Obesity, male infertility, and the

sperm epigenome
James R. Craig, M.D.,a,b Timothy G. Jenkins, Ph.D.,a Douglas T. Carrell, Ph.D., H.C.L.D.,a,c,d
and James M. Hotaling, M.D., M.S., F.E.C.S.M.a,b,c
a
Division of Urology, Department of Surgery, b Center for Men's Health and Reconstructive Surgery, and c Department of
Obstetrics and Gynecology, University of Utah; and d Department of Human Genetics, University of Utah School of
Medicine, Salt Lake City, Utah

Obesity is a growing epidemic and a common problem among reproductive-age men that can both cause and exacerbate male-factor
infertility by means of endocrine abnormalities, associated comorbidities, and direct effects on the delity and throughput of spermato-
genesis. Robust epidemiologic, clinical, genetic, epigenetic, and nonhuman animal data support these ndings. Recent works in the
burgeoning eld of epigenetics has demonstrated that paternal obesity can affect offspring metabolic and reproductive phenotypes
by means of epigenetic reprogramming of spermatogonial stem cells. Understanding the impact of this reprogramming is critical to
a comprehensive view of the impact of obesity on subsequent generations. Furthermore, and perhaps more importantly, conveying
the impact of these lifestyle changes on future progeny can serve as a powerful tool for obese men to modify their behavior. Reproduc-
tive urologists and endocrinologists must learn to assimilate these new ndings to better counsel men about the importance of paternal
preconception health, a topic recently being championed by the Centers for Disease Control and Prevention. (Fertil Steril 2017;107:
84859. 2017 by American Society for Reproductive Medicine.)
Key Words: Obesity, male infertility, sperm epigenetics, transgenerational inheritance
Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/
16110-fertility-and-sterility/posts/15227-23552

O
besity, dened as a body mass mellitus, sexual dysfunction, and sperm logic evidence was not available until
index (BMI) of >30 kg/m2, is epigenetic perturbations. In addition to a decade ago. In 2006, Sallmen et al.
a disease approaching the immediate effects that obesity has (11) described a group of 20,620 fam-
pandemic proportions, affecting more on the father, there is evidence that ilies in Iowa and North Carolina. They
than 1.9 billion adults over the age of negative effects may be transmitted to illustrated a dose-response relationship
18 years worldwide (1, 2) (Fig. 1). In the offspring via genetic and epigenetic between BMI and male infertility, with
the United States alone, the prevalence alterations of germ cell DNA (810). worsening male fertility for every 3-
of obese men who are of reproductive The objective of the present review is point increase in BMI >25 kg/m2,
age has tripled since the 1970s and to explore the epidemiology and patho- with an odds ratio (OR) of 1.12 (95%
currently affects 33.9% of the physiology of obesity-induced male condence interval [CI] 1.011.25).
population over the age of 20 years (3). infertility with an emphasis on the role These ndings were conrmed in later
The rise in obesity rates have paral- of epigenetics. studies across the globe, including in
leled reports of rising rates of Danish (12) and Norwegian (13) cohorts
poor sperm quality and male infertility that showed an association between
OBESITY AND MALE obesity and male infertility with
(4, 5). With the rate of male-related infer-
tility contributing to 45%50% of infer-
INFERTILITYTHE ORs of 1.53 (95% CI 1.321.77) and
tile couples (6, 7), there is an enlarging EPIDEMIOLOGIC 1.36 (95% CI 1.321.77), respectively
body of evidence linking male infertility ASSOCIATION (1219). A complete review of these
to obesity. Mechanisms by which obesity The negative effects of obesity on studies is presented in Table 1.
may affect spermatogenesis include semen parameters and androgen
thermal effects, hyperestrogenism, hypo- proles have been well established;
gonadotropic hypogonadism, diabetes however, population-based epidemio- OBESITY AND FERTILITY-
RELATED COMORBIDITIES
Received December 12, 2016; revised February 21, 2017; accepted February 25, 2017.
J.R.C. has nothing to disclose. T.G.J. has nothing to disclose. D.T.C. has nothing to disclose. J.M.H. has Obesity-related health decits include
nothing to disclose. increased risks of diabetes mellitus,
Reprint requests: James M. Hotaling, M.D., M.S., F.E.C.S.M., Department of Surgery (Urology), Univer-
sity of Utah, Suite 201, 675 Arapeen, Salt Lake City, UT 84108 (E-mail: jim.hotaling@hsc.utah.edu). cardiovascular disease, epigenetic
alterations, and certain malignancies
Fertility and Sterility Vol. 107, No. 4, April 2017 0015-0282/$36.00
Copyright 2017 American Society for Reproductive Medicine, Published by Elsevier Inc.
(2022). Obese men are also at greater
http://dx.doi.org/10.1016/j.fertnstert.2017.02.115 risk of developing hypogonadism,

848 VOL. 107 NO. 4 / APRIL 2017


FIGURE 1
Worldwide obesity incidence.
Craig. Obesity and sperm epigenetics. Fertil Steril 2017.
impaired spermatogenesis, and erectile dysfunction (2326).
All of these factors are potential contributors to increased
rates of male infertility in these patients.
Obesity-Induced Endocrine Axis Derangements
Normal intratesticular testosterone levels are a prerequisite for
normal spermatogenesis (27). Currently, our understanding of
the hypothalamic-pituitary-gonadal (HPG) axis constitutes the
core of our understanding of male reproduction. However,
recent evidence has indicated that a number of neohor-
mones, which include leptin (28, 29) and kisspeptin (30),
may also impact this axis. Furthermore, many of the
comorbidities of obesity, such as diabetes (24) and sleep
apnea (3134), exacerbate these endocrine derangements.
Below, we discuss in more detail the HPG axis, the effect of
obesity on the HPG axis, and how these neohormones effect
these pathways.
Testosterone levels measured within the testicle are found
to be 25125-fold greater than levels in serum (3539). The
physiologic need for elevated intratesticular levels is not
completely understood; however, levels >70 nmol/L have
VOL. 107 NO. 4 / APRIL 2017
Fertility and Sterility
been shown to be required for normal spermatogenesis (40).
Thus, even a small decrease of the systemic testosterone
levels can reect a major reduction of the intratesticular
levels. GnRH is produced by the hypothalamus in a pulsatile
manner and stimulates LH and FSH. Normally, LH is
produced by the pituitary gland and acts to induce
steroidogenesis of testosterone by the Leydig cells. Once
testosterone diffuses out of the Leydig cells, it is bound by
proteins in circulation, mainly SHBG, and is then
metabolized to estrogen by aromatase (41). FSH, while not
strictly required for spermatogenesis in humans, does
augment Sertoli cell function, making it a core component
of optimal testicular function (42).
Hypogonadism in obesity can be mediated by both
reduced pulse amplitude of the cyclical secretion of LH from
the pituitary as well as decreased response to LH by the
testis (25). Reductions in SHBG, FSH, and inhibin B and
elevated E2, via increased aromatization of testosterone to
E2 peripherally, are also commonly seen (17, 4345). All of
these changes result in reductions in the throughput and
delity of human spermatogenic function and, possibly,
alter the sperm epigenome (46).
849
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VIEWS AND REVIEWS

TABLE 1

Epidemiologic studies on male infertility.

Study n Location Design Variables studied Association with male BMI
Studies on association between BMI and male infertility
Sallmen et al. 1,329 United States Secondary analysis of data from the Infertility (dened as not conceiving Adjusted for female BMI, male and female ages,
2006 (11) Agricultural Health Study on couples a pregnancy after R12 mo of smoking status, alcohol use, and exposure to
with a certied pesticide applicator unprotected intercourse) solvents and pesticides:
and spouse 1. OR for infertility 1.12 (95% CI 1.011.25).
2. Positive dose-effect relationship, with maximal
effect in the BMI 3243 kg/m2 group and a
plateau beyond that.
Ramlau-Hansen et al. 47,835 Denmark Prospective study: Danish Birth Cohort of Subfecundity (time to pregnancy) Adjusted for the partner's BMI:
2007 (12) couples from 1996 to 2002 1. OR 1.18 (95% CI 1.101.27) in overweight men.
2. OR 1.53 (95% CI 1.321.77) in obese men.
Nguyen et al. 26,303 Norway Retrospective study: Norwegian Mother Subfecundity (time to pregnancy) Adjusted for partner's BMI, coital frequency, and
2007 (13) and Child Cohort Study on pregnancies the ages and smoking habits of both partners:
from 1999 to 2005 1. OR 1.20 (95% CI 1.041.38) in overweight men.
2. OR 1.36 (95% CI 1.131.63) in obese men, with
a plateauing effect over a BMI of 32 kg/m2.
Stewart et al. 225 Australia Cross-sectional study. Initiated by WHO on 1. Time to pregnancy 1. Obesity was signicantly related to reduced total
2009 (14) male partners of women who conceived 2. Semen analysis sperm count (mean 324 vs. 231 million;
naturally 3. Hormone prole P< .05).
4. Physical exam to rule out local 2. Obese men (BMI >30 kg/m2) had signicantly
causes for infertility lower T, SHBG, and inhibin but not FSH.
Studies on association between BMI and sperm parameters
hormone prole
Jensen et al. 1,558 Denmark Prospective study on military recruits 1. Semen analysis 1. BMI >25 kg/m2 had a reduction in sperm
2004 (15) from 1996 to 1998 2. Hormone prole concentration of 21.6% (95% CI
3. Physical exam to rule out local 4.0%39.4%) and reduced total sperm count of
causes for infertility and to 23.9% (95% CI 4.7%43.2%). Nonsignicant
measure testis size reduction in sperm count. Testis size, semen
volume, and percentage of motile spermatozoa
were not affected by high BMI.
2. Decreased serum T, SHBG, and inhibin B. E2
demonstrated a positive relationship.
Kort et al. 520 United States Prospective study on normal Semen parameters, including sperm 1. Signicant decrease in sperm motility: normal
2006 (16) healthy men chromatin integrity (DNA BMI 18.6  106 cells; overweight 3.6 
fragmentation index [DFI]) 106 cells; obese 0.7  106 cells.
2. Signicant increase in DFI: normal BMI 19.9%
(
1.96%); overweight 25.8% (
2.23%); obese
27.0% (
3.16%).
Craig. Obesity and sperm epigenetics. Fertil Steril 2017.
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TABLE 1

Continued.
Study n Location Design Variables studied Association with male BMI
Aggerholm et al. 1,989 Europe Prospective study on men aged 1869 y. Data from 1. Semen analysis 1. Overweight group had slightly lower sperm
2008 (17) ve previous population-based environmental 2. Hormone prole concentration (56  106 per mL; 95% CI
studies of semen quality were combined 5260) compared with normal-BMI group
into one database. (59  106 per mL; 95% CI 5563) and lower
total sperm count (154  106; 95% CI
142168) compared with normal-BMI group
(168  106; 95% CI 157180). Obese men had
higher sperm density (68  106 per mL; 95% CI
5878) and total sperm count (190  106;
95% CI 161223) than the reference group of
normal-weight men. None of these differences
were statistically signicant.
2. Decreased T and inhibin (25%32% lower) in
obese men. E2 concentration 6% higher in
obese men.
Martini et al. 794 Argentina Prospective study on male partners of infertile 1. Semen analysis 1. Decreased sperm motility in the high-BMI group.
2010 (18) couples from 2006 to 2007 2. Seminal hormone and Percentage of sperm motility: normal BMI
biochemical prole 51.4% (95% CI 50.2%52.6%); overweight
50.2% (95% CI 49.2%51.2%); obese 46.6%
(95% CI 44.9%48.3%).
2. No association between BMI and sperm
concentration.
3. No signicant differences were detected in
seminal T levels between groups.
Bieniek et al. 4,440 North America Prospective multicenter study from 2002 to 2014 1. Semen analysis 1. BMI had weak but signicant negative
2016 (19) 2. Hormone prole correlations with ejaculate volume (r 0.04),
sperm concentration (r 0.08), motility
(r 0.07), and morphology (r 0.04).
2. Rates of azoospermia and oligospermia were
also more prevalent among obese (12.7% and
31.7%, respectively) compared with normal-
weight (9.8% and 24.5%) men.
3. Testosterone had a signicant negative
correlation, with BMI. E2 demonstrated a
positive relationship.
4. Neither FSH nor LH demonstrated signicant
correlations with BMI.
Note: BMI body mass index; CI condence interval; OR odds ratio; WHO World Health Organization.

Fertility and Sterility

Craig. Obesity and sperm epigenetics. Fertil Steril 2017.
851
VIEWS AND REVIEWS

FIGURE 2

Obesity and male infertility: mechanisms. Obesity operates through multiple pathways to alter male reproductive potential. It creates epigenetic
changes, some of which can inuence subsequent generations. In addition, it alters the male androgenic axis, inuences a host of other
neohormones, and raises insulin levels. Finally, it has been linked to erectile dysfunction and causes stress, inammation and sleep apnea, all
of which can further reduce male fertility. Kp kisspeptin.
Craig. Obesity and sperm epigenetics. Fertil Steril 2017.

In addition to perturbations by these standard
pathways, obesity is associated with dysregulation of a number
of neohormones which act to further disrupt the male
endocrine axis (2830). Under normal physiologic control,
adipocytes release leptin, increasing release of kisspeptin
from KISS neurons. This acts to increase the release of GnRH
from the hypothalamus, elevating FSH and LH secretion from
the anterior pituitary, which in turn increases testicular
testosterone biosynthesis. Obesity induces changes via
multiple pathways in the HPG axis that lead to
hypogonadotropic hyperestrogenic hypoandrogenism (Fig. 2).
Obese men have increased adipocyte-related aromatiza-
tion of testosterone into E2 and estrone (47). These increased
levels of E2 and estrone down-regulate the release of kisspep-
tin from KISS neurons and decrease the activity of the HPG
axis (48, 49). In addition to aromatization of testosterone,
adipocytes also produce a hormone called leptin, a critical
factor in regulating energy homeostasis (50). Mutations in
the leptin gene or leptin receptor leads to increased food
intake and decreased energy expenditure. However, in obese
individuals without mutations in the leptin gene or receptor,
leptin levels are chronically elevated, leading to leptin
resistance (51). This resistance is seen centrally in the
hypothalamus, where leptin is unable to stimulate the HPG
axis in these leptin-resistant men, leading to decreased testos-
terone levels (28, 29).

852 VOL. 107 NO. 4 / APRIL 2017


Comorbidities in Obesity and Their Impact on the
Androgenic Axis
Diabetes is associated with obesity and can negatively
affect the androgenic axis. The prevalence of diabetes in
the obese population is signicant, with 3.4% of the
American population affected by both conditions (52).
The obese man with diabetes exhibits both central and
peripheral insulin resistance, leading to reduction of
SHBG synthesis by the liver. The reduction of SHBG
allows for a greater fraction of testosterone to remain
free, which magnies the negative feedback effect of E2
through aromatization (52). Thus, obese men with diabetes
have further down-regulation of the androgenic axis.
Although data are conicting, generally fecundity rates
and semen quality have been shown to be decreased in
men with diabetes (53).
Sleep apnea affects 4% of adult men, with two-thirds of
those men being obese. Sleep apnea, common in obese men,
can down-regulate testosterone. The nocturnal apneic events
characteristic of sleep apnea lead to sleep fragmentation. This,
in turn, decreases nocturnal LH production, further reducing
circulating testosterone levels (31, 54). Furthermore,
nonhuman animal models demonstrate that intermittent
hypoxia can affect gene expression, sperm motility, and
fertility (55).
Obesity-related accumulation of toxic substances,
particularly endocrine disruptors, is thought to disrupt
both the male endocrine axis and perturb spermatogenesis
(56, 57). This is compounded by the fat solubility of many
of these toxins, making obese men more susceptible to
their effect (56, 57).
Impairment of scrotal and testicular thermoregulatory
mechanisms by excess adipose tissue leads to impaired
spermatogenesis. Obese men have increased lower abdom-
inal fat, thigh fat, and scrotal fat that function as an
insulator for the testicles, leading to increased testicular
temperature. This negatively impacts both testosterone
synthesis and spermatogenesis (58, 59).
Sexual Dysfunction
The ability to sustain an erection rigid enough for penetration
is a prerequisite for natural conception. Unfortunately,
impaired coitus due to erectile dysfunction is commonly
seen in infertile men (60). Compared with fertile control
subjects, men with infertility have signicantly worse Sexual
Health Inventory for Men scores, with 36% reporting a score
of <22 (60). In addition, 79% of men who report having
erectile dysfunction are obese (61). The relationship between
obesity and erectile dysfunction is multifactorial, but is
thought to stem from decreased testosterone levels and
elevated proinammatory factors (tumor necrosis factor a
and interleukin 6) (62, 63). These inammatory substances
lead to vascular endothelial dysfunction, resulting in
erectile dysfunction. Testosterone deciency can lead to
sexual dysfunction in a myriad of ways, mainly through
decreased libido and lack of androgenic augmentation of
cavernosal smooth muscle function (64, 65).
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Fertility and Sterility
Sperm Parameters
The impact of male obesity on the androgenic axis is well
understood. However, unlike the impact of obesity on ovula-
tion and the oocyte, the impact of obesity on sperm parameters
is complex and likely multifactorial (16, 66). Although
derangements of the androgenic axis and epigenetic changes
in spermatogonial stem cells are thought to play a role, the
exact cause remains elusive.
Obesity drives changes in bulk seminal parameters and,
perhaps more importantly, sperm DNA packaging and epige-
netics (46). Observational studies demonstrate that over-
weight (BMI >25 kg/m2) and obese (BMI >30 kg/m2) men
are at higher risk of oligozoospermia (count <20  106/mL)
(15, 66, 67), with an OR of 3.3 (95% CI 1.199.14) (66).
Obesity affects not only count, but also total progressive
motile count, with obese men being at greater risk for
total progressive motile counts <10  106, with an OR of
3.4 (95% CI 1.1210.60) (66). DNA fragmentation index
(DFI) in obese men ranges from 21.9% to 27% compared
with 15%19.9% in men with normal body weight. Obese
men also have elevated risk of having signicantly elevated
DFI, with an OR of 2.5 (95% CI 1.25.1) (16, 68).
Despite the associations between obesity and semen
parameters, it is clear that men with high levels of body fat
are, in general, still capable of siring offspring. This fact high-
lights an important problem. Specically, the fact that sperm
are competent to fertilize an egg does not guarantee that these
sperm are entirely unaffected in obese men or that normal
embryonic development will progress uninhibited after fertil-
ization. In fact, clear data indicate that epigenetic patterns in
sperm, described in more detail below, are affected in obese
men and include differences in sperm microRNA content
and DNA methylation variations (46, 69). These important
markers in sperm, when altered, are thought to be
implicated in abnormal phenotypes in the offspring and
perturbations in embryogenesis. Therefore, even if fertility
issues can be overcome in obese patients, additional
consideration should be given to potentially unt gametes
resulting from exposure to the testicular environments seen
in obese men.
MALE OBESITY AND ADVANCED
REPRODUCTIVE TECHNOLOGY OUTCOMES
Although the male contribution to assisted reproductive tech-
nology (ART) success has historically been minimized, it is
now well accepted that sperm have a signicant effect (70).
Male obesity, similarly to female obesity, appears to affect clin-
ical pregnancy, miscarriage, and live birth rates (71, 72).
Campbell et al. have shown that obese men undergoing
ART have a statistically signicant decrease in live birth
rate compared with normal-weight men: OR 0.65 (95% CI
0.440.97) (72). The odds of having a nonviable pregnancy
are signicantly greater for couples with an obese male
partner compared with a normal-weight partner: OR 2.87
(95% CI 1.346.13), with an absolute risk difference of 10%.
Another study has reported lower pregnancy rate in males
undergoing IVF, but no signicant difference if ICSI was used
for ART therapy. In contrast, Thomsen et al. have reported no
853
VIEWS AND REVIEWS
decrease in semen quality or IVF outcome in obese men under-
going ART (73).
These studies still leave much unknown about the exact
impact of male obesity on ART outcomes. Answering these
questions will require well controlled studies. For example,
the age and obesity of the female partner may well modulate
the effects of sperm defects, both independently from and
depending on the male factors. For example, lower maternal
age results in improved oocyte quality, which may indepen-
dently improve outcomes but may also provide an improved
opportunity for correction of some defects, such as sperm
epigenetic abnormalities, after fertilization (74, 75).
MECHANISMS BEHIND INFERTILITY IN THE
OBESE MAN: HORMONAL, INFLAMMATION,
GENETIC, EPIGENETIC
The etiology of obesity-driven male infertility is multifacto-
rial, with many likely contributing factors, including
hormonal perturbations and potentially reversible epigenetic
alterations (Fig. 2). It is important to emphasize that each of
the mechanisms described as potential factors of altered
spermatogenesis may have isolated or interdependent actions
on fertility. For example, epigenetic alterations in sperm,
affecting embryogenesis and health of offspring, may be
induced by a number of factors, including endocrine alter-
ations, thermal effects, and gene expression pathways result-
ing from sleep apnea, stress, etc. Therefore, although isolated
studies of individual factors may point to important features
of the syndrome, well designed systems analyses are crucial to
understand the complete scope of the problem.
ADIPOSITY-INDUCED EPIGENETIC CHANGES
IN SPERM
Epigenetic marks provide a mechanism by which environ-
mental factors can inuence our cells by leaving biochemical
imprints on our genome capable of gene regulation in the
absence of mutations to DNA sequence. This modiable
nature makes epigenetic signatures very interesting
candidates to explain obesity-associated alterations to
fertility (810, 7679). A complete review of these studies is
presented in Table 2. Epigenetic signatures include three
major categories: DNA methylation, nuclear protein
composition (with specic consideration of histone
modications and localization), and expression proles of
noncoding RNAs (80). In short, these marks drive (or, at a
minimum, inuence) gene expression patterns in the cell.
Plasticity is a hallmark of epigenetic marks in both somatic
tissues and the germ line. Epigenetic signatures can be
readily altered by various modiers, including, but not both. Recent studies have shown that epigenetic marks in
limited to, diet, BMI, activity level, aging, and exposure to
various toxins and environmental agents (46, 81).
The epigenome helps to ensure proper regulation of
transcription patterns in all cell types by means of multiple
mechanisms. DNA methylation has been shown in multiple
studies to be important in gene regulation (8285).
Specically, when enriched at gene promoters, DNA
methylation has been shown to inhibit the accessibility of
854
promoter regions to transcriptional machinery. This, in
turn, can inhibit gene expression. Nuclear proteins,
specically histones, can be post-translationally modied
by means of methylation, acetylation, phosphorylation,
and others. These modications promote chromatin
compaction and control the access of transcription factors
to DNA (86). In addition, multiple RNA species (mRNA,
microRNA [miRNA], Piwi-interacting RNA [piRNA], etc.)
can directly and indirectly affect a cell's expression prole.
Small regulatory RNAs are noncoding RNAs that regulate
gene expression at the transcriptional or post-
transcriptional step, or via chromatin remodeling (87).
Because of the epigenome's role in transcription regula-
tion, epigenetic alterations can drive many abnormal
fertility phenotypes, and these perturbations have been
implicated in multiple cases in humans. A study by Sonnack
et al. showed that men exhibiting qualitative or quantitative
infertility have signicantly decreased levels of histone H4
acetylation associated with impaired spermatogenesis (88).
Furthermore, it has been established that human spermato-
zoa is composed of miRNAs (7%) piRNAs (17%), and
repeat-associated small RNAs (65%) (89), and some of these
have been implicated in the process of infertility. Addition-
ally, obesity-associated comorbidities, including inamma-
tion, glucose intolerance, stress, and hypercholesterolemia,
were good predictors for sperm miRNA abundance and
offspring phenotypes (90). That study also showed that
alteration in preconception diet or exercise interventions
in obese fathers resulted in normalization of miRNA proles.
Although the impact of these alterations on sperm function
is unclear, it is important to note that multiple studies have
shown associations between sperm DNA methylation alter-
ations and various semen analysis parameters. This is most
pronounced with sperm motility, count, and viability (91).
Therefore, it is not unreasonable to assume that at least a
portion of these obesity-induced alterations have the poten-
tial to affect normal sperm function and, in turn, fertility. In
the context of obesity specically, multiple studies have
been performed. In brief, it has been shown that sperm
epigenetic patterns are altered in individuals with high
BMIs (46, 92). Importantly, these alterations do appear to
be, at least to some degree, reversible.
Although it appears from studies that perturbations to
the sperm epigenome can drive alterations to normal
gamete function, it is important to consider the down-
stream implications. Because the sperm has two major
functional rolessafe delivery of the paternal DNA blue-
print to the oocyte and competence to contribute to
embryogenesis and offspring developmentit is important
to assess the impact of sperm epigenetic alterations on
sperm are unique and are at regions important in embry-
onic development (93). Other studies have suggested that
various individual miRNA species (most notably the
mir34 C family) and collective RNA proles (RNA
elements) play a role in normal embryogenesis (94).
Furthermore, in very recent studies, sperm DNA methyl-
ation patterns have been tightly linked to male infertility,
embryo quality, and fecundity (95, 96).
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TABLE 2

Studies on paternal obesity and trans generational inheritance.

Study
Ng et al. 2010 (62)
Fullston et al. 2012 (63)
Fullston et al. 2013 (8)
Soubry et al. 2013 (10)
McPherson et al. 2014 (9)
Ng et al. 2014 (64)
Masuyuma et al. 2016 (65)
Craig. Obesity and sperm epigenetics. Fertil Steril 2017.
Hypothesis tested
Paternal chronic high-fat diet
(HFD) causes beta-cell
dysfunction in the female
offspring.
Impact of diet-induced paternal
obesity on the reproductive
health of two subsequent
generations.
Impact of diet-induced paternal
obesity on offspring
metabolic, testicular
transcriptome, and sperm
microRNA prole.
Association between obesity
and DNA methylation
proles in the offspring.
Dietary and exercise regimes in
obese men improve the
reproductive health of
subsequent generations.
Paternal high-fat diet
consumption in rats alters
the transcriptomes of
retroperitoneal adipose and
pancreatic islet tissues of
female offspring.
Paternal HFD-induced obesity
affects the metabolic status
of offspring through
epigenetic changes in
adiponectin and leptin
genes.
Study subjects and
methodology
Expression of pancreatic islet-cell
genes in female offspring of
obese male rats
Transgenerational assessment of
reproductive health by
mating F0 and then F1 mice
to CD (control diet) mice
Transgenerational assessment of
metabolic health by mating
F0 and then F1 mice to CD
mice
DNA from the umbilical cord of
79 newborns whose
mothers had been enrolled
in the Newborn Epigenetics
Study
Male mice were fed an HFD and
randomized to control or diet
and exercise regimen for
9 wk, with analysis of
offspring sperm health
Transcriptome alterations in islet
cells of female offspring of
obese male rats
Effects of paternal HFD over
multiple generations with
examination of offspring
metabolic prole, including
weight and fat gain, glucose
intolerance,
hypertriglyceridemia,
abnormal adipocytokine
levels, hypertension,
adiponectin and leptin gene
expression, and epigenetic
changes
Results
Paternal HFD causes progressive
early onset of impaired
insulin secretion and glucose
tolerance, but offspring had
normal adiposity.
HFD induces paternal initiation
of subfertility in both male
and female offspring of two
generations of mice.
Diet-induced paternal obesity
modulates sperm microRNA
content and germ cell
methylation status,
programming offspring
health and propagating
obesity and impaired
metabolic health to future
generations.
Paternal obesity is associated
with insulin-like growth
factor 2 hypomethylation.
Sperm parameters were
improved in the offspring of
obese male rats that were
allocated to diet
exercise.
Paternal HFD consumption
triggers unique gene
signatures consistent with
premature aging and chronic
degenerative disorders.
After paternal HFD exposure,
resumption of normal diet by
subsequent generations
diminished and ultimately
abolished the impact of
paternal HFD on offspring
metabolic prole and
adipocytokine promoter
epigenetic signatures initially
seen in the offspring.

TRANSGENERATIONAL AND
INTERGENERATIONAL INHERITANCE OF
OBESITY
Transgenerational and/or intergenerational inheritance
occurs when induced epigenetic changes in the gametes are
passed on to the subsequent generation (97). This epigenetic
inheritance can theoretically result in phenotypic alterations
in the offspring, the grand-offspring, and beyond. When
considering transmission of epigenetic signatures for the
paternal gamete, it is important to understand the difference
between intergenerational and transgenerational inheritance
patterns. In effect, intergenerational epigenetic inheritance
includes any sperm epigenetic signatures altered throughout
a man's life (or even that were induced in utero) from the
father to the child only (typically from F0 to F1). Whereas
the inheritance of an altered epigenetic state to the grand-
offspring and beyond (F2 or beyond) is termed transgenera-
tional inheritance. Based on epidemiologic evidence, many
types of environmental challenges imposed on the parent,
such as hunger, specic diets, toxins, and trauma, have
been found to inuence the development of the offspring
(98). Paternal age, subfertility, smoking, obesity, and
exposure to a range of environmental inuences, including
air pollution, radiofrequency electromagnetic radiation, and
xenobiotics, have also been implicated (99).
The strongest epidemiologic association of intergener-
ational inheritance is recorded by the Dutch famine study,

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VIEWS AND REVIEWS
which, among other items, assessed the outcomes of severe
caloric restriction and poor nutrition in the offspring of in-
dividuals exposed to famine conditions. One particular
analysis assessed a cohort of 300,000 young men born
around the time of Dutch famine of 1944. Their mothers
had been exposed to caloric rations of <1,000 calories
per day during their pregnancies. Their offspring exhibited
a signicant increase in glucose intolerance, coronary
heart disease, increased stress responsiveness and
obesity. The association was more signicant when the
mother took the very low calorie diet during early gesta-
tion (100, 101). Another well known epidemiologic study,
in the United Kingdom by Barker et al., established an
association between intrauterine growth restriction and
subsequent cardiovascular morbidity and mortality in the
offspring (102).
Obesity has been shown to directly drive transgenera-
tional effects in successive generations. Studies with the use
of nonhuman animal models have found altered metabolic
processing in offspring sired by obese fathers (103). Further
studies in mice have shown similar patterns of offspring
metabolic perturbations but have also identied specic
epigenetic alterations in the sperm (8). In humans, an
intriguing recent study found alterations in DNA methylation
at the insulin-like growth factor 2 gene in newborns sired by
obese fathers (10). Taken together, these data strongly suggest
that obesity is capable of affecting sperm function, embryo-
genesis, and even offspring health.
STRATEGIES TO COUNTER OBESITY
Although the full scope of treatment of obesity as it relates
to male infertility is the beyond the scope of this review, we
think that it is important to highlight a few of the basic steps
that can be taken to improve the reproductive prole of
these men. Perhaps the most important point to remember
is to council these men that their lifestyle choices now
have consequences for the entire life course trajectory of
their progeny.
Diet and Exercise
Traditionally, men seek health care at lower rates than
women and are less likely to have a primary care provider
(Summary Health Statistics: National Health Interview Sur-
vey, 2014). When men do seek health care, it is typically for
a specic health concern, such as infertility (104). Therefore,
an infertility evaluation may represent a unique opportunity
to improve a man's health, and, by extension, the health of
his progeny. Despite seeking health care at lower rates than
women, men are actually slightly more likely to lose
weight through diet, exercise, and behavioral modication
(105, 106). Infertility and the burgeoning recognition of
the effect of paternal lifestyle on offspring health provides
a powerful motivator for many men to lose weight. Once
achieved, weight loss has been shown to improve
testosterone levels, SHBG, erectile dysfunction, sperm
motility, sperm mitochondrial function, and epigenetic
prole (9, 107109).
856
Pharmacotherapy
The goal of medical management of infertility in the obese
man is to optimize androgenic hormonal pathways. Typical
manifestations of obesity include low testosterone, high E2,
or a combination of both (17, 4345). Clomiphene citrate, a
selective estrogen receptor modulator, is used to augment
endogenous testosterone production via elevation of LH and
spermatogenesis via elevation of FSH (110). Aromatase
inhibitors, such as anastrozole or letrozole, are used to
block the conversion of testosterone to E2 by aromatase,
resulting in restoration of the optimal testosterone to E2
ratio of >10:1 (111, 112).
Gastric Bypass Surgeries
The American Society for Metabolic and Bariatric Surgery
recommends bariatric surgery for a person with BMI
R40 kg/m2, >100 pounds overweight, or with BMI
R35 kg/m2 and at least two obesity-related comorbidities
(113). In obese men who undergo bariatric surgery, gastric
bypass and banding operations are proven to be highly suc-
cessful in treating morbid obesity, reducing obesity-related
comorbidities, correcting hormonal balance, and improving
sexual function (114116). Azoospermic men undergoing
gastric bypass demonstrate increased serum testosterone
and sperm count after bariatric surgeryinduced weight loss
(117), but studies about sperm motility, morphology, and
DNA fragmentation show mixed results (114). Sudden
severe weight loss associated with bariatric surgery may
result in a negative effect on spermatogenesis and initially
result in oligoasthenozoospermia (118). The exact impact of
preconception paternal extreme weight loss on offspring
remains unknown, but much can be inferred from
nonhuman animal studies demonstrating improved
epigenetic proles in metabolic genes. For example, a
comparison of children born before and after maternal
gastrointestinal bypass surgery found that genes were
differentially methylated in these two groups. The children
born after gastric bypass surgery had markedly improved
epigenetic proles of receptor signaling in insulin, leptin,
and glucoregulatory pathways that were seen up to 18 years
after conception (119).
CONCLUSION
Male obesity is a signicant problem that has grown to
epidemic proportions. Obese men are more likely to be infer-
tile. Although the cause is not exactly known, it is likely a
combination of obesity-induced endocrine derangements
and its deleterious effects on spermatogenesis. Recent epige-
netic evidence suggests that the metabolic memory of a
man's obesity at the time of conception may be directly
transmitted to his offspring through his sperm and thus
may have major consequences for their somatic health.
Improved understanding of intergenerational inheritance
and epigenetics is crucial to both understanding these mech-
anisms and using them as a powerful tool for preconception
behavioral change in men. Just as it is now well established
that morbidly obese women have higher chances of
VOL. 107 NO. 4 / APRIL 2017

complications during ART and of higher-risk pregnancies, it
may become established that obese men father children who
are also at higher risk of metabolic derangements. It is prob-
able that we may, one day in the not too distant future,
establish protocols focusing on male weight loss before
conception to improve offspring health.
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