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Obesity and Male Fertility

33
Stephanie Cabler, Ashok Agarwal,
and Stefan S. du Plessis

Abstract
The obesity pandemic has grown to concerning proportions in recent years, not only in the
Western world but in developing countries as well. The corresponding decrease in male
fertility and fecundity may be explained partially by obesity, and obesity should be consid-
ered an etiology of male subfertility. Studies show that obesity contributes to infertility by
reducing semen quality, changing sperm proteomes, contributing to erectile dysfunction,
and inducing other physical problems related to obesity. Mechanisms for explaining the
effect of obesity on male infertility include abnormal reproductive hormone levels, an
increased release of adipose-derived hormones and adipokines associated with obesity, and
other physical problems including sleep apnea and increased scrotal temperatures. Recently,
genetic factors and markers for an obesity-related infertility have been discovered and
may explain the difference between fertile obese and infertile obese men. Treatments are
available for not only infertility related to obesity but also for the other comorbidities arising
from obesity. Natural weight loss and bariatric surgery are options for obese patients and
have shown promising results in restoring fertility and normal hormonal profiles. Therapeutic
interventions including aromatase inhibitors, exogenous testosterone replacement therapy
and maintenance, and regulation of adipose-derived hormones, particularly leptin, may also
be able to restore fertility in obese males. The increasing prevalence of obesity calls for
greater clinical awareness of its effects on fertility, better understanding of underlying
mechanisms, and exploration into avenues of treatment.

Keywords
Male fertility Male obesity Abnormal semen parameters Body mass index
Hypothalamicpituitarygonadal axis Aromatase polymorphism ALMS1 mutation
Hypogonadism

In the past 510 years, obesity has become a worldwide


epidemic that has brought attention to learning more about
the various causes, effects, and treatments. A combination of
S. Cabler, BSc (*) A. Agarwal, PhD
Center for Reproductive Medicine, Glickman Urological an increasingly acceptable sedentary lifestyle and unhealthy
and Kidney Institute, Cleveland Clinic Foundation, diet in the Western world has resulted in an increasing num-
9500 Euclid Avenue, Desk A19, Cleveland, OH 44195, USA ber of overweight and obese children and adults. According
e-mail: agarwaa@ccf.org
to the WHO, approximately 1.6 billion adults were classified
S.S. du Plessis, PhD, MBA as being overweight and 400 million adults were obese in 2005 [1].
Department of Medical Physiology,
It is predicted that globally, in the next 5 years, more than
Faculty of Health Sciences, Stellenbosch University,
PO Box 19063, Tygerberg, Western Cape 7505, South Africa 700 million adults will suffer from obesity [1]. Once considered
e-mail: ssdp@sun.ac.za a problem only in high-income countries, overweight and

S.J. Parekattil and A. Agarwal (eds.), Male Infertility: Contemporary Clinical Approaches, Andrology, ART & Antioxidants, 349
DOI 10.1007/978-1-4614-3335-4_33, Springer Science+Business Media, LLC 2012
350 S. Cabler et al.

obesity are now dramatically on the rise in all countries. Evidence impair health. However, there are other specific requirements
of this is the five unit increase in body mass index (BMI) for that qualify an individual as obese. The most accurate mea-
the period 19972006 in the 95th percentile BMI level among sures are to weigh a person underwater or to use an X-ray
children aged 69 years in China. These children in the 95th test called dual energy X-ray absorptiometry. These methods
percentile have a BMI of 24.8, which is surprisingly higher than are not practical for the average individual and are conducted
that of the USA (22.2), Australia (20.1), and the UK (20.1) [2]. only in research centers with special equipment. There are
Parallel to the global increase in obesity is the reported simpler methods to estimate body fat such as BMI, skin fold
world decrease in male fertility and fecundity [3]. measurements, waist-to-hip ratio (WHR), waist circumfer-
Interestingly, men with increased BMI were significantly ence, and also methods such as bioelectrical impedance anal-
more likely to be infertile than normal-weight men, accord- ysis, risk factors and comorbidities [7]. The two tools that are
ing to research conducted at the National Institute of most commonly used to identify obese patients are BMI, a
Environmental Health Sciences (NIEHS) [4]. According to waist-to-height ratio, and waist circumference. An individual
Carlson et al., the quality of semen has substantially is normally defined as being overweight if their BMI is
declined, which has subsequently lead to decreased male between 25 and 30 kg/m2 and obese if it exceeds 30 kg/m2.[8]
fertility [5]. This could likely contribute to overall reduced A problem with this method is that individuals with a high
male reproductive potential. Some studies estimate that BMI may be mesomorphic and have a high amount of muscle
male sperm counts continue to decrease at a rate of approxi- mass. Therefore, BMI may not be the most accurate marker
mately 1.5% per year in the USA and similar findings have for total body fat percentage and is an even less suitable tool
been found in other Western countries as well [3]. In addi- to assess body fat distribution.
tion, there is also a significant increase in the incidence of Waist circumference is a slightly less common method
obesity in patients with male factor infertility, and couples used to predict obesity in an individual, but may be more accu-
with obese male partners are more likely to experience sub- rate in predicting obesity-related health issues. For females,
fecundity, a correlation that seems necessary to address [6]. a waist circumference of 88 cm or greater is considered
Due to the fact that this decline has occurred in close parallel unhealthy. For men, a waist circumference of 102 cm or
with increasing rates of obesity, it is necessary to focus on greater is considered unhealthy. If waist circumference is
the possibility of obesity as an etiology of male infertility used as the criterion, then according to a study conducted in
and reduced fecundity. The obesity pandemic seen in many 2006, the prevalence of being overweight among Australian
countries is a serious threat to public health, and a reduced adults, and probably other Caucasian populations, may be
capacity to reproduce is a potential but less well-known significantly greater than indicated by surveys relying on self-
health hazard that can often be attributed to obesity. reported height and weight. The development of valid self-
It is therefore necessary to explore the links between obe- reported measures of waist circumference for use in population
sity and male infertility, as well as to explain how it disrupts surveys may allow more accurate monitoring of overweight
the male reproductive system at a mechanistical level. and obesity and should be considered instead of BMI [9].
Treatment and prevention of obesity and associated fertility A WHR can also be used to predict unhealthy consequences
disorders will also be discussed in a clinical context. as a result of increased body fat (normal WHR: males = <0.9;
females <0.85), especially related to the risk of coronary heart
disease as it relates to obesity [10]. WHR may be the most
What Is Obesity? useful measure of obesity and the best simple anthropomet-
ric index in predicting a wide range of risk factors and
Obesity is a medical condition in which excess body fat, or related health conditions [11].
white adipose tissue, accumulates in the body to the extent
that the excess fat adversely affects health, often reducing life
expectancy. The fundamental cause of obesity and over- How Does Obesity Affect Male Fertility?
weight is an energy imbalance, where the energy consumed
exceeds the energy expended. Global increases in overweight The relationship between male infertility and obesity has
and obesity are attributable to a number of factors, including more concrete evidence than solely studies showing reduced
a shift in diet toward increased intake of energy-dense fecundity among couples, one of whom is an obese male.
foods that are high in fat and sugars, and a trend toward Although spermatogenesis and fertility are not impaired in a
decreased physical activity, resulting from increasingly majority of obese men, a disproportionate number of men seek-
sedentary nature of work, changing modes of transportation, ing infertility treatment are obese. There have been a number
and increasing urbanization. of studies analyzing the relationship between semen quality
Currently, overweight and obesity are defined more and obesity, with a common finding that there is an inverse
broadly as abnormal or excessive fat accumulation that may correlation between BMI and quality of semen parameters.
33 Obesity and Male Fertility 351

Abnormal Semen Parameters Hofny et al. [16] found that the BMI correlated negatively
with sperm motility, and Hammoud et al. [21] concluded that
Altered semen parameters attributed to obesity include the incidence of low progressively motile sperm count
decreased sperm concentration, abnormal morphology, increased with increasing BMI. Fejes et al. [22] found that the
compromised chromatin integrity, and abnormal motility. waist to hip circumference of men correlated negatively with
Although there is a convincing amount of evidence to the total motile sperm count as well as the rapid progressively
demonstrate the adverse affect of excess body fat on sper- motile sperm count. Another study by Martini et al. found that
matogenesis, not all studies have come to the same conclusions. there was a negative association between BMI and motility
Individual studies are conflicting in evidence, but a recent and rapid motility [23]. Despite this evidence, not all studies
meta-analysis by MacDonald et al. [12] combined 31 studies have come to the same conclusions, and a majority of studies
containing data and information relating to obesity and male measuring semen parameters neglect to include motility in
infertility. Reproductive hormones studied included testos- their measurements [14, 19].
terone, free testosterone, estradiol, FSH, LH, inhibin B, and
sex hormone-binding globulin (SHBG). This meta-analysis
was conducted to investigate sperm concentration and total DNA Fragmentation
sperm count but found no evidence for a relationship
between BMI and sperm concentration or total sperm count. Kort et al. found that an increase in the DNA fragmentation
Examination of further studies may present more insight in index (DFI) accompanied an increase in BMI, demonstrating
the relationship between obesity and semen quality. that obesity might compromise the integrity of sperm chro-
matin, their only genetic material [24].
DFI is the percent of sperm in a semen sample that have
Decreased Sperm Count and Concentration increased levels of single or double strand breaks in their
nuclear DNA. A young and healthy man has about 35% of
Obese men are three times more likely than healthy men of sperm with fragmented DNA while a level of 2530% DFI
normal weight to have a sperm count of fewer than 20 million/ places a man attempting natural conception at a statistical risk
ml, an indicator of oligospermia [13]. In one of the largest for infertility [25]. An increase in the BMI above 25 kg/m2
studies on male fertility and obesity, done on Danish men, causes an increase in sperm DFI and a decrease in the number
Jensen et al. measured BMI in relation to semen quality and of normal chromatin-intact sperm cells per ejaculate, relative
reproductive hormones and found significant relationships to the degree of obesity [24]. Men with type 2 diabetes also
between sperm concentration and BMI. A lower sperm con- present with a significantly higher number of severe structural
centration was observed in not only obese and overweight defects in sperm compared with sperm from controls (p < 0.05)
males, but also in males who were significantly underweight. [47]. Typically, males presenting with a high DFI will have
This could serve as an indication that there may be an ideal reduced fertility, and their partners will display an increased
range of BMI for normal spermatogenesis. Subjects whose incidence of miscarriage as a consequence [26].
BMI was within the normal range showed a higher sperm con- A new breakthrough in gel electrophoresis has been used to
centration, as well as a higher total sperm count, and a lower identify obesity-associated changes of the sperm proteome.
percentage of abnormal spermatozoa [14]. According to a Semen samples from obese males differed from those of
study by Chavarro et al., men with a BMI greater than 25 kg/ normal-weight men with 12 spots seen after running their dif-
m2 had a lower total sperm count than men of normal weight, ference gel electrophoresis (DIGE) of fluorescently labeled
and the measured volume of ejaculate decreased steadily with human sperm proteins. Tryptic digestion of the 12 spot pro-
an increasing BMI [15]. These findings have been corrobo- teins and mass spectrometric analysis of the corresponding
rated by other studies as well [16, 17]. Although several reports peptides identified nine sperm proteins associated with obe-
exist indicating a considerable negative effect of BMI on sity. This can now be considered a noninvasive experimental
sperm count and concentration, some discrepancies have been tool in the diagnosis of male infertility and monitoring device
noted. In these studies, a correlation between sperm count and for fertility-restoring therapy in obese males [27]. This finding
concentration in obese men compared to controls was demon- clearly demonstrates the differences or changes in the protein
strated but was not deemed significant [1820]. composition of spermatozoa in obese men.

Sperm Motility Sperm Morphology

Some consensus on the effects of obesity on sperm motility Measuring differences in the morphology of sperm between
has been established, but there is no overall agreement. obese and normal-weight men can be difficult owing to
352 S. Cabler et al.

differences in what is classified as normal morphology and from an unfavorable genotype and because obesity can cause
high individual variability within individual patient samples. infertility, a genetic link between these two factors might
However, most studies have shown no correlation between explain this discrepancy. Patients with Klinefelter, Prader
obesity and abnormal sperm morphology [14, 15, 19, 21]. Willi, or LaurenceMoonBardetBiedel syndromes all
In the large retrospective study of Danish military recruits, display, to varying degrees, both obesity and infertility.
no association between obesity and poor sperm motility or In addition, men who are both infertile and obese show
morphology was reported [14]. Identifying the specific hor- significantly lower testosterone levels than obese fertile men
mones, proteins, and mechanisms involved in regulating [28]. Although the specific genes involved and mechanism(s)
sperm morphology might help to explain how and why obesity explaining these syndromes are quite well understood, it is
affects normal spermatogenesis. possible that other, less severe genetic mutations exist. These
small mutations might explain the discrepancies between
obese fertile and infertile men and shed light upon a possible
What Are the Proposed Mechanisms? genetic link between obesity and infertility.
Also, mutations in the human ALMS1 gene are responsi-
Although environmental and lifestyle factors might help to ble for Alstrm syndrome, a disorder in which key metabolic
explain the growing numbers of obese adults and children, and endocrinological features include childhood-onset obesity,
there is less evidence explaining how obesity causes male metabolic syndrome, and diabetes, as well as infertility [29].
infertility. The mechanisms responsible for effects on male Scientists still need to accurately establish which particular
infertility are mostly ambiguous and undefined. Several genes are involved in these different syndromes, but the linkage
mechanisms have been proposed, all of which are described of obesity and infertility in extreme genetic cases points to
below (Fig. 33.1). Most of these mechanisms contribute to some degree of genetic linkage. Hammoud et al. [30] recently
the dysregulation of the hypothalamicpituitarygonadal discovered that an aromatase polymorphism modulates the
(HPG) axis, one of the most important functions of which is relationship between weight and estradiol levels in obese
to regulate aspects of reproduction. men. This could explain why only certain obese men experi-
ence this rise in estradiol and subsequent fertility problems,
while others experience no fertility issues. It seems possible
Genetic Link that there are other less severe genetic markers than chromo-
some 15 abnormalities and ALMS1 mutations that may clar-
Despite there being a known effect of obesity on infertility, ify the discrepancies between obese fertile and infertile men
many obese males are fertile and have normal reproductive and give explanation to a possible genetic link between obe-
function and fecundity. However, because obesity can result sity and infertility.

Hormonal Mechanisms

Abdominal or visceral fat is more likely to lead to changes in


hormone levels and to cause inflammation than fat stored in
other parts of the body. This is predominantly due to the fact
that white adipose tissue, found in high levels in obese men,
exhibits elevated aromatase activity and secretes adipose-
derived hormones, as well as adipokines.

Reproductive Hormones

The reproductive hormonal profiles of most obese men deviate


from what is considered the norm. Obese men tend to present
with elevated estrogen and low testosterone and FSH levels.
Androgen deficiency or hypogonadism found in males who are
obese or have metabolic syndrome can account for problems
with erectile dysfunction and spermatogenesis. However,
Fig. 33.1 The effects of obesity on male fertility and mechanisms many other hormones associated with obesity may alter the
involved male reproductive potential. In morbidly obese individuals,
33 Obesity and Male Fertility 353

reduced spermatogenesis associated with severe hypotestos- health, excess leptin may be an important contributor to the
teronemia may contribute to infertility [31, 32]. This estro- development of reduced androgens in male obesity [38]. In
gen excess is explained by overactivity of the aromatase addition to a higher prevalence of infertility, obese individu-
cytochrome P450 enzyme, which is expressed at high levels als are reported to have higher circulating levels of leptin
in white adipose tissue and is responsible for a key step in the than nonobese individuals [39, 40]. An increasing body of
biosynthesis of estrogens. High levels of estrogens in obese data suggests that leptin is also involved in glucose metabo-
males result from the increased conversion of androgens into lism as well as in normal sexual maturation and reproduction
estrogens, owing to the high bioavailability of these aro- [16]. Leptin receptors are not only present in testicular tissue
matase enzymes [33]. Visceral obesity can serve as a major but also on the plasma membrane of sperm suggesting that
endocrine disrupter and can also influence the endocrine leptin may directly affect sperm via the endocrine system,
interactions by reducing the levels of luteinizing hormone independent of changes in the HPG axis [38, 41]. Diet-
(LH) and testosterone, resulting in hypogonadotropic hypog- induced obesity in mice caused a significant reduction in
onadism, a condition which contributes to male infertility. male fertility and resulted in a fivefold increase in leptin lev-
Although abnormal levels of reproductive hormones could els compared to control mice. Sperm from these obese males
be the source of fertility problems in obese males, Qin et al. exhibited decreased motility and reduced hyperactivated
[34] established that the associations between BMI and progression compared to the lean mice.
semen quality were found statistically significant even after
an adjustment for reproductive hormones, thereby demon-
strating that reproductive hormones cannot fully explain the Oxidative Stress and Reactive Oxygen Species
association between BMI and semen quality [35]. Perhaps,
altered hormone levels themselves do not explain poor semen As mentioned previously, adipocytes secrete various adipok-
quality but instead a deregulation of the normal HPG axis. ines (e.g., tumor necrosis factor a (TNF-a), interleukin 6
Regardless, studies indicate that the association between (IL-6), plasminogen activator inhibitor-1 (PAI-1), and tissue
BMI and semen quality is clearly more complex than what factor) [37]. A number of these adipokines have been con-
can be accounted for simply by reproductive hormones. nected to infertility and testicular cancer. Bialas et al. [42]
Instead, it may be a result of other factors such as ones life- found that changes in the activity of intratesticular cytokines
style and increased adipokine release. may promote various distinct pathologies such as testicular
cancer or infertility. Also, increased release of adipokines
from excess white adipose tissue, resulting in inflammation,
can have a toxic effect on spermatozoa through the release of
White Adipose Tissue as an Endocrine Organ excess reactive oxygen species (ROS) and reactive nitrogen
species (RNS) [43]. ROS and RNS are free radicals, highly
White adipose tissue is a major secretory and endocrine
reactive and unstable molecules that arise as a consequence
organ that secretes approximately 30 biologically active pep-
of oxidative stress or inflammation that can induce significant
tides and proteins that can be grouped as either adipose-
cellular damage throughout the body. Two adipocyte-re-
derived hormones (e.g., leptin, adiponectin, resistin) or
leased adipokines, TNF-a and IL-6, significantly reduced
adipokines (immunomodulating agents). Adipose-derived
human sperm progressive motility in a dose- and time-de-
hormones play a central role in body homeostasis including
pendent manner by promoting the elevation of nitric oxide
the regulation of food intake and energy balance, insulin
production to pathological levels [44]. Numerous authors
action, lipid and glucose metabolism, angiogenesis and vas-
have noted that obesity and several of its causative agents,
cular remodeling, coagulation, and the regulation of blood
namely insulin resistance and dyslipidemia, are associated
pressure [35]. Due to an excess of white adipose tissue in
with increased oxidative stress [45, 46]. This association is
obese men, levels of adipose-derived hormones are often
most likely the result of the elevated metabolic rates that are
elevated, and their action is thought to modify many obesity-
required to maintain normal biological processes and
related diseases, including reproductive functioning.
increased levels of stress in the local testicular environment,
both of which naturally produce ROS. The local influences
of biologically active substances (cytokines) released by
Leptin activated leukocytes in the course of the inflammatory
response to obesity may damage sperm and inhibit spermato-
One such adipose-derived hormone is leptin, which is best genesis. Agarwal et al. [47] found that abnormal patterns of
known as a regulator of food intake and energy expenditure increased ROS were associated with male factor infertility
via hypothalamic-mediated effects [36, 37]. Although nor- and are responsible for abnormal sperm concentration, motility,
mal levels of leptin are required for overall reproductive and morphology found in obese males.
354 S. Cabler et al.

Inhibin B and testosterone production can still be demonstrated [32].


Therefore, the levels of SHBG might be important only as a
In a study by Winters et al. [48], the levels of inhibin B, marker of altered hormone profiles in obese infertile men.
another hormone involved in the HPG axis, declined with
increasing obesity in young adult men, and values were 26%
lower in men who were obese compared to normal-weight Environmental Toxins
men. As it was shown that inhibin B is positively correlated
with the number of Sertoli cells in normal adult rhesus mon- Most environmental toxins are fat soluble and therefore
keys, the reduced levels of inhibin B in the Winters study accumulate in fatty tissue. Their accumulation not only
may indicate that obese men have fewer Sertoli cells than around the scrotum and testes, but also elsewhere in the body
men of normal weight [49]. Since each Sertoli cell is thought may disrupt the normal hormone profile because they are
to support a finite number of germ cells, fewer Sertoli cells as proven endocrine disruptors in male fertility [21]. Since
a result of obesity may result in a lower sperm count [48]. morbidly obese males present with excess scrotal fat, envi-
ronmental toxins accumulating in white adipose tissue sur-
rounding the scrotum may also have a direct localized effect
Resistin Secretion and Insulin Resistance on spermatogenesis in the testes. Lipophilic contaminants
such as organochlorines, organic compounds containing at
Resistin is another adipose-tissue-specific factor, which is least one covalently bonded chlorine atom whose uses are
reported to induce insulin resistance. Almost 80% of men controversial because of the often toxic effects of these com-
with type 2 diabetes are also obese, and an increase in resis- pounds on the environment, are associated with decreased
tin secretion owing to a higher number of adipocytes links sperm production and thus decreased male reproductive
obesity to type 2 diabetes [37, 50]. As a consequence of insu- potential, even if fat is not localized in the scrotal area [34].
lin resistance in patients with type 2 diabetes, increased renin Other toxic species that may induce abnormal spermatogen-
secretion was associated with increased oxidative stress esis are ROS discussed in the previous section. Despite
[45, 46]. This association is most likely the result of the reports that certain toxins can negatively affect fertility,
higher-than-usual metabolic rates required to maintain nor- Magnusdottir et al. [6] found that poor semen quality was
mal biological processes and an increased level of stress in found to be associated with sedentary work and obesity, but not
the local testicular environment. Hyperinsulinemia, which with increased plasma levels of persistent organochlorines.
often occurs in obese men, has an inhibitory effect on normal
spermatogenesis and can be linked to decreased male fertil-
ity. In a group of diabetic men, semen parameters (concen- Dysregulation of HPG Axis
tration, motility, and morphology) did not differ from the
control group, but the amount of nuclear and mitochondrial Excess body weight can impair the feedback regulation of
DNA damage in the sperm was significantly higher [51]. the HPG axis, and all of the factors above might contribute to
This sperm DNA damage can impair male fertility and repro- or be a result of this dysregulation, contributing to apparent
ductive health. In addition to inducing sperm DNA damage, semen quality abnormalities. Sex steroids and glucocorti-
high insulin levels also have been shown to influence the coids control the interaction between the hypothalamic
levels of sex hormone binding globulin (SHBG), a glycopro- pituitaryadrenal (HPA) and the HPG axes, and any amount
tein that binds to sex hormones, specifically testosterone and of disturbance might, in turn, affect spermatogenesis and
estradiol, thereby inhibiting their biologic activity as a male reproductive function. Men of normal weight with low
carrier. levels of testosterone regularly present with elevated levels
High circulating insulin levels inhibit SHBG synthesis in of LH and FSH, in contrast with obese men, who usually
the liver, whereas weight loss has been shown to increase present with low LH and FSH levels [53]. Inhibin B, a
SHBG levels [52]. In obese males, the decrease in SHBG growth-like factor, is produced by Sertoli cells in the testis
means that less estrogen will be bound, resulting in more and normally acts to inhibit both FSH production and stimu-
biologically active, free estrogen. In addition to the conver- lation of testosterone production by Leydig cells in the testis.
sion of testosterone to estrogen in obese patients, the Surprisingly, the expected compensatory increase in FSH
decreased ability of SHBG to sustain homeostatic levels of levels in response to low levels of inhibin B is not observed
free testosterone also contributes to abnormal testosterone in obese men. A low level of inhibin B might result from the
levels [14]. This failure to maintain homeostatic levels might suppressive effects of elevated estrogen levels. A study by
magnify the negative feedback effect of elevated total estro- Globerman et al. [54] also found that there was no increase
gen levels. Even when the presence of SHBG is accounted in FSH levels in obese men whose inhibin B levels remained
for, an independent relationship between insulin resistance low after weight loss. Obese, infertile men exhibit endocrine
33 Obesity and Male Fertility 355

changes that are not observed in men with either obesity or Elevated Scrotal Temperature
infertility alone. This defective response to hormonal changes
might be explained by partial or complete dysregulation of An elevated BMI can impair or arrest spermatogenesis by
the HPG axis. causing an increase in scrotal temperature. Increased fat dis-
tribution in the upper thighs, suprapubic area, and scrotum in
conjunction with the sedentary lifestyle often associated with
Physical Mechanisms obesity can result in increased testicular temperature [21, 28].
Studies of cyclists, truck drivers, and individuals that almost
Many obese men face physical problems that could be related constantly experience elevated scrotal temperatures, like those
to their decreased fecundity and fertility, including erectile with undescended testes demonstrate a negative influence of
dysfunction, scrotal lipomatosis leading to increased scrotal genital heat stress on spermatogenesis. Many studies have
temperatures, and sleep apnea that can cause disruptions in focused on genital heat stress as a potential cause of impaired
the nightly testosterone rise. semen quality in cases of sedentary occupations, the occur-
rence of frequent fever, and varicocele [59]. Hjollund et al.
[60] concluded that even a moderate physiological elevation
Sleep Apnea in scrotal skin temperature is associated with substantially
reduced sperm concentrations. Additionally Magnusdottir
Sleep apnea is a disorder affecting 4% of middle-aged men. et al. [6] found that the duration of sedentary posture corre-
The disorder is characterized by repetitive collapse of the lated positively with increased scrotal temperatures, leading to
pharyngeal airway during sleep resulting in hypoxia and a decrease in sperm density.
hypercapnia. About two-thirds of middle-aged men with
obstructive sleep apnea suffer from obesity, particularly cen-
tral obesity [55]. Sleep apnea is characterized by a fragmented Are There Solutions?
sleep course owing to repeated episodes of upper airway
obstructions and hypoxia and is often diagnosed in obese and From the preceding literature, it is evident that obesity is an
diabetic males. Patients with sleep apnea have a disrupted influencing factor in male infertility. Many experts believe
nightly rise in testosterone levels and, therefore, lower mean that overweight and obesity, as well as their related chronic
levels of testosterone and LH compared with controls. In a diseases, are largely preventable and measures can be taken
study analyzing sleep apnea in obese, control, and lean patients, to reverse both the unhealthy consequences associated with
Luboshitzky et al. [56] concluded that the condition is associ- obesity and the negative impacts on male fertility. Therefore,
ated with decreased pituitarygonadal function and that the the treatment approach will predominantly focus on the
accompanying decline in testosterone concentrations is the management of obesity (Fig. 33.2). The rapid rise in the
result of obesity and, to a lesser degree, sleep fragmentation incidence of obesity has prompted researchers to not only
and hypoxia. This disruption has been associated with abnor- look at natural treatment methods but also for new treat-
mal spermatogenesis and male reproductive potential. ments in order to manage the pandemic and its subsequent
comorbidities.

Erectile Dysfunction
Lifestyle Changes
Whereas the effects of sleep apnea on reproduction are con-
founding owing to obesity itself being a cause of infertility, Lifestyle changes that can lead to weight loss can include
erectile dysfunction is significantly associated with obesity. diet modifications (eating smaller meals, cutting down on
Patients who are overweight or obese make up of 76% of certain types of food) as well as making a conscious effort to
men who report erectile dysfunction and a decrease in libido exercise more in order to achieve a normal energy balance.
[19]. Many studies have found an association between an Several studies showed that natural weight loss through diet
increased incidence of erectile dysfunction and an increase and/or exercise resulted in an increase in androgen, inhibin
in BMI; hormonal dysfunction is central to the connection B, and SHBG levels and decreased serum concentrations of
between obesity and erectile dysfunction [57]. Erectile dys- insulin and leptin, thereby improving semen parameters in
function is highly prevalent in men with both type 2 diabetes obese men [15, 28, 38, 61, 62]. In addition, reducing adipose
and obesity and might act as a forerunner to cardiovascular tissue mass through weight loss in association with exercise or
disease in this high-risk population. Conversely, improved a low-energy and low-fat diet decreases levels of TNF-a,
diabetes control and weight loss have been found to improve IL-6, and other inflammatory cytokines associated with
erectile function [58]. infertility [63, 64].
356 S. Cabler et al.

Fig. 33.2 Approaches to


treatment of obesity-related male
infertility

Gradual weight loss is best achieved through a sensible tested the effects of anastrozole on nonobstructive azoospermic
eating plan that can be maintained over long periods of time. patients who presented with normal or decreased levels of
The likelihood of maintaining weight loss is increased when testosterone and elevated levels of estradiol. Anastrozole
the diet is combined with regular exercise, cognitive behavior treatment normalized the testosterone-to-estrogen ratio and
therapy, and connecting with a supportive group environ- total testosterone levels and improved semen parameters
ment [65]. Therefore, adoption of these principles in a [67]. Zumoff et al. [68] found that by inhibiting estrogen bio-
primary health-care setting can aid in the treatment of infer- synthesis (through administration of the aromatase inhibitor
tility related to obesity. testolactone), there was an alleviation of possible infertility
as a result of hypogonadotropic hypogonadism in obese male
subjects. In another case study, a patient diagnosed with
Pharmacological Interventions infertility secondary to morbid obesity was treated with the
aromatase inhibitor, anastrozole. This led to normalization of
Medication can be used to either treat obesity by addressing the patients testosterone, LH, and FSH hormone levels, as
weight loss or dealing with the obesity-related effects on the well as suppression of the serum estradiol levels and the nor-
male reproductive system. Currently, only two anti-obesity malization of spermatogenesis and fertility [33]. In a study
medications are approved by the Food and Drug including normal, overweight, and obese men, treatment with
Administration for long-term use [66]. One is orlistat anastrozole led to an increase in testosterone-to-estradiol
(Xenical), which reduces intestinal fat absorption by inhibit- ratio that occurred in association with increased semen
ing pancreatic lipase; the other is sibutramine (Meridia), parameters. Anastrozole and testolactone have similar effects
which acts in the brain to inhibit deactivation of the neu- on hormonal profiles and semen analysis, but anastrozole
rotransmitters norepinephrine, serotonin, and dopamine, appears to be at least as effective as testolactone for treating
therefore decreasing appetite. However, weight loss with men with abnormal testosterone-to-estradiol ratio [67].
these drugs is modest. New directions in pharmacological treatment might
Aromatase inhibitors are an option for obese males facing include testosterone replacement therapy and maintenance
infertility problems, especially if they have elevated estrogen and regulation of adipose-derived hormones, particularly
and lowered testosterone levels. Aromatase inhibitors pre- leptin, which is produced by fat cells in the body and known
vent the excess aromatase enzymes from converting testos- to affect appetite and the bodys energy balance, and also
terone to estrogen. They interfere with the aromatase p450 reproductive function. Testosterone replacement therapy has
enzyme that is highly expressed in white adipose tissue. been shown to suppress the levels of circulating leptin,
Currently available aromatase inhibitors include anastrozole, although no information regarding the effect of the treatment
testolactone, and letrozole. Numerous case studies have on semen parameters was reported [16, 38]. Quennell et al.
found this to be an effective treatment in not only restoring [69] discovered that leptin indirectly regulates gonadotropin-
normal hormone levels, but also fertility. Raman and Schlegel releasing hormone neuronal function, affecting forebrain
33 Obesity and Male Fertility 357

neurons that induce infertility. By decreasing elevated leptin secondary infertility, even though natural weight loss has
levels in obese patients, it might be possible to reverse some shown promising results in terms of restoring fertility [74].
of the potential suppressive effects of excess leptin on the Bariatric surgery should therefore not be recommended as a
HPG axis and restore normal spermatogenesis and sperm treatment for obesity-linked infertility until extensive, long-
function. Ghrelin, a hormone which is secreted by cells in term studies have been performed to determine the definite
the lining of the stomach, also affects appetite and the bodys effects on male fertility.
energy balance. Further studies of these hormones may lead
to the development of new medications to control appetite
and provide an option for treating obesity-related health Conclusion
problems and infertility.
Obesity is a modern-day pandemic with serious comorbidi-
ties, both physical and psychological. Studies clearly show
Surgical Options that obese men have an increased chance of subfertility and
subfecundity due to various mechanisms (physical, genetic,
In vitro fertilization may be an option for obese patients hormonal, adipokine, cytokine) that ultimately lead to ED
facing problems such as erectile dysfunction or other purely and abnormal semen parameters. The central factor behind
physical fertility problems. Although morbid obesity is asso- these mechanisms is the abnormal regulation of the HPG
ciated with unfavorable IVF/ICSI cycle outcome as evi- axis. An abnormal hormonal profile, and more specifically
denced by lower pregnancy rates in females, there is no increased adipose-derived hormones and adipokine levels,
evidence for a contributing male factor when assisted repro- may explain the association between BMI, altered semen
ductive methods are used [70]. It is recommended that mor- parameters, and infertility more accurately as it is clearly
bidly obese patients undergo appropriate counseling before the more complex than can be accounted for simply by abnormal
initiation of this expensive and invasive therapy. Fortunately, levels of reproductive hormones.
studies show that obesity in men may not adversely affect the New studies point to many causes for abnormal semen
results of their partners who are undergoing in vitro fertiliza- parameters, including genetic markers, excess adipose-
tion or embryo transfer [71]. derived hormone and adipokine release, as well as oxidative
Scrotal lipectomy is a treatment option available for infer- stress. The consistent decrease in inhibin B levels and
tility in obese men whose excess fat accumulation may be increase in leptin levels, and specific proteomic sperm
contributing to their infertility, either through increased scro- changes observed in obese infertile males, all may have neg-
tal temperature or excess toxin accumulation. One-fifth of ative impacts on spermatogenesis. Increased cytokines, such
patients who were previously considered infertile and under- as IL-6, are connected with oxidative stress and impaired
went scrotal lipectomy to remove excess fat were able to reproduction and could also contribute to abnormal semen
achieve a successful pregnancy [28]. For individuals who are parameters observed in obese men facing fertility issues.
severely obese, dietary changes and behavior modification These markers point toward a true suppression of normal
may be accompanied by surgery to reduce or bypass portions spermatogenesis and sperm quality despite some inconsis-
of the stomach or small intestine. The risks of obesity sur- tency in the results of studies performed to measure the
gery have declined in recent years, but it is still only per- effects of obesity on semen parameters.
formed on patients for whom other strategies have failed and In treating obesity-linked sperm disorders and male infer-
whose obesity seriously threatens their health. tility, few controlled studies have been performed, and effec-
Bariatric surgery (weight loss surgery) is the use of sur- tive therapeutic treatments, advice for lifestyle changes, and
gical intervention in the treatment of obesity by reducing or surgical options should be explored further. In addition,
bypassing portions of the stomach or small intestine. As it is determining the most accurate measure for qualifying
a rather extreme intervention, it is only recommended for patients as obese could more accurately clarify the cause of
severely obese people (BMI > 40) who have failed to lose their infertility and other health issues that might accompany
sufficient weight following dietary modification and phar- their state of obesity. Neither the reversibility of obesity-
macological treatment [72]. Gastric bypass and banding sur- associated male infertility in response to weight loss nor
geries are very effective in the treatment of morbid obesity effective therapeutic treatments or interventions have been
and its comorbid conditions. One study reported that a extensively studied. The increasing prevalence of obesity
significant decrease in estrogen, increase in testosterone, and worldwide in conjunction with a perceived declining male
normalization of other hormone and adipokine levels were sperm count in modern man calls for more research and
experienced by patients who underwent vertical banded gas- attention to obesity as an etiology of male infertility.
troplasty [73]. However, others speculate that the drastic Clinicians should consider obesity when a male patient with
weight loss that accompanies this procedure might induce idiopathic infertility is confronted.
358 S. Cabler et al.

Physical problems that may contribute to decreased fertility


Expert Commentary include ED; scrotal lipomatosis, which leads to increased
scrotal temperatures; and sleep apnea that can cause dis-
The purpose of this chapter was to discuss obesity as a newly
ruptions in the essential nightly testosterone rise.
discovered etiology of male infertility. The growing inci-
There are solutions that often lead to restoration of fertility
dence of obesity and apparent decrease in male fertility
that include lifestyle changes, pharmacological interven-
makes this topic especially relevant when dealing with the
tions, and surgical procedures.
infertile male. Although data on abnormal semen parameters
The rapid rise in the incidence of obesity has prompted
and evidence of obesity as it affects male fertility is abun-
researchers to not only look at natural or lifestyle changes
dant, the specific mechanisms are not definite. Discovery and
as treatment methods but also for new therapies in order to
proof of significant mechanisms that contribute to this issue
manage the pandemic and its subsequent comorbidities.
are important when treating infertility as it relates to obesity.
Clinicians should consider obesity when a male patient
The recognition of adipose tissue as an endocrine organ and
with idiopathic infertility is confronted.
discovery of adipokines have contributed greatly in explain-
ing the mechanisms behind this problem, but it appears many
other factors are involved. Further understanding of adipose
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