutive weeks of administration. Animals were divided into the following groups: control, SMI positive control (200 mg/kg/day), Eth1 (1 g/kg/day), Eth2 (2 g/kg/day), Eth1+SMI, and Eth2+SMI. Plasma testosterone concentration, epididymal spermatozoa biology, and testicular and epididymal MDA, GSH and GPx levels were evaluated. The results indicated a significant decrease in testis and epididymis weight, testosterone level, sperm concentration, sperm vitality and sperm motility (total motility, progressive motility, curvilinear velocity, straight-line velocity, velocity average path, beat cross frequency, and lateral head displacement) in both Eth1 and Eth2 compared to the control groups and the combined-treatment groups (Eth1+SMI and Eth2+SMI). Furthermore, results showed a significant elevation in MDA concentration with a significant decrease of testicular and epididymal GSH concentration and GPx activity in theEth1 and Eth2 groups compared to the combined-treatment groups. The administration of SMI succeeded in improving the parameters cited above in the combined-treatment groups compared to the Eth1 and Eth2 groups, and bring them to the levels seen in the control groups. To conclude, SMI has clearly protected reproductive indices against ethanol-induced reprotoxicity in male rats Keywords: Ethanol; Reprotoxicity; Protective role; Spermatozoa; Rat; Silybum marianum
... Studies have shown that the male partners contributed 50% of infertility cases because of low sperm count and poor sperm quality, or both [3][4][5]. Male infertility may be attributed to numerous factors such as smoking [6], depression and anxiety [7], the influence of medical conditions such as diabetes [8] and heart disease, environmental toxicants [9], and lifestyle [10]. Ageing may also contribute to male infertility due to DNA damage to sperm [11]. ...
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The number and quality of sperm are decreased due to bisphenol A (BPA) exposure, an endocrine-disrupting chemical on the male reproductive system, especially in advanced paternal age (APA). Procyanidin C-1 (PCY-1), an antioxidant from grape seed (Vitis vinifera L.), has demonstrated anti-viral, anti-melanogenic and immunostimulatory effects. Therefore, this study aims to determine the effects of PCY-1 intervention on sperm parameters, testis morphological changes, serum testosterone, oestradiol, and luteinizing hormone (LH) concentrations and the expression of apoptotic (Bax and Bcl-2) and mitochondria-related (Mfn1 and Opa1) genes in BPA-exposed aged mice. Results revealed that PCY-1 intervention improves aged male fertility in BPA-exposed conditions by decreasing abnormal sperms percentage and increasing spermatogenic cell diameter and epithelial height. PCY-1 also decreased oestradiol, and increased LH and testosterone levels. The gene expression of Bax was significantly down-regulated by PCY-1 intervention. In contrast, Bcl-2 was substantially up-regulated. Expression of Mfn1 and Opa1 genes were also significantly up-regulated in the PCY intervention group. Hence, it is demonstrated that PCY-1 was able to mitigate the adverse effects of BPA on reproductive parameters of aged mice. Collectively, we postulated that PCY-1 has a potential role in protecting the ageing male reproductive system against the damaging impacts of BPA.
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Background and aims: Collection of epidemiological data has become a crucial step in every fertility evaluation, especially regarding idiopathic male infertility. Information on data such as tobacco smoking, alcohol intake, and body mass index can provide crucial information regarding the dynamics between fertility status and everyday practices. We aim to set the base for epidemiological studies on male infertility in the Greek population. Methods: Four hundred and fourteen Greek volunteers were asked to fill in a questionnaire regarding their characteristics and lifestyle preferences, followed by a seminogram. Depending on their answers, they were divided into groups and data were analyzed for correlation with seminogram parameters using Spearman's rank correlation test. Results: Our results indicate that a high body mass index (BMI) is negatively correlated with all three seminogram parameters (number, motility, and morphology) and exposure to radiation or chemicals is negatively correlated with sperm motility, with a p < 0.01. Conclusions: These findings indicate negative correlations of BMI and exposure to radiation/chemicals with semen parameters in the Greek population. Such information can be used to plan a diagnostic approach or even therapeutic interventions.
Article
Objective: Semen analysis is performed as one of the screening tests for infertility, including motility, morphology, and concentration observation. We aimed to investigate the expression rates of tumor necrosis factor-α (TNF-α) and heat shock protein (HSP)-70 as two opposite affectors of apoptosis in men with normal semen parameters and abnormal parameters to find the possible effect of this pathway on sperm parameters. We also aimed to investigate the apoptotic markers (DNA fragmentation and Caspase-3 expression) to observe the correlation of this pathway with apoptosis. Materials and Methods: A total of 32 men who applied for infertility evaluation were included in the study. Semen analysis was performed according to WHO criteria. Liquefaction time, appearance, volume, pH, viscosity, sperm concentration, total motility rate, sperm motility, and percentage of spermatozoa with normal morphology were determined. TNF-α, HSP-70, and Caspase-3 immunolocalization were scored histologically. A sperm chromatin dispersion test was used to observe DNA fragmentation. Results: There was no significant difference in TNF-α protein expression rate (mild level). The HSP-70 expression rate was lower, especially in the head region of normo. Caspase-3 was higher totally in non-normo. DNA fragmentation levels were similar in both the groups. Conclusion: From TNF-α protein expression at the mild level in both the groups, it may be hypothesized that the apoptotic pathway might not be triggered by the extrinsic pathway. We found a negative correlation between HSP-70 and Caspase-3 expressions, providing further evidence that HSP-70 works as an inhibitor to apoptosis. This, particularly on specific points, made us think the communication might begin in the anterior chamber, then flow through the cell body to the tail. HSP-70 expression was lower in normo than in non-normo, indicating the possible role of HSP-70 as an answer to any type of stressor in non-normozoospermic patients. Correspondingly, it may be concluded that HSP has an antiapoptotic effect, causing inhibition in the elimination of abnormal sperm cells impairing sperm parameters.
Chapter
Nowadays, about 14% of couples have difficulty in conceiving, and half of the cases are attributed to men. Asthenozoospermia or poor sperm motility is considered as the cause of infertility in males which is most common. Even though energy metabolism is considered the main reason for the etiology of asthenospermia, few attempts are made to determine the pathway of its metabolic potential. Recognition of cellular as well as molecular pathways that lead to reduced sperm motility may lead to the implementation of new therapeutic strategies to eliminate low sperm motility in people with asthenozoospermia. This review article discusses the key causes of decreased sperm motility and some of the muted genes and metabolic causes of the same.
Book
Personalized medicine is a clinical concept that divides patients into various categories, often referred to as precision medicine, with healthcare choices, procedures, treatments, and/or products customized to the individual patient depending on their expected response or disease risk. Of the 14 Grand Challenges for Engineering, an initiative funded by the National Academy of Engineering (NAE), 'Personalized Medicine' was recognized as a central and futuristic approach to "achieve optimal individual health decisions," thus overcoming the "Engineer Better Medicines" obstacle. Diagnostic testing is also used in personalized medicine to select adequate and suitable treatments based on genetic content or other molecular or cellular examination of a patient. Modern and transformative approaches in health care can be adapted to the principles of personalized medicine. Personalized medicine is focused on system biology dynamics. It uses statistical methods to assess health threats and design personalized treatment to help patients manage risks, avoid, and reliably treat disease as it happens. Modern developments in personalized medicine rely on technology that confirms the basic biology, DNA, RNA, or protein of a patient, eventually leading to disease confirmation. A process such as RNA-seq will demonstrate which RNA molecules are involved in specific diseases. Sequencing RNA may also provide a more comprehensive understanding of the state of health of an individual. Recent studies have linked genetic differences to RNA expression, translation, and protein levels among individuals. A more unified clinical strategy unique to the individual and their genome would be generated through personalized medicine advancements. With earlier intervention, more effective drug production, and more tailored treatments, personalized medicine will improve diagnosis. Similarly, identifying the patients' mutations can help them get personalized medicine based on the genetic pattern. This research topic focuses on personalized medicine and is intended to analyze novel research, techniques, instruments, and algorithms in the broader area (e.g., genes, molecules, cells, tissues, organs, people, and populations) and in association with computational, animal experiments and clinical data. • Personalized medicine approaches in drug discovery and clinical trials • Role of Proteomics and structural biology in the development of personalized medicine • Multi-omic contributions to improving phenotypes of disease and association of gene-phenotypes (including epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics) • Genotype-phenotype correlations (GWAS study) • Clinical perspectives on targeted therapies for personalized medicine • Accelerating novel medicine and better patient care from bedside to the benchtop • Gene ontology, Pathway, interactome and Network analysis • Various modeling techniques (computational, statistical, mathematical, etc.) • Machine learning, deep learning, artificial intelligence • Computer-aided drug discovery (CADD) • High-performance computing system application including software, web-tools, and databases development
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Background: Infertility is a global public health issue, affecting 15% of all couples of reproductive age. Male factors, including decreased semen quality, are responsible for ~25% of these cases. The dietary pattern, the components of the diet and nutrients have been studied as possible determinants of sperm function and/or fertility. Objective and rationale: Previous systematic reviews have been made of the few heterogeneous low-quality randomized clinical trials (RCTs) conducted in small samples of participants and investigating the effect of specific nutrients and nutritional supplements on male infertility. However, as yet there has been no systematic review of observational studies. Search methods: A comprehensive systematic review was made of the published literature, from the earliest available online indexing year to November 2016, in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We have included cross-sectional, case-control and prospective and retrospective studies in which fertile/infertile men were well defined (men with sperm disorders, sperm DNA damage, varicocele or idiopathic infertility). The primary outcomes were semen quality or fecundability. With the data extracted, we evaluated and scored the quality of the studies selected. We excluded RCTs, animal studies, review articles and low-quality studies. Outcomes: A total of 1944 articles were identified, of which 35 were selected for qualitative analysis. Generally, the results indicated that healthy diets rich in some nutrients such as omega-3 fatty acids, some antioxidants (vitamin E, vitamin C, β-carotene, selenium, zinc, cryptoxanthin and lycopene), other vitamins (vitamin D and folate) and low in saturated fatty acids and trans-fatty acids were inversely associated with low semen quality parameters. Fish, shellfish and seafood, poultry, cereals, vegetables and fruits, low-fat dairy and skimmed milk were positively associated with several sperm quality parameters. However, diets rich in processed meat, soy foods, potatoes, full-fat dairy and total dairy products, cheese, coffee, alcohol, sugar-sweetened beverages and sweets have been detrimentally associated with the quality of semen in some studies. As far as fecundability is concerned, a high intake of alcohol, caffeine and red meat and processed meat by males has a negative influence on the chance of pregnancy or fertilization rates in their partners. Wider implications: Male adherence to a healthy diet could improve semen quality and fecundability rates. Since observational studies may prove associations but not causation, the associations summarized in the present review need to be confirmed with large prospective cohort studies and especially with well-designed RCTs.
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Background: Reported declines in sperm counts remain controversial today and recent trends are unknown. A definitive meta-analysis is critical given the predictive value of sperm count for fertility, morbidity and mortality. Objective and rationale: To provide a systematic review and meta-regression analysis of recent trends in sperm counts as measured by sperm concentration (SC) and total sperm count (TSC), and their modification by fertility and geographic group. Search methods: PubMed/MEDLINE and EMBASE were searched for English language studies of human SC published in 1981-2013. Following a predefined protocol 7518 abstracts were screened and 2510 full articles reporting primary data on SC were reviewed. A total of 244 estimates of SC and TSC from 185 studies of 42 935 men who provided semen samples in 1973-2011 were extracted for meta-regression analysis, as well as information on years of sample collection and covariates [fertility group ('Unselected by fertility' versus 'Fertile'), geographic group ('Western', including North America, Europe Australia and New Zealand versus 'Other', including South America, Asia and Africa), age, ejaculation abstinence time, semen collection method, method of measuring SC and semen volume, exclusion criteria and indicators of completeness of covariate data]. The slopes of SC and TSC were estimated as functions of sample collection year using both simple linear regression and weighted meta-regression models and the latter were adjusted for pre-determined covariates and modification by fertility and geographic group. Assumptions were examined using multiple sensitivity analyses and nonlinear models. Outcomes: SC declined significantly between 1973 and 2011 (slope in unadjusted simple regression models -0.70 million/ml/year; 95% CI: -0.72 to -0.69; P < 0.001; slope in adjusted meta-regression models = -0.64; -1.06 to -0.22; P = 0.003). The slopes in the meta-regression model were modified by fertility (P for interaction = 0.064) and geographic group (P for interaction = 0.027). There was a significant decline in SC between 1973 and 2011 among Unselected Western (-1.38; -2.02 to -0.74; P < 0.001) and among Fertile Western (-0.68; -1.31 to -0.05; P = 0.033), while no significant trends were seen among Unselected Other and Fertile Other. Among Unselected Western studies, the mean SC declined, on average, 1.4% per year with an overall decline of 52.4% between 1973 and 2011. Trends for TSC and SC were similar, with a steep decline among Unselected Western (-5.33 million/year, -7.56 to -3.11; P < 0.001), corresponding to an average decline in mean TSC of 1.6% per year and overall decline of 59.3%. Results changed minimally in multiple sensitivity analyses, and there was no statistical support for the use of a nonlinear model. In a model restricted to data post-1995, the slope both for SC and TSC among Unselected Western was similar to that for the entire period (-2.06 million/ml, -3.38 to -0.74; P = 0.004 and -8.12 million, -13.73 to -2.51, P = 0.006, respectively). Wider implications: This comprehensive meta-regression analysis reports a significant decline in sperm counts (as measured by SC and TSC) between 1973 and 2011, driven by a 50-60% decline among men unselected by fertility from North America, Europe, Australia and New Zealand. Because of the significant public health implications of these results, research on the causes of this continuing decline is urgently needed.
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Introduction In order to obtain information about the relationship between sleep disturbances and sperm parameters, we analyzed data from a study conducted in a Italian Fertility Clinic, in men of couples seeking help for infertility. Patients and methods Male partners with or without a medical history of reproductive organ diseases (cryptorchidism, varicocele, orchitis, testicular torsion) were eligible for the study. There were 382 men evaluated from May 2014 to November 2016, all of whom completed a self-administered questionnaire on general lifestyle habits. Then all men underwent semen analysis. A total of 382 men aged 26 to 67 years (median age 39 year interquartile range 37–42) were recruited. Main results A total of 46.3% reported having sleep disturbances. In multivariate analysis, in absence of reproductive organ diseases, semen volume was lower in patients with difficulty in initiating sleep (2.0 ml, IQR 1.5–3.0 vs 3.0 ml, IQR 2.0–3.3, p = .01), whereas in presence of reproductive organ diseases motility A was lower in patients with early morning awakening (25.0%, IQR 15.0–35.0 vs. 40.0%, IQR 30.0–50.0, p = .001). In overweight men, semen volume was lower in patients with difficulty in initiating sleep (2.0 ml, IQR 1.5–3.0 vs 3.0 ml, IQR 2.0–3.0, p = .03). Moreover, among current smokers, patients with difficulty in initiating sleep had semen volume lower (1.5 ml, IQR 1.5–2.5 vs 3.0 ml, IQR 2.0–3.5, p = .0003) and sperm concentration higher (40 millions/ml, IQR 15–60 vs 10 millions/ml, IQR 5–50 p = .03) but total sperm count was not significant different. Conclusion Further studies are necessary to elucidate the relationship between sleep quality and semen parameters, which may have important public health implication. Electronic supplementary material The online version of this article (doi:10.1186/s12610-017-0060-0) contains supplementary material, which is available to authorized users.
Article
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Background Semen quality, a predictor of male fertility, has been suggested to be declining worldwide. Among other life style factors, male caffeine/coffee consumption was hypothesized to influence semen parameters, but also sperm DNA integrity. To summarize available evidence, a systematic review of observational studies on the relation between coffee and caffeine intake and parameters of male fertility including sperm ploidy, sperm DNA integrity, semen quality and time to pregnancy. Methods A systematic literature search was performed up to November 2016 (MEDLINE and EMBASE). We included all observational papers that reported the relation between male coffee/caffeine intake and reproductive outcomes: 1. semen parameters, 2. sperm DNA characteristics, 3. fecundability. All pertinent reports were retrieved and the relative reference lists were systematically searched in order to identify any potential additional studies that could be included. Results We retrieved 28 papers reporting observational information on caffeine/coffe intake and reproductive outcomes, including 19,967 men. 1. Semen parameters did not seem affected by caffeine intake, at least caffeine from coffee, tea and coca drinks, in most studies. Conversely, others suggested a negative effect of cola-containing beverages and caffeine-containing soft drinks on semen volume, count and concentration. 2. As regards sperm DNA defects, caffeine intake seemed associated with aneuploidy and DNA break, but not with other markers of DNA damage. 3. Finally, male coffee drinking was associated to impaired time to pregnancy in some, but not all, studies. Conclusions The literature suggests that caffeine intake, possibly though sperm DNA damage, may negatively affect male reproductive function. Evidence from epidemiological studies on semen analyses and fertility is however inconsistent and inconclusive. Well-designed studies with predefined criteria for semen analyses and for subject selection, as well as defining life style habits, are essential to reach a strong evidence on the effect of coffee on semen parameters and male fertility.
Article
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Purpose: To investigate whether the sperm concentration of European men is deteriorating over the past 50 years of time. Materials and methods: We analysed the data published in English language articles in the past 50 years in altering sperm concentration in European men. Results: A time-dependent decline of sperm concentration ( r = -0.307, p = 0.02) in the last 50 years and an overall 32.5% decrease in mean sperm concentration was noted. Conclusion: This comprehensive, evidence-based meta-analysis concisely presents the evidence of decreased sperm concentration in European male over the past 50 years to serve the scientific research zone related to male reproductive health.
Article
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Individuals who smoke generally do so with the knowledge of potential consequences to their own health. What is rarely considered are the effects of smoking on their future children. The objective of this work was to review the scientific literature on the effects of paternal smoking on sperm and assess the consequences to offspring. A literature search identified over 200 studies with relevant data in humans and animal models. The available data were reviewed to assess the weight of evidence that tobacco smoke is a human germ cell mutagen and estimate effect sizes. These results were used to model the potential increase in genetic disease burden in offspring caused by paternal smoking, with specific focus on aneuploid syndromes and intellectual disability, and the socioeconomic impacts of such an effect. The review revealed strong evidence that tobacco smoking is associated with impaired male fertility, and increases in DNA damage, aneuploidies, and mutations in sperm. Studies support that these effects are heritable and adversely impact the offspring. Our model estimates that, with even a modest 25% increase in sperm mutation frequency caused by smoke-exposure, for each generation across the global population there will be millions of smoking-induced de novo mutations transmitted from fathers to offspring. Furthermore, paternal smoking is estimated to contribute to 1.3 million extra cases of aneuploid pregnancies per generation. Thus, the available evidence makes a compelling case that tobacco smoke is a human germ cell mutagen with serious public health and socio-economic implications. Increased public education should be encouraged to promote abstinence from smoking, well in advance of reproduction, to minimize the transmission of harmful mutations to the next-generation.
Article
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Background Cigarette smoking has been associated with worse infertility treatment outcomes, yet some studies have found null or inconsistent results. Methods We followed 225 couples who underwent 354 fresh non-donor assisted reproductive technology (ART) cycles between 2006 and 2014. Smoking history was self-reported at study entry. We evaluated the associations between smoking patterns and ART success using multivariable discrete time Cox proportional hazards models with six time periods: cycle initiation to egg retrieval, retrieval to fertilization, fertilization to embryo transfer (ET), ET to implantation, implantation to clinical pregnancy, and clinical pregnancy to live birth to estimate hazard ratios (HR) and 95% CIs. Time-dependent interactions between smoking intensity and ART time period were used to identify vulnerable periods. ResultsOverall, 26% of women and 32% of men reported ever smoking. The HR of failing in the ART cycle without attaining live birth for male and female ever smokers was elevated, but non-significant, compared to never smokers regardless of intensity (HR = 1.02 and 1.30, respectively). Female ever smokers were more likely to fail prior to oocyte retrieval (HR: 3.37; 95% CI: 1.00, 12.73). Every one cigarette/day increase in smoking intensity for females was associated with a HR of 1.02 of failing ART (95% CI: 0.97, 1.08), regardless of duration or current smoking status. Women with higher smoking intensities were most likely to fail a cycle prior to oocyte retrieval (HR: 1.07; 95% CI: 1.00, 1.16). Among past smokers, every additional year since a man had quit smoking reduced the risk of failing ART by 4% (HR: 0.96; 95% CI: 0.91, 1.00) particularly between clinical pregnancy and live birth (HR: 0.86; 95% CI: 0.76, 0.96). Conclusions Female smoking intensity, regardless of current smoking status, is positively associated with the risk of failing ART cycles between initiation and oocyte retrieval. In men who ever smoked, smoking cessation may reduce the probability of failing ART, particularly between clinical pregnancy and live birth. Trial registrationNCT00011713. Registered: 27 February 2001.
Article
Numerous health consequences of tobacco smoke exposure have been characterized, and the effects of smoking on traditional measures of male fertility are well described. However, a growing body of data indicates that pre-conception paternal smoking also confers increased risk for a number of morbidities on offspring. The mechanism for this increased risk has not been elucidated, but it is likely mediated, at least in part, through epigenetic modifications transmitted through spermatozoa. In this study, we investigated the impact of cigarette smoke exposure on sperm DNA methylation patterns in 78 men who smoke and 78 never-smokers using the Infinium Human Methylation 450 beadchip. We investigated two models of DNA methylation alterations: (i) consistently altered methylation at specific CpGs or within specific genomic regions and (ii) stochastic DNA methylation alterations manifest as increased variability in genome-wide methylation patterns in men who smoke. We identified 141 significantly differentially methylated CpGs associated with smoking. In addition, we identified a trend toward increased variance in methylation patterns genome-wide in sperm DNA from men who smoke compared with never-smokers. These findings of widespread DNA methylation alterations are consistent with the broad range of offspring heath disparities associated with pre-conception paternal smoke exposure and warrant further investigation to identify the specific mechanism by which sperm DNA methylation perturbation confers risk to offspring health and whether these changes can be transmitted to offspring and transgenerationally.
Article
Purpose of review: The prevalence of obesity has risen steadily for the past 35 years and presently affects more than a third of the US population. A concurrent decline in semen parameters has been described, and a growing body of literature suggests that obesity contributes to the male infertility. The purpose of this review is to examine the effects of obesity on male fertility, the mechanisms by which impaired reproductive health arise, and the outcomes of treatment. Recent findings: Obesity alters the hypothalamic-pituitary-gonadal axis both centrally and peripherally, resulting in hypogonadotropic, hyperestrogenic hypogonadism. Adipose tissue-derived factors, like leptin and adipokines, regulate testosterone production and inflammation, respectively. Increased systemic inflammation results in increased reactive oxygen species and sperm DNA fragmentation. Increased testicular temperature because of body habitus and inactivity impairs spermatogenesis. The degree to which obesity affects hormone levels, semen parameters, sperm DNA integrity, and pregnancy rates is variable, which may be the result of other comorbid conditions. Treatment in the form of weight loss has also had inconsistent results. Summary: Multiple interdependent mechanisms contribute to the detrimental effect of obesity on male fertility. Large, randomized control trials are needed to better characterize the therapeutic benefits of weight loss to restore male reproductive potential.
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The aim was to examine the value of different covariates in the prediction of intrauterine insemination (IUI) success. Between July 2011 and September 2015, data from 1401 IUI cycles with homologous semen in 556 couples were collected prospectively, by questionnaire, in a tertiary referral infertility centre. Statistical analysis was performed using generalized estimating equations (GEEs). GEEs were used instead of an ordinary logistic regression model to take into account the correlation between observations from the same person. The primary outcome parameter was clinical pregnancy rate (CPR), confirmed with a gestational sac and fetal heartbeat on ultrasonography at 7–8 weeks. An overall CPR of 9.5% per cycle was observed. Univariate statistical analysis revealed female and male age, male smoking, female body mass index, ovarian stimulation and inseminating motile count (IMC) as covariates significantly influencing CPR per cycle. Multivariate GEE analysis revealed that the only valuable prognostic covariates included female age, male smoking and infertility status (i.e. primary/secondary infertility). IMC showed a significant curvilinear relationship, with first an increase and then a decrease in pregnancy rate.