Male factor infertility or subfertility is responsible for up to 50% of infertility cases. A considerable body of recent studies indicates that lifestyle as well as environmental and psychological factors can negatively affect male fertility, more than previously thought. These negative effects have been shown in many cases to be reversible. This review aims to provide a rationale for early clinical attention to these factors and presents a non-exhaustive evidence-based collection of primary relevant conditions and recommendations, specifically with a view to making first line diagnostics and recommendations. The presently available evidence suggests that considering the high cost, success rates, and possible side effects of assisted reproduction techniques (ART), such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), early efforts to improve male fertility appear to be an attainable and worthwhile primary goal. A series of searches was conducted of Medline, Cochrane and related databases from November 14th, 2010 to January 26th, 2012 with the following keywords: male, fertility, infertility, sperm defects, IVF, ICSI, healthy habits, and lifestyle. Subsequent follow-up searches were performed for upcoming links. The total number of studies contemplated were 1265; of these, 296 studies were reviewed with criteria of relevance; the date of study or review; study sample size and study type; and publishing journal impact status. Data were abstracted based upon probable general clinical relevancy and use. Only a selection of the references has been reflected here because of space limitations. The main results obtained were evidence-supported indications as to the other causes of male infertility, their early detection, and treatment.
Causes of male infertility may be reversible and
their treatment can benefit from early clinical verification
and intervention. A selection of the newer
published evidence is given here. In about 50%
of cases, male factors play a role in a couple's infertility
(1, 2). Medical science still has problems
determining when and whether a male (sperm)
problem is the primary or contributing cause for
problems with fertility. Thus any factors that may
affect sperm quality are relevant for any attempt at
pregnancy; more so since more evidence points at
an increased risk for birth defects in children conceived
by in vitro fertilization (IVF) and intracytoplasmic
sperm injection (ICSI) (3).
Professional ethics and good clinical procedure
require that, before high-tech methods are considered,
systemized efforts be employed to improve
fertility and ergo sperm quality by changes
in lifestyle and environmental and psychological
factors (4). This “staircase-principle” has not yet
been incorporated into the world’s main practice
guidelines and is not always sufficiently applied in
clinical practice.
Men react to infertility in their own particular
way and study data should not be generalized between
genders. “The information-seeking coping
style was significantly correlated with infertility
distress only among men (p<0.05)” (5). Thus, in
order to motivate men to actively participate in attempts to resolve infertility issues, clear and concise
information should be provided. This article
cannot be all inclusive given the scope of the issue,
but the intent is to provide a reasonable indication
of the need to verify the presence of certain specific
factors of male infertility, a subject that warrants
further in-depth analysis and studies.
Male infertility and undefined interactions
Men with a low sperm count can have children
and those whose sperm counts are normal can be
infertile. Many other aspects of sperm may influence
infertility; rather, commenting on these in
greater detail falls outside the scope of this article,
which is not meant to analyze causes of male infertility,
but to initially document the need for early
attention to avoidable or remediable causes. The
same goes for structural problems such as varicocele.
Sperm problems can be roughly divided into
three categories: i. sperm morphology and defects,
which include low motility or insufficient
sperm (6); ii. DNA and chromosomal damage (7);
and iii. surface markers or biochemical/acrosome
problems (8). These categories possibly overlap,
but studies affirm that they may be influenced by
lifestyle, environmental, and psychological factors.
For example, smoking reduces motility and
sperm count, among its other effects. Thus when
a smoker’s sperm is first analyzed, a low motility
diagnosis and low sperm count can be forthcoming
(9). Laboratory evidence has found smoking
to also cause biochemical problems which prevent
the sperm from binding to the ovum. Sperm carry
a nicotinic cholinergic receptor, and it has been
shown that chronic laboratory exposure to nicotine
results in the binding of available nicotine to that
receptor, causing a significant loss in the fertilizing
capacity of sperm (10). Finally, smoking may
produce DNA damage that is less easily diagnosed
and has long-term negative effects (11). A 2011
study reviewing the frequency and distribution of
disomy in sperm by multicolor-FISH analysis has
indicated that lifestyle factors such as smoking are
risk factors for sex chromosome abnormalities and
disomies (12). A 2010 study reported that only 6%
of smokers had normozoospermia, whilst 37% of
nonalcoholic nonsmokers had normal sperm parameters
(13). Smoking has a negative impact on
semen variables and there is a correlation with increased
sperm caspase-9, Smac/DIABLO and percent
of DNA fragmentation, particularly in heavy
smokers. Importantly, males who stopped smoking,
after three months had a distinctive improvement
in sperm concentration, fast spermatozoa, sperm
vitality, percentage of spermatozoa that recovered
after an enrichment technique and protein tyrosine
phosphorylation. In this study no changes were
observed in the number of germinal cells, sperm
morphology and sperm DNA fragmentation. The
authors concluded that “physicians should strongly
advise their patients to quit smoking before undergoing
medical treatment or assisted reproduction
techniques (ART) to achieve pregnancy” (14).
Numerous other factors related to smoking have
been identified but for our purpose the cited information
is sufficient to consider the effects of
smoking on male fertility as an example of an exogenous
cause that can be identified and its effects
reduced or (partly) reversed, thereby possibly restoring
or achieving better levels of fertility.
Main exogenous causes of male factor infertility
Available data suggest that at least 10% of
male factor infertility is exogenous and reversible
(15-17). The impacts of lifestyle, environmental,
and psychological factors in the context
of fertility treatments and in male factor infertility
warrant close scrutiny as shown by the rapidly
growing number of studies on this issue. In
2005, the American Society for Reproductive
Medicine and the Canadian Fertility and Andrology
Society dedicated annual meetings to
this subject, after which the number of identified
exogenous causes has grown considerably
(18). In 2010, the European Society of Human
Reproduction and Embryology (ESHRE) Task
Force on Ethics and Law published a report on
the influence of lifestyle factors on reproduction,
which confirmed lifestyle to be “increasingly
recognized as an outcome-determining
factor in assisted reproduction, not only with
regard to the cost-effectiveness but also in view
of the balance of benefits and risks, including
risks related to the welfare of the future child”.
The report summarized evidence concerning the
impact of obesity, tobacco smoking, and alcohol
consumption on both natural and ART (19).
The following is indicative of some of the main
evidence-supported factors that influence male
fertility, which could benefit from early detection
and treatment.
Lifestyle factors
Acrylamide and glycidamide ingestion
Acrylamide, a xenobiotic compound present in
certain foods (fried, baked, and starchy) and in
the environment (tobacco smoke) is converted to
its active metabolite glycidamide by the CYP2E1
enzyme. Large numbers of animal studies have
shown this compound to be both carcinogenic and
mutagenic. Reproductively it causes a decrease in
sperm count, motility and morphology. Acrylamide
produces clastogenic effects inducing disruption or
breakage of chromosomes, whereas glycidamide
has mutagenic effects. A number of possible protective
measures against the effects of acrylamide
include a more selective diet, probiotics, increased
use of compounds known to decrease acrylamide
production, and on a different scale, bioengineering
of precursor foods such as potatoes (20).
Alcohol
Studies have identified the ingestion of alcohol as
a testicular toxin that provokes abnormalities such as
low sperm count and impaired sperm motility (21).
These effects have been shown to be duration-dependent
and reversible. Vicari et al. (22) have found
that pregnancy was achieved three months after the
cessation of alcohol consumption in the partner of
an azoospermic patient which was secondary to
heavy alcoholic intake. Sermondade et al. (23) have
shown that stopping alcohol consumption led to a
rapid, dramatic improvement in semen characteristics
(azoospermia). In this study, strictly normal semen
parameters were observed after three months.
These findings confirmed several earlier studies.
Alcohol, body mass index (BMI), other eating and
social factors have been found to be detrimental to
different aspects of male fertility according to another
study in 2011 on 250 cases (24).
Bicycling (excessive)
Contrary to earlier indications, Wise et al. (25)
found no significant influence of physical activity
on overall sperm parameters, except for a negative
influence from bicycling for more than five hours
a week which was associated with low sperm concentration
[odds ratio (OR): 1.92, 95% confidence
interval (CI): 1.03-3.56] and low total motile sperm
(TMS; OR: 2.05, 95% CI: 1.19-3.56). These associations
did not vary appreciably by age, BMI, or
history of male factor infertility.
Hot baths
Jung and Schuppe (26) reviewed the evidence
on scrotal temperature and fertility. Studies that
addressed professional exposure to high temperatures
delivered conflicting results concerning
fertility parameters. However, contraception via
genital heat stress has been demonstrated using hot
sitting baths or insulating suspensors. In a small
study, wet heat exposure was a potentially reversible
cause of low semen quality in infertile men,
and scrotal cooling was found efficient in improving
semen quality (27).
Recreational drug use
Anabolic-androgenic steroids, marijuana, cocaine,
methamphetamines, and opioid narcotics
have been demonstrated to be detrimental to male
fertility. The hypothalamic-pituitary-testicular
axis, sperm function, and testicular structure are
adversely affected (28). Badawy et al.(29) have
shown the two main active cannabinoids of the
marijuana plant, delta-8 and 9-THC, to be potent
inhibitors of mitochondrial oxygen consumption in
human sperm, thus affecting sperm respiration and
reducing fertility. Delta 9-THC has been found to
increase ejaculation problems, reduce sperm count
and motility, and generate loss of libido and impotence
in men (30). Most adverse effects from drugs
and medications have been shown to be reversed
by discontinuing use of the offending agents (31).
Physical stress/exertion
Vigorexia, even in mild forms, affects fertility
both through a higher incidence of structural
problems such as varicocele and through sperm
damage. After 24 weeks of exercise, those who
performed high intensity exercise demonstrated significant declines in their semen parameters
compared to those who exercised at a moderate
intensity (p=0.03) (32).
Smoking tobacco (active and passive)
Zitzmann et al. (33) calculated the OR for treatment
failure with paternal smoking compared to
non smoking to be 2.65 for IVF and 2.95 for ICSI.
Venners et al. (34) found a 77% increase in the
OR for early pregnancy loss with paternal heavy
smokers compared to “light” (<20/day) smokers.
Marchetti et al. found that exposure to cigarette
smoke (passive smoking) induced mutations at an
expanded simple tandem repeat locus (Ms6-hm) in
mouse sperm. However, it did not provoke genetic
damage in somatic cells thus indicating that, as
with acrylamide, the reproductive consequences of
parent passive smoking affect future generations
(35). Although recent reviews cite ample evidence
(36, 37), the effects of smoking on male fertility
warrant a specific in-depth review.
Vaginal lubricants and ultrasound gels
Agarwal et al. (38) have researched different
types of vaginal lubricants detrimental to sperm.
In their study, percentage motility did not differ
significantly between controls and the U.S. brand
Pre-Seed, whereas FemGlide, Replens, and Astroglide
lubricants demonstrated a significant decrease
in motility. A significant decline in sperm
chromatin quality occurred with FemGlide and
K-Y Jelly. Some lubricants and gels have been
incorrectly labeled as “non-spermicidal”. A 2011
study has confirmed these results (39).
Dietary factors
Body mass index (BMI)
Obesity leads to lower testosterone levels and
other endocrine abnormalities are the usual consequence
of obesity in conjunction with a higher
scrotal temperature and higher incidence of erectile
dysfunction. Weight reduction can improve
the chances of natural conception according to the
ESHRE Task Force (40). A 2009 Harvard Medical
School study found that, contrary to earlier human
and animal studies and despite major differences
in reproductive hormone levels with increasing
body weight, only extreme levels of obesity negatively
influence male reproductive potential (41).
This coincides with the findings of a 2011 Danish
cohort study on the effects of weight reduction in
severely obese (BMI>33) males which established
an association between obesity and poor semen
quality. However a 14-week (15%) weight loss
led to improvements in total sperm count, semen
volume, testosterone, sex hormone-binding globulin
(SHBG) and anti-Müllerian hormone (AMH).
The study group that lost more weight had a statistically
significant increase in total sperm count
and normal sperm morphology (42). Apart from
natural weight loss, several therapeutic weight loss
interventions are available, including minimally
invasive surgical procedures (43).
Dietary supplements
Attempts at self-tuning health increasingly include
dietary supplements which are often consumed
without previous medical advice or control.
Many supplements will probably not affect male
fertility unless taken in high doses; some may be
beneficial, whereas others are possibly harmful. In
a prospective, randomized double-blind placebocontrolled
trial (n=60), an antioxidant supplement
has been shown to cause a statistically significant
improvement in viable pregnancy rate (38.5%)
compared to the control group (16%) (44). Omega-
3 polyunsaturated fatty acid supplementation
has been found to improve the semen profile of
infertile men diagnosed with idiopathic oligoasthenoteratospermia
according to a recent doubleblind,
placebo-controlled, randomized study (45).
The administration of coenzyme Q10 was found
to increase both ubiquinone and ubiquinol levels
in semen and effective in improving sperm kinetic
features in patients affected by idiopathic asthenozoospermia
(46). Increasing evidence has supported
the importance of adequate vitamins F and
C, selenium, and zinc levels (47).
Hormones and hormone disruptors (endocrinedisrupting
compounds, EDC)
Although many factors may affect male hormone
levels, these do not always produce infertility. The
cumulative effects of various low-dose exposures to endocrine disruptors in our environment produce
case-dependent adverse effects in the male reproductive
system (48). Semen quality may be the
most sensitive marker of the total sum of adverse
environmental exposures. The negative effects of
anabolic steroids are documented (49), as well as
those related to polychlorinated biphenyls, dioxins,
polycyclic aromatic hydrocarbons, phthalates,
bisphenol A, pesticides, alkylphenols and heavy
metals (arsenic, cadmium, lead, and mercury) (50).
Luccio-Camelo and Prins (51) have cited in vivo
evidence for male reproductive tract disturbances
that have arisen from these disruptors, which have
the capacity to ligand the androgen receptor.
There are some indications that phyto-estrogens
such as soy isoflavones may alter reproductive
hormones, spermatogenesis, sperm capacitation
and fertility. However, numerous other studies
have neglected to observe the adverse effects on
male reproductive physiology (52).
Oxidants
Free radicals are absorbed from the food or environment.
Normal sperm function requires a
certain level of free radicals, however excessive
amounts of free radicals affect sperm function,
fertilization and offspring health. Oxidative stress
results when the balance is disrupted between free
radicals and anti-oxidants. Oxidative stress is a
well-established cause of male infertility, affecting
up to 50% of infertile men. Reactive oxygen
species (ROS) primarily cause infertility by impairing
sperm motility and DNA integrity. Most
clinical studies suggest that dietary antioxidant
supplements are beneficial in terms of improving
sperm function and DNA integrity (7). Oxidative
stress tests include chemiluminescense, flow cytometry
or the nitro blue tetrazolium (NBT) assay
(53). In a 2009 study, oral antioxidant therapy has
been shown to result in significant improvements
in sperm DNA integrity (p=0.002) and protamine
packaging (p<0.001), accompanied by a reduction
in seminal ROS production (p=0.027) and apoptosis
(p=0.004) (54). An earlier study (n=161) established
that patients with normal seminal parameters
and lower seminal leukocyte levels might benefit
from this type of therapeutic intervention to lower
ROS levels and improve semen quality (55). Oxidative
stress is relevant for female fertility as well
(56). Several herbal treatments have been found
to mitigate oxidative stress. In infertile subjects,
treatment with the herbal preparation Withania
somnifera effectively reduced oxidative stress and
improved the levels of semen quality indicators of
total testosterone (T), luteinizing hormone (LH),
follicle-stimulating hormone (FSH) and prolactin
(PRL) (57). Several studies have found that Mucuna
pruriens seed powder significantly improved
sperm count and motility in infertile men. A 2011
proton nuclear magnetic resonance [(1) H NMR]
spectroscopy study (n=180) found this substance
to rectify perturbed alanine, citrate, glycerophosphocholine
(GPC), histidine and phenylalanine
content in seminal plasma (58).
Environmental factors
Heavy metals
Cadmium, mercury, lead and arsenic levels are
relevant for male fertility. Several well-designed
studies with sufficient populations, appropriately
adjusted for potential confounders, have noted
their harmful effects on male reproduction. The evidence
for the effects of low exposure was strongest
for cadmium, lead, and mercury and less certain
for arsenic. Conversely, traces of metals such
as copper and manganese have been shown to be
essential for sperm quality although excesses may
cause adverse reproductive effects (59). Adequate
levels of other metals such as zinc are beneficial
for male fertility (60). Antioxidants and natural
chelators play a role in the elimination of metals
from the body. Occupational hazards, in general,
need to be taken into account when considering
male infertility (61).
(Soft) plastics and plasticizers
In many animal studies, phthalates have been
shown to act as endocrine disruptors. In humans,
males are most affected by the anti-androgenic action
of several phthalates. A 2011 study of polyvinyl
chloride pellet (PVC) factory workers in Taiwan
was the first to demonstrate a link between
di(2-ethylhexyl) phthalate (DEHP) concentration
in ambient air and the adverse effects on sperm
motility and chromatin DNA integrity (63, 63).
Bisphenol A has shown to cause male infertility.
Specific inhibitors and/or antagonists may be able to 'reverse' and/or 'block' the disruptive effects of
toxicant-induced damage (64).
Pollution
There are numerous environmental toxicants
whose negative effects on male fertility are often
attributed to their combined interference (65).
Radiation
Exposure to radiation, both ionizing and nonionizing,
has been shown to be a hormone disruptor.
Cell phone radiation or radio-frequency
electromagnetic fields (RF-EMFs) have become
omnipresent factors. A 2006 Finnish study obtained
the in vitro cell response to mobile phone
radiation (900 MHz GSM signal) with two variants
of a human endothelial cell line: EA.hy926
and EA.hy926v1. Gene expression changes were
registered in three experiments using cDNA expression
arrays and ten experiments examined
protein expression changes. Gene and protein
expression was shown to be altered in both cell
lines after a one hour weight-specific exposure to
mobile phone radiation (66). In a recent Canadian
study, patients who used a cell phone showed significantly
higher free testosterone and lower LH
levels than those who did not, and sperm quality
was negatively affected (67). A 2011 review
has concluded that according to the total present
data, human spermatozoa exposed to RF-EMF
have decreased motility, morphometric abnormalities,
and increased oxidative stress, whereas
the use of mobile phones may decrease sperm
concentration, motility (particularly rapid progressive
motility), normal morphology, and viability.
The abnormalities seemed to be directly
related to the duration of mobile phone use (68).
However, present evidence is inconclusive. Mobile
phones produce radiation which may affect
male fertility. In a 2011 prospective in vitro study
(n=29), Avendaño et al. (69) found that donor
normozoospermic samples, which were exposed
ex vivo during four hours to a wireless internetconnected
laptop showed a significant decrease
in progressive sperm motility and an increase in
sperm DNA fragmentation. These results showed
a nonthermal negative effect on sperm, thus the
researchers advised against locating a laptop near
the testes.
Other
Medical treatment factors
Antidepressants, tranquilizers, anti-hypertensives,
medication for psoriasis, diabetes, rheumatism,
gastric problems, seizure disorders, bowel
disease, erectile dysfunction, and viral disease
may all affect male fertility and should be critically
evaluated and alternatives considered. A recent
compilation can be found in Anderson, Nisenblat,
Norman, 2010 (70). Again, it is important to
note that even total medication-induced infertility
has been shown to be reversible (71). A well designed
study (n=165) by Hayashi et al. (72) has
found that, in infertile men who were medicated
with commonly used non-related drugs the semen
quality improvement rate (93%) and conception
rate (85%) were much higher in the study group
that stopped or changed their medication when
compared with the control group who had a 12%
semen quality improvement rate and 10% conception
rate. After changing medical treatments, the
time interval before conception was 7.3 months in
oligozoospermia and significantly shorter in asthenozoospermia.
Psychological conditions
Psychological distress and trauma, mood disorders,
inadequate coping abilities, in addition to
other psychological conditions may affect male
fertility both psychologically (lack of motivation)
and biologically (as a consequence of medical
treatment) (73). A 2011 meta analysis of 57 crosssectional
multinational studies (n=29914) showed
that psychological stress could lower sperm density
and sperm progressive motility and increase
abnormal sperm (74). Endocrinologic processes
are highlighted as the likely cause for reduced
fertility on account of stress. Circulating levels of
glucocorticoids increase stress and affect gonadal
function at multiple levels in the hypothalamopituitary-
gonadal axis by decreasing the synthesis
and release of gonadotropin-releasing hormone
(GnRH) in the hypothalamus, inhibiting synthesis
and release of LH and FSH in the pituitary gland
and directly modulating steroidogenesis and/or
gametogenesis in the testes or ovaries (75).
Psychological treatment of mood disorders and
psychosocial problems appears comparable in efficacy
to medication and the preferred treatment
when fertility is at stake (76).
Healthy habits and male infertility
Being healthy does not imply being fertile. Even
the healthiest of men can suffer fertility problems
at any moment in life. Unsuspected outside and
inside factors have been shown to play a decisive
role. Evidence of the negative effects on fertility
of some outside factors, such as smoking, is conclusive.
Other factors, although identified by initial
evidence, are still issues of debate. As recently as
2008, a questionnaire study cum opinion article
considered “healthy habits” to be unrelated to improving
fertility, and stated "falsely believing that not engaging in unhealthy habits actually increases
health". (77). However, a well-designed 2011 study
in a university outpatient clinic in the Netherlands
has shown that tailored preconception counseling
about unhealthy dietary and lifestyle behaviors of
subfertile couples had a positive effect on reproductive
performance and pregnancy outcome (78).
Lifestyle, environmental and psychological factors affecting male fertility
Exogenous negative factors
Reversible?
Treatment
(in order of recommendation)
Tobacco smoke
Partly (3 months)
Self-help
Therapy*
Medication
Alcohol
Often (3 months)
Self-help
Therapy
Medication
Marijuana
Often (3 months)
Self-help
Therapy
Cocaine
Often (1-3 months)
Self-help
Therapy
Medication
Endocrine disruptive substance (EDS)
Often
Self-help
Hormones
Often (1-3 months)
Self-help
Scrotal heat exposure (?)
Possibly
Self-help
Medication
Often (1-7 months)
Expert advice
Self-help
Endogenous factors
Reversible?
Treatment
BMI
Yes (3-9 months)
Therapy
Self-help
Surgical
Psychological stress
Yes
Self-help
Therapy
Other mental disorders
Often
Therapy
Medication
Healthy habits
Duration of positive effects
Relevance prior to ART
No tobacco
± one sperm cycle
High
Low alcohol versus addiction
long term
High
No recreative drugs
± one sperm cycle
High
Antioxidant-rich diet
± one sperm cycle
High
Moderate exercise
± one sperm cycle
Medium
* Therapy; Counseling or psychotherapy.
The present study results suggest that no generally
applicable “safe” and “unsafe” thresholds can
be established for lifestyle, environmental and
psychological factors which have proven to possibly
be negative for infertility, making individual
analysis and guidance essential.
Conclusion
Male factor infertility and subfertility are clinical
concepts that do not necessarily reflect an
unchangeable situation. A considerable, growing
body of evidence indicates that male fertility
is co-determined by lifestyle, environmental and
psychological factors whose negative influences,
to a considerable extent, can be reversed or halted.
Thus, early systemized efforts to detect and treat
any negative influences on male fertility from
lifestyle, the environment and psychological conditions
could provide better chances for natural
conception and enhanced success rates for ART.
Efforts to improve male fertility may lead to delaying
assisted reproductive treatment in justified
cases and for relatively short periods. Controlled
trials as to the effectiveness of a systemized application
of such a preliminary step are needed.
Campagne, D. M. (2013). Can Male Fertility Be Improved Prior to Assisted Reproduction through The Control of Uncommonly Considered Factors?. International Journal of Fertility and Sterility, 6(4), 214-223.
MLA
Daniel M. Campagne. "Can Male Fertility Be Improved Prior to Assisted Reproduction through The Control of Uncommonly Considered Factors?". International Journal of Fertility and Sterility, 6, 4, 2013, 214-223.
HARVARD
Campagne, D. M. (2013). 'Can Male Fertility Be Improved Prior to Assisted Reproduction through The Control of Uncommonly Considered Factors?', International Journal of Fertility and Sterility, 6(4), pp. 214-223.
VANCOUVER
Campagne, D. M. Can Male Fertility Be Improved Prior to Assisted Reproduction through The Control of Uncommonly Considered Factors?. International Journal of Fertility and Sterility, 2013; 6(4): 214-223.