T h e E p i d e m i o l o g y of M a l e

Infertility
Brian R. Winters, MD, Thomas J. Walsh, MD*

KEYWORDS
 Epidemiology  Fertility  Research  Treatment  Diagnosis

KEY POINTS
 The goal of epidemiologic research is to describe and interpret patterns of disease occurrence in
populations in order to generate knowledge that can be used to prevent and/or treat disease.
 The epidemiology of male infertility is difficult to study for well-described reasons:
 Male infertility is not a reportable disease.
 Male infertility is diagnosed and treated in the outpatient clinical setting.
 Infertility care is often paid for out of pocket and, therefore, may not be noted on insurance billing.
 Frequently, the empiric treatment of male factor infertility involves assisted reproductive technol-
ogy (in vitro fertilization) that primarily treats the female partner.
 The true nature of male infertility incidence remains elusive and the prevalence has been weakly
estimated in heterogeneous studies.
 Equally perplexing is the assertion of a global decline in male infertility, with many contradictory
studies leading to significant debate.
 One consistency throughout this review of literature is that male infertility is variable, with a multi-
tude of influencing factors (race, country, geography, and unique at-risk groups), many of which
need further study to better characterize them.
 Future, large-scale, prospective epidemiologic studies may help physicians bridge these gaps in
understanding male infertility.

INTRODUCTION considered elective. In contrast, a disease is

defined as any deviation from or interruption of
Understanding the occurrence of disease in a pop- the normal structure or function of any part, organ,
ulation is important because it allows both quanti- system, or combination thereof of the body that is
fying and qualifying the burden of disease. Gaining manifested by a characteristic set of symptoms or
such an understanding allows for societal pre- signs. Based on this definition, male infertility
paredness, provides direction to scientists, and al- meets these criteria.
lows health care providers to counsel patients The purpose of this review is to integrate under-
appropriately. Recently, infertility has been desig- standing of epidemiology and infertility. A primer
nated as a disease according to the Americans on epidemiologic science is provided and an
with Disabilities Act. This represents a difference example disease presented for which the design
from prior thinking, wherein infertility was deemed of epidemiologic investigations is readily apparent.
a disorder of inconvenience and its treatment
urologic.theclinics.com

Funding Sources: None.

Conflict of Interest: None.
Department of Urology, University of Washington School of Medicine, 1959 Northeast Pacific, Box 356510,
Seattle, WA 98195, USA
* Corresponding author.
E-mail address: walsht@uw.edu

Urol Clin N Am 41 (2014) 195–204

http://dx.doi.org/10.1016/j.ucl.2013.08.006
0094-0143/14/$ – see front matter Published by Elsevier Inc.
196 Winters & Walsh

Key features are then described of infertility that however, no one treatment seemed superior to
limit epidemiologic investigation and a survey of another and patients with DZ did uniformly poorly,
available data on the epidemiology of infertility often never regaining normal pulmonary function.
provided. Finally, the work that must be completed Two years after the first patient was identified
to move this area of research forward is proposed with DZ, a researcher in Boston identified 51
and what the epidemiology of infertility may be patients hospitalized with DZ in a single city over
able to teach 20 years from now described. Lastly, a 1-year period. He compared these individuals
with this new perspective of “infertility as a dis- with a second group of 290 patients, hospitalized
ease,” improvements in public health that may in the same locations with routine viral or bacterial
be gained through improved understanding of (non-DZ) pneumonia. His research team systemat-
the epidemiology of male infertility are envisioned. ically reviewed the hospital records and, when
necessary, interviewed the patients, their families,
EPIDEMIOLOGY and their doctors. They compared the patients
by age, race, occupation, socioeconomic status,
The goal of epidemiologic research is to describe and place of residence. They also compared
and interpret patterns of disease occurrence in patients by their other medical illnesses, medica-
populations in order to generate knowledge that tions, and their lifestyle habits, including tobacco
can be used to prevent and/or treat disease. A smoking, alcohol consumption, and dietary habits.
majority of epidemiologic studies are based on In doing so, they investigated no fewer than 45
the concept of identifying all cases of a disease potential risk factors as part of the same basic
in a defined population at risk. These disease research design: studying each factor required
cases are then studied in relation to the base just gathering more information about each sub-
population, from which they arose, in an effort to ject. Furthermore, the information needed on
better understand the condition, generally for ther- these cases of DZ and the controls without DZ
apeutic purposes.1 generally concerned events that had already
To better understand the power of epidemio- happened by the time of data collection; therefore,
logic research, it is useful to imagine a fictitious, the study could be completed quickly. As a result
prototypic disease, Disease Z (DZ). Imagine that of this study, 2 factors, X and Y, were found asso-
several decades ago a physician was at a commu- ciated with DZ, and patients with DZ had 3 and 4
nity hospital when he identified a patient with a times the exposure to X and Y, respectively,
unique set of symptoms and signs that led to compared with those without DZ. When the
severe respiratory failure requiring hospitalization. research performed an analysis that grouped indi-
The patient had a circular rash on his chest unlike viduals by their race, it seemed that the associa-
any the doctor had ever seen. This initially seemed tion between X and Y and DZ was far more
an isolated case of disease but, over the next pronounced in patients of Asian descent relative
3 months, the same physician cared for several to other patients. These findings prompted
more patients with respiratory disease of identical another group of doctors to treat their patients
quality, all with the circular rash. The doctor with DZ with a drug (Drug A) that was known to
described this case series in the Miscellaneous counter the effects of X and Y, and early success
Journal of Disease, where he noted the pathog- was reported in several observational studies.
nomonic finding of a circular rash, and he gave it These strong associations also prompted the
the name, DZ. As a result of his publication, cases National Institutes of Health to sponsor a DZ
of DZ began being reported across the country prevention and treatment trial. This randomized
with subsequent publication of several descriptive controlled trial was specifically oversampled for
analyses from different hospitals. Doctors began Asian Americans and assigned one group to
to suspect that DZ accounted for more than 20% Drug A and the other to placebo. Among those
of patients who were hospitalized for acute respi- individuals treated with Drug A, no cases of DZ
ratory failure. Because of the frequency, severity, developed compared with those not treated, in
and life-threatening nature of DZ, the Centers for whom 10% developed DZ.
Disease Control and Prevention (CDC) instituted The story of DZ could go on further; however, it
a requirement that each case of DZ be reported is clear from this narrative how epidemiologic
to state public health authorities. No case of DZ research has the power to alter the future of DZ:
escaped recognition due to the need for hospital-
ization and the unambiguous findings that made  It can identify the occurrence of disease in a
the diagnosis. The cause of DZ remained unclear base population.
and various therapies were trialed, including  It can acknowledge an increase incidence in
antibiotics, antifungals, and antiviral therapies; disease over time.
 The Epidemiology of Male Infertility 197

 It can identify risk factors for the disease that these data sets are able to derive prevalence
can narrow the search for a cause. and, on occasion, incidence of a disease in a
 And, it can identify subgroups of individuals population at risk and help quantify disease
who have elevated risk for disease, eventually burden. Understanding of these disease pro-
designing interventional trials of prevention or cesses can then stimulate further research and,
treatment. potentially, therapeutic innovations focused on
the affected population.
As with DZ, the full evaluation of any disease or There are several factors that have impeded the
condition that affects the human condition re- study of male infertility:
quires epidemiologic study if understanding and
advancements in treatment are to be made. The  Male infertility is not a reportable disease.
study of male infertility is no exception.  For example, a diagnosis of prostate
In 2007, the Urologic Diseases of America (UDA) cancer is easily found within large-scale
project consolidated the available literature and databases such as the Surveillance, Epi-
data on male infertility in an attempt to better demiology and End Results database.
understand the burden of disease.2 Unfortunately, Epidemiologic data are easily queried to
the authors thought that insufficient data and quantify many aspects of disease, including
literature were available to draw meaningful con- prevalence, treatment outcomes, and sur-
clusions about the cause of infertility and the char- vival characteristics, with the goal of
acteristics of infertile men. improved therapies over time.
To better define the disease demographics  Male infertility is diagnosed and treated in the
of male infertility, the authors think the epidemio- outpatient clinical setting.
logic characteristics of interest should include dis-  Outpatient data are not accrued into
ease incidence, secular or birth cohort trends in large databases and, therefore, quantifying
diagnosis, racial variation, geographic variation, disease burden effectively is often not
and infertility in unique exposure populations. possible.
 Infertility care is often paid for out of pocket
INFERTILITY and, therefore, may not be noted on insurance
billing.
Infertility is the inability to conceive after 12 months  For obvious reasons, if there are no insur-
of regular, unprotected intercourse3 and infertility ance claims to track diagnoses and treat-
affects approximately 15% to 20% of all cou- ments of a disease, it is difficult to quantify
ples.4–7 The study of male infertility specifically its true nature.
presents a vexing clinical problem because both  Frequently, the empiric treatment of male
male and female partners make an independent factor infertility involves assisted reproductive
contribution to a couple’s fertility; however, the technology (in vitro fertilization) that primarily
outcomes of fertility are only manifested by treats the female partner.2
conception or giving birth to a child. As a result,  The CDC tracks in vitro fertilization out-
epidemiologic studies of male infertility present a comes and requires that an actual cause
formidable challenge, because the primary be assigned for the woman whereas only
outcome of interest may be difficult to link to the a single variable, “Male Factor–Yes/No,” is
male partner. This difficulty in confirming which assigned for men.
partner makes the greatest contribution to a
couple’s disease is a distinguishing characteristic Whereas data were able to be compiled on DZ
of infertility and should be contrasted with DZ, in for advancement in understanding, given these
which pathognomonic findings make for diag- described limitations with male infertility, there
nostic certainty. are neither repositories of data nor readily avail-
Historically, epidemiologic and outcomes re- able means of identifying a population-based
search has benefited from large repositories of sample of infertile men in government, hospital,
administrative and reportable data. Such reposi- or standard claims data. As a result, most studies
tories take the form of insurance or Medicare of male infertility to date have been case series
claims, hospitalization records, or requirements data typically drawn from tertiary care or referral
from the federal government to report specific centers, population-based surveys, or high-risk
diseases and outcomes. There are limits to these occupational cohorts. For these reasons, a clear
types of data, however; such data derive strength picture of the epidemiology or the underlying
in numbers and have the ability to represent large causes of male infertility in a population represen-
segments of the US population. Furthermore, tative sample has never emerged.8–10
198 Winters & Walsh

MALE INFERTILITY occurs and is described as “cases per X number of

person-time.” Prevalence, alternatively, is gener-
Several areas of investigation provide evidence for ally easier to calculate given that it may be as-
the public health burden of male infertility. Reports sessed at a single point in time and is presented
have suggested that male infertility has been as a proportion of the total (%).
increasing over the past several decades; however, In order to calculate a disease incidence or prev-
the extent and causes of declining male reproduc- alence, the base population at risk for a disease
tive health remain largely unknown. The assertion must first be defined. In the DZ example, all indi-
that male infertility is increasing on a global level viduals in the Boston area were at risk for the
is controversial and challenging to confirm.3,11,12 disease; therefore, they comprise the denominator
Beyond the increasing burden of disease, male of the equation whereas new cases of DZ are the
infertility causes significant psychosocial and mar- numerator. Frequently it is easiest to define a
ital stress8,13,14 and is associated with a high cost population at risk by geography, because popula-
of infertility care.15 Recent work has suggested tion census data may be used as the denominator
that male infertility may be associated with reduced and, to date, most studies aimed at describing the
longevity9 and that male factor infertility is an incidence or prevalence of male infertility have
increased risk factor for certain malignancies.10 done so for specific geographic regions.
Although the cause of male infertility is understood Several efforts have been made to quantify the
in some cases (eg, cryptorchidism, specific genetic burden of infertility in certain parts of the world
causes, and medical disease), most cases are due (Table 1). Thonneau and colleagues16 deployed a
to poor semen quality (oligozoospermia, astheno- cross-sectional design and conducted a large-
zoospermia, or teratozoospermia—alone or in scale survey of 1686 couples who were at risk for
combination) of unknown causes.16 Additionally, infertility in a specific French region in 1991. They
up to 12% of couples have no identifiable cause were able to quantify prevalence despite the title
of infertility.17 mentioning incidence of infertility. Their principle
findings were 14.1% overall infertility, with 39%
INCIDENCE OF MALE INFERTILITY having both a male and female component and
approximately 20% due to male factors alone.
Incidence is defined as the number of new cases In 1994, Gunnell and Ewings5 sent a postal
of a disease in a specific population at risk over questionnaire to 3141 British women. With a
a specific period of time. This is in contrast to prev- response rate of 76.7%, the overall prevalence of
alence, which is defined as the total number of primary infertility was 16.1% and of secondary
cases of disease (both old and new) present in a infertility was 15.8%; 26.4% of women were likely
specified population at a single point in time. to suffer from infertility at some point in their lives.
These terms are occasionally used incorrectly in A component of male infertility could certainly be
medical literature but have important distinctions at play in the population; however, only female
(Fig. 1). Incidence is a rate at which a new disease outcomes were described.

Fig. 1. Conceptual model detailing the difference between prevalence and incidence. Yellow circles represent dis-
ease of interest and blue circles represent controls. Prevalence involves a snapshot of the disease burden, whereas
incidence describes new events of disease over a given time period.
 The Epidemiology of Male Infertility 199

Table 1
Examples of population-based studies focused on describing the scope of infertility in men and
women

Female Male Both?

Title Author, Year Population Factor? (%) Factor? (%) (%)
Incidence and main Thonneau et al,16 1686 Couples 30 20 39
causes of infertility in 1991
a resident population
(1,850,000) of three
French regions
(1988–1989)
Infertility prevalence, Gunnell & Ewings,5 3141 Surveyed 26.4 N/A N/A
needs assessment 1994 women
and purchasing
Estimation of the Philippov et al,6 2000 Married 52.7 6.4 38.7
prevalence and 1998 women surveyed,
causes of infertility 186 couples
in Western Siberia
High prevalence of Ikechebelu et al,18 314 Couples 25.8 42.4 20.7
male infertility in 2003
southeastern Nigeria
Clinical patterns and Bayasgalan et al,19 430 Couples 45.8 25.6 18.8
major causes of 2004
infertility in Mongolia

Philippov and colleagues6 studied 2000, ran- infertility were thought related to pelvic inflamma-
domly selected, married women in Tomsk, West tory disease (PID) because 25% of women had 1
Siberia, using World Health Organization (WHO) or more episodes of PID and 32.8% of female fac-
questionnaire data. These revealed an overall tors of infertility were tubal in origin.
infertility of 16.7% (3.8% primary and 12.9% sec- An overall view of these studies reveals that
ondary) with 52.7% and 6.4% attributed to female some attempted to quantify prevalence, but most
and male factors, respectively. The high rate of were descriptive in nature, and none was able to
female factors was thought related to a high rate define the incidence of male infertility. These
of complications after births (24.1%) and artificial studies suggest that male factor infertility can
performed abortions. In 38.7%, both partners suf- vary widely based on geography (eg, Nigeria vs
fered from infertility factors. Mongolia) as well as inherent risk factors. Forget-
In 2003, a Nigerian study revealed an inordi- ting the differences in methodology of these
nately high prevalence of male infertility in the studies and evaluating additional existing literature,
country’s southeastern region. Ikechebelu and a component of male factor infertility may range
colleagues18 performed a retrospective review of widely, from 6% to 50%, with many groups esti-
314 couples evaluated for infertility in gynecologic mating 30% to 50%.2,4,6,7,16,18–22
clinics at 2 hospitals between 1997 and 1998. Male In the United States, the UDA project made
factor infertility was estimated at 42.4% whereas an initial effort to quantify male infertility in the
female factors were estimated at 25.8%. In United States. Meacham and colleagues used a
20.7% of couples, both partners were affected. variety of databases (Center for Health Care Eval-
Sexual promiscuity and sexually transmitted uation, Healthcare Cost and Utilization Project,
diseases (and inadequate treatment) have been National Survey of Ambulatory Surgery, National
implicated in the high rate of male factors. Ambulatory Medical Care Survey, Veterans Health
Finally, a similar retrospective review was per- Administration, Society for Assisted Reproductive,
formed in Mongolia at the State Research Center Technology, and others) to explore many aspects
on Maternal Child Health in Ulaanbaatar. Bayas- of this topic.23 These investigators speculated that
galan and colleagues19 found that female factors infertility due to male factors alone might be closer
accounted for 45.8% and male factors for to the 30% when accounting for bias (selection
25.6%, and 18.8% of couples had both male and bias based on differential referral, modification of
female factors. High percentages of female risk behavior based on reproductive outcomes,
200 Winters & Walsh

and so forth) and study methodology in the exist- revealed a significant decrease in mean sperm
ing available literature.2,24 count (113–66 million/mL) and volume (3.4–
The true extent of male infertility is likely 2.75 mL) over this 53-year period. Using the
underestimated due to a lack male evaluation WHO definition of normal semen parameters
in infertile couples. Eisenberg and colleagues25 (count >20 million/mL, volume 2–6 mL),7 whether
recently evaluated frequency of the male infertility this decrease makes an appreciable impact on
evaluation using National Survey of Family male factor infertility is unclear but teleologically
Growth (NSFG) data and found that 18% to makes sense.
27% of men within infertile couples were not eval- This study was scrutinized by Fisch and Golub-
uated, which corresponds to 370,000 to 860,000 off27 (among many others), who pointed out signif-
men who may have undiagnosed male factor icant flaws within the analysis. These investigators
infertility. Additional studies have shown that re-evaluated the 61 studies described but limited
race, education level, and socioeconomic status their analysis to more robust studies with sample
can also be significant predictors of infertility utili- sizes greater than or equal to 100 men. They found
zation, potentially leaving many at-risk men undi- a significant trend toward geographic variation
agnosed. For example, Hotaling and colleagues26 (eg, high counts in the United States in early years
examined data from the 2002 NSFG (cycle 6) and vs low counts in developing countries in later
found college or advanced degree and marital years) and suggested comparing markedly dif-
status significantly associated with infertility care ferent populations may simply reflect “clustering
whereas income, increasing number of children, of significant geographic variations rather than a
age, religion, and private insurance were all asso- decline over time.”27 Further scrutiny suggested
ciated on bivariate but not multivariate models for other flaws, including high variability of methods
infertility resource utilization. Given these findings, for sperm collection, lack of control for absti-
the investigators concluded that the current avail- nence, smoking and drug use, and failure to
able data garnered on male infertility from centers include some positive studies.28 In a re-analysis
of excellence case series might not reflect the of Carlsen and colleagues’ data, however, Swan
true population at risk. and colleagues29 found significant declines in
Together these data suggest that male factor sperm density in the United States, Europe, and
infertility comprises a significant component of Australia when controlling for abstinence, age,
global infertility and needs to be better quantified percent of men with proved fertility, and specimen
and qualified with larger-scale, well-controlled, collection method.
population-based studies. As one can see, the data is mixed with the following
two examples yielding different conclusions:
SECULAR OR BIRTH COHORT TRENDS IN 1. In 1996, Fisch and colleagues30 performed a
DIAGNOSIS retrospective review of semen parameters in
1283 men at 3 United States sperm banks
Secular trends refer to the changes in incidence of over a 25-year period. When controlling for
pattern of disease that occur over time. Presum- age and duration of abstinence, this review
ably, such changes reflect ever-changing expo- found a slight increase in mean sperm concen-
sures that occur as a result of a population’s tration but no change in semen volume or
changing environment. This is in distinction to birth motility over time.
cohort trends that refer to changes in incidence or 2. A more recent review by Rolland and col-
pattern of disease that result from the era in which leagues31 from a representative population in
an individual was born. For example, during the France looked at partners of women undergoing
era of diethylstilbestrol use as a means of control- assisted reproductive technology procedures
ling preterm labor, children born (in the 1950s and and showed a decline in semen concentration
1960s) to women who used the drug are now at and normal morphology over a 17-year period.
risk for breast cancer and reproductive disease.
There are few data on birth cohort trends in Many other studies exist with equally conflicting
diagnosis and the majority of male infertility litera- results. For example, a recent systematic review
ture examining this relationship involves semen looking at 35 major semen analysis studies showed
analysis. In 1992, Carlsen and colleagues12 made a total of 8 (18,109 men) suggesting a decline over
the first attempt to quantify changes in semen time; 21 (112,386 men) showing no change or an in-
quality (and, in theory, male infertility). This group crease in semen quality; and 6 (26,007 men)
evaluated 61 articles addressing this question, showing ambiguous or conflicting results.28 Well-
spanning from 1938 to 1991, including 14,947 controlled, prospective data are needed to examine
subjects. Their findings based on linear regression this question further.
 The Epidemiology of Male Infertility 201

RACIAL VARIATION In a study by Swan and colleagues35 looking at

geographic variations in semen quality of 512
Data on male factor infertility as it pertains to race fertile couples in 4 cities across the United States
are lacking in the current literature. Age-adjusted, (Columbia, Mississippi; Minneapolis, Minnesota;
VA-based data have shown that Hispanic men New York, New York; Los Angeles, California),
have the highest frequency of treatment of male sperm concentration and motility were found
factor infertility, followed by African Americans, reduced in semirural and agricultural areas rela-
then whites. This is in opposition to National tive to more urban settings. This association sug-
Ambulatory Medical Care Survey data suggesting gests that male factor infertility can likewise be
a higher utilization of male infertility treatment affected in these regions. This is further corrobo-
therapies in white men in the private sector.2 Addi- rated by large meta-analyses, systematic reviews,
tionally, recent data from the NSFG suggest and other individual studies showing stark differ-
that white individuals are more likely to undergo ences in sperm counts varying between countries,
infertility evaluations than other races.25 The both industrialized and not.12,27–31 Additionally,
cause of discrepancy between these populations exposure to various environmental toxins and
is unclear. In a recent study looking at an equal trends in genitourinary infections based on geog-
access no-cost health care system, military raphy can contribute to male infertility.18,22,36–38
personnel seeking treatment showed no signifi-
cant trends in race, and the race distribution was
balanced, based on enlisted demographics.32 INFERTILITY IN UNIQUE EXPOSURE
In 2008, Walsh and VanDenEeden described a POPULATIONS: OBESITY AS AN EXAMPLE
cohort of men who were evaluated for infertility The WHO body mass index (BMI) categories are
within Kaiser Permanente of Northern California less than 18.5 (underweight), 18.5 to 24.9 (normal),
(KPNC). KPNC offered a unique opportunity to 25.0 to 29.9 (overweight), 30 to 39.9 (obese), and
investigate male infertility in a population-based greater than 40 (morbidly obese).39 Using these
cohort of men given that it is an integrated health definitions, data from the 2009–2010 National
delivery system for more than 3.2 million members Health and Nutrition Examination Survey indicate
(>2 million adults; 48% men) and provides compre- that 35.7% of the United States population is
hensive health care to 43% of covered lives in obese, which equates to approximately 37 million
Northern California. KPNC is also known to provide men over the age of 20.40 Although there is well-
care to a racially and ethnically diverse population known morbidity associated with chronic obesity,
that is generally not seen in other referral centers. including heart disease, stroke, type 2 diabetes
In this work, the investigators queried a population mellitus, and certain types of cancer, whether
database of more than 1.5 million men older than this plays a significant role in male factor infertility
18 years and found approximately 30,000 men is a subject of debate.
evaluated for infertility by semen analysis. Overall, Using the definition of infertility as the inability to
there was a 36% prevalence of semen abnormal- conceive after 12 months of regular unprotected
ities, with clear association between advancing intercourse, data from epidemiologic studies,
age and an increasing proportion of abnormalities. including the Agricultural Health Study (a large-
Of greater significance, however, was the finding scale study of 1300 couples, studying pesticide
that 49% of African Americans were found to applicators and their spouses),41,42 the Danish
have an abnormal test compared with 37%, 38%, National Birth Cohort (10,000 pregnant women
and 39% of white, Asian, and Hispanic men, interviewed for subfecundity relative to spouse
respectively.33 BMI),43 and the Norwegian Mother and Child
GEOGRAPHIC VARIATION Cohort Study (26,000 pregnant women assessed
for infertility relative to spouse BMI) suggest a
When looking at men seeking care, data from the dose-response increase in male infertility with
National Survey of Ambulatory Surgery in the increasing BMI.44 There were, however, limitations
mid-90s revealed a tendency toward increased to each of these analyses, calling applicability into
outpatient visits in the Northeastern United States question.44 For example, in the latter 2 analyses,
followed by the South, Midwest, and the West.2 only pregnant women were surveyed, indicating
This is potentially due to the preponderance of a selection bias, whereas in the Agricultural Health
infertility clinics in the Northeast compared with Study, there were confounders, including pesti-
the rest of the United States. A more recent review cide exposure (a well-known gonadotoxin36) and
of these data suggests that this finding persists a significantly higher overall infertility rate of 28%.
in 2009.34 Geographic differences in insurance Data regarding semen are also conflicting in
coverage may also play a role in this trend. regards to obesity. Studies have shown obesity
202 Winters & Walsh

can have a negative effect on both sperm count45 and suggest further study is needed to understand
and motility,46 with limited data on morphologic the true pathologic relationship between obesity
effects. Kort and colleagues46 also showed evi- and male factor infertility.
dence of increased DNA fragmentation correlated Although obesity is one example of a potential
with obesity. These studies (and others) were risk factor of male infertility in a unique exposure
examined in a large systematic review and meta- population, it illustrates the need to examine all
analysis looking at semen parameters in obesity. potential associated risk factors. In the DZ
Although some studies did show a trend with example, studying separate risk factors within
adverse effects of obesity on sperm parameters, different groups led to development of specific
the trend of all the available research did not sup- targeted therapies. This remains the goal in treat-
port definitive conclusions.47 An updated system- ment of male factor infertility.
atic review by Sermondade and colleagues,48
looking at sperm count alone, re-reviewed the SUMMARY AND LIMITS TO EPIDEMIOLOGIC
data of these studies (plus additional data col- ANALYSIS OF MALE INFERTILITY
lected in the interim) and concluded that elevated
BMI (both overweight and obese categories) was Understanding the occurrence of disease in a
associated with significantly decreased sperm population is important because is allows both
counts, defined as less than 40 million per ejacu- quantifying and qualifying the burden of disease.
late. Their findings revealed a J-shaped curve As in the hypothetical example of DZ, epidemi-
with a nonsignificant increase in decreased sperm ology can help make advancements in both under-
counts with underweight individuals. Whether this standing and treatment of disease for the
decreased trend in sperm count, with the cutoff improved care of patients.
of 40 million per ejaculate, definitively manifests The epidemiology of male infertility is difficult to
as infertility and is directly related to obesity is study for well-described reasons, including not
debatable. being a reportable disease, predominantly outpa-
Obesity has also been shown in various studies tient treatment, lack of insurance coverage and
to be associated hormonal aberrations, including paying out of pocket, and underestimation of out-
decreased follicle-stimulating hormone and leuti- comes based on the nature of male and female
nizing hormone, decreased total and free testos- fecundity.
terone (T), increased estrone and estradiol (due The true nature of male infertility incidence
to peripheral aromatization of androgens), de- remains elusive and the prevalence has been
creased inhibin B levels (a marker for Sertoli cell weakly estimated in heterogeneous studies.
function), and reduced sex hormone–binding Equally perplexing is the assertion of a global
globulin (SHBG) (thought to be related to insulin decline in male infertility, with many contradictory
resistance in obesity and poor hepatic synthetic studies in the available literature leading to signif-
function), all of which can interfere with male icant debate. Perhaps the only consistency
reproduction through various mechanisms.44 A throughout this review is that male infertility is
meta-analysis and review of these studies by variable with a multitude of influencing factors
MacDonald and colleagues47 found a strong (race, country, geography, unique at-risk groups,
negative relationship between BMI and T and and so forth), many of which need further study
SHBG but no definitive conclusions about the to better characterize them. In the end, future
more biologically active free T. Findings regarding large-scale, prospective, epidemiologic studies
estradiol were mixed overall and available data did may help physicians bridge these gaps in
show a decrease in inhibin B with elevated BMI. understanding.
The available data seem to show trends in obesity
effects on male infertility through hormonal mech- RESEARCH MOVING FORWARD
anisms; however, further study is required for
more definitive conclusions. A potential goal moving forward is to establish a
Finally, obesity increases the risk of erectile large, diverse longitudinal cohort of men with infer-
dysfunction49 and erectile dysfunction is more tility. This cohort could be compared with appro-
common in infertile men.50 This may be explained priately matched populations, including fertile
by the decreased T levels in obese males as well men with infertile or fertile partners or a general
as increased circulating proinflammatory cyto- population of age-matched men. These data
kines found in obesity (postulated to interfere via would then be linked to socioeconomic and envi-
nitric oxide pathway).51 ronmental variables and, depending on the ques-
Together these findings show a complicated tion asked, the epidemiologic data could spur
relationship between obesity and male infertility new research avenues and treatments.
 The Epidemiology of Male Infertility 203

A proposed framework to answer continued 13. Eisenberg ML, Smith JF, Millstein SG, et al.
questions about male infertility: Perceived negative consequences of donor gam-
etes from male and female members of infertile
 Establish a longitudinal database and register couples. Fertil Steril 2010;94(3):921–6.
all men with infertility. 14. Nelson CJ, Shindel AW, Naughton CK, et al.
 Accrue subjects from all possible care centers Prevalence and predictors of sexual problems,
and varied backgrounds. relationship stress, and depression in female part-
 Follow detailed variables on these patients ners of infertile couples. J Sex Med 2008;5(8):
over time (eg, laboratory data). 1907–14.
 Link these data to other national databases 15. Smith JF, Glidden D, Walsh TJ, et al. Is socioeco-
and/or disease registries. nomic status associated with higher infertility
 Link assisted reproductive technology or costs? An analysis of the interaction between edu-
intervention data to patient outcomes. cation and income on total cost among infertile
 Use these epidemiologic findings to further couples followed for 18 months. Fertil Steril 2008;
elucidate the nature of disease and improve 90(Suppl).
patient outcomes. 16. Thonneau P, Marchand S, Tallec A, et al. Inci-
dence and main causes of infertility in a resident
REFERENCES population (1,850,000) of three French regions
(1988-1989). Hum Reprod 1991;6(6):811–6.
1. Koepsell TW, Weiss NS. Epidemiologic methods: 17. SART. Clinical summary report, 2011. Available at:
studying the occurence of illness. 1st edition. New http://www.sart.org. Accessed January 6, 2013.
York: Oxford University Press, Inc; 2003. p. 513. 18. Ikechebelu JI, Adinma JI, Orie EF, et al. High prev-
2. Meacham RB, Joyce GF, Wise M, et al. Male infer- alence of male infertility in southeastern Nigeria.
tility. J Urol 2007;177(6):2058–66. J Obstet Gynaecol 2003;23(6):657–9.
3. Skakkebaek NE, Jorgensen N, Main KM, et al. Is 19. Bayasgalan G, Naranbat D, Tsedmaa B, et al.
human fecundity declining? Int J Androl 2006; Clinical patterns and major causes of infertility in
29(1):2–11. Mongolia. J Obstet Gynaecol Res 2004;30(5):
4. Sharlip ID, Jarow JP, Belker AM, et al. Best practice 386–93.
policies for male infertility. Fertil Steril 2002;77(5): 20. Mosher WD, Pratt WF. Fecundity and infertility in
873–82. the United States: incidence and trends. Fertil Steril
5. Gunnell DJ, Ewings P. Infertility prevalence, needs 1991;56(2):192–3.
assessment and purchasing. J Public Health Med 21. Brugh VM 3rd, Matschke HM, Lipshultz LI. Male
1994;16(1):29–35. factor infertility. Endocrinol Metab Clin North Am
6. Philippov OS, Radionchenko AA, Bolotova VP, et al. 2003;32(3):689–707.
Estimation of the prevalence and causes of infer- 22. Leke RJ, Oduma JA, Bassol-Mayagoitia S, et al.
tility in Western Siberia. Bull World Health Organ Regional and geographical variations in infertility:
1998;76(2):183–7. effects of environmental, cultural, and socioeco-
7. Sabanegh E, Agarwa A. Male infertility. In: Wein A, nomic factors. Environ Health Perspect 1993;
editor. Campbell-walsh urology. 10th edition. Phila- 101(Suppl 2):73–80.
delphia: Elsevier Saunders; 2011. p. 616–47. 23. Litwin MS, Saigal CS, Yano EM, et al. Urologic
8. Smith JF, Walsh TJ, Shindel AW, et al. Sexual, diseases in America Project: analytical methods
marital, and social impact of a man’s perceived and principal findings. J Urol 2005;173(3):933–7.
infertility diagnosis. J Sex Med 2009;6(9):2505–15. 24. Tielemans E, Burdorf A, te Velde E, et al. Sources
9. Jensen TK, Jacobsen R, Christensen K, et al. of bias in studies among infertility clients. Am J
Good semen quality and life expectancy: a Epidemiol 2002;156(1):86–92.
cohort study of 43,277 men. Am J Epidemiol 25. Eisenberg ML, Lathi RB, Baker VL, et al. Frequency
2009;170(5):559–65. of the male infertility evaluation: data from the
10. Walsh TJ, Croughan MS, Schembri M, et al. national survey of family growth. J Urol 2013;
Increased risk of testicular germ cell cancer among 189(3):1030–4.
infertile men. Arch Intern Med 2009;169(4):351–6. 26. Hotaling JM, Davenport MT, Eisenberg ML, et al.
11. Auger J, Kunstmann JM, Czyglik F, et al. Men who seek infertility care may not represent
Decline in semen quality among fertile men in the general U.S. population: data from the Na-
Paris during the past 20 years. N Engl J Med tional Survey of Family Growth. Urology 2012;
1995;332(5):281–5. 79(1):123–7.
12. Carlsen E, Giwercman A, Keiding N, et al. 27. Fisch H, Goluboff ET. Geographic variations in
Evidence for decreasing quality of semen during sperm counts: a potential cause of bias in studies
past 50 years. BMJ 1992;305(6854):609–13. of semen quality. Fertil Steril 1996;65(5):1044–6.
204 Winters & Walsh

28. Fisch H, Braun SR. Trends in global semen param- 40. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of
eter values. Asian J Androl 2013;15(2):169–73. Obesity in the United States. Data from the National
29. Swan SH, Elkin EP, Fenster L. Have sperm Health and Nutrition Examination Survey, 2009-
densities declined? A reanalysis of global trend 2010. CDC; 2012.
data. Environ Health Perspect 1997;105(11): 41. Alavanja MC, Sandler DP, McMaster SB, et al. The
1228–32. Agricultural Health Study. Environ Health Perspect
30. Fisch H, Goluboff ET, Olson JH, et al. Semen ana- 1996;104(4):362–9.
lyses in 1,283 men from the United States over a 42. Sallmen M, Sandler DP, Hoppin JA, et al. Reduced
25-year period: no decline in quality. Fertil Steril fertility among overweight and obese men. Epide-
1996;65(5):1009–14. miology 2006;17(5):520–3.
31. Rolland M, Le Moal J, Wagner V, et al. Decline in 43. Olsen J, Melbye M, Olsen SF, et al. The Danish Na-
semen concentration and morphology in a sample tional Birth Cohort–its background, structure and
of 26,609 men close to general population between aim. Scand J Public Health 2001;29(4):300–7.
1989 and 2005 in France. Hum Reprod 2013;28(2): 44. Hammoud AO, Gibson M, Peterson CM, et al. Impact
462–70. of male obesity on infertility: a critical review of the
32. Costabile RA, Spevak M. Characterization of pa- current literature. Fertil Steril 2008;90(4):897–904.
tients presenting with male factor infertility in an 45. Jensen TK, Andersson AM, Jorgensen N, et al.
equal access, no cost medical system. Urology Body mass index in relation to semen quality and
2001;58(6):1021–4. reproductive hormones among 1,558 Danish
33. Walsh TF, Schembri M, Croughan MS, et al. Epidi- men. Fertil Steril 2004;82(4):863–70.
miologic characterisitics of men evaluate for infer- 46. Kort HI, Massey JB, Elsner CW, et al. Impact of
tility in a large, pre-paid insurance plan. Fertil body mass index values on sperm quantity and
Steril 2008;90(Suppl):S63. quality. J Androl 2006;27(3):450–2.
34. CDC. Assisted Reproductive Technology, National 47. MacDonald AA, Herbison GP, Showell M, et al. The
Report. 2009. Available at: http://www.cdc.gov. Ac- impact of body mass index on semen parameters
cessed January 6, 2013. and reproductive hormones in human males: a sys-
35. Swan SH, Brazil C, Drobnis EZ, et al. Geographic tematic review with meta-analysis. Hum Reprod
differences in semen quality of fertile U.S. males. Update 2010;16(3):293–311.
Environ Health Perspect 2003;111(4):414–20. 48. Sermondade N, Faure C, Fezeu L, et al. BMI in rela-
36. Swan SH. Semen quality in fertile US men in rela- tion to sperm count: an updated systematic review
tion to geographical area and pesticide exposure. and collaborative meta-analysis. Hum Reprod
Int J Androl 2006;29(1):62–8 [discussion: 105–8]. Update 2013;19(3):221–31.
37. Cates W, Farley TM, Rowe PJ. Worldwide patterns of 49. Bacon CG, Mittleman MA, Kawachi I, et al. Sexual
infertility: is Africa different? Lancet 1985;2(8455): function in men older than 50 years of age: results
596–8. from the health professionals follow-up study. Ann
38. Mehta RH, Makwana S, Ranga GM, et al. Preva- Intern Med 2003;139(3):161–8.
lences of oligozoospermia and azoospermia in 50. O’Brien JH, Lazarou S, Deane L, et al. Erectile
male partners of infertile couples from different dysfunction and andropause symptoms in infertile
parts of India. Asian J Androl 2006;8(1):89–93. men. J Urol 2005;174(5):1932–4 [discussion: 4].
39. Organization WH. Obesity: preventing and man- 51. Sullivan ME, Thompson CS, Dashwood MR, et al.
aging the global epidemic. Report Who Consul- Nitric oxide and penile erection: is erectile dysfunc-
tation. World Health Organ Tech Rep Ser 2000; tion another manifestation of vascular disease?
894:i–xii. Cardiovasc Res 1999;43(3):658–65.