nature reviews urology https://doi.org/10.

1038/s41585-023-00820-4

Expert recommendation Check for updates

Frequency, morbidity and

equity — the case for increased
research on male fertility
Sarah Kimmins1,2,3, Richard A. Anderson 4, Christopher L. R. Barratt5, Hermann M. Behre 6, Sarah R. Catford 7,8,
Christopher J. De Jonge9, Geraldine Delbes 10, Michael L. Eisenberg 11, Nicolas Garrido 12, Brendan J. Houston 13,
Niels Jørgensen 14, Csilla Krausz 15, Ariane Lismer1, Robert I. McLachlan16,17, Suks Minhas18, Tim Moss19, Allan Pacey 20
,
Lærke Priskorn 14, Stefan Schlatt 21, Jacquetta Trasler22, Leonardo Trasande23, Frank Tüttelmann 24,
Mónica Hebe Vazquez-Levin 25, Joris A. Veltman 26, Feng Zhang 27 & Moira K. O’Bryan 13
Abstract Sections

Currently, most men with infertility cannot be given an aetiology, which Introduction

reflects a lack of knowledge around gamete production and how it is Methods

affected by genetics and the environment. A failure to recognize the burden The most pressing questions
of male infertility and its potential as a biomarker for systemic illness facing andrology
exists. The absence of such knowledge results in patients generally being Recommendations
treated as a uniform group, for whom the strategy is to bypass the causality
Conclusions
using medically assisted reproduction (MAR) techniques. In doing so,
opportunities to prevent co-morbidity are missed and the burden of MAR
is shifted to the woman. To advance understanding of men’s reproductive
health, longitudinal and multi-national centres for data and sample
collection are essential. Such programmes must enable an integrated view
of the consequences of genetics, epigenetics and environmental factors
on fertility and offspring health. Definition and possible amelioration of
the consequences of MAR for conceived children are needed. Inherent in
this statement is the necessity to promote fertility restoration and/or use
the least invasive MAR strategy available. To achieve this aim, protocols
must be rigorously tested and the move towards personalized medicine
encouraged. Equally, education of the public, governments and clinicians
on the frequency and consequences of infertility is needed. Health options,
including male contraceptives, must be expanded, and the opportunities
encompassed in such investment understood. The pressing questions
related to male reproductive health, spanning the spectrum of andrology
are identified in the Expert Recommendation.

A full list of affiliations appears at the end of the paper. e-mail: moira.obryan@unimelb.edu.au

Nature Reviews Urology

Expert recommendation
Introduction
Infertility affects at least one in seven heterosexual couples of repro-
ductive age, globally1. Up to middle age (from 40 years to 65 years old),
the incidence of infertility is almost equal in women and men, 35% and
30%, respectively; in 20% of instances combined factors are involved
and in 15% of instances no attribution can be made2. For most men
with infertility, aetiology remains undefined, in part owing to a lack of
foundational knowledge around the processes of gamete production
and quality and how they are affected by environmental and lifestyle
factors. This difficulty is compounded because of the failure of health
systems to recognize the burden of male infertility at a population
level and its potential as a biomarker of systemic illness. Equally, the
opportunities to be reaped by improving men’s reproductive health
broadly, including improving medically assisted reproduction (MAR)
technologies, are not currently recognized. The absence of a research
focus on defining the precise molecular causes of male infertility
results in men with infertility generally being treated as a uniform
group, for whom the strategy is to bypass a physiological deficit with-
out treating the underlying causality. In doing so, opportunities to
prevent co-morbidity are missed and the burden of MAR is shifted
to the woman3.
Alarmingly, tests to provide a precise diagnosis of male infertility
are rare and, consequently, few targeted treatment options exist. For
the majority of men, the designation of ‘infertility’ is assigned based
on family history, physical examination, semen analyses and hormone
profiles (that is, surrogate markers) and without systematic rigor-
ous molecular analysis4. As a consequence, men presenting for MAR
are grouped into broad categories based on semen phenotype, such
as azoospermia, oligozoospermia, asthenozoospermia, teratozoo-
spermia (or a combination of these descriptors)5, each of which can
have multiple causes. Importantly, the designation of many of these
terms is based on normative population data that are largely unlinked
to fertility potential. As a result, the identification of who has infertility
and is in need of medical intervention, even if treatments were to exist,
is surprisingly difficult.
For most cases of suspected male infertility, the default MAR
strategy requires the woman to carry a large burden3: a woman with
no identified reproductive disease or history becomes the patient to
‘treat’ a presumed male fertility issue. The misnomer of ‘treatment’ for
male infertility is emotionally taxing for the man and woman, involves
considerable time and financial commitment, is invasive, and includes a
risk to the woman’s health. Although unintended and the consequence
of a complex history, this occurrence is a stark example of gender
inequity in medical treatment, and one that extends in both directions.
Treating one partner to circumvent a medical deficiency in the other is
questionable. Equally, the failure to develop male-centred treatment
options is a failure to accept male infertility as a substantial medical
condition that affects a notable portion of the global population.
Increased emphasis on developing protocols that directly address the
aetiologies of male infertility would address this inequity and probably
lead to improved clinical outcomes.
We argue that an urgent need to determine the underlying causes
of male infertility exists, including the interplay between genetics,
epigenetics, the environment and lifestyle. This imperative extends
well beyond the ability to conceive a child. An increasing and concern-
ing body of evidence indicates that men with infertility have a higher
disease burden and die younger than fertile men6, and that infertility
and ill-health can be transmitted to children conceived using MAR
techniques7. The realization that a man’s health beyond his genetics
Nature Reviews Urology
can be a primary determinant of offspring health is not reflected in
current health-care policy or social awareness. Concerted basic and
epidemiological research to test this possibility, then inform policy,
social programmes and environmental and lifestyle remediation
strategies, are required.
The clinical integration of genetic analyses is already identifying
bona fide causes of male infertility8. However, such applications are
narrowly applied and lag considerably behind other areas of clinical
medicine. When they are used, they generally only consider a portion
of the genome and a tiny fraction of genes known to be expressed in
spermatogenesis and the male reproductive tract. A shift in clinical
approach and health funding to facilitate the adoption of genetic
technologies pioneered in other medical fields to the field of andrology
will unequivocally improve the diagnostic rate. In turn, the provision of
molecular diagnoses will, in many circumstances, provide an evidence
base for patients and clinicians to choose the MAR strategy with the
best risk:reward profile. Equally, it will enable realistic predictions of
the consequences of genetic variation for the health of both the man
and the offspring, and ultimately a pathway for the development of
targeted treatment strategies.
Lifestyle and environmental factors are known to contribute to
poor male reproductive health and infertility in a spectrum ranging
from definitively causal to potential risk factors, such as the abuse
of anabolic steroids compared with environmental exposures to
plasticizers or pharmaceuticals9. Emerging data suggest that factors
such as sedentary lifestyle, poor nutrition, adiposity, exposure to
chemicals, alcohol, tobacco and cannabis increase the chances of
male infertility; however, such correlations must be tested. Encourag-
ingly, many lifestyle factors are modifiable or correctable. However,
for such changes to occur, men must first be made aware of any del-
eterious inter-relationships and then be provided with the options to
effect change. Accumulating evidence indicates that fertility can be
influenced throughout the lifespan9. Thus, men in late adolescence and
early adulthood, for example, need to be armed with knowledge about
the risks to their reproductive and overall health if they participate in
unhealthy behaviours through educational and supportive social pro-
grammes. Widespread implementation of such programmes requires
effective policies and the appropriation of funds by governments to
ensure awareness and access for boys and men of peri-reproductive
and reproductive age (>13 years old). Furthermore, men must be
encouraged to increase self-awareness about their health and adopt
active health-care-seeking routines. In return, but within a long time
frame, such behavioural changes should decrease infertility rates and
other diseases.
This recommendation document was requested by the Male
Reproductive Health Initiative (MRHI), which is a working group of
the European Society of Human Reproduction and Embryology, in
an effort to provide clarity for the field, governments and the public
on the current status of andrology research and medicine and where
future resources can be most gainfully deployed. Within this Expert
Recommendation we have identified the most pressing questions
related to male reproductive health. The formulation of this guidance
document comes from experts from around the globe, spanning the
spectrum of andrology research, clinical practice and public policy.
These questions encompass and highlight many opportunities to influ-
ence the wellness of future generations. For each question, we briefly
summarize the current state of knowledge, and identify resource gaps
and opportunities, to deliver a roadmap to improve male reproductive
health and treatment.
Expert recommendation
Methods
Following a period of consultation between MHRI members via online
meetings and e-mail, 13 questions were formulated. Lead authors for
each question were appointed and asked to contact any additional
experts (or emerging leaders) within the field they felt would add to the
quality of the section. Each section or topic was written by two or more
internationally recognized experts in the particular sub-area. Authors
were free to review all forms of literature from any source. Sections were
integrated by the first and last listed authors before several rounds of
review by the entire author team. For each question, we briefly sum-
marize the current state of knowledge and identify resource gaps and
opportunities, to deliver a roadmap to improve male reproductive
health and treatment.
The most pressing questions facing andrology
In total, 13 questions were devised concerning pressing issues in male
infertility (Box 1). To improve diagnosis, research and treatment, these
questions need to be answered.
The proportion of men with infertility
The first question to answer is, what proportion of men are infertile
(Box 1, question 1)? Surprisingly, relatively little information exists
on the prevalence of male infertility at a global level (Fig. 1). In an epi-
demiological study including 15,162 couples in the UK, 1 in 8 women
and 1 in 10 men had experienced infertility10. However, these data are
almost certainly underestimated. Determining an accurate percentage
of men who have infertility is challenging for a number of reasons: first,
the possibility of a female factor will confound a clinician’s ability to
attribute causality to either partner, that is, infertility is by definition
a two-person condition; second, there is a dearth of precise diagnostic
tests, so men are frequently not thoroughly examined; and third, any
calculation or prediction of prevalence and incidence is dependent on
the population examined. For example, the incidence of male infertility
in heterosexual couples presenting at clinics for MAR will differ from
those first attempting a pregnancy naturally. Whole-population-based
assessments of male infertility are rare, with the vast majority of studies
on male infertility deriving data from infertility treatment centres or the
assessment of men in at-risk populations (such as those living in regions
with high toxicant concentration). Addressing these challenges through
high-quality studies at global, regional and national levels is crucial, as
these data might ultimately contribute to the establishment of holis-
tic health-care systems with increased efficiency. Moreover. without
understanding the incidence of a disease, providing resources, estimat-
ing effect, making effective health economic arguments, presenting
rational research questions and managing patients are difficult11.
The most commonly used data points to assess male fertility come
from a semen analysis (Fig. 1). Clinicians and patients should be aware
of its limited prognostic accuracy, and that natural conception might
or might not occur across a range of semen analysis values. Data from
before the widespread use of modern MAR (that is, before intracyto-
plasmic sperm injection (ICSI)) showed that ~30% of couples for whom
the man had a sperm concentration of 1–5 million/ml and the woman
was healthy conceived naturally over a 2-year period, usually in the first
18 months12. This reality notwithstanding, in an unselected popula-
tion, conception rates rise until a plateau at a sperm concentration of
~40 million/ml (ref. 13). Thus, many men with what might be regarded
as impaired spermatogenesis achieve fertility without medical inter-
ventions, or only come for medical attention when their partner also
has reduced fertility.
Nature Reviews Urology
To date, most studies on the frequency of male infertility have
reported on high-income countries, and often those referred to MAR
programmes. A need exists to greatly expand epidemiological studies
outside the MAR field, which ought to feature a thorough and stand-
ardized male evaluation, aetiological classification and to consider
environmental and geographical factors and ethnicity. This limita-
tion aside, we can definitively agree that male infertility is common,
accounts for a high percentage of MAR interventions and carries an
enormous personal and economic burden.
The diagnosis of male infertility
The second question that needs addressing is how male infertility is
diagnosed (Box 1, question 2). A comprehensive infertility diagnostic
process including both partners is essential to provide informed predic-
tion, counselling and management. Despite widely available guidelines
for male evaluation14–17, treating physicians in the MAR setting might
not be male fertility specialists18. An inescapable need exists for a clini-
cal history focusing on the reproductive system, physical examination
(including of the testes), a semen analysis and guided laboratory testing
(endocrine profile, genetics, imaging and histology). Such an evalua-
tion could enable identification of reversible causes permitting natural
conception, or serious comorbidities (Box 1, questions 3 and 8).
The diagnostic yield for a small number of male infertility sub-types
is good (for example, chromosomal abnormalities and hypogonado-
tropic hypogonadism), but for the majority of men, the aetiology
of the infertility remains unknown, that is, a physiological or cellu-
lar deficit will be identified but the underlying causality is unknown.
Box 1
The most pressing questions
facing andrology
1. What proportion of men are infertile?
2. How is male infertility diagnosed?
3. What treatments are available for male infertility and what
treatments are needed?
4. What are the genetic causes of male infertility?
5. Environmental and lifestyle factors impact male fertility: what is
needed to prevent and reduce their impacts?
6. Is male fertility declining?
7. What is the economic burden of male infertility?
8. Do men with infertility have a higher disease burden than fertile
men and do they die younger?
9. Is it possible to develop robust gamete storage and restoration
protocols for boys and men prior to other medical interventions?
10. Do changes in epigenetic processes lead to male infertility or
have inter-generational consequences?
11. What are the long-term health outcomes for children born to
men with compromised fertility and do these consequences
vary with conception via natural or via medically assisted
reproduction?
12. Can we develop additional male-based contraceptive methods?
13. How can andrology as a discipline communicate effectively with
the public, health professionals and funding agencies?
Expert recommendation

Germany Denmark Finland Poland

16 23 15 15 7.3 9.1 13 8.9

Switzerland Czechia
17 21

USA Spain
15.8 23.1 15.2 16.5 12 17.5 Japan
9 8.8 6.7

4.65 19.7 5.1

China
Study year Number of participants 18.1

1980 100 4.8 6.2 8

500 10,000
1990

2000 1,000

30,000 New Zealand

2010 19.8 12.2
5,000 Tunisia Libya
39.8 14

Lower limit sperm counts

<20 million/ml <15 million/ml

Fig. 1 | Worldwide, limited data exist on sperm concentration in men.
A summary of sperm concentration from a selection of available studies (blue)
for world regions spanning the years 1992 to 2019. Studies were selected to
exclude patients with infertility or men in regions associated with toxicant
exposures. Comparative interpretation with regard to worldwide fertility trends
is difficult owing to a lack of available data (grey), variation in sample size and
population diversity. The size of the circle represents the number of study
participants from which the data are derived (Supplementary Table 1), and a
solid versus dashed circle indicates that the average sperm concentration in that
population in relation to reference limits at the time of the study <20 million/ml
(lower limit 4th edition of WHO andrology laboratory manual, 1999 (ref. 383)) or
<15 million/ml (lower limit, 5th edition of WHO andrology laboratory manual and
based on male partners who had a time to pregnancy of ≤12 months384). Data from
refs. 168,170,171,385–406.

This limitation does not detract from the value of the examination as it
will inform MAR strategy. In addition to probable physiological causes
of male infertility being identified through a comprehensive examina-
tion of the man, other conditions that are risk factors for male infertility
might be identified and addressed. For example, varicocele or high
levels of white blood cells in semen are twice as prevalent in men with
infertility as in those who are fertile, and obesity and chronic disease
are also more prevalent in patients with infertility19.
A fundamental consideration when analysing results from
a semen analysis is that the WHO set the lower 5th percentile of
whole-population levels as the level under which semen composition
is classified as abnormal20. Thus, by definition 5 in 100 men will be
classified as having an abnormal result for any particular parameter.
As such, problems arise when studies simplistically use semen param-
eters as a standalone fertility end point. For example, an assumption
that a set percentage of men with one or more parameters below the
WHO ‘reference ranges’20 will be infertile is inaccurate. However, and
providing that the analysis process was reproducible and accurate,
a semen analysis can provide an opportunity for comparisons between
populations. Importantly, an abnormal semen result is only a descrip-
tive marker of an underlying disease. For example, oligoasthenozoo-
spermia is not a diagnosis per se. Thus, although semen analysis is likely
to remain a key tool for assessing male infertility, its use in isolation is
considerably limited.
Beyond a semen analysis, serum follicle-stimulating hormone
(FSH) is the best, albeit imperfect, endocrine marker of spermatogenic
output: serum FSH levels rise as spermatogenic failure worsens owing
to falling serum inhibin B levels21. The upper limit of FSH in carefully
characterized, healthy men is 8.4 IU/l (ref. 22); the higher upper limits
(for example, 12 IU/l) suggested by some FSH assay manufacturers are
because of the inclusion of older men (>70 years) and of those with
unrecognized reproductive defects, potentially leading to a distor-
tion of the ‘normal’ range23–27. Serum luteinizing hormone (LH) and
testosterone concentrations are an indication of testicular endocrine
function: around 1 in 8 men presenting for fertility care show evidence
of biochemical (if not clinical) hypogonadism28. As evidence of the
value of a full reproductive work-up, low LH and testosterone levels
often indicate secondary testicular failure and require investigations
(such as iron studies and pituitary imaging) that demand specific care
for fertility and broader health14–16,29–31.
A holistic approach that goes beyond semen analysis is endorsed
by many clinical practice guidelines (for example, American Urologi-
cal Association–American Society for Reproductive Medicine guide-
lines Part II and European Association of Urology guidelines on male

Nature Reviews Urology

Expert recommendation
infertility15,31). The range of potential underlying molecular aetiologies
is expansive, and has relevant implications for the health of the patient
and future offspring (Box 1, question 11). To improve the diagnosis of
male infertility, suggestions for clinical practice for data collection
and research relevance will be of value for therapeutic innovation and
ultimately to improve long-term patient outcomes: the development
of national MAR data collection that includes male infertility char-
acteristics following clinical practice guidelines as above — inherent
in this goal is that MAR unit participation should be enforced, with
auditing of a minimum data set and evaluation approaches for the
men (this possibility is feasible, as exemplified by the Australia and
New Zealand Assisted Reproduction Database 3.0 data collection)32;
the development of fertility tests with improved predictive value,
including tests that reduce subjectivity and/or make use of artificial
intelligence technologies, which are already showing promise 33
(in order to develop improved fertility tests to the highest standards,
long-term clinical outcomes for men and children born as a result of
using MAR techniques will be required)34; improved and increasingly
effective education in male health at all levels of society, analogous
to the current state for women and children’s health (for example,
in medical schools, an andrology curriculum should be integrated
with urology, internal medicine, endocrinology and gynaecology
(fertility)); increased awareness of the frequency and consequences
of male infertility by primary care physicians to accelerate referral to
specialist clinics, avoiding delay in diagnosis and treatment (this latter
point is increasingly important owing to societal changes in advancing
parental age at conception)35,36; and an awareness, action plan, and data
collection protocol to detect the effects of environmental and lifestyle
factors on the male gamete, fertility and offspring outcomes. From a
discovery perspective, the first and final points should be accompanied
by an expansive biospecimen collection that can be linked back to the
clinical features and fertility outcome data37.
What treatments are available or needed?
The third question that needs to be considered is what treatments are
available for male infertility and what treatments are needed (Box 1,
question 3)? Disappointingly and frustratingly, given the frequency of
male infertility, evidence-based therapies to restore natural fertility are
uncommon and many clinical interventions are based on low-level, or
no, evidence. Although often described as a treatment for male infer-
tility, most MAR strategies neither address the underlying pathology
nor provide a treatment for the man. Rather, they use the most mature
germ cell type from anywhere in the reproductive tract in procedures
to achieve fertilization in vitro38. With notable exceptions, such as tes-
ticular sperm extraction (TESE), for the most part, such strategies place
the majority of the burden on the woman.
Management strategies for male infertility can be divided into
‘rational’ (based on a good understanding of the pathophysiology
and strong evidence of effectiveness), ‘symptomatic’ (bypassing the
pathology through the use of MAR) and ‘empirical’ (with potential merit
but lacking evidence)39.
The best example of a rational medical therapy is the treatment
of men with hypogonadotropic hypogonadism (HH) using a combina-
tion of FSH and human chorionic gonadotropin (hCG, as a surrogate
for LH) as a replacement for endogenous deficiencies. In many men
this treatment leads to fertility40. However, this approach is not a ‘cure
all’: approximately 50% of men with HH can be provided with a precise
molecular diagnosis for their hormone deficiency41, but, for reasons
that are unclear, the germinal epithelium remains unresponsive to the
Nature Reviews Urology
hormonal therapy in 15–20% of patients with congenital HH40. For these
men, hypothetically, either the treatment was suboptimal or they have
mutations in genes that are essential both for the central hormonal
regulation of the testis function and for spermatogenesis, or that coex-
isting but distinct genetic disorders are involved at the two sites. As HH
is a rare disease accounting for 1–2% of men with infertility42, multicen-
tre studies are required to unravel the reason for non-responsiveness.
If non-responsive genotypes do exist, genetic screening would help
to avoid prolonged (on average, 12 months) hormonal treatments in
these patients.
Other rational treatments include the surgical removal of obstruc-
tions in some instances of obstructive azoospermia43–48, and the
treatment of varicocele in highly selected men16,49. However, these treat-
ments are only applicable for a small fraction of men with infertility
and symptomatic management of male infertility is by far the most
common approach taken16. In most circumstances, MAR strategies
are aimed at bypassing obstructions or physiological barriers to
fertility. For example, for men with obstructive azoospermia, a near
100% sperm retrieval rate is obtained using surgery16,50. For men with
non-obstructive azoospermia (NOA), surgical TESE is typically the
only clinical option available and sperm are retrieved in approximately
~50% of procedures, which is impressive as they have no sperm in their
ejaculate51. However, the aetiologies of NOA are diverse and although
TESE success can be partially predicted based on genetic analyses
(for example, virtually no success in men with 46,XX and those with
complete azoospermia factor a (AZFa) or AZFb deletions on the
Y chromosome), in many men, the prediction is imperfect, with similar
outcomes achieved from a range of aetiologies, including NOA caused
by chemotherapy, Klinefelter syndrome and idiopathic instances51.
Notably, success only modestly correlates with testis size, serum FSH
or inhibin B14. Thus, the development of improved predictive tests to
indicate use of or avoidance of such highly invasive surgical procedures
are desperately needed14,51–53.
A plethora of empirical strategies for male infertility are avail-
able for which the rationale and evidence are limited or non-existent.
Administration of exogenous hormones and anti-oxidants are two
notable categories of empirical treatments because of their frequency
of use49. The clinical evidence for hormonal stimulation in men with HH
is established, but pharmacological application in men with idiopathic
oligoasthenoteratozoospermia is not. The rationale for this strategy
is presumably aimed at increasing baseline gonadotrophin levels to
promote sperm output, but the strategy has a low evidence base54–56.
Other examples, such as selective oestrogen receptor modulators
(clomiphene, tamoxifen) and aromatase inhibitors57–60, are proposed
to enhance gonadotrophin stimulation and consequently spermato-
genesis, but also have a low evidence base. Similarly, hCG, human
menopausal gonadotropin (hMG) or recombinant hFSH are used with
the same goal61. Even in men with NOA, presurgical hormones are given
in the hope of inducing spermatogenesis or increasing the probability
of sperm extraction at the time of TESE62. FSH administration in idi-
opathic oligoasthenoteratozoospermia with FSH in the normal range
is approved in a few countries by their national health-care system
(for example, Italy63), but selective oestrogen receptor modulators
and aromatase inhibitors are considered off-label treatments for male
infertility in most countries64. The FDA does not approve and practice
guidelines do not recommend these treatments, pointing out the lim-
ited randomized, controlled trial data concerning their effectiveness
and warning about a delayed transition to proven effective MAR15,60.
Despite such warnings, 65.9% of urologists in the USA prescribed some
Expert recommendation
form of empirical gonadotrophin therapy to treat idiopathic male
infertility65,66. Clearly, such indiscriminately applied strategies are a
burden on the health-care system and could actually harm fertility or
delay using more effective interventions. Thus, an urgent need exists
within the discipline of andrology to train health providers on the risks
associated with these practices and to establish randomized clinical
trials to resolve any uncertainty.
In some instances a rationale for the use of such strategies exists,
suggesting that when targeted correctly, the application of exoge-
nous hormones or hormone regulators might enhance fertility, avoid-
ing MAR or improving MAR success. The difficulty arises when the
approach is applied too broadly and in the absence of data. For exam-
ple, with regard to FSH administration, the possibility of pre-selecting
responders based on distinct genetic polymorphisms in FSHB and
FSHR has been proposed as a potential pharmacogenetic approach67–69.
However, to date, results of this approach are contradictory and based
on relatively small study populations67–69. For this question, along with
many others, patient outcomes could be improved by transnational
collaborative trials.
The other major agents used in the ‘treatment’ of male fac-
tor infertility are antioxidants and nutritional supplements70. In a
questionnaire-based study involving 1,327 reproductive-specialist
participants from six continents, antioxidants were prescribed by
85.6% of clinicians, with a marked variation of types, including zinc,
vitamins E, C, B1, B9, B12 and D, l-arginine and co-enzyme Q, to name a
few71. These agents are attractive for patients owing to their relatively
low costs, accessibility and favourable safety profile. The proposed
beneficial effects of these agents are related to their potential positive
effects on spermatogenesis, sperm capacitation and fertilization via a
number of mechanisms of action, including their antioxidant effects72.
However, caution must be exercised as overuse of supplements could
actually harm spermatogenic output and sperm function73. For exam-
ple, over-supplementation with folic acid or zinc could harm male
fertility74. One particular area of interest is the use of antioxidants to
reduce sperm DNA fragmentation, secondary to the effects of oxidative
stress induced by reactive oxygen species75. Reactive oxygen species are
a normal part of many biological systems and are required for sperm
functions including capacitation76–78; however, in excess they outweigh
the minimal antioxidant defences of sperm and are damaging for sperm
motility and DNA integrity79. Equally, endogenous antioxidant activity
within the male reproductive tract can modulate oxidative germ cell
DNA damage and thereby reproductive outcomes80,81. The degree to
which this activity operates within the seminiferous epithelium is
unclear; however, after removal of the cytoplasm and most of its anti-
oxidant content during the process of spermiation, the epididymis and
the female reproductive tract are the mostly likely enactors of sperm
DNA oxidative damage76,82,83. In this setting, the beneficial role of these
supplements (or dietary changes) to supplement endogenous antioxi-
dant levels or in the treatment of male factor infertility remains to be
established. The utility of antioxidants, or not, is also confounded by
the fact that oxidative stress and sperm DNA fragmentation meas-
urements are not robust84. The lack of clear data in this area is evi-
denced by Cochrane analyses70,85, in which only low-quality evidence
from a handful of highly heterogenous studies showed that antioxi-
dants improved pregnancy and live birth rates for couples experi-
encing subfertility. Thus, the use of antioxidants in the treatment of
male infertility is controversial and an open question60,72,75,85. Large
and well-controlled trials are clearly needed74,86. Similarly, clinicians and
patients need to be informed about the potential complications of
Nature Reviews Urology
unregulated antioxidant use. The same comments equally apply for any
form of unproved pharmacological intervention and herbal remedies.
In summary, evidence of efficacy exists for some treatment
approaches to male infertility, but additional high-quality, compre-
hensive, randomized trials are required. The field urgently needs to
move towards the precise diagnosis of male infertility, the realization
that many hundreds of aetiologies could exist and that different types
of infertility will require different treatment strategies, that is, personal-
ized medicine. Equally, a great opportunity exists for pharmacogenom-
ics in defining subgroups of currently ‘idiopathic’ male infertility that
might be amenable to pharmacological treatment.
The genetic causes of male infertility
Fourth, what the genetic causes of male fertility are needs addressing
(Box 1, question 4). Genetic factors have an important role in the aeti-
ology of male infertility. Well-accepted genetic causes of human male
infertility include variant karyotypes (such as 47,XXY for Klinefelter
syndrome) and submicroscopic genomic deletions on the Y chromo-
some (Yq)87. As an indication of the incidence of these particular types
of infertility, in a 2011 study of 1,583 consecutive men with azoospermia
(comprising ~10% of the total patient population of a tertiary fertility
centre), 21% had a molecular diagnosis, including 15% with Klinefelter
syndrome and 2% with Yq deletions88. A further 15% had malignancy,
11% had obstruction and 7% endocrine or chronic disease. The remain-
ing 46% of patients did not receive an adequate causal diagnosis. The
latter was most likely substantially caused by the fact that sequencing
of genes was not and is still not widely used for the diagnosis of male
infertility. Specifically, in many clinics the only sequencing undertaken
is of CFTR when obstructive azoospermia owing to congenital absence
of the vas deferens is found89. As evidence of the potential benefit of
moving to a comprehensive genome analysis, results showed that
applying an exome-based panel of only 21 genes strongly linked to
human male infertility provides a diagnostic yield of 8.5% in previously
unexplained idiopathic azoospermic men and that the results have
predictive power for TESE90.
With the advances of genomic technologies, mutations in
hundreds of new candidate genes have been reported as potential
monogenic causes of human male infertility8. Of these genes, 120 are
currently supported by compelling evidence, including having been
replicated in multiple cohorts8. This number is certainly a consider-
able under-estimate of the reality. The molecular diagnosis of mul-
tiple morphological abnormalities of the sperm flagella (a sub-type
of teratozoospermia) is a notable success story, in which the major-
ity of instances seem to be genetic in origin and can be diagnosed at
a molecular level if genome or exome sequencing is undertaken91.
Despite these advances, the vast majority (60–70%) of instances of male
infertility remain unexplained. Uncovering these missing aetiologies,
many of which are probably genetic in origin, requires researchers to
resolve a number of substantial challenges, including extreme genetic
heterogeneity, the existence of dominant causes of male infertility,
non-coding variation and complex regions in our genome, and the
varying consequences of rare and common genomic variation and
gene–environment interactions.
Extreme genetic heterogeneity. Individual genetic variants result-
ing in human infertility are expected to be extremely rare in human
populations, owing to purifying selection. Thus, large cohorts and
multicentre collaborations across populations are essential to facilitate
the identification of novel infertility-related genes and variants that are
Expert recommendation
shared between men with infertility. Similarly, the validation of causal-
ity using animal models might be required. Although considerable
progress has been made in this area, including by the International Male
Infertility Genomics Consortium92,93, the Genetics of Male Infertility
consortium94,95 and several individual laboratories96–99, many opportu-
nities remain. As other genetic causes of male infertility are discovered,
early interventions might be realized, for example, the early collection
of sperm samples from men with damaging genetic variants in genes
required for spermatogonial stem cell renewal or similar.
The existence of dominant causes of male infertility. To date, most
attention regarding genetic causes of male infertility has been on
studying recessive and X-linked causes. The study of dominant causes
of male infertility, either maternally inherited or, more likely, occurring
de novo, requires patient–parent trio-based genetic studies100–103. This
area of research is crucial and will require a clinical shift from con-
sidering just the patient with infertility to also including his parents.
Adoption of this strategy is essential if the field hopes to develop a com-
prehensive understanding of the genotype–phenotype relationship
for human male infertility.
Non-coding variation and complex regions in our genome. Based
on data from other disease conditions, the likelihood that some forms
of male infertility will be caused by variations (for example, mutations)
in the non-coding regions of the genome is high, but this possibility
is virtually unexplored. Improved genomic coverage using low-cost,
whole-genome sequencing has strong potential to be used to iden-
tify such pathogenic variants in non-coding regions, and a detailed
analysis of the role of structural genomic variation in male infertility.
For example, the male-specific region on the human Y chromosome
is full of long genomic repeats but multi-copy genes in this region
are difficult to sequence and haplotype104. The analysis of such com-
plex regions requires the use of relatively new technologies such as
long-read sequencing for accurate analysis.
Rare and common genomic variation. Interactions will occur between
rare (mutations) and common (polymorphisms) variants. Currently,
very few examples are known, but the widely divergent effects on
infertility of the gr/gr Y chromosome microdeletion in European versus
Japanese men might serve as one. Specifically, gr/gr deletions appear to
cause infertility in European men but permit fertility in Japanese men105.
Gene–environment interactions. Environmental and lifestyle expo-
sures (Box 1, question 5) are linked with infertility in some populations
or genotypes but not others106. Equally, as is observed in several other
diseases, including kidney, neurological and urological diseases107–109, a
percentage of instances of male infertility is highly likely be the result of
genetic variants in multiple genes interacting to cause infertility (poly-
genic). This possibility is virtually unexplored in the field of andrology.
The corollary of these complex types of male infertility is that a predis-
position to male infertility might be inherited via the paternal germ line
(in addition to the maternal germ line). Although poorly understood,
evidence of this possibility already exists for Y chromosome variants
in the AZFc region — most men with variants in this region are infertile,
yet rare examples of fertility exist110.
An additional consideration is that although damaging
genetic variants frequently block natural fertility, MAR might allow
the transmission of such variants to the next generation 111. For
autosomal-recessive loci of male infertility, children born as a result
Nature Reviews Urology
of MAR technology are generally healthy but have risk alleles. For
example, for autosomal-dominant loci, ~50% of boys will have the
paternal pathogenic mutation and will probably experience male
infertility. For Y-linked loci, almost 100% of boys born as a result of MAR
intervention will be affected by the paternal mutation112. How much of
an effect MAR practices are having on the propagation and expansion
of male infertility remains unknown. However, patients and clinicians
must consider this reality.
In summary, severe forms of male infertility have a strong genetic
component that is currently understudied, limiting personalized medi-
cine approaches in this field. To fully understand the role of genetics
in male infertility large-scale, genome-wide studies are required and
genomics needs to become part of routine patient diagnostics work-up.
Negative environmental and lifestyle effects
Fifth, environmental and lifestyle factors impact male fertility; thus,
what is needed to prevent and reduce their effects needs elucidating
(Box 1, question 5). Humans are exposed to thousands of factors that can
be damaging to reproductive health, beginning in utero and continuing
throughout life. These factors include sub-optimal diet, pesticides, cos-
metics, plastics, cannabis, medicines, alcohol and cigarette smoking,
among others113–117. Spermatogenesis is a complex process involving
the coordinated action of thousands of genes and is sensitive to envi-
ronmental factors118. In utero and early life, exposures can affect the
establishment and programming of gonadal cells and the developing
reproductive tract, which can influence hormonal homeostasis, cell
differentiation, gamete production and function119. This concept is
extremely difficult to prove in humans, but evidence does exist.
Widespread use of and exposure to endocrine-disrupting chemi-
cals (EDCs, compounds that disrupt the body’s own hormones) is a
particularly insidious risk with adverse effects on fertility120. Such
exposures can be exogenous and/or anabolic steroids or EDCs found
in compounds used as plasticizers, pesticides for agriculture, industry
or via environmental contamination121. Experimental evidence from
animal models combined with epidemiological studies involving men
indicate that exposure to EDCs is associated with reproductive impair-
ment, including testicular cancer, disorders of sex development, crypto­
rchidism, hypospadias and decreased sperm count115,121–123. Early life is a
crucial environmentally sensitive period, but exposures throughout
a man’s life might also have damaging and even irreversible conse-
quences for fertility. For example, exposures to the EDC insecticide
dichlorodiphenyltrichloroethane (DDT), which is used for malaria vec-
tor control in South Africa, is associated with impaired semen quality124.
Toxicology research in relation to male fertility remains difficult and
controversial owing to the complexities of epidemiological studies
that have a multitude of confounding factors, such as behavioural and
socioeconomic factors. These challenges are compounded by much
of what is known regarding repro-toxicant effects, most of which are
based on animal models and single, rather than complex, exposures.
Specifically, regulation of environmental chemicals based on linear
dose–response and assessing one compound at a time is not reflective
of real-life exposure125,126. This limitation is illustrated by the fact that
European men have been found to have combined exposures to chemi-
cals known to affect semen quality, namely bisphenol A, bisphenol F and
bisphenol S, polychlorinated dibenzodioxins and paracetamol, among
others. Of great concern is that tolerable exposures were exceeded for
these chemicals127.
In addition to environmental contaminants, which arguably men
have little control over, recreational drug use, stress, diet and some
Expert recommendation
types of physical activity are modifiable lifestyle factors that might
negatively effect male fertility, and potentially the health of their chil-
dren, which men have some control over15,128–132. For example, stress
has a psychological and a physiological effect that includes alteration
to the function of the hypothalamic–pituitary–gonadal axis and has
been implicated in male factor infertility in both humans and animal
models133. Major life events, such as job loss, war and bereavement,
correlate with reduced semen quality134,135. Chronic stress elevates glu-
cocorticoids, reduces LH secretion and in turn can lower testosterone
production by Leydig cells. Moreover, stress, obesity and metabolic
dysfunction activate inflammation and immunomodulatory responses,
all of which disrupt the hypothalamic–pituitary–gonadal axis and
spermatogenesis136,137. Equally, emerging data suggest that such stress
might have negative transgenerational consequences129,138,139.
As such exposures, physiological changes and lifestyle factors
could negatively influence fertility, whether the effect is permanent
or reversible is a pertinent question. The use of intervention strategies
such as weight-loss, diet, micronutrient supplementation, antioxidants
or folic acid supplementation remain controversial140. Nonetheless,
positive effects of weight loss on sperm concentration and count in
men with obesity demonstrate the potential of lifestyle intervention
for improved fertility141. Similarly, data from animal models indicate
that changes in diet can modify the composition of seminal plasma
and that such changes have functional consequences for immune
responses in the female tract and offspring health142. Similarly, inter-
ventions to reduce stress in couples with infertility showed a positive
association with pregnancy rates143.
However, frequently, human trials examining these factors are
poorly targeted and controlled, and use a wide range of end points,
often not including key ones such as pregnancy and live birth rates
rather than sperm functional or integrity assessment144. However, if
the trial quality can be improved, strong prospects exist to develop
evidence-based pre-conception guidelines for men to improve
reproductive health, fertility status and the health of children.
Valid concerns exist that the use of cannabis products (another
example of a modifiable risk factor) could negatively affect fertility. Can-
nabis is the third most widely used recreational drug worldwide, and is
predominantly used by men of reproductive age145. Detrimental effects
of regular cannabis use (more than once per week) on fertility include
reduced sperm motility, and concentration that is associated with
impaired functioning of the hypothalamic–pituitary–testicular axis146.
A particular worry is that with the growing legalization of cannabis, use
could increase and whether these negative effects on fertility are per-
manent or will cease with use is not known. At a minimum, appropriate
health warnings should include potential for impaired fertility.
The focus of the field to date has largely been on EDCs, but the same
arguments apply to any environmental pollutant within the environ-
ment or food chain. An emphasis on answering these questions has
added benefits: the effects might be reversible, providing a genuine
hope of improving human (and other animals) male reproductive
health and the possibility could exist to remove the contaminating
factors.
Considerable challenges exist for the field of andrology, govern-
ment regulators and funding agencies that need to be addressed: first,
implement restricted use, replacement or bans on chemicals that
have been demonstrated to compromise male fertility. For example,
policies need to be enacted that tightly regulate the use of EDCs, or
other repro-toxicants, in products and their contamination of the
environment, while investing in research to develop safe chemical
Nature Reviews Urology
alternatives. Such alternatives must undergo testing before introduc-
tion to the market. Second, meaningful testing requirements for male
reproductive safety need defining, and assays capable of reflecting the
complexity of human behaviour and spermatogenesis need develop-
ing. Ideally, toxicity testing would include specific assessment of germ
cell toxicity and end points including genotoxicity and epigenetic
responses including intergenerational transmission126,147–149. Third,
experimental models that better replicate the reality of multiple or
transgenerational exposures to repro-toxicants than current models
need developing. Fourth, epidemiological studies should be inclusive
of women, men and their offspring to determine the consequences of
exposures beginning in utero, throughout life and into future genera-
tions. Finally, knowledge translation should be improved for general
practitioners and the public on lifestyle and environmental factors that
can influence fertility in men throughout their life (Box 2).
Is male fertility declining?
Whether male fertility is declining is the sixth pressing question (Box 1,
question 6). Worldwide, fertility rates defined as the number of chil-
dren born per woman have been, or are, declining9,150. In Denmark, the
proportion of childless men has increased across birth cohorts151. How-
ever, such rates are poor proxies of male fertility (the biological ability
to conceive or the time frame within which conception is achieved)
and socioeconomic factors can largely explain these trends. Nonethe-
less, indications suggest that male fertility and reproductive health in
general have declined, including a decrease in semen quality and an
increase in testicular cancer and congenital urogenital malformations
(cryptorchidism and hypospadias)150. However, any conclusions remain
controversial152, and should be rigorously tested.
A couple’s chances of conceiving are decreased when the man has
a sperm concentration below 40 million/ml (resulting in a prolonged
average time-to-pregnancy)13,153,154. Thus, semen quality is an indirect,
albeit imperfect, measure of fertility. Of direct relevance to the poten-
tial of environmental factors that affect male fertility (Box 1, question 5)
are data suggesting that sperm output in men has declined in past
decades. A potential decline was suggested in the 1970s155,156. This
observation was strengthened in 1992 in an analysis of sperm count
data from studies published between 1938 and 1990 that suggested
that sperm counts had indeed declined157. In a meta-analysis pub-
lished in 2017 (ref. 158), including data from 42,935 men who provided
semen samples between 1973 and 2011, a 1.4% per year decrease in
sperm concentration and 1.6% per year decrease in total sperm count
was observed among men from the general Western populations.
The trends did not differ among studies from Europe, Australia and
America and continued up to the end of the study period, indicating
that the decline is contemporary158. Other studies were subsequently
published159–161, among them a meta-analysis of Chinese data show-
ing that sperm concentration and total sperm count within an ejacu-
late from healthy Chinese men had decreased between 1981 and 2019
(ref. 159). The decline was primarily observed in men from Northern
China, suggesting regional variations within the same country. Data
from multiple countries within Africa showed evidence that sperm
count decreased in the African population from 1965 to 2015 (ref. 162)
and results of a study including fertile men in India showed a small
downward trend in sperm concentration during a 37-year period
between 1993 and 2005 (ref. 163). For the latter two studies, and several
others, the potential selection biases (such as including men with infer-
tility in trend analyses) might be pronounced. However, in a follow-up
analysis of the meta-analysis from 2017, a sufficient number of studies
Expert recommendation
Box 2
Considerations for men’s health and fertility throughout life
1. The developing male (conception to birth)
During embryo and fetal development several crucial periods of
gonad differentiation occur that are susceptible to environmental
exposures in utero and postnatally. Primordial germ cells, the
precursors of gonocytes, form during week 7 and persist during
the fetal and neonatal stages. Male sexual differentiation is
dependent on androgen production by the fetal Leydig cells
and the spermatogenic support cells, the Sertoli cells. The fetal
period is marked by epigenome reprogramming of the germ
cells and cellular differentiation. These cellular processes are
susceptible to environmental perturbation by factors such as
maternal diet or endocrine disruptor exposure. Such exposures in
turn could affect lifetime spermatogenesis, susceptibility to testis
cancer and fertility. Long-term follow-up studies are needed for
babies conceived by medically assisted reproduction.
2. Childhood (birth to 12 years old)
Childhood is a period of testicular growth. Research on
determinants of testicular growth and the prevention of
spermatogenic failure is needed including the influence
of factors such as childhood obesity. Prepubertal boys treated
for cancer are at increased risk of impaired fertility in adulthood.
Chemotherapeutic agents can be gonadotoxic and can be
causative of adult infertility or sterility. Methods are currently
being developed for fertility preservation in prepubertal and
peripubertal boys.
3. Teenagers (13 to ~17 years old)
Puberty marks the onset of spermatogenesis, which is fuelled
by the differentiation of adult Leydig cells that are responsible
for androgen production throughout adult life. Health education
from Asian countries have now been published and a decline in sperm
count among unselected men from Asia was shown. Furthermore,
the data also showed that the decline in Western countries continued
and perhaps actually at an accelerated pace compared with what was
previously suggested164. Given the rapidity of this change, the causality
must be driven by environmental and lifestyle factors; if so, the hope
of them being reversed exists.
Although not ideal with regard to study design, the existing analy-
ses of historical data have been, up to this point, the best that could
be done, and the results point to adverse temporal trends in sperm
numbers and, by extension, a decline in male reproductive health, at
least among Western and Asian men. However, this issue continues
to be an area of debate and ongoing careful analysis is required165.
Furthermore, and as we have attempted to emphasize, such declines
cannot be strictly translated to the binary definition of fertile or infer-
tile but are rather an alarming suggestion that environmental factors
are adversely affecting the chances and/or frequency of infertility and
other forms of reproductive tract disease (Box 1, question 5). Given the
normal range of human sperm output even in healthy populations,
and the increased age at which men and women are now starting their
families, assuming that an increased number of men will be in need
Nature Reviews Urology
offered in school should include information on lifestyle factors
that can influence health and future fertility.
4. Young adults (~18 to ~24 years old)
Annual check-ups are often missed at this age, yet are key for
long-term health including fertility. General practitioners should
include discussion of factors that influence health and fertility,
including obesity, cannabis use, smoking and alcohol.
5. Future fathers (~25 to ~40 years old)
Future fathers should consider lifestyle factors (such as diet,
prescription and recreational drug use, alcohol and hot tub use)
that could influence fertility and time to conception. Men who
have or will engage in occupations associated with exposures
that are hazardous to fertility (for example, firefighters, pilots,
armed forces, welders) should be informed of the potential
negative effects and be offered sperm analysis to establish
baseline fertility. Sperm freezing as a means of protecting future
fertility should be discussed.
6. Middle age (~40 to ~50 years old)
Men have a biological clock, with fertility declining past the age
of 40 years. Reduced sperm quality is associated with increased
time to conception and rates of miscarriage. Reduced fertility
can be associated with comorbidities, be an indicator of poor
overall health and cardiovascular disease, and is associated with
increased risks of prostate cancer.
7. Older men (>50 years old)
Pregnancies conceived when the father is >50 years old are at a
high risk of miscarriage and obstetric complications. Children
conceived when their father is older are at an increased risk of
autism and schizophrenia.
of MAR is reasonable166. Thus, as a field, establishing well-designed
studies that can be used to describe the current situation and longitu-
dinal future measures and investigating potential reasons for changes
in sperm numbers are essential. Equally, ‘surveillance populations’ in
which semen samples are systematically analysed using reproducible
methods from defined geographic regions need to be established
across the globe. Recognizing that population profiles do not remain
static over time152, assessing cross-sectional regional differences in
sperm output might further enable the indication of environmental
and lifestyle factors that compromise or improve reproductive health.
Since the 1990s, cross-sectional, standardized and coordinated
studies have been conducted to investigate the sperm counts of men
from the general population (unselected regarding fertility status)
primarily in western Europe, the USA and Japan19,167–171, and minor geo-
graphical differences were detected in medians of sperm concentration
and total sperm counts. When these studies are interpreted according
to the association between sperm number and the likelihood of achiev-
ing pregnancy13,153,154, they indicate that a substantial proportion of men
from general populations now have sperm outputs that raise concerns
for their fertility or infertility150,166,172,173. Given the association between
the number of sperm, their structure and function in an ejaculate, the
Expert recommendation
disease burden, and early mortality174 (Box 1, question 8), these data
also raise alarm about the potential consequences for other areas of
the health system.
Answering the question of whether male fertility is declining, or
hopefully with intervention improving, will require the establishment
and analysis of longitudinal prospective studies to document the
current situation and assess causes of potential decline in male fertil-
ity. These studies need to include men from geographically diverse
locations, and take into account migration patterns of the human
population.
The economic burden of male infertility
Seventh, what the economic burden of male fertility is needs to be
discerned (Box 1, question 7). The provision of a comprehensive
health-care system is expensive, and inevitably governments will be
forced to make decisions as to which treatments and procedures should
be funded, and what research priorities should be supported based on
economic imperatives. Thus, a fundamental challenge is to determine
the economic health effects of poor male reproductive health, which
is a difficult challenge.
Limited economic assessments of fertility broadly (such as man-
aging population declines using MAR techniques in Japan175) and
estimates of the multibillion-dollar value of the MAR industry exist.
However, for male infertility, only one economic impact assessment has
been published and this study relates to the effect of EDCs176. This analy-
sis is important as it enabled identification of a 40–69% probability of
phthalates leading to 618,000 additional MAR procedures in Europe,
costing €4.71 billion annually. In the USA, 240,100 MAR procedures
annually were attributed to EDCs at a cost of US$2.5 billion177. These
analyses are limited by the available human studies of individual EDCs
and the uncertainty of the effects of EDCs in mixtures. However, col-
lectively, the economic impact data suggest that reducing preventable
EDC exposures will result in substantial economic benefit.
Little accurate information exists on the economic impact assess-
ment of male infertility in all of its forms, whether it be for a given
country, region or globally. Important for addressing this void is assess-
ment related to the Global Burden of Disease modelling178. The global
cost of male infertility, as measured by disability-adjusted life years
(DALYs), currently ranks at 232 (321,829 DALYs) on a list of 272 condi-
tions affecting men, between hookworm (336,015 DALYs) and breast
cancer (315,126). Among countries with high sociodemographic index,
male infertility ranks 204 of 266 in DALYs. However, the current DALY
assessment for male infertility is suboptimal as it only presents idi-
opathic instances of male infertility in individuals who were unable to
conceive a child after 5 years of unprotected sexual intercourse — an
estimate that is not an accurate representation of the disease. DALYs are
used to assess the effect of a disease, and achieving a comprehensive
analysis is important. An integral part of making a high-quality global
burden of disease assessment must also include evaluation of the
mental health effects of infertility on men179. Information is increas-
ing through the use of tools such as structured surveys, for example,
Fertility Quality of Life tools180, documenting the negative effect of
male infertility on the individual, couple, immediate family and society.
Given the diversity in cultural, socioeconomic and political
structures between regions of the world, considerable variations in
the health economic impact of male reproductive health are likely.
Moreover, this effect is likely to depend on context, such as low-income
versus middle-income resource settings. Thus, assessment for one
region is important and informative, but it might not be globally
Nature Reviews Urology
applicable. Overall, determining the health economic impact of poor male
reproductive health is urgent.
Is disease burden and mortality comparable?
Whether men with infertility have a higher disease burden than fertile
men and whether they die younger is the eighth question to address
(Box 1, question 8). Growing evidence indicates that male infertility is an
indicator of poor overall health and/or lifestyle and could be predictive
of future disease. Study results have demonstrated higher incidences of
cancer, metabolic and cardiovascular disease in infertile men, who have
more comorbidity at the time of evaluation, than fertile men or men with
semen quality within normal ranges6,181–183.
The mechanisms linking male fertility and health remain unre-
solved, but study results have demonstrated that men with infertility
are at increased risk of certain conditions: investigations have linked
impaired semen quality or a diagnosis of male infertility with increased
risk of cancers including testis184–186, prostate186–188, melanoma and
lymphoma189–195. Non-malignant diseases have also been examined.
Increased incidence of diabetes, hypertension, and heart disease have
been reported in the years following an infertility evaluation even
after accounting for any baseline comorbidities196–199. In addition, an
increased risk of hospitalization has been reported among men with
reduced semen quality200. Moreover, the association between semen
quality and hospitalization was independent of, and stronger than,
the links between hospitalization and obesity, smoking and educa-
tion, which are all established drivers of health201. Finally, results of
several studies have demonstrated an association between male infer-
tility and early mortality202–206: a dose–response relationship exists,
whereby the increasingly severe male infertility (reflected by poor
sperm parameters) increases the risk of death.
Given these links, several important questions arise. Most impor-
tant is the question of the clinical implications of these observations.
As associations do not prove causation, understanding the aetiology
of the association between a man’s reproductive and overall health is
imperative before giving definitive guidance. Disentangling causality
from reverse causality of the links will be crucial as we develop strate-
gies to incorporate fertility testing, including genetic testing, into the
broad context of health for men. For example, spermatogenesis could
possibly provide an easily measured assay for genetic syndromes or
sensitivity to environmental exposures for men, in which case, early
semen testing might be helpful.
Several plausible cause–effect and effect–cause pathway hypoth-
eses have been proposed to explain how a man’s reproductive poten-
tial could be linked to morbidity207. One hypothesis is based on the
idea of shared genetic links, including alterations in the expression of
disease genes connecting fertility and health. Of the ~20,000 protein-
coding genes in men, 84% are expressed in the testis208–210. Of these
genes, at least 2,274 (11.5%) are notably enriched within the testis208, rais-
ing the possibility that genetic variants in these genes, which alter gene
expression or function, will lead to male infertility. However, few of these
genes are solely expressed within the testis, raising the possibility that
spermatogenesis might be the first process to fail, but it will not be the
only one to fail. We predict that the timing of somatic tissue failure will
be modified based on compounding factors, including environmental
exposures and/or the presence of other disease risk gene variants, but
this hypothesis is poorly explored. This idea underpins the concept of
male infertility as an early indicator of long-term health at an individual
as well as a population level. Validated examples of this phenomenon
occurring include mutations in DNA mismatch repair genes identified
Expert recommendation
in men with spermatogenic dysfunction and cancer, mutations asso-
ciated with infertility and cystic fibrosis, primary ciliary dyskinesia
(including Kartagener syndrome) associated with respiratory infec-
tions, and infertility owing to flagellar dysfunction211–214. Comparable
links between these cellular pathways and reproductive health and
long-term somatic health are also becoming evident in women215.
Conversely, perturbations in systemic health could influence tes-
ticular function. Systemic inflammation is understood to have direct
and indirect effects on spermatogenesis136,216. These effects are affected
by, at least in part, the key roles that cytokines have in the regulation
of spermatogenesis and testosterone production, including in the
maintenance of an immunologically privileged state217.
Regardless of whether a man presents with primary or secondary
infertility, additional studies are needed to provide improved predic-
tive power for men, including robust mechanistic data to improve
characterization of their metabolic, immune and genetic state. As
precision medicine continues to provide novel insights into disease
trajectory, early predictions into later health problems might enable
the formulation of clinical interventions to improve fertility and avoid
extra-testicular morbidity.
Thus, men with infertility need to be assessed comprehensively
and such information needs to be included in an accessible database.
This information should include genomic data, information on environ-
mental exposures, medical history and fertility characteristics. In addi-
tion, information should be gathered from multiple locations around
the globe to enable detection of broad geographical and temporal
trends in fertility and health.
Gamete storage and restoration protocols
The ninth question is whether developing robust gamete storage and
restoration protocols for boys and men before other medical interven-
tions is possible (Box 1, question 9). Gamete or spermatogonial stem
cell storage is broadly aimed at providing fertility preservation (that is,
insurance) for fertility restoration or creation protocols for men and
children to avoid the consequences of either predictable or unpredict-
able losses of fertility. Foreseeable losses of fertility include patients
receiving chemotherapy and/or radiotherapy218 or men undergoing
orchidectomy during the final stages of gender reassignment219,220.
A considerable percentage of these men would become infertile or
sterile and might not be able to benefit from standardized procedures
for fertility preservation221. From the preventive viewpoint, when indi-
viduals can produce an ejaculate and spermatozoa are available, or if
sperm can be extracted from tissue obtained by testicular tissue biopsy,
the option of sperm banking is desirable, well-established and provides a
good cost–benefit equation222. Sperm quality declines with cryopreser-
vation and thawing, but almost all banked semen samples provide a good
chance of achieving fertilization and resulting in a live birth when ICSI
is used223, and the same is true for spermatozoa obtained using TESE224.
The main limitation with sperm cryopreservation is misinfor-
mation, despite evidence-based and standardized protocols for use
by oncologists having been put forward to cryopreserve human
spermatozoa225–227. Understanding of the potential value of such pro-
cedures is limited and treatment plans fail to include oncology and
fertility specialists specifically when offering and performing fertility
preservation procedures in young patients225,228. Continuous improve-
ments in these aspects of patient care are being implemented, but
ongoing efforts are needed221,229–231.
Concerning testicular stem cell-based strategies for male fertility
preservation and restoration, spermatogonial stem cells are target cells
Nature Reviews Urology
for fertility preservation in patients at risk of losing their fertility owing
to gonadotoxic treatments232. Men with no active spermatogenesis,
specifically prepubertal boys, cannot have semen cryopreserved.
These patients might benefit from bioptic collection of immature
tissue containing spermatogonial stem cells. Testis tissue fragments
can be cryobanked using dimethyl sulfoxide-based cryopreserva-
tion protocols233,234. Testicular biobanking was initiated in specialized
centres and is being further developed in research networks (such as
NordFertil and Androprotect235) storing hundreds of samples from new-
born to adolescent ages232. The nature of the testicular stem cells and
their somatic niches have been extensively explored and various experi-
mental strategies have been successfully applied in animal models.
Germ cell transplantation, testicular grafting and testicular organoids
seem promising tools for providing future avenues for stem cell-based
fertility preservation233. Despite this progress, several challenges remain
before spermatogonial stem cell transplantation becomes routine236.
The risk of tumour cell contamination and the low efficiency of this
strategy renders it necessary to improve the protocols before clinical
applications237. Techniques are needed for highly accurate detection
as well as a selection of tumour cell contaminants. However, testicular
grafting and germ cell transplantation have been successfully applied
in primates and their successful preclinical application suggests that a
positive outcome is possible in the clinical setting238,239.
Alternative strategies using germline stem cells for fertility pres-
ervation have been developed. The target cells can be pluripotent pre-
cursors, spermatogonial stem cells or induced pluripotent stem cells.
Protocols for in vitro culture and expansion of such cells are available
and strategies for their subsequent differentiation into germ cell-like
cells have been established233,234. To generate gametes from germline
stem cells, it seems necessary to bring germline stem cells into contact
with gonadal cells233,234. Testicular organoids have been successfully
used to generate offspring from primary cells from rodents240–242. In
mouse models, protocols to achieve full spermatogenesis ex vivo have
been established243. The strategies for in vitro spermatogenesis offer
promise for clinical application, but also concern for its safe and legal
application244.
Another aspect of gamete storage to consider is sperm freez-
ing, that is, gamete for fertility preservation unrelated to a medical
condition245. Probably the most frequent application of non-medical
freezing is pre-vasectomy, for which about 20% of men might sub-
sequently use their frozen sperm246,247. In this case, men can avoid a
reversal operation or a TESE followed by an in vitro fertilization (IVF) or
ICSI procedure224. Other potential users of non-medical sperm freezing
include men in positions for which a high risk of injury exists, such as
the armed forces, firefighters, and other professions with related toxic
exposures248. In addition, compelling data indicate that pregnancy
outcomes and mutation load are increased in older men and their
children249–253. These risks could be related to age-induced changes
in the heritable sperm epigenome254–256. Conversely, any use of such
technologies must be accompanied by a discussion about the possibil-
ity that gamete storage and MAR are also associated with conception,
pregnancy and health risks for future offspring257. Thus, the risks of
social sperm freezing must be carefully balanced.
Complex ethical and legal questions around gamete preservation
remain in some parts of the world. For children, informed consent for
tissue retrieval surgery when the protocols to use that stored tissue
to produce sperm have not yet been developed is an issue232. Unan-
swered ethical questions remain related to the length of cryostorage;
healthy live births have been attained from samples frozen beyond
Expert recommendation
two decades258. Last, the experimental nature of fertility restoration
or creation approaches in combination with the lack of consensus
as to what evidence should be available before granting clinical use
remains a problem.
In summary, within the area of gamete preservation many ques-
tions remain relating to protocol development, patient and clinician
education, and the ethics and legal regulation of such procedures. This
debate should be led by the field of andrology and preferably occur
across borders and continents.
The consequences of epigenetic change
The tenth question is, do changes in epigenetic processes lead to male
infertility or have inter-generational consequences (Box 1, question 10)?
The epigenome refers to the biochemical modifications linked to and
associated with DNA that affect chromatin (DNA) organization and gene
expression259. The epigenome includes three known layers of biochemi-
cal information: first, the modification of the nucleosome proteins
(the histones including the protamines) by the addition or removal of
methylation, acetylation, and phosphorylation among others; second,
DNA methylation that occurs at the 5′-position of cytosine residues
within CpG dinucleotides; and third, small non-coding RNAs260–262.
DNA can be thought of as storing genetic information (analogous to
computational hardware) and epigenetic processes provide the instruc-
tions and architecture to read the genome (analogous to computational
software) and are crucial for development, through the provision of
cell-specific gene expression. Changes in epigenetics are associated
with numerous human diseases, including cancer, diabetes and male
infertility263,264.
Studies in mouse models have clearly demonstrated that the com-
plete disruption of pathways that affect histone modification, DNA
methylation and each of the piwi-interacting RNA, microRNA and
small RNA pathways lead to sterility261,265–269. Genetic studies are rare
in humans and in need of replication, but available results suggest
that similar losses of function in men can cause infertility270–274. Of
great relevance, evidence indicates that environmental insults perturb
the establishment of the sperm epigenome during spermatogenesis
and that such changes are associated with infertility and poor MAR
or natural conception outcomes, but this possibility is difficult to
investigate in men275. Indeed, differences in sperm DNA methylation,
histone modifications and sperm RNA content have been linked to
poor fertility276,277. For example, a subgroup of men presenting with
oligozoospermia and infertility produced sperm with altered DNA
methylation278–280. How these changes arise during spermatogenesis
or epididymal sperm maturation is unknown; however, evidence con-
necting paternal health to an altered sperm epigenome and infertil-
ity is accumulating. In a study investigating the connection between
obesity and the sperm epigenome, DNA methylation was assessed in
sperm before and after bariatric surgery. Remarkably, an altered sperm
epigenome was detected after weight loss from bariatric surgery281,282.
This study did not explore the connections of an obesity-altered
sperm methylome with fertility283, but an elevated BMI is known to be
associated with an increased risk of infertility284. Importantly, and
given that production of sperm is continuous, these observations
suggest that a potential opportunity exists to rapidly modify the sperm
epigenome and improve fertility through the development of lifestyle
interventions.
Additional evidence that DNA methylation of the sperm epig-
enome could be responsive to diet was demonstrated when men con-
sumed supplemental folic acid285. High-dose folic acid supplementation
Nature Reviews Urology
was associated with differential methylation of regions of DNA that
were in what is referred to as ‘the intermediate range of methylation’
(20–80%), and occurred at genes implicated in neurological devel-
opment and function285. Similarly, urine phthalate concentration
(a biomarker of phthalate exposure) has been connected with dif-
ferential methylation of sperm DNA at genes implicated in develop-
ment and cell function117. Moreover, a modest number of differentially
methylated regions are correlated with low blastocyst quality117. These
studies in men, among others, offer proof-of-principle that the sperm
methylome is responsive to the environment.
In humans, research regarding the intergenerational heritability
of complex diseases (such as diabetes, metabolic disorders and almost
certainly infertility) via the sperm epigenome in relation to pollutants,
diet and health is limited to epidemiological studies and is compli-
cated by population variability286. However, considerable advances
have been made using rodent models287–289. Conservation of the epi-
genetic landscape in mice and men indicates that mice are a reliable
model for identifying epigenetic factors in sperm that are sensitive to
environmental exposures and escape epigenetic reprogramming in
the embryo, for example, those likely to affect offspring health289–292.
A range of environmental stressors, including poor diet, toxicants
and trauma, affect multiple facets of the sperm epigenome and have
been associated with negative effects on offspring health286–289. As an
extension of the conservation of the mechanism between humans and
rodents, studies conducted in mice have demonstrated that the sperm
epigenome is responsive to diet at functional loci that correlate with
offspring phenotypes. In male mice, diets with altered micronutrients,
including either folate deficiency or folate supplementation293,294,
affected gene-activating histone methylation in sperm (histone H3
lysine 4 trimethylation; H3K4me3) and DNA methylation in sperm.
Moreover, these alterations to histone methylation have been shown to
be retained in the pre-implantation embryo and to be linked to aberrant
embryo transcriptomes and developmental abnormalities288. Similarly,
a low-protein diet in male mice was associated with variation in sperm
non-coding RNA content295,296, gene-silencing histone methylation
(histone H3 lysine 4 trimethylation (H3K9me3)) in sperm296 and DNA
methylation297. High-fat diets influence sperm H3K4me1 (ref. 298),
H3K4me3, non-coding RNAs288 and DNA methylation,299,300; further-
more, offspring sired by obese males showed metabolic disturbances,
reduced lean muscle mass, increased fat deposition and in some studies
these paternal effects were transmitted transgenerationally, showing
that paternal factors can affect child metabolism298–300.
Investigations have begun to identify specific mechanisms that
underpin the epigenetic transmission of environmental exposures
from the father to the embryo288,289,295,301. Importantly, these mecha-
nisms seem to be conserved between mice and men. For example,
retained histones are conserved across species and found at important
regulatory genes involved in housekeeping, spermatogenesis and
development and have been determined to be responsive to envi-
ronmental signals and implicated in epigenetic inheritance289,290,292.
Likewise, DNA methylation has been shown to be responsive to envi-
ronmental exposures in sperm from rodents and men. For example,
in a rodent model of DDT exposure DNA methylation and nucleosome
retention was altered in sperm from F1 males exposed in utero302.
Similarly in two DDT-exposed populations of men, Greenlandic Inuit
and Vhavenda South Africans, common alterations were evident in
the sperm epigenome at the level of DNA methylation and chromatin,
at genes implicated in fertility and embryo development. Moreover,
epimutations occurred in regions that are predicted to persist in the
Expert recommendation
early embryo and were associated with embryonic gene expression and
population health (based on data discussed in one preprint article)303.
The relevance of intergenerational and potentially transgenerational
epigenetic inheritance for human health remains unresolved and
should be a priority to understand.
In summary, alterations to the sperm epigenome are associated
with human infertility and might have negative consequences for off-
spring conceived naturally or via MAR techniques. This area is crucial
to study as improved understanding of environmental triggers and
mechanisms will offer an opportunity to avoid, and potentially reverse,
infertility. Questions that are currently outstanding include whether
epigenome signatures are consistent among men with infertility and if
can they be used to diagnose or predict infertility; whether the changes
to the sperm epigenome are a direct consequence of lifestyle and/or
environmental exposures and whether causality can be established;
what the effects are of an abnormal sperm epigenome on the embryo
and long-term offspring health; how an abnormal sperm epigenome and
the heritability of disease are connected; and whether an abnormal
sperm epigenome can be reversed to improve fertility. An extension
of this concept is whether changes (shifts towards the norm) could be
used as a biomarker for improved gamete quality before MAR.
Health outcomes for children
What the long-term health outcomes for children born to men with
compromised fertility are and whether these consequences vary with
conception via natural or via MAR is the 11th question to answer (Box 1,
question 11). The long-term health consequences of MAR into adult-
hood remain unknown. Moreover, few studies have considered the
relative contribution of parental infertility and the MAR procedure to
offspring health outcomes or the effects of paternal infertility. These
questions are crucial, the answers to which might alter clinical practice.
A large percentage of male infertility is likely to be genetic in origin
and environmental exposures will be risk factors for infertility and/or
alter sperm epigenetic content, each of which could affect offspring
health. Thus, concerns for children born as a result of MAR techniques
include potential intergenerational inheritance of infertility beyond
the genetic examples7 (Box 1, questions 3 and 4) and the broad effects
of poor-quality spermatozoa on somatic aspects of offspring health,
including aspects beyond fertility. Complicating the picture are epige-
netic changes arising from MAR procedures themselves304–307. What the
consequences of ICSI compared with IVF are for epigenetic composition
in embryos and offspring is a notable question.
Changes in imprinted gene methylation and expression have been
identified in cord blood, buccal swabs and placental tissue of children
conceived using MAR techniques308–313, but few high-resolution molecu-
lar studies have been performed and their results are conflicting314–319;
furthermore, epigenetic variation at birth could resolve later in
life306,320. Epigenetic changes linked to MAR have been associated with
underlying parental infertility and the technique itself, but no definite
answers have been obtained307,321,322.
In terms of short-term health outcomes, children conceived using
IVF or ICSI are at an increased risk of adverse perinatal outcomes,
congenital malformations and imprinting disorders compared with
naturally conceived children305,323–328. Assessments of short-term health
outcomes associated with MAR and male factor infertility using large
cohort studies have started. For example, evidence of increases in birth
defects associated with MAR has been reported, which was further
increased with the use of ICSI and again still with ICSI and male factor
infertility329. These results strongly support the rationale and need for
Nature Reviews Urology
studying long-term health outcomes and could ultimately encourage
the use of less invasive MAR strategies than ICSI. Some long-term health
outcomes, such as neurodevelopment and growth, seem similar in
children conceived using ICSI and in naturally conceived children330.
First reports on the reproductive health of men conceived using ICSI
suggested impaired spermatogenesis compared with those conceived
naturally331,332, whereas results of a larger subsequent study are reas-
suring, showing similar sperm output and excluding major differences
in reproductive health333. However, all studies to date have contained
relatively small numbers of participants, meaning that concluding
anything about disease transmission from fathers to sons is difficult.
In relation to female fertility, antral follicle count and reproductive
hormone levels were similar in young adult women conceived using ICSI
and those conceived naturally in one study334. Some studies including
children conceived using IVF have suggested poorer cardiovascular and
metabolic profiles than those conceived naturally257,335, but long-term
data are sparse and few studies have examined the metabolic health of
children conceived using ICSI336,337. The comparison groups for almost
all of these studies are children of fertile parents, making it difficult to
differentiate between underlying genetic factors, exposures associated
with infertility and effects of the MAR procedure. Few studies have
explored the contribution of underlying infertility compared with the
MAR procedure338–341, and no studies have examined paternal fertility
status as a source of potential health differences.
At present, whether observed differences in health outcomes
between those conceived using ICSI and those conceived naturally
are caused by treatment factors, parental characteristics, or related to
adverse obstetric outcomes associated with MAR treatment is unclear.
Careful examination of the potential role that underlying paternal
infertility and MAR procedures have on outcomes at both the molecular
and the phenotypic level is required. Male infertility is a multifactorial
heterogenous condition with potential genetic and environmental
aetiologies8. Thus, consequences for children’s health will depend on
the underlying cause. Large prospective longitudinal studies with unbi-
ased control groups that stratify men by underlying molecular cause
of infertility will be crucial in untangling this issue. Whole-genome and
epigenome analyses of parents and children born as a result of using
MAR techniques will almost certainly be needed. To distinguish the ICSI
technique from background paternal infertility effects, two naturally
conceived control groups, ideally from the same source population,
are required: naturally conceived children from men with subfertility
men and those from age-matched fertile men. Detailed medical and
clinical histories for both parents are required, including evidence of
exposures to toxins and drugs, reproductive histories and individual
MAR procedures used.
To improve understanding of the mechanistic underpinning of
late-onset health outcomes (for example, metabolic disease and can-
cer), prospective studies should be accompanied by the collection
of appropriate biological samples to enable high-resolution genetic
and epigenetic studies to be done. Samples to be considered include
triad DNA (mother, father and baby), sperm, cord blood and placenta,
with some samples taken at multiple time-points (such as from the
child throughout life). For epigenomic studies, the cell make-up of
samples must be considered: for instance, lack of contamination
of sperm samples with somatic cells is crucial for the interpretation of
any comparison of DNA methylation profiles between fertile men and
those with infertility342,343. Effects of paternal age on the sperm genome
and epigenome344 suggest that having a baseline semen analysis (with
sperm cryopreserved) carried out routinely in early adulthood might
Expert recommendation
help clinicians to distinguish between genetic, epigenetic, age and/or
exposure-related effects when men return later in life with fertility
issues. Animal studies are necessary to help to extract combinatorial
effects (for example, individual techniques, interactions between
parental infertility and techniques such as culture to blastocyst or
cryopreservation) and design preventive strategies (such as methyl
donor supplementation of men with subfertility).
Additional male contraceptives
Whether we can develop additional male contraceptive methods is the
12th question to answer (Box 1, question 12). The development of steroid
pharmacology since the 1950s has led to a wide and growing range of
highly effective hormonal methods of contraception for women, with
hormonal intrauterine systems and progestogen-only oral and implant
preparations joining older methods in providing choices for women345.
This progress is in stark contrast to the absence of new contraceptive
methods for men, despite the development of hormonal approaches
to male contraception having a comparably long history346. The only
commercially available reversible male method, condoms, remains
an invaluable option both for contraception and for the prevention of
sexually transmitted infection, and in terms of ‘ever use’ can be con-
sidered the most widely used method of contraception that exists.
Surveys continue to demonstrate that a considerable population of men
would welcome and use novel methods, and perhaps equally impor-
tantly, women would support and welcome their partner in using a
male contraception method347. Undeniably, men are much involved
in contraception, with the likelihood of increased engagement in new
methods that might additionally offer health benefits analogous to the
non-contraceptive benefits of many female methods347.
Whether new male-based contraceptive methods can be devel-
oped is a pertinent question. Trials of hormonal contraceptive
approaches have been conducted for several decades, and the land-
mark WHO-supported studies of the early 1990s showed that a hormo-
nal approach could provide effective and reversible contraception348.
Current approaches are based on progestogen and testosterone com-
binations, with the progestogen providing most of the necessary gon-
adotrophin suppression with ‘add-back’ physiological testosterone
replacement to support androgen-dependent functions in men349. The
National Institute of Child Health and Human Development in the USA
now leads the way in funding major trials of existing compounds and
early studies of novel steroids350. The involvement of pharmaceutical
companies in large trials in the early 2000s351 provided encourage-
ment that this approach was finally going to result in a product as well
as improving methodological rigour (double-blinded, randomized,
controlled trials) and technical innovations (such as centralized
semen analysis and fluorescent detection of sperm), but unfortunately
changing business priorities meant that this hope was short lived.
Given the obvious downside of interfering with the function of
testosterone in male non-reproductive physiology, non-hormonal
approaches would probably have substantial advantages.
Such approaches could target spermatogenesis, sperm maturation
in the epididymis, ejaculation, and/or sperm function352 in the female
reproductive tract (and so, include methods taken by the woman, or
even by either men or women). Almost certainly because of a virtual
absence of funding for this area, progress with non-hormonal contra-
ceptive approaches has been slow and although several well-established
targets exist, such as retinoic acid receptor-α353, minimal progress
has been made in developing compounds for testing in clinical trials.
Moreover, high-confidence targets are sparse350,354 and more targets,
Nature Reviews Urology
particularly in the mature human spermatozoon, need to be identified,
which will greatly facilitate development of compounds manipulating
function355. For this possibility to be realized, considerable investment
in defining the processes that underpin normal male fertility is crucial.
Thus, availability of new male methods of contraception remains an
ambition rather than an imminent reality. The hormonal approach has
a track record in clinical trials, but non-hormonal approaches might
be more successful if they have a rapid-onset, universally active but
reversible approach. Global contraceptive development initiatives
such as Family Planning 2030 can minimize or even fail to recognize
the involvement of men as vital participants in both existing and future
contraceptive availability and development, despite its clear alignment
with United Nations Sustainable Development Goals 3 and 5. As with
female contraception, clearly, a huge unmet need and market exist,
which requires the application of modern scientific approaches356.
However, the outlook is optimistic, as, following substantial invest-
ment by the Bill and Melinda Gates Foundation and the emergence of
organizations such as the Male Contraceptive Initiative, funding in this
area is improving, which will accelerate translation. What is required
now is a substantial research and development funding portfolio from
a wider collection of organizations than currently support this field.
Effective communication
Finally, the 13th question is how andrology as a discipline can com-
municate effectively with the public, health professionals, and funding
agencies (Box 1, question 13). Men, unlike women, are often not encour-
aged from a young age to be conscious of their future fertility and role as
parents, making approaches to fatherhood circumstantial357. Temporal
isolation of men’s reproductive lives from their development of health
literacy, health-care-seeking behaviours and lifestyle choices prob-
ably contribute to behaviour that compromises fertility (for example,
the perception of gains from androgen abuse at the potential cost to
fertility358). However, behaviours that place future reproduction at risk
(such as smoking, sexual practices that increase the risk of contracting
sexually transmitted infections and increasing age at parenthood) are
evident in both sexes251,359. An understanding of the motivations for
such behaviour and how to mitigate them is needed.
Health services can improve provision of men’s needs in various
ways360, but men’s own behaviour needs to change if their fertility is
to be optimized. Men tend to monitor disease symptoms themselves
for a period before seeking health care361, which delays presentation
until late stages of disease. Ailments that are debilitating, or considered
serious or amenable to effective treatment are most likely to lead to
help-seeking behaviour361. For example, Australian men consider infor-
mation about fertility unnecessary unless a problem arises362. Thus,
consideration of male infertility as an acute problem that is solvable
using MAR is likely to appeal to men. This approach might achieve a
successful pregnancy, but it could be a missed opportunity to address
underlying behavioural issues that probably damage multiple aspects
of health in addition to fertility.
Consideration of male infertility as a chronic, rather than acute,
disease state might help to facilitate deliberate approaches to
health-care provision that empower and motivate changes, such as
the Adaptive Leadership Framework for Chronic Disease, to improve
men’s overall health and well-being, and their roles as fathers363.
Information about men’s attitudes to becoming parents, their
fertility knowledge and responses to infertility is lacking364. Men and
women desire parenthood equally but their knowledge about fertility
in men, as a generalization, is deficient365–368. The limitations of men’s
Expert recommendation
knowledge, and the misconceptions they hold, probably influence
delays to fatherhood367.
Men’s fertility awareness (understanding of reproduction, risk
factors for infertility and family planning) seems to be positively asso-
ciated with their education level369 and many men are interested in
improving their knowledge of male fertility and reproductive health370.
Improving men’s knowledge about their fertility, and awareness of
the risks associated with delays in starting a family would be likely to
motivate behavioural changes to optimize fertility and family plan-
ning. Notably, female fertility declines more rapidly than male fertility
with age371.
The effects of social expectations, career paths and individuals’
economic circumstances on reproductive behaviours must also be
addressed365, but the best ways of achieving the changes required in
these areas are unknown. Fertility awareness might be improved by
the online delivery of fertility education372, which could cater to young
men’s use of irony and humour as central learning mechanisms for
health-related social media373. Public information that causes alarm
about infertility is less effective at educating people than less sensa-
tionalized messages, and can create feelings of susceptibility and worry
in individuals374. The suggestion by young Danish men that fertility
awareness should be a mandatory component of education in primary
and secondary schools, with more personalized education provided
closer to when it is relevant, is sensible375. Unfortunately, education
about fertility is not well covered in sex education programmes for
school children376. Certainly, the knowledge that individuals’ general
health and well-being influences fertility should be delivered before
young people make decisions about behaviours that influence their
chances of becoming parents later.
We need to understand what happens before men become patients
with infertility. Part of this awareness relies on understanding basic
reproductive physiology, the origins of infertility and removing precon-
ception risk. Awareness and effort in the provision of pre-conception
care to men is increasing377,378, but it is still in its infancy. An important
feature of current recommendations is a reproductive life plan, which
can improve men’s fertility awareness379 and provides an opportunity
for assessment of risk factors for infertility, and timely intervention if
needed377. A shift to preconception care for men380 presents myriad
research opportunities to improve understanding of male infertility.
Such information will provide key indicators of male reproductive
health, including opportunities to continually assess fertility pre-
diction and examination of diagnostic markers in different regional
populations20.
Effective ways of optimizing men’s fertility before conception are
largely unexplored, and the reproductive outcomes of any resulting
interventions are unknown. Research funding agencies, health insti-
tutions and governments must respond to the need for knowledge in
this area to ensure that interventions are evidence based, acceptable,
effective and affordable. An example of the work required is provided
by the Australian Male Infertility Exposure Study, funded by the Austral-
ian Medical Research Future Fund. The aim of the study is to understand
how health, lifestyle and environmental factors can influence male
infertility and treatment outcomes for male infertility.
Young men and women consider that their general practitioners
are an appropriate and desirable source of fertility information367;
thus, education and resources for primary care providers are essential.
Unfortunately, many general practitioners have limited knowledge
about male fertility, which they appreciate is a barrier to discussing
fertility with their patients: education and information for clinicians,
Nature Reviews Urology
and quality resources they can recommend to their patients should,
therefore, be a priority381. The necessity for education of health pro-
fessionals is illustrated by evidence suggesting that the language and
approach used by them could confuse men rather than inform them382.
A reproductive life plan-based counselling approach (Box 2),
which centres on identifying reproductive intentions and strategies
to achieve them, is effective for raising men’s awareness of reproduc-
tive health and fertility379, but is reliant on investment in education for
health professionals’ development and rollout of patient education
and resources.
Changes in health policy and research funding will be needed to
properly address male infertility, including the provision of additional
funding to define the fundamental mechanism underpinning male fer-
tility. These require a comprehensive assessment of economic impact,
without which making structured arguments for investments in diagno-
sis, research, prevention and treatment will be difficult. A coordinated
effort from all interested parties is needed for such change11.
Recommendations
To improve the diagnosis and treatment of male infertility and, ulti-
mately, prevent infertility, we make ten recommendations for action. The
global implementation of such strategies promises to revolutionize
the understanding and practice of andrology and improve male health
at a population level.
1. The formal acknowledgement by health-care systems, insur-
ance companies and ultimately the public that male infertility
is a common and serious medical condition and that patients have
a right to meaningful diagnoses and treatments. Inherent in this
statement is the acceptance that many hundreds of aetiologies
could exist and that different types of infertility will require
different treatment strategies, that is, personalized medicine.
2. The establishment of a network of national registries and
biobanks containing standardized clinical and lifestyle informa-
tion, and tissue from fertile men and those with infertility, their
partners and children. Such registries should be linked to health
data within national health-care systems. They should be dis-
tributed across the globe, co-ordinated to enable data sharing,
and with time, expanded to include information and tissue from
multiple generations. Such repositories should become epicen-
tres for studying the effects of epigenetic, genetic, environmen-
tal and lifestyle factors on men’s health, and for the monitoring
of temporal changes in men’s health, including sperm output.
3. The implementation of protocols and incentives by health-care
systems and insurance companies for clinics to adhere to clinical
guidelines and the centralization of de-identified information
to accelerate discovery.
4. The expanded use of international collaborative research net-
works to undertake epigenomic, genomic, lifestyle and environ-
mental exposure studies to define aetiologies of male infertility.
Such studies should include a diverse range of patients to provide
improved interpretations of cause–effect relationships.
5. The rapid integration of whole-exome and whole-genome sequ­
enc­ing into the diagnosis of male infertility. The results of such
screening should be pooled globally to accelerate discovery and,
ultimately, the formulation of medical interventions.
6. The formulation of additional tests capable of enabling the dis-
cernment of the aetiology of male infertility and/or the success
of highly invasive MAR procedures with increased accuracy and
precision.
Expert recommendation
7. The rigorous testing of compounds for negative effects on male
fertility and the sharing of results globally. The most urgent need
is in the area of EDCs, including the need to test complex cocktails
of compounds. In parallel, regulatory policies that tightly regu-
late the use of EDCs and other repro-toxicants in products, the
workplace and the environment must be enacted and adhered
to, while investing in research to develop safe chemical alter-
natives. Such alternatives must undergo rigorous testing using
model systems of relevance to human reproduction before
introduction on the market.
8. The rigorous testing of MAR treatment strategies via high-quality
clinical trials before their integration into standard clinical prac-
tice. Such testing should span the gamut of pharmaceutical
products, dietary supplements and MAR ‘add-on’ protocols.
9. The development of education and public health campaigns to
normalize the discussion of male fertility and infertility across
diverse population demographics. Such campaigns should span
the life course of men, be easily understandable and accessible
and linked into health-care systems to encourage earlier and
more frequent engagement of men in health seeking than is
currently the case.
10. Improved and continuous education of the health-care work-
force in the broad area of male reproductive health. This endeav-
our includes an emphasis on training during medical school, the
provision of on-going training and resources to primary care
physicians and nurses and the integration of services across
urology, internal medicine, endocrinology, gynaecology and
paediatrics.
Conclusions
In summary, in this Expert Recommendation, considerable gaps in
scientific and medical databases, socio-economic impact data and
social awareness and education regarding male reproductive health
and infertility are identified; we believe that if investment is made in
these factors, several aspects of society will improve. Scoping of the
literature by acknowledged experts in the field for each question cul-
minated in the overarching conclusion that an urgent need exists for
an increased focus on male fertility and infertility at the discovery level,
diagnostics, the development of targeted treatments and education.
To achieve each of these formidable goals in an optimal manner,
male infertility must be recognized as a common, serious and expen-
sive disease, made up of many sub-types. The global andrology disci-
pline, in its totality, must also work together to undertake definitive,
well-controlled experiments to generate robust outcomes reflective
of diverse geographic and socio-economic populations. Doing so will
have many benefits, including an ability to directly address the root
causes of infertility and potentially preventing somatic disease later
in life. Doing so should also improve the long-term health outcomes of
children conceived naturally or using MAR techniques, and of women
for whom invasive medical interventions will be avoided. Benefits to
the health-care system, with time, will involve a decreased frequency
of interventions to achieve fertility (MAR). Equally, changes should
lead to decreased somatic disease, or, at a minimum, the detection
of infertility-associated somatic disease at an earlier time point in
progression than currently. Shifting from a descriptive (phenotypic)
understanding of male infertility to a molecular diagnosis is essen-
tial, and ultimately, the development of targeted therapies that will
address the root cause of infertility rather than its symptoms needs
to be accelerated. Accepting that human male fertility, like that in
Nature Reviews Urology
other animals, is affected by genetics and environmental exposures,
often in combination, is a necessity; also, depending on the timing of
such exposures (acute and chronic), fertility could be compromised
to differing extents.
The size of the tasks is considerable, but we are not starting from
zero. Many laboratories have made impressive advances in defining
how sperm are produced, including the development of in vitro systems
that recapitulate many of the in vivo pathways, facilitating the rapid
testing of compounds on germ cell health. The adoption of exome
and genome sequencing technologies is revealing a rapidly expanding
number of genetic causes of human infertility and the use of animal
models is shifting discoveries from association to proof. If we are able
to merge these data with those of environmental, lifestyle-induced
epigenetic changes, the chance of developing interventions to avoid
or reverse infertility is good, or at a minimum, realistic predictions of
the consequences of such changes on the health of children conceived
using MAR and the long-term health of the men with infertility will be
possible. As exemplified by genetic studies, many of the necessary
technologies already exist.
Arguably the two biggest challenges to progress are the necessity to
generate large tissue biobanks and datasets across the globe — certainly
beyond those that currently exist, which are skewed towards men of
European descent — and for the ‘re-education’ of the medical profes-
sion and the public to consider male reproductive health as a staple
of health care, rather than something to be considered only when
infertility is present. Overcoming these challenges can be achieved
through coordinated action by professional societies, engagement with
education at all ages and effective communication with governments
and the public.
Men’s health, from fetal development to old age, is affected by
what they eat, drink, breathe and touch (Box 2). Some of these inter-
actions are beyond an individual’s control (for example, exposure to
environmental oestrogens), whereas other exposures can be controlled
(such as avoidance of heavy drinking and recreational drug use). Thus,
improving education around reproductive health will be a considerable
tool for teenagers and young adults beginning sexual relations and
broad social interactions, for young couples considering conception
(natural or assisted) and for adults who have delayed starting a family.
Educational content should be tailored to demographic and socio­
economic groups and presented in an understandable and practical
way, with an emphasis on self-control, self-care and self-seeking for
health care. For men, these positive behaviour practices have histori-
cally been particularly challenging, so determining what men need in
order to ‘buy-in’ as active participants is important.
With success in research leading to improved diagnostics and
treatment of male reproductive disorders, implementation into stand-
ardized global health-care practices, men, their partners and future
generations will live long and healthy lives.
Published online: xx xx xxxx
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Acknowledgements
Thanks goes to R. Agnew, E. Heighton and A. Mergo from The University of Dundee for
their assistance with data collection for Fig. 1. Thanks also goes to A. O’Connor from the
University of Melbourne for assistance with referencing. This research was supported in part
by funding by the National Health and Medical Research Council of Australia to M.K.O., R.I.M.
and J.A.V. (APP1120356); S.K. is a Canada Research Chair in Epigenomics, Reproduction and
Development and funding for this study is provided by the Canada Research Chairs program,
and the Canadian Institutes of Health Research grants (DOHaD Team grant 358654 and
Operating grant 350129). The authors thank ESHRE for financial and logistical support of
the MRHI.
Author contributions
All authors researched data for the article. S.K., R.A.A., C.L.R.B., C.J.D.J. and M.K.O. contributed
substantially to discussion of the content. All authors wrote the article. S.K., R.A.A., C.L.R.B.,
H.M.B., S.R.C., C.J.D.J., G.D., M.L.E., N.G., N.J., C.K., A.L., R.I.M., S.M., T.M., A.P., L.P., S.S., J.T., L.T.,
F.T., M.H.V.-L., J.A.V., F.Z. and M.K.O. reviewed and/or edited the manuscript before submission.
Competing interests
C.L.R.B. is supported in part by the Bill and Melinda Gates Foundation in the area of
contraceptive development, Chief Scientist Office (Scotland), NHS and Genus Healthcare.
C.L.R.B. has received fees from Cooper Surgical for lectures on scientific research methods
outside the submitted work and Ferring for a lecture on the future of male reproductive health.
M.L.E. is an adviser to Ro, Doveras, VSeat, and Next. R.A.A. reports grants and personal fees
from Roche Diagnostics, personal fees from Ferring Pharmaceuticals, IBSA, Merck Serono,
outside the submitted work. S.K. is an inventor on a Provisional patent 14647-P68337CA00
10 June 2022: Methods for identifying epigenetic modifications in sperm, diagnosing
infertility, and identifying treatment strategies. A.P. has undertaken paid consultancy for
Cryos International, Cytoswim Ltd, Exceed Health, Meals Group, and Merck Serono in the
last 2 years, but all monies have been paid to the University of Sheffield (former employer).
M.K.O. is supported in part by the Bill and Melinda Gates Foundation in the area of
contraceptive development. All other authors declare no competing interests.
Additional information
Supplementary information The online version contains supplementary material available at
https://doi.org/10.1038/s41585-023-00820-4.
Peer review information Nature Reviews Urology thanks Marco Alves and Gerhard Haidl for
their contribution to the peer review of this work.
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Related links
Australian Male Infertility Exposure Study: http://www.mcri.edu.au/research/projects/
australian-male-infertility-exposure-amie-study
European Society of Human Reproduction and Embryology: http://www.eshre.eu/
Specialty-groups/Special-Interest-Groups/Andrology/MRHI
Family Planning 2030: https://fp2030.org/
Male Contraceptive Initiative: http://www.malecontraceptive.org
NordFertil: https://nordfertil.org
United Nations Sustainable Development Goals 3 and 5: https://sdgs.un.org/goals
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1
Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. 2The Centre de Recherche du Centre
Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada. 3The Département de Pathologie et Biologie Cellulaire, Université de Montréal,
Montreal, Quebec, Canada. 4MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK. 5Division of Systems Medicine, School of
Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. 6Center for Reproductive Medicine and Andrology, University
Hospital, Martin Luther University Halle-Wittenberg, Halle, Germany. 7Hudson Institute of Medical Research, Melbourne, Victoria, Australia. 8Department
of Obstetrics and Gynaecology, The Royal Women’s Hospital, Melbourne, Victoria, Australia. 9Department of Urology, University of Minnesota,
Minneapolis, MN, USA. 10Institut National de la Recherche Scientifique, Centre Armand-Frappier Sante Biotechnologie, Laval, Quebec, Canada.
11
Department of Urology and Obstetrics and Gynecology, Stanford University, Stanford, CA, USA. 12IVI Foundation, Instituto de Investigación Sanitaria La
Fe, Valencia, Spain. 13School of BioSciences and Bio21 Institute, The University of Melbourne, Parkville, Melbourne, Australia. 14Department of Growth and
Reproduction, International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Copenhagen
University Hospital, Rigshospitalet, Copenhagen, Denmark. 15Department of Experimental and Clinical Biomedical Sciences, ‘Mario Serio’, University
of Florence, University Hospital of Careggi Florence, Florence, Italy. 16Hudson Institute of Medical Research and the Department of Obstetrics and
Gynaecology, Monash University, Melbourne, Australia. 17Monash IVF Group, Richmond, Victoria, Australia. 18Department of Surgery and Cancer Imperial,
London, UK. 19Healthy Male and the Department of Obstetrics and Gynaecology, Monash University, Melbourne, Victoria, Australia. 20Faculty of Biology,
Medicine and Health, University of Manchester, Manchester, UK. 21Centre for Reproductive Medicine and Andrology, University of Münster, Münster,
Germany. 22Departments of Paediatrics, Human Genetics and Pharmacology & Therapeutics, McGill University and Research Institute of the McGill
University Health Centre, Montreal, Quebec, Canada. 23Center for the Investigation of Environmental Hazards, Department of Paediatrics, NYU Grossman
School of Medicine, New York, NY, USA. 24Institute of Reproductive Genetics, University of Münster, Münster, Germany. 25Instituto de Biología y Medicina
Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Fundación IBYME, Buenos Aires, Argentina. 26Biosciences
Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. 27Obstetrics and Gynecology Hospital, Institute of Reproduction
and Development, Fudan University, Shanghai, China.

Nature Reviews Urology