Semen Quality Obesity Plus

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Mechanisms of obesity-induced
male infertility
Expert Rev. Endocrinol. Metab. 5(2), 229–251 (2010)
Karen P Phillips† and Male infertility, characterized by hypogonadism, decreased semen quality or ejaculatory
Nongnuj Tanphaichitr dysfunction, accounts for approximately 20% of infertility cases. Obesity and metabolic
†
Author for correspondence dysfunction have been identified, among other causal factors, to contribute to male infertility.
University of Ottawa, In the context of the Western world’s ‘obesity epidemic’, this article discusses three main
43 Templeton Street, Room 215, biological mechanisms linking obesity to impaired male reproductive function: hypogonadism,
Ottawa, ON K1N 6N5, Canada testicular heat stress/hypoxia-induced apoptosis and endocrine disruption by ‘obesogens’.
Tel.: + 1 613 562 5800 ext. 8678 Among these, obesity-induced hypogonadism is undoubtedly the most clinically significant
[email protected] and is easily assessed. Rapidly expanding areas of research in this area include leptin modulation
of kisspeptins and hypothalamic–pituitary–testicular hormone pathways, and roles of other
adipocytokines in male infertility, as well as the impact of exposure to obesogens on the quality
of semen.
Keywords : endocrine disrupters • estrogen • hypogonadism • leptin • obesity • obesogens • semen
Approximately 30–40% of infertility cases head, midpiece and tail (Figure 3) . These struc-
can be attributed to problems with the male tural entities of sperm are used as landmarks
partner [1] . Obesity and related concomitant for morphological categorization. Testicular
metabolic abnormalities are among the pro- injury, disease or impairments of the HPT axis
posed causes of male infertility [2] . Metabolic can produce abnormalities of spermatogenesis
syndrome has been characterized as a constel- with consequences, including the production
lation of disorders, including Type 2 diabetes, of fewer, abnormal or underdeveloped sperm,
coronary heart disease, obesity with visceral characterized by morphological defects or
abdominal fat distribution, dyslipidemia, hyper- reduced motility. Further modifications of bio-
tension and impaired glucose metabolism/insu- chemical and kinetic properties of sperm take
lin resistance [3–5] . In the context of the ‘obesity place in the female reproductive tract; a pro-
epidemic’ in the Western world, this paper dis- cess known as capacitation, which includes the
cusses three main biological mechanisms linking acquisition of hyperactive motility (Figure 4) [6,7] .
obesity to impaired male reproductive function. Once bound and penetrating the egg zona
These mechanisms include hypogonadism, testi pellucida, sperm undergo the zona pellucida-
cular heat-stress-/hypoxia-induced apoptosis and induced acrosome reaction (Figure 3) , an acro-
endocrine disruption by ‘obesogens’. somal exocytosis event that involves the release
of hydrolytic acrosomal enzymes, followed by
Spermatogenesis & the assessment of fusion of one of these acrosome-reacted sperm
male fertility with the egg plasma membrane and sperm
Testicular function is regulated by the hypo- incorporation into the egg (fertilization).
thalamic–pituitary–testicular (HPT) axis The determination of spermatozoa concen-
(F igur e 1) . Gonadotropin-releasing hormone tration, morphology and motility remains the
(GnRH) is released by hypothalamic neu- primary clinical tool for the assessment of male
rons and stimulates the release of pituitary infertility [8] . Reproductive hormone profiles
gonadotropins, luteinizing hormone (LH) and (free and total testosterone, estradiol, LH and
follicle-stimulating hormone (FSH) [2] , both FSH) in addition to semen parameters are typi-
of which play major roles in the regulation of cally used to assess male reproductive function.
testicular steroidogenesis and spermatogenesis, Development of clinical assays to delineate new
respectively (Figure 2) . The mature spermatozoa parameters that better reflect sperm fertilizing
(sperm) are polarized cells, each consisting of a competence are needed.
www.expert-reviews.com 10.1586/EEM.09.65 © 2010 Expert Reviews Ltd ISSN 1744-6651 229

Review Phillips & Tanphaichitr
density, this technology differentiates between absorption of

x-rays in bone vs soft tissue) or whole-body adipose tissue com-
puted tomography (CT) and MRI combined with waist:hip ratio
Hypothalamus
measurements [16] .
– GnRH Reproductive parameters in obese men

The relationship between semen quality and BMI has been exam-
ined in several observational studies (Table 1 & 2) . Studies set in infer-
tility clinics have the advantage of investigating obesity trends within
Pituitary infertile populations whereas populations of unselected healthy men
across BMI categories enable evaluation of the association between
obesity and fertility without a preconceived bias. Studies designed to
– FSH, LH
measure sperm parameters for obese men tended to report a negative
association between semen quality and BMI (Table 1) [17–21] . By con-
trast, the large INUENDO study of European infertility patients
reports no reduction in sperm concentrations or sperm motility in
T Testis the obese group, whereas moderately overweight men exhibit a small
decrease in sperm concentrations [22] , which is supported by more
Expert Rev. Endocrinol. Metab. © Future Science Group (2010) recent studies [23,24] that also report no associations between semen
parameters and BMI. However, time-to-pregnancy studies support
Figure 1. Hypothalamic–pituitary–testicular axis. Systemic an association between subfecundity and high BMI (Table 1) [25–27] .
regulation of testicular function is provided by the hypothalamic–
pituitary–testicular axis. Briefly, the hypothalamus releases GnRH,
Sperm concentration/total sperm count seem most likely to be nega-
which acts on the anterior pituitary to release FSH and LH. FSH tively associated with BMI above 25 kg/m2 (Table 2) [17–18,20,21,28]
binds to receptors on testicular Sertoli cells to regulate with reduced normal sperm morphology and motility less consistent
spermatogenesis. LH binds receptors on testicular Leydig cells. across studies (Table 2) .
FSH: Follicle-stimulating hormone; GnRH: Gonadotropin- Many population studies are limited by the small sample size of
releasing hormone; LH: Luteinizing hormone; T: Testosterone.
the obese study population, and tend to report overweight/obese
data as a single group, which would be expected to reduce the
Adipogenesis & the assessment of obesity strength of the associations measured. Possible explanations why
Adipocytes are the main cellular constituents of the adipose tissue these population studies are not more consistent could include lack
and play an important role in regulating triglyercide and free fatty of sensitivity of BMI as a measurement of adiposity, presence of sub-
acid levels. Adipocytes are derived from multipotent stem cells that fertility, which may manifest by more subtle changes in testicular/
differentiate into preadipocytes and, subsequently, mature adipo- sperm physiology not captured by traditional semen assessments,
cytes [9] . Estrogen is a positive regulator of adipogenesis, stimulat- and finally, heterogeneity within the overweight/obese populations.
ing preadipocyte proliferation and growth of mature adipocytes [10] . The association between infertility and obesity has also been
By contrast, adipocyte differentiation and maturation is negatively examined using reproductive hormone profiles of infertility
regulated by androgens such that high androgen levels both drive patients across BMI categories. BMI is negatively correlated with
differentiation of the multipotent stem cells toward myogenesis, serum testosterone but positively correlated with serum estradiol
thereby inhibiting adipogenesis [11] , and inhibit adipogenic differ- in these patients [15,22,28,29] ; consistent with original reports that
entiation of existing preadipocytes [12] . Adipose tissue has endocrine visceral obesity in men is associated with decreased free- and total-
function and synthesizes chemical messengers, known as adipocy- testosterone levels [30–32] and with increased estrone and estradiol
tokines or adipocyte-derived hormones, in addition to the aromati- levels [9,33–35] . Therefore, it seems likely that important reproduc-
zation of androgens to estrogens. Basal aromatase activity decreases tive features of morbid obesity in men include hypogonadism,
during adipocyte maturation with tenfold less aromatase activity hyperestrogenemia and subfertility (Figure 5) [36] .
in mature adipocytes compared to preadipocytes. Aromatase activ-
ity is also site dependent with higher activity in preadiopocytes in Mechanisms of obesity-induced male infertility
subcutaneous tissue compared with omental cells [13] . Hypogonadism
The obese male is generally characterized as having greater than Hypogonadism in males encompasses disrupted testicular func-
25% body fat of total body mass with a BMI in excess of 30 kg/m2 tions, including deficient steroidogenesis and/or spermatogenesis.
[14] . BMI is used as the chief indicator of obesity, with stratified Hypogonadism is classified by the origin of dysfunction, either at
BMI categories as follows: 18.5–24.9 kg/m2 (normal), 25 kg/m2 the testis or within the HPT axis. Primary hypogonadism results
and above (overweight) and 30 kg/m2 and above (obese). Other from a testicular deficit (Figure 6A) and may be caused by genetic dis-
more accurate methods to assess obesity include measurement of eases, including Klinefelter’s syndrome or 5α-reductase deficiency,
skinfold thickness [15] , hydrostatic weighing, dual-energy x-ray congenital abnormalities, including cryptorchidism or testicular
absorptiometry (originally designed to measure bone mineral feminization, or testicular insults, such as trauma, mumps orchitis,
230 Expert Rev. Endocrinol. Metab. 5(2), (2010)

Obesity & semen quality Review
radiation or chemotherapy [1] , testicular

heat stress [37] or varicocele (associated with 1
impaired testicular venous drainage) [38] .
Primary testicular deficit is also classified Mitosis
as hypergonadotropic hypogonadism and 2
is clinically characterized by hypogonadism
(low free and/or total testosterone and low Mitosis
sperm production) with increased FSH and 3
LH levels, caused by inadequate testoster-
one levels to provide negative feedback to
the HPT axis. Hypogonadism may also be Meiosis I
4
caused by deficits within the hypothalamus
or pituitary, a so-called secondary hypogo- Meiosis II
nadism, also termed hypogonadotropic 5
hypogonadism (Figure 6B) . This is charac-
terized by low–normal FSH and LH levels
and subsequently low testosterone, and is 6
featured in men with Kallman’s syndrome,
pituitary disorders and serious illnesses,
such as AIDS [39] . We will discuss sev-
7
eral hypogonadal mechanisms with either
testicular or hypothalamic origins that
explain the association between obesity and
Expert Rev. Endocrinol. Metab. © Future Science Group (2010)
male hypogonadism.
Figure 2. Mammalian spermatozoa. Spermatogenesis is supported by Sertoli cells
Adipocyte-derived estrogen contained within testicular seminiferous tubules. Spermatogonium (type A) continuously
& hypogonadism replicates by mitosis. Spermatogonium (type B) undergoes mitosis followed by two
rounds of meiosis to produce spermatocytes and spermatids. Round spermatids undergo
Adipocyte-derived estrogens in obese men
differentiation (spermiogenesis) including remodeling of the cytoplasm to form
provide feedback inhibition to the HPT elongated spermatids and ultimately testicular spermatozoa. Major stages include:
axis, modulated by the presence of estro- spermatogonium type A and type B; primary spermatocyte (shown pachytene
gen receptors (ER-α and -b) localized to spermatocyte); secondary spermatocyte; round spermatid; elongated spermatid; and
the hypothalamus and pituitary, shown testicular spermatozoa.
in mouse [40] and rat [41,42] . A plausible
biological mechanism for obesity-induced hypogonadotropic inhibitors, letrozole and anastrozole, can be used to prevent enzy-
hypogonadism may result, in part, from increased feedback inhi- matic conversion of androgens to estrogens in adipocytes and
bition of the HPT axis due to high serum levels of estrogens in other tissues [49,50] , thereby reducing serum estradiol and suppres-
obese males [43] . This may lead to a hypogonadal–obesity cycle sion of the HPT axis by interrupting the hypogonadal–obesity
[44] , wherein an increased adipose tissue mass represents a sig- cycle [46] .
nificant peripheral source of estrogens, which, in turn, suppress
the HPT axis and increase central adiposity (Figure 7) . The sub- Inter-relationship between hypogonadism
sequent reduction in circulating testosterone leads to increased & non-insulin-dependent diabetes mellitus
deposits of visceral/abdominal adipose tissue [45–47] and subfer- Insulin resistance, together with obesity, are cardinal features
tility, whereas the increased production of circulating estrogens of metabolic syndrome [2] . However, it is important to note that
supports differentiation of adipocytes [10] . not all obese individuals will develop non-insulin-dependent dia-
Obesity-induced hypogonadism in males may be treated by betes mellitus (NIDDM) or Type 2 diabetes, a disease that also
weight loss, which should reduce estrogen levels to normal and manifests in normal-weight individuals [51] . Consideration must,
alleviate the HPT feedback inhibition. Roux-en-Y gastric bypass therefore, be granted to the differential impacts of adiposity and
surgery, one option for the treatment of morbid obesity, has been insulin resistance in the context of fertility in the obese male.
shown in one study to seemingly reverse abnormal reproduc- Non-insulin-dependent diabetes mellitus is generally charac-
tive hormonal profiles, such that total testosterone is increased terized by obesity, insulin resistance, hypogonadism, low sex-
and serum estradiol is decreased [48] . Other treatment options hormone binding globulin (SHBG) and reduced free and total
for hypogonadism include supplementation with alternative or testosterone [2,52] . However, it is unclear which of these parameters
recombinant gonadotropins (e.g., human chorionic gonadotropin are causal factors and which are independent. Hypogonadism,
[hCG] and recombinant FSH), which stimulate testicular func- for example, has been demonstrated in several studies to predict
tion, including testosterone production [49] . Finally, aromatase NIDDM risk (e.g., Multiple Risk Factor Intervention Trial cohort
www.expert-reviews.com 231
Table 1. Male obesity and infertility: observational studies of sperm parameters and BMI.
232
Study (year) Study design Population (n) Parameters Support relationship between obesity and Ref.
male infertility?
Review
Jensen et al. Cross-sectional 1558 Danish men, Semen volume, sperm concentration, Yes, sperm concentration and total sperm count reduced in [17]
(2004) general population motility, morphology, total sperm underweight men (BMI <20 kg/m2) and in overweight/
count, testis volume, obese men (BMI > 25 kg/m2) compared with normal-weight
reproductive hormones men (BMI: 20–25 kg/m2)
Hammoud Retrospective, 526 male patients attending Sperm concentration, progressive Yes, results support association between obesity and [18]
et al. (2008) cross-sectional US fertility center, motility, morphology, BMI oligospermia, reduced motile sperm count, increased
390 included incidence of abnormal sperm morphology
Kort et al. Cross-sectional 520 men attending Semen volume, sperm concentration, Yes, inverted relationship between BMI and total normal [19]
(2006) US andrology laboratory motility, morphology, sperm motile sperm, obese men have fewer chromatin-intact
chromatin index, BMI normal motile sperm
Phillips & Tanphaichitr
Koloszar et al. Cross-sectional 274 Hungarian Sperm concentration, BMI Yes, results indicate reduced sperm concentration in obese [20]
(2005) normozoospermic group of men (BMI >30.1 kg/m2) compared with
andrology patients underweight, normal-weight and overweight groups
Hofny et al. Prospective 122 obese, Egyptian Total sperm count, sperm motility, Yes, BMI inversely related to sperm concentration, motility [21]
(2009) andrology patients morphology, BMI, reproductive and normal morphology
hormones, leptin
Aggerholm Retrospective, 2139 Danish men, Total sperm count, motility, semen Unclear, results support a slight reduction in total sperm [22]
et al. (2008) cross-sectional 1989 included volume, BMI, reproductive hormones count among overweight men (BMI: 25.1–30 kg/m2)
(INUENDO study) compared with normal weight men; no reduction in sperm
count in obese men
Pauli et al. Prospective 87 US men, included fathers Semen volume, sperm concentration, Unclear, no correlation between semen parameters with [15]
(2008) and men attending motility, BMI, skin-fold thickness, obesity (BMI/skinfold thickness), men unable to conceive,
fertility center testicular volume, had higher body fat (BMI/skinfold measurements) compared
reproductive hormones with men with paternity
Duits et al. Prospective cohort 1466 male patients attending Sperm concentration, motility, No, results did not support association between high BMI [23]
(2009) Dutch fertility center, morphology, total sperm count, and any of the sperm parameters measured
1401 included semen volume, BMI
Nicopoulou Retrospective, 349 Greek andrology patients Total sperm count, BMI No, results did not support a significant association between [24]
et al. (2009) cross-sectional BMI and total sperm count
Fecundity and BMI
Ramlau- Cohort 64,167 pregnant women, BMI (women’s report), Yes, overweight/obese men associated with subfecundity [25]
Hansen et al. (Danish National Birth 47,835 couples included time to pregnancy (time to pregnancy >12 months)
(2007) Cohort)
Sallmén et al. Cohort (Agricultural 52,395 US pesticide BMI (self-report), time to pregnancy Yes, overweight/obese men associated with subfecundity, [26]
(2006) Health Study [US]) applicators, 1329 included dose–response relationship
Nguyen et al. Retrospective cohort 45,132 Norwegian couples, BMI (women’s report, self-report), Yes, risks of infertility associated with underweight [27]
(2007) (Norwegian Mother 26,303 included time to pregnancy (BMI <20 kg/m2), increased risk of infertility with increase
and Child Cohort) in BMI
Expert Rev. Endocrinol. Metab. 5(2), (2010)

Table 2. Semen quality parameters in overweight/obese men (BMI >25 kg/m2).
Study (year) Obese sample size Population Association with BMI? Ref.
(total sample size [n])
Jensen et al. 299 (1558) Danish men Sperm concentration/total sperm count: yes, BMI >25 kg/m2 group exhibited significantly reduced [17]
(2004) sperm count and reduced sperm concentration; large sample, general population
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Sperm motility: no association between sperm motility and BMI; large sample, general population;
young population
Sperm morphology: no significant association; large sample, general population, very young (mean
age: 19 years)
Hammoud et al. 296 (390) Fertility patients Sperm concentration/total sperm count: yes, oligospermia associated with increasing BMI; moderate [18]
(2008) sample size, large proportion of overweight/obese men
Sperm motility: yes, increasing BMI associated with low sperm motility; moderate sample size, large
proportion of overweight/obese men
Sperm morphology: yes, reduced in obese group vs others; moderate sample size, large proportion of
overweight/obese men
Koloszár et al. 149 (274) Normo-zoospermic Sperm concentration/total sperm count: yes, sperm concentration significantly reduced in men with [20]
(2005) Infertility patients BMI >30 kg/m2, not in overweight men (BMI: 25.1–30 kg/m2); simple analysis, determined age effect in
obese group, men with abnormalities in reproductive hormones were excluded
Hofny et al. 122 (122) Fertile/oligospermic Sperm concentration/total sperm count: yes, BMI negatively correlated with sperm count; [21]
(2009) andrology patients homogenous sample; BMI >30 kg/m2
Sperm motility: yes, BMI negatively correlated with sperm motility; sperm motility significantly decreased
in oligospermic group. Entire sample had BMI >30 kg/m2, excluded major illness diabetes, hypertension
Sperm morphology: yes, BMI positively correlated with abnormal sperm morphology; entire sample had
BMI >30kg/m2, excluded major illness diabetes, hypertension
Fejes et al. 25 (42) Oligospermic Sperm concentration/total sperm count: yes, reduced sperm concentration vs normal/underweight [28]
(2006) patients men; small sample size, subfertile population
Sperm motility: no difference vs normal/underweight men; small sample size, subfertile population
Sperm morphology: no difference vs normal/underweight men; small sample size, subfertile population
Duits et al. 733 (1401) Fertility patients Sperm concentration/total sperm count: no association with BMI; thorough analysis, large sample, [23]
(2009) reduced semen volume in overweight group
Sperm motility: no association with BMI; thorough analysis, found reduced semen volume in
overweight group
Sperm morphology: no association with BMI; thorough analysis, found reduced semen volume in
overweight group
Pauli et al. Not listed, mean Fathers/infertility Sperm concentration/total sperm count: no association between BMI or skinfold thickness with sperm [15]
(2008) BMI >25 kg/m2 (87) patients concentration; proportion of sample with BMI >30 kg/m2 not identified, small sample
Sperm motility: No association between BMI or skinfold thickness with sperm motility; proportion of
sample with BMI >30 kg/m2 not identified, small sample
Obesity & semen quality
Kort et al. Not listed, mean Andrology patients Sperm motility: yes, BMI negatively correlated with total number of normal motile sperm; [19]
(2006) BMI >25 kg/m2 (520) analysis used normal motile sperm that combines sperm concentration, volume, morphology and motility,
no raw data reported
Review
233
hyperinsulimia, somehow directly suppressed Leydig cell testos-

Acrosomal
terone production in a cohort of men with mild-to-moderate
cap region obesity [65] . In vitro, Leydig cells express insulin receptors, and
Head
Nucleus insulin has been shown to induce testosterone secretion from
Leydig cell cultures [67,68] . The molecular mechanism wherein
insulin modulates Leydig cell steroidogenesis is unknown, with
Mitochondria
Midpiece the possibility that the testis, as with other organs in individuals
Acrosome with NIDDM, is resistant to insulin signaling [66] .
reaction Non-insulin-dependent diabetes mellitus and, therefore, insulin
resistance, appears to be associated with ‘mixed hypogonadism’,
reflecting the dual actions of insulin resistance at the testis (hyper-
gonadotropic hypogonadism); and the hypothalamus/pituitary
(hypogonadotropic hypogonadism). Insulin is predominantly
Tail stimulatory, acting at hypothalamic neurons to induce GnRH
secretion and gonadotropin secretion from the pituitary gonado-
trophs, demonstrated in vitro [69] . In obese men with NIDDM,
insulin resistance may blunt the normal, insulin stimulation of the
HPT axis [66] . More studies are needed to identify the mechanisms
of HPT insulin signaling and the consequences of insulin resistance
to the normal endocrine function of these glands.
Figure 3. Mature spermatozoon undergoes the acrosome Although reproductive hormonal profiles have been fairly well
reaction upon binding to the egg’s extracellular matrix,
the zona pellucida. Featured on the left is a mature established for men with NIDDM, semen quality has been examined
spermatozoon with three morphological structures: head, in only a few studies. Generally, sperm count is normal or increased,
midpiece and tail. The head contains the acrosome and the with decreases in sperm motility [70] and semen volume [71] , and
nucleus. The midpiece is the ‘engine’ of the spermatozoon, increases in abnormal sperm morphology [72] . Unfortunately, many
densely packed with mitochondria that power the flagellum or published studies of ‘diabetic men’ do not disaggregate the insulin-
tail. Spermatozoa initially lack the ability to fertilize an egg,
necessitating further remodeling (capacitation) induced by dependent diabetes mellitus (IDDM) and NIDDM groups; a criti-
contact with the female reproductive tract. Capacitation is cal reporting gap in the literature as it appears that NIDDM may be
accompanied by cholesterol efflux, protein tyrosine more of a concern with respect to male reproduction. The pathology
phosphorylation and rupture of the acrosomal membrane, of IDDM (autoimmune and insulin deficiency) is different from
releasing acrosomal enzymes (acrosome reaction), as shown on NIDDM (insulin resistance). The stimulatory effects of insulin on
the right. Acrosome reaction involves fusion of outer acrosomal
membrane with sperm plasma membrane, progressive loss of the HPT axis in IDDM patients are continued through exogenous
outer acrosomal membrane and acrosomal contents and, finally, insulin, the standard intervention. Insulin resistance in NIDDM
exposure of the inner acrosomal membrane. patients, however, leads to aberrance in testicular cell signaling and
subsequent hypogonadism. With so few studies examining the asso-
study [53] , Massachusetts Male Aging Study [54] , Rancho Bernardo ciation between semen quality and insulin resistance, it is impossible
Study [55] , Kuopio Ischaemic Heart Disease Risk Factor Study to profile ‘typical’ semen parameters of a NIDDM man. More stud-
[KIHD] [56–58]). Men with NIDDM are more likely to exhibit ies using NIDDM men and animal models are urgently needed to
hypogonadism with reduced serum testosterone and SHBG [59–61] . verify the causal effect of insulin resistance on hypogonadism, as
These studies are consistent with established associations between well as to discern the molecular mechanisms involved.
obesity and hypogonadism, and between obesity and insulin
resistance. SHBG and testosterone are inversely correlated with Leptin’s roles in hypogonadism
BMI [17] and insulin [62,63] , such that obese males exhibit high Leptin is a 16-kDa protein hormone, encoded by the ob gene [73]
serum insulin with low SHBG and bioavailable testosterone [52] . and secreted by adipocytes. This adipocytokine plays a major role
The inverse relationship between total serum testosterone and in energy homeostasis, including neuroendocrine regulation of
insulin appears to be independent of central adiposity, demon- bodyweight. Leptin is the endogenous agonist for the leptin recep-
strated in the Health in Men study [64] . Hyperinsulinemia fea- tor (Ob‑R), a member of the class I cytokine receptor superfamily.
tured in NIDDM patients appears to produce hypergonadotropic Ob‑R is produced as alternatively spliced forms and further classi-
hypogonadism by directly reducing testicular testosterone levels. fied as short (Ob-Ra, Ob-Rc, Ob-Rd and Ob-Rf), long (Ob-Rb)
Pitteloud and colleagues demonstrated a positive correlation and secreted (Ob-Re) receptor types, all with extracellular, trans-
between insulin sensitivity and serum testosterone levels in a membrane and variable intracellular domains with the exception of
cohort of 60 men, across a broad range of BMI categories [65] . Ob-Re [74–76] . Ob-Rb has the longest intracellular domain and is the
In a subsequent study, Pitteloud’s group reported no correlation functional isoform in the hypothalamus, whereas Ob-Ra and Ob-Rc
between insulin sensitivity and LH, suggesting no hypothalamic are proposed to participate in leptin transport across the blood–brain
or pituitary deficit [66] . Instead, insulin resistance, associated with barrier (BBB) [76,77] . Ob-Re is the putative soluble leptin receptor

Cholesterol contrast to the hypogonadism featured in

EGF receptor Leptin efflux congenital leptin deficiency cases, hypo-
gonadism in obese men is associated with
Ob-R
high serum leptin. Altered leptin dynamics
JAK2 SACY may, therefore, contribute to male infertil-
P P ity via at least two mechanisms, both of
Y Y
Na+ which may produce hypogonadism. These
include leptin resistance or leptin insuf-
HCO3- HCO3- Ca2+ ficiency at the hypothalamus and leptin
cAMP
modulation of testicular physiology.
PDE
Leptin resistance or leptin insufficiency at
Ras the hypothalamus
5´AMP
Raf PKA Consider the perplexing presence of the
same phenotype (obesity and hypogonad
otropic hypogonadism) in individuals with
MEK high serum leptin due to obesity, and in
Tyrosine Sperm-motility activation humans/animals with leptin deficiencies
kinase Hyperactivated sperm motility due to mutations. Leptin resistance has
activation Preparation for acrosome reaction
been proposed to explain this apparent
ERK
paradox in the former group, referring to
the inability of leptin to act at the hypo
Figure 4. Sperm capacitation signaling. The process of capacitation includes changes thalamus, either due to reduced levels of
to the sperm membrane and the acquisition of hyperactive motility. Hallmark
characteristics of sperm capacitation including intracellular increases in cAMP and HCO3-, bioavailable leptin (leptin insufficiency) [95]
cholesterol efflux and tyrosine phosphorylation. Ob-R signal crosstalk is also shown (see or impaired leptin signaling [96] , thereby
text for details). Dotted lines indicate proposed pathways and solid lines indicate mirroring the leptin deficiency present in
established pathways. animal models and congenital genetic con-
cAMP: Cyclic adenosine monophosphate; EGFR: EGF receptor; ERK: Extracellular ditions [97] . There does not appear to be a
signal-regulated kinase; JAK: Nonreceptor tyrosine kinase; MEK: Mitogen-activated
protein kinase; PDE: Phosphodiesterase; PKA: Protein kinase A; SACY: Soluble adenylyl model for central leptin excess, in spite of
cyclase; Y-P: Phosphorylated tyrosine residue. the increased serum leptin levels exhibited
by morbidly obese individuals.
lacking the transmembrane and intracellular domains, and pro- Peripheral adipocyte-derived leptin circulating in the blood-
posed to buffer circulating leptin levels, thereby regulating leptin stream can cross the BBB via a saturable transport system [95]
bioavailability [78] . to act centrally via Ob-Rb in the brain, particularly at the
Leptin was initially characterized in ob/ob mice, which, because
of a natural mutation, possess no ob gene and are, therefore,
leptin deficient [79] . Both male and female ob/ob mice are mor-
bidly obese and infertile [80] . Similar phenotypes are observed
in Ob-R-deficient mice [81] and the Zucker fatty (fa/fa) rat [82] .
Several human families have also been identified with congeni-
tal leptin deficiency owing to recessive mutations in the leptin
Obese male
gene (Delta133G [83] , R105W [84,85] and N103K [86]) or the leptin
receptor [87] . Clinical features of human congenital leptin defi- • BMI >30 kg/m2
ciency [84–85] include early onset of obesity, hyperphagia (over- • High serum estradiol
• Insulin resistance
eating), hypogonadotropic hypogonadism and delayed pubertal • High serum leptin
onset. Congenital leptin deficiency caused by leptin receptor • Hypogonadism
mutation is associated with a slightly less severe phenotype [87] . • Subfertility
Recombinant leptin administration has been used successfully
to mitigate some of the features of congenital leptin deficiency,
resulting in weight loss and reversal of hypogonadism [83,88,89] .
In healthy men, serum leptin positively correlates with BMI
and adipose mass [90] . A number of studies in overweight and
obese participants report an inverse relationship between serum Expert Rev. Endocrinol. Metab. © Future Science Group (2010)
levels of leptin and testosterone [91–94] but no significant corre-
lation between levels of leptin and the gonadotropins [91,93] . In Figure 5. Endocrine profile of the obese male.
was first considered following reports that the ratios of cerebro-

spinal fluid leptin to plasma leptin are reduced in obese individu-
A
Hypothalamus als compared with lean counterparts [95] . Thus, in spite of large
circulating leptin plasma levels in obese individuals, cerebro-
– GnRH
spinal fluid leptin levels are not proportionately high [95,100] . As
peripheral leptin is ordinarily released in a pulsatile fashion, any
number of factors, including circadian rhythm, meal spacing and
aging could disrupt this initial leptin pulsatile signal and pro-
duce leptin receptor downregulation, thereby attenuating leptin
Pituitary transport at the BBB [101] . Reduced hypothalamic leptin stimu-
lation may produce the morbidly obese phenotype in humans
– FSH, LH ,as these individuals lack leptin-induced suppression of appetite
or stimulation of energy expenditure [81] , thereby producing
a phenotype similar to the ob/ob mouse [102] . The molecular
mechanisms of leptin transport saturation at the BBB are not
Hypergonadotropic
Testicular well characterized; however, triglyceride inhibition/reduction of
hypogonadism
deficit leptin transport at the BBB has been proposed [99] . Alternatively,
leptin resistance, characterized by deficits in Ob-R signaling
Testosterone pathways, may impair leptin regulation of eating and energy
expenditure. Candidate signaling pathways include SOCS3 and
B STAT3, both downstream of Ob-Rb [103] . Although impair-
Hypothalamic
deficit
ments in leptin signaling may well accompany central leptin
insufficiency, perturbed signaling as a basis for leptin resistance
– GnRH remains to be elucidated [101]. As described previously, ob/ob
mice are obese, infertile and exhibit hypogonadism; however,
this phenotype can be reversed, including restoration of fertility,
by treatment with exogenous leptin [102,104,105] . Gonadotropins
Pituitary and sex-steroid hormones are low in ob/ob mice, consistent with
deficit hypogonadotropic hypogonadism and a role for leptin in the
regulation of the HPT axis [102] . Leptin acts indirectly to regu-
– FSH, LH late gonadotropin secretion in the hypothalamus by modulating
kisspeptins in the arcuate nucleus (Figure 8A) [106] . Kisspeptins
are proteins encoded by the Kiss1 gene, transcribed as KiSS1
Hypogonadotropic mRNA and act via a G-protein-coupled receptor (GPR54) [107]
hypogonadism to stimulate GnRH release, thereby triggering the gonadotropin
Testis
cascade [108] . Peripheral leptin, once transported across the BBB
to the hypothalamus, binds leptin receptors in the forebrain.
Testosterone
Arcuate nucleus neurons in the mouse express both Ob-Rb and
KiSS-1 mRNA in approximately 40% of cells, suggesting that
Figure 6. Hypogonadism. (A) Hypergonadotropic hypogonadism. so-called KiSS1 neurons (kisspeptins-expressing neurons) are
Also known as primary hypogonadism, reduced testosterone levels direct targets of leptin. Further, the numbers of KiSS1 neurons
and impaired spermatogenesis are caused by testicular deficit. are decreased in the hypothalamus of ob/ob mice, indicating that
Reduced testosterone levels leads to attenuation of the
testosterone-induced negative feedback loop to the secretory
leptin regulates KiSS1 neurons, and indirectly gonadotropin
activities of the hypothalamus and pituitary. Increased amounts of release [108,109] . Modulation of the gonadotropin levels is almost
GnRH and FSH/LH are thus secreted. (B) Hypogonadotropic certainly limited to an indirect role of leptin, since leptin recep-
hypogonadism. Secondary hypogonadism is caused by deficit at the tors are not present on rat GnRH neurons. Supporting these data
hypothalamus and/or pituitary. FSH and LH are, thus, secreted at is the observation of normal fertility in transgenic mice lacking
reduced levels, which also lead to decreased stimulation of Leydig
cells to secrete testosterone.
GnRH neuronal leptin receptors [110] .
FSH: Follicle-stimulating hormone; GnRH: Gonadotropin-releasing Testicular stress induced by leptin-modulated reductions in cir-
hormone; LH: Luteinizing hormone. culating gonadotropins, established antiapoptotic agents [111] , can
induce apoptosis [112] . FSH, a prosurvival factor in rat testis, upreg-
hypothalamus [98,99] . Saturation of this BBB transport system is ulates expression of antiapoptotic protein Bcl-w in rat Sertoli cells,
believed to produce central leptin insufficiency, as leptin is pres- spermatogonia and spermatocytes, but not spermatids, in vitro [113] .
ent in large quantities in plasma without corresponding leptin Germ cell death is a normal event during spermatogenesis and
action at the hypothalamus [97] . Impaired central leptin action may serve to regulate the size of the germ cell population [112,114] ;

however, in the event of central leptin insuf-

ficiency and reduced gonadotropins release,
testicular apoptosis may be pathological. Hypothalamus
This has been demonstrated in leptin-defi-
cient ob/ob mice that exhibit upregulation of E2
Pituitary
nine testicular pro-apoptotic genes involved
in both intrinsic and extrinsic apoptosis
pathways [115] . Abnormal spermatogenesis
and infertility in these mice is likely due to Abdominal/
inadequate gonadotropin support of sper- visceral
matogenesis and accelerated germ cell death adiposity
by apoptosis [115,116] .
Deficiency in hypothalamic leptin sig- Adipose
T E2
naling resulting in hypogonadotropic aromatase
hypogonadism is observed in ob/ob mice Testis T
and humans with leptin deficiency. It
would appear that central leptin insuffi-
ciency is the causal mechanism of deficient
hypothalamic leptin signaling and, thus, Expert Rev. Endocrinol. Metab. © Future Science Group (2010)
the underlying cause of hypogonadotropic Figure 7. Hypogonadal–obesity cycle: peripheral estrogen synthesis. Adipocytes
hypogonadism (Figure 8B) . The stimulation express the enzyme aromatase that converts androgens (T and androstendione) to
of KiSS1 neurons by leptin provides a link estrogens (17b-E2 and estrone). Adipose tissue represents a rich source of peripheral
between energy homeostasis and repro- estrogens that regulate testicular function. In response to an increased adipose tissue
duction. Moderate elevations in serum mass, peripheral E2 is elevated, which, in turn, modulates the differentiation of
adipocytes and suppresses the Hypothalamus–pituitary–testis axis (hypogonadism).
leptin levels due to seasonal weight gain Reduced T contributes to abdominal adipose tissue distribution.
in response to changing environmental E2: Estradiol; T: Testosterone.
conditions may signal reproductive oppor-
tunity [80] . While moderate fluctuations in leptin may prove cells in the rat [121,126] and human [117] , but not mouse [127] ,
physiologically relevant to seasonal breeders and other animals, express leptin receptors, thus providing a mechanism for direct
high serum leptin levels in the obese human male may be detri- leptin modulation of Leydig cell functions. In rat Leydig cul-
mental, as this leads to saturation of the BBB transport system ture, leptin suppresses hCG-stimulated testosterone secretion,
and central leptin insufficiency. supporting a role for leptin in the negative regulation of steroido-
genesis [126,128,129] . Leydig cells exhibit differential sensitivity
Leptin modulation of testicular physiology to leptin, according to the developmental expression profiles of
Leptin is found in human and rodent Sertoli cells, Leydig cells, Ob-R, such that embryonic and adult but not prepubertal rat
seminiferous tubules and germ cells [117,118] and is able to cross Leydig cells demonstrate leptin suppression of hCG-induced
the testis–blood barrier (TBB) [119] , suggesting both testicular testosterone secretion [121] . In an elegant experiment designed by
and peripheral sources of leptin may be involved in reproduction. Tena-Sempere and colleagues [122] , hCG-stimulated rat testicu-
Unlike the BBB’s saturable transport system for leptin, the TBB lar samples exposed to increasing doses of human recombinant
system is nonsaturable, enabling leptin to ‘leak’ across the barrier leptin decreased expression of steroidogenic enzymes mRNAs
between the blood and the testicular interstitium and traverse the and, subsequently, reduced testosterone secretion. Leptin is also
Sertoli cell barrier, dividing the interstitium from the seminiferous able to decrease hCG-induced expression levels of steroidogenic
tubule fluid. The mechanism at the Sertoli cell barrier has not factor (SF)-1, steroidogenic acute regulatory protein (StAR)
been elucidated as saturable or leakage [119] . Thus, as serum leptin and cytochrome P450 cholesterol side-chain cleavage enzyme
levels increase, intratesticular leptin levels would be expected to (P450scc) in a dose-dependent manner [122] .
similarly increase with leptin action limited by receptor expres- Drawing from the findings reported by the teams of Caprio
sion in the testis. Ob-R have been localized to isolated Sertoli and Tena-Sempere, a model of leptin regulation of Leydig
and Leydig cells, and testicular germ cells in rodents [119–122] , and cell steroidogenesis is proposed (Figure 9) . Leptin signaling via
in seminiferous tubules in humans [117,123,124] . Together, these Ob-R is relatively well characterized [76] and is mediated by the
results strongly suggest that leptin directly modulates testicular JAK–STAT pathway [130–132] , with JAK2 [133] and STAT3, pri-
functions [80,102] . marily described [134] . STAT3 ultimately regulates expression
Leptin is a negative regulator of testicular steroidogenesis; it of steroidogenic genes including SF-1, StAR and P450scc [135] .
acts directly on testicular Leydig cells. In response to LH, Leydig Alternatively, steroidogenic gene expression can be regulated via
cells activate PKA-dependent gene expression, which triggers the PI3K/Akt or MAPK cascades, triggered by leptin binding to
steroidogenesis (i.e., the production of testosterone) [125] . Leydig Ob-R [76] . Leptin’s repression of steroidogenic gene expression,
A Hypothalamus B Hypothalamus
Arc Arc
KiSS KiSS
neurons neurons
GnRH
GnRH
1
Leptin
BBB BBB
resistance
1
Leptin Leptin
Pituitary Pituitary
Adipocytes Adipocytes
FSH, LH FSH, LH
2 2
Leptin Leptin
Testis Testis
X
Testosterone Testosterone
Figure 8. Leptin modulation of hypothalamic–pituitary–testis axis. (A) Normal leptin action. Leptin provides a physiological link
between energy expenditure and reproduction by stimulating expression of KiSS, located in the hypothalamic arcuate nucleus. KiSS
neurons stimulate GnRH release and trigger the gonadotropin cascade and, in turn, testicular steroidogenesis and spermatogenesis.
Leptin may also negatively regulate steroidogenesis through direct actions on Leydig cells. (B) Leptin resistance. In obese men, leptin is
unable to cross the BBB and stimulate release of GnRH via KiSS neurons, thereby resulting in hypogonadism. With insufficient
gonadotropic stimulation, testicular dysfunction occurs. Higher circulating leptin levels may also impair testicular function through
inhibition of steroidogenesis. Dotted lines indicate proposed mechanisms and solid lines indicate established mechanisms.
Arc: Arcuate nucleus; BBB: Blood–brain barrier; FSH: Follicle-stimulating hormone; GnRH: Gonadotropin-releasing hormone;
KiSS: Kisspeptin; LH: Luteinizing hormone; T: Testosterone.
particularly StAR, the rate-limiting step in steroidogenesis [136] of potency while triggering later-stage spermatocytes to undergo
would, therefore, counteract LH-mediated testosterone produc- development and differentiation [118,120] . In obese males, serum
tion. Leptin’s negative regulation of steroidogenesis provides leptin levels are elevated, which may lead to downregulation of
subtle control over reproductive functions and represents yet testicular Ob-R, previously demonstrated in vitro in the rat [138] .
another mechanism for leptin in reproduction. Downregulation of leptin receptor expression would disrupt auto-
Leptin’s modulation of male infertility also involves direct crine/paracrine testicular signaling and perhaps spermatogene-
action of leptin on the sperm itself. Studies in mice indicate that sis. Taken together, the localization studies demonstrating testis
leptin and its receptor are expressed in specific types of male germ and spermatocyte-specific leptin and leptin receptor expression
cells, implicating leptin in cell proliferation and differentiation. [117,123,124] , along with the studies of testicular leptin signaling [122] ,
Leptin protein and mRNA expression are present in gonocytes suggest that elevated serum leptin levels exhibited by obese males
from neonatal mice, spermatogonia from 10-day-old mice and are likely to perturb normal testicular physiology.
in spermatocytes from adult mice [118] . Neonatal and adult mice Ejaculated sperm are not able to fertilize the egg and must
express Ob-Ra, Ob-Rb and Ob-Re in the testes [118,120] , suggest- undergo further structural and functional changes during capaci-
ing leptin normally functions in an autocrine or paracrine manner tation (Figure 3 & 4) . The purpose of seminal plasma leptin is still
to regulate spermatogenesis. It remains to be elucidated whether unclear [117,123,139–143] , and is required to modulate sperm capacita-
leptin exclusively acts as a positive or negative regulator of sper- tion and the acquisition of hyperactive motility. Human seminal
matogenesis, or whether leptin’s role is more refined, dependent on plasma leptin levels are positively correlated with serum leptin
the receptor isoforms expressed at different stages of spermagogen- levels [117,139–141] but inversely correlated with serum testosterone
esis. Leptin signaling via STAT3 suggests a role in the proliferation and normal sperm parameters [123,139,142] . Seminal plasma leptin
of undifferentiated germ cells [120] ; consistent with reports that levels tend to be disproportiately lower than serum leptin levels
stem cell STAT3 phosphorylation prevents differentiation and [139] but are still positively correlated [139,142] . Obese men would be
enables continuous stem cell renewal [137] . Leptin STAT3 signaling expected to have greatly increased seminal plasma levels of leptin,
may enable undifferentiated germ cells to replicate without loss relative to their lean counterparts; however, very few studies have

reported seminal plasma leptin levels in LH

morbidly obese men, and the capacitation/ Leptin
acrosome reaction status of their sperm has
not been investigated. JAK2 JAK2
A role for leptin in sperm capacitation
Ob-Rb
has been proposed by the Aquila research Y Grb2
team, drawing upon their studies in SHP-2
humans and boars. Leptin and leptin recep- Gα
-
tor expression are localized exclusively on Ras Cholesterol StAR Cholesterol
the plasma membrane overlying the acro- Raf -
some in boar sperm, consistent with their STAT3 STAT3 ? P450scc
putative regulations of sperm fertilizing
ability [135,144] . Leptin has been localized to MEK
midpiece/equatorial segment in uncapaci-
PKA
tated human sperm, undergoing an overall
decrease in expression and more uniform ERK Pregnenolone
localization in capacitated sperm [141,145] , -
with leptin receptor confirmed at the tail +
Gene expression - Steroidogenesis
region in ejaculated spermatozoa [145,146] .
StAR
These expression patterns support a physio- SF-1
logical role for leptin, perhaps in the modu- P450scc
Testosterone
lation of human sperm motility. Following
SF-1
acute leptin exposure (30–60 min), unca-
pacitated boar and human sperm undergo
leptin-enhanced cholesterol efflux and Figure 9. Model of leptin action in the Leydig cell. In response to LH, Leydig cells
protein tyrosine phosphorylation [135,141] , activate PKA-dependent gene expression and downstream steroidogenesis pathways,
both hallmark steps in capacitation [143] . including production of testosterone. Leptin-bound Ob-Rb captures JAK2, a non-
receptor tyrosine kinase, which phosphorylates STAT3 and Y on the Ob-Rb.
Furthermore, boar sperm acrosin activity
Phosphorylated STAT3 dimers translocate to the nucleus and negatively regulate
(acrosomal trypsin-like enzyme) is stimu- expression of steroidogenic genes, including SF-1, StAR and P450scc. Leptin-inhibition of
lated by leptin [135] . It is important to note gene expression may also occur via recruitment of SHP-2 to phosphotyrosine residues on
that leptin’s stimulation of these capacita- the Ob-Rb. SHP-2 recruits Grb2 and leads to activation of the MAPK pathway (Ras, Raf,
tion-related events in both studies [135,141] is MEK and ERK). Leptin-dependent reduction of testicular expression of StAR, the
rate-limiting step in steroidogenesis at the mitochondria, would negatively regulate
not dose dependent, with very low concen-
steroidogenesis and, thereby, counteract LH-mediated activation of Leydig cells. Dotted
trations of leptin (0.63 nM human leptin lines indicate proposed pathways and solid lines indicate established pathways.
and 1–10 nM porcine leptin) producing the LH: Luteinizing hormone; Ob-Rb: Leptin receptor; P450scc: Cytochrome P450 cholesterol
greatest response. This may be explained by side-chain cleavage enzyme; SF-1: Steroidogenic factor-1; StAR: Steroidogenic acute
receptor downregulation at higher leptin regulatory protein; Y: Tyrosine residue.
levels [138] and may hold significance for
obese men who would be expected to exhibit seminal plasma In summary, leptin regulation of normal male reproduction
leptin levels in the highest ranges. includes central (HPT) and testicular actions. In morbidly obese
A model of capacitation signaling crosstalk emerges, wherein men, central leptin insufficiency produces hypogonadotropic
leptin signaling via the leptin receptor induces tyrosine phos- hypogonadism, reducing circulating gonadotropins [95,98,99] ,
phorylation downstream of MAPK pathway activation (Figure 4) . and subsequently inducing testicular apoptosis [111] . It is believed
The process of capacitation includes changes to the sperm mem- that high serum leptin is able to perturb testicular steroidogen-
brane and the acquisition of hyperactivated motility. Molecular esis and spermatocyte differentiation and development [118,120] .
events include HCO3- -dependent increase in intracellular cAMP, It can also be hypothesized that ejaculated sperm from obese
subsequent activation of PKA and, ultimately, tyrosine kinase males exhibit reduced capacitation through leptin receptor
activation and protein tyrosine phosphorylation, necessary for downregulation in response to high seminal plasma leptin [138] .
acquisition of hyperactivated sperm motility [6,7] . Leptin acti- Many knowledge gaps remain to be elucidated, including a
vation of prosurvival pathways may lead to the activation of greater understanding of BBB and TBB leptin transport, the
ERK1/2 signaling [135,140] , representing capacitation signaling differential roles and associated signaling pathways associated
crosstalk. It is intriguing to speculate that acrosomal leptin recep- with soluble and transmembrane leptin receptor isoforms in the
tor expression is associated with cholesterol efflux and acrosome brain, testis and sperm, with further study required to enable
reaction, whereas tail leptin receptor expression in human sperm the characterization of leptin’s modulation for reproduction in
may reflect leptin’s modulation of hyperactivated sperm motility. the obese male.
Research studies using animals provide

Heat-stress better models and opportunity to inves-
hypoxia tigate the biological effects of thermal
P stress on testicular functions and struc-
Caspase-2 p38MAPK
2 Bcl2 ture. Various experimental approaches
1 have been used. One mechanism used to
Disrupted X
Bax:Bcl2 elevate testicular temperatures in rats [153]
and mice [154,155] is transient exposure of
Cytochrome C the animals to temperatures exceeding
Apoptosis 4 3 40°C. Alternatively, surgically induced
cryptorchidism is used in mice to elevate
Caspase-3 testicular temperature to the body tem-
perature [156] . In another design, mice
ICAD 3
are housed at 35–38°C over a period of
several hours to induce thermal stress
HSF1
[157,158] . Major reproductive outcomes
in responses to hyperthermia include
CAD
decreased testicular weights, germ cell
HSE
loss and increased rates of apoptosis.
Testicular heat-stress responses involve
Downregulated Upregulated complex signaling pathways with inter-
DNA repair genes Hif1α
connection among hypoxia, apoptosis,
ICAD HSF1
Hsp70 Testicular antioxidants gene expression and inhibition of DNA
Germ cell antioxidants repair, which eventually culminates in
altered spermatogenesis.
Figure 10. Model of testicular heat stress. In response to testicular heat stress, Elevations in temperature and other
apoptosis pathways may be activated through several mechanisms. Caspase-2 perturbs environmental stressors, including oxi-
the ratio of apoptotic proteins Bax:Bcl2 and directly activates apoptosis. p38MAPK (also dative stress and chemical exposures, are
known as MAPK14) phosphorylates Bcl2, thereby removing the inhibitory block to known to trigger intracellular changes in
apoptosis. Caspase-2 and/or caspase-3 degrade ICAD, leading to activation of CAD and
gene expression, resulting in altered cell
DNA fragmentation. Caspase-2 activates HSF1, which downregulates expression of DNA
repair genes, ICAD, Hsp70, germ cell antioxidants, upregulates Hif1a, HSF1 and testicular survival/apoptosis pathways. Heat stress
antioxidants, and induces apoptosis. Dotted lines indicate proposed mechanisms and induces increased expression of a class of
solid lines indicate established mechanisms. 70-kDa heat-shock proteins (Hsp70), a
CAD: Caspase-activated DNase; HSF: Heat-shock factor; Hsp: Heat-shock protein; class of chaperone proteins that help regu-
ICAD: Inhibitor of caspase-activated DNase; P: Phosphorylation
late protein folding and assembly [159,160] .
Hsp70 also play an important role in
Heat stress, hypoxia-induced testicular apoptosis the prevention of apoptosis [161,162] . At least two testis-specific
It is well established that the testis is sensitive to heat, evidenced Hsp70 have been identified. Spermatocyte-specific Hsp70.2
by the approximately 3°C lower temperature of the scrotum com- (mice) is continuously expressed by pachytene spermatocytes
pared with core body temperature, a condition critical for efficient during meiosis and is not heat inducible [159] . Testis-specific
spermatogenesis [147] . Many environmental/lifestyle factors are Hsc70t is similarly expressed in round spermatids. Expression
associated with elevated testicular temperatures including varico- of inducible Hsp70 by germ cells is conflicting. Rockett and
cele [148,149] , tight fitting undergarments, sedentary work positions, colleagues demonstrated upregulation of Hsp70-1 and Hsp70-3
laptop position of portable computers, saunas and occupational in mouse spermatocytes following acute hyperthermia (10 min
heat exposures [37] . Although it is likely that suprapubic and inner at 43°C) [163] . Other researchers reported that testicular heat
thigh adipose tissue in obese males combined with sedentary stress did not increase expression of heat shock genes at the
behaviour increases scrotal temperatures [37] , there are no studies mRNA or protein levels in mouse germ cells [161,164] . Transgenic
that report scrotal temperature measurements in an obese popula- mice designed to express constitutively active heat-shock factor
tion. As increased scrotal temperature during sedentary activities (HSF1) in spermatocytes did not induce Hsp70 gene expres-
is associated with impaired semen quality [150–152] , it follows that sion but did activate caspase-dependent apoptosis pathways in
obese men would be at risk of genital heat stress and infertility. the absence of heat shock [161] . HSF1 is a transcription factor
Testicular scrotal temperature measurements are difficult to obtain activated during stress (hypoxia and hyperthermia); it trimer-
in humans and data regarding duration of sustained sedentary izes, translocates to the nucleus and binds heat-shock response
position is not often collected, underscoring the need for more elements in the promoter regions of HSF1 target genes [165,166].
well-designed testicular thermal stress research studies. Hsp70 does not appear to be sufficient to prevent HSF1-induced

apoptosis as mouse spermatocytes with constitutive expression

of both Hsp70 and HSF1 exhibited characteristic DNA strands
breaks consistent with apoptosis [161] .
The mechanism underlying heat-stress-induced apopto- Mitosis Spermatogonia
sis appears to be primarily regulated by HSF1 (F igur e 10) . Susceptibilty to
heat stress
Intriguingly, the endogenously established temperature ‘set-
point’ for HSF1 activation is higher for core somatic tissues
compared with the testis, consistent with external location of Mitosis
the male reproductive organ in mammalian species. Thus, tes-
Pachytene
ticular tissues are exquisitely sensitive to even mild hyperther- spermatocyte
mia through regulation by HSF1. Persistent testicular HSF1
activation is observed in cryptorchid mice and is associated Meiosis I
with disrupted spermatogenesis [164] . HSF1 may even down- Secondary
regulate Hsp70 to ensure unopposed activation of apoptosis spermatocytes
pathways. In early developmental stages of mouse spermato- Meiosis II
cytes that express HSF1, Hsp70.2 protein undergoes trans- Round spermatids
location from the cytoplasm to the nucleus. At later stages of
development, germ cells exhibit HSF1-mediated repression
of Hsp70.2 following hyperthermia. Widlak and colleagues
propose that a reduction in both Hsp70.2 mRNA and protein Elongated
levels occurs prior to heat-stress induction of apoptosis, with spermatids
both events mediated by HSF1 [167] . Depending on the condi-
tions of experimentally induced testicular heat stress and the
subsequent assays to detect Hsp70, HSF1’s negative regulation
of Hsp70 expression and nuclear translocation may explain the Testicular
spermatozoa
inconsistencies regarding spermatocyte expression of Hsp70 in
the literature discussed earlier. Expert Rev. Endocrinol. Metab. © Future Science Group (2010)
Other important changes in testicular cells in response to Figure 11. Spermatocytes exhibit stage-specific
heat stress include downregulation of DNA repair pathways susceptibility to heat stress. Testicular germ cells exhibit
and activation of p38MAPK signaling (Figure 10) . Mouse testis stage-specific susceptibility to heat stress. Pre-meiotic germ cells
exposed to acute heat stress (43°C for 10 min) downregulate express cell survival factors that protect them against heat stress.
DNA repair genes, including Ogg1 (base excision repair), Xpg By contrast, meiotic germ cells (pachytene spermatocytes and
round spermatids) are most susceptible to heat stress; they also
(nucleotide excision repair) and Rad54 (double-strand break have limited capacity for DNA repair.
repair) [163] . Decreased expression of poly (ADP-ribose) poly-
merase PARP (base excision repair/nucleotide excision repair stress, apoptosis and reduction in DNA repair gene expression
pathways) also occurs in the rat testis in response to heat stress (F igure 10). Increases in testicular cell metabolism during heat
[168] . With DNA repair pathways disabled, apoptosis is induced stress may be so high that testicular blood flow cannot provide
via multiple mechanisms, including direct hyperthermic/ sufficient tissue oxygenation, thereby creating oxidative stress
hypoxic stress. Heat stress induces activation of p38MAPK to the tissue [155] . During hypoxia, hypoxia-inducible factor
(also known as MAPK14), which, in turn, phosphorylates (Hif )-1a translocates from the cytoplasm to the nucleus to
Bcl2, thereby removing the inhibitory block to apoptosis form a heterodimer with Hif-1b (also known as aryl hydrocar-
[169] . Apoptosis is regulated, in part, by the balance between bon receptor nuclear translocator), now known as HIF1. The
proapoptotic proteins (e.g., Bax) and antiapoptotic proteins formation of the Hif-1a–Hif-1b heterodimer provides genomic
(e.g., Bcl2). Caspase-2 is proposed to be activated upstream protection from oxidative stress [172] . Following mild hyperther-
of p38MAPK by hyperthermia and/or reactive oxygen spe- mia, the mouse testis undergoes hypoxia and oxidative stress
cies produced during hypoxia. Caspase-2 may also perturb the and responds with increased expression of Hif-1a mRNA/pro-
ratio of Bax:Bcl2 [170] and directly activate caspase-3, thereby tein in the interstitial compartment and increased expression
promoting apoptosis [170,171] . Finally, heat-stress-induced cleav- of Hif-1a protein in the nuclei of germ cells [155] . Antioxidants,
age of inhibitor of caspase-activated DNase (ICAD) via cas- expressed during hypoxia, are downregulated in mouse germ
pase-3 activation [154] or directly via caspase-2 activation [171] cells following hyperthermia [163] , but not in testicular somatic
produces the final fragmentation of nuclear DNA. Another cells, as whole mouse testis exhibit increased expression of tes-
mechanism, yet to be defined, links hyperthermic stress with ticular antioxidants (HMOX1, GPX1 and GSTA) following
induced activation of HSF1, which, in turn, promotes apop- heat stress [155] . Thus, germ cells are particularly vulnerable to
tosis of pachytene spermatocytes [164] . Testicular heat stress hypoxia and hyperthermia, which, in turn, induce apoptosis
is accompanied by localized hypoxia that induces oxidative pathways and ultimately loss of male germ cells.
apoptosis of actively dividing germ cells

would reduce sperm counts, thus con-
tributing to male infertility in morbidly
Adult-onset diseases
obese men. Animal studies also point to
Obesity diminished embryo survival following
Diabetes paternal heat stress [157,158,163,174] , provid-
Cardiovascular disease ing another mechanism by which testicu-
Reproductive cancers
Infertility
lar heat stress contributes to reproductive
loss. There remain significant technical
limitations in measuring scrotal tempera-
tures in humans in a relatively noninva-
0 10 20 30 40
sive manner. These limitations must be
Weeks overcome to further investigate the rela-
tionship between testicular hyperthermia,
obesity and male infertility.
Figure 12. Fetal origins of adult-onset diseases. Endocrine disruption

It has been well established that envi-
The testis exhibits germ cell stage-specific susceptibility to heat ronmental chemicals (endocrine disrupters) are reproductive
stress (Figure 11) . As described previously, premeiotic germ cells toxicants and can be associated with impaired semen quality
express cell survival factors, including HSF1 and Hsp70, that protect and reproductive potential in animals and humans [175–178] . An
against heat stress [161,164] . In response to heat stress, as spermatocytes endocrine disruptor is defined as [176] :
undergo meiosis, they begin to exhibit significant DNA damage that
subsequently initiates apoptosis pathways [154] . HSF1 seems to be “as an exogenous agent that interferes with the synthesis, secretion,
associated with cell survival only in premeiotic and somatic cells, transport, binding, action or elimination of natural hormones in
such that meiotic (pachytene spermatocytes and early spermatids) the body that is responsible for the maintenance of homeostasis,
and postmeiotic stages are most susceptible to heat stress [153,154,173] . reproduction, development and/or behavior.”
Taken together, it can be speculated that a combination of fac-
tors, including sedentary lifestyle and suprapubic and inner thigh Baillie-Hamilton proposed that the obesity epidemic over
adipose tissue deposits, increase testicular temperatures, thereby the past 40 years may also be related to the increased use of
triggering apoptosis pathways. As discussed, heat-stress-induced industrial chemicals with demonstrated endocrine-modulating
A B Fatty acids, ‘obesogens’

Estrogens Retinoid acid
Estrogen-dependent Adipocyte differentiation/
gene expression proliferation
ER-α
RXR PPAR-γ
ERE PPRE
C D Fatty acids, ‘obesogens’

Diethylstilbestrol Retinoid acid
Adipogenic effects? Unknown effects?
ER-α
RXR PPAR-γ
PPRE ERE
Figure 13. ER-α- and PPAR-γ-dependent gene expression. (A) ER-α. Following ligand (estrogens) binding, ER-α forms a homodimer
that together with transcription factors, assemble as a pre-initiation complex at the ERE present in the promoter region of estrogen-
responsive genes. (B) PPAR-γ. Once activated by ligand (fatty acids, putative obesogens), PPAR-γ forms a heterodimer with RXR and
binds as a complex to PPRE in target gene promoter regions. (C) DES-mediated ER-α and PPAR-γ signal crosstalk. ER-α may also bind the
PPRE consensus sequence. DES-binding to ER-α induces adipogenic effects in the rodent penis, possibly through PPAR-γ signal crosstalk.
(D) PPAR-γ and ER-α signal crosstalk. Similarly, PPAR-γ may bind the ERE consensus sequence. Although the consequences on male
reproduction are unknown, such signal crosstalk may represent yet another mechanism by which putative obesogens including
phthalates, organotins and phytoestrogens may disrupt endocrine function.
DES: Diethylstilbestrol; ER: Estrogen receptor; ERE: Estrogen response element; PPRE: PPAR response elements; RXR: Retinoid X receptor.

activity [179–181] . Male infertility and obes-

ity may therefore share an environmental A GnRH B
GnRH
etiology caused by perturbations in normal
Insulin Leptin
endocrine pathways. FSH, LH
resistance resistance
The Barker hypothesis relates poor fetal FSH, LH
nutrition to adult-onset diseases including T Insulin
coronary heart disease, Type 2 diabetes Leptin
and metabolic dysfunction [182] , and has 1 2
formed the basis for the developmental ori-
1
gins of health and disease paradigm, which
Leptin
similarly posits a correlation between peri- T E2
T 1
natal health and the eventual develop-
T
ment of chronic diseases (Figure 12) [183,184] .
Toxicologists have also identified neona- 3 t°C
2
tal development as a ‘critical window of Chemical
exposure’, such that chemical exposures obesogens
(e.g., endocrine disrupters) have been
linked to adult-onset reproductive cancers
[177,185,186] . Taken together, these models
support the extreme sensitivity of the neo-
natal period to environmental influences, Expert Rev. Endocrinol. Metab. © Future Science Group (2010)
and as proposed by Baillie-Hamilton [179]
Figure 14. Mechanisms of obesity-induced male infertility. (A) Normal-weight
and Newbold and colleagues [187] , the males. In normal-weight individuals, male reproduction is stimulated by the
models provide an explanation for fetal hypothalamus–pituitary–testis (HPT) axis, with negative feedback provided by
origins of adult obesity risk. testosterone. Increasing evidence points to the stimulatory roles of leptin and insulin in
The intersection between estrogenic the HPT axis including testis functions. (B) Obese males. Male obesity is characterized by
and adipogenic pathways has been best high serum estrogen, leptin and insulin levels. Testicular testosterone production is
reduced, but may still provide negative feedback to the HPT axis (not shown), although
examined in a series of studies defining to a lesser extent than in the normal-weight males. Three main biological mechanisms
adipogenesis in penile corpus cavernosum link obesity to impaired male reproductive function: (1) hypogonadism:
induced by activation of ER-α by potent hypogonadotropic hypogonadism caused by negative feedback by estrogens or
estrogen disrupter, diethylstilbestrol insulin/leptin resistance, and hypergonadotropic hypogonadism caused by direct actions
(DES) (Figure 13A) [188–190] . Neonatal expo- of leptin on the testis, (2) testicular heat-stress-/hypoxia-induced apoptosis, and (3)
endocrine disruption by ‘obesogens’: environmental chemicals that may be stored in
sure to DES (3–4 mg/kg) generates adult adipose tissue and have the potential to modulate both estrogenic and adipogenic
rats that are infertile with gross penile pathways. Dotted lines indicate proposed mechanisms and solid lines indicate
abnormalities, including the appearance established mechanisms.
of adipocytes in the cavernous spaces of E2: Estradiol; FSH: Follicle-stimulating hormone; GnRH: Gonadotropin-releasing
the corpora cavernosa penis. Similarly, his- hormone; LH: Luteinizing hormone; T: Testosterone; t: Temperature.
tological changes to the penis along with
male infertility were observed following postnatal exposures to genes involved in fatty acid storage and the repression of genes
DES (1 mg/kg) [188,189] . Goyal and colleagues have hypothesized necessary for adipocyte lipolysis. Once activated by ligand (fatty
that estrogen-dependent differentiation and proliferation of stro- acids, putative obesogens), PPAR-γ forms a heterodimer with
mal cells occur following estrogen exposure during a critical retinoid X receptor and binds as a complex to PPAR response
development period (1–12 postnatal days) [190] . This transforma- elements in target gene promoter regions (Figure 13B) [193] . ER-α
tion replaces endothelial and smooth muscle cells in the corpora and PPAR-γ pathways exhibit several instances of ‘signal cross-
cavernosa with adipocytes, resulting in grossly abnormal mor- talk’, including shared coactivators involved in adipocyte dif-
phology of the penis and infertility. Transgenic mice lacking ferentiation such as the recently identified constitutive coactiva-
ER-α (α-ERKO) are ‘resistant’ to neonatal DES exposure and tor of PPAR-γ [193] . ER-α and PPAR-γ may each bind directly
do not exhibit penile deformities. These studies thereby confirm to either PPAR response elements [194] or estrogen response
a role for ER-α in DES-mediated abnormalities of the corpora elements (Figure 13C & D) [195–197] . It is the latter mechanism that
cavernosa in both rats and mice [191] . Furthermore, this develop- is proposed to trigger DES-induced differentiation of stromal
mental disruption has been recently elucidated as a ‘biological cells and subsequent penile abnormalities in rodents [192] .
overlap’ between PPAR-γ and ER-α (Figure 13B & C) [192] . Modulation of adipocyte function and differentiation is
The PPAR family includes three isotypes PPAR-α, -b and -γ. now recognized as a subset of endocrine disruption. Such envi-
PPAR-γ, a nonsteroidal nuclear receptor, regulates proliferation ronmental chemicals have been termed ‘metabolic disrupt-
and differentiation of adipocytes through the promotion of ers’ [198] or ‘obesogens’ [199] . Obesogenic pathways proposed
include nuclear receptors involved in lipid metabolism, such as male fertility. Information on exposure to endocrine disrupters
PPAR-γ, liver X receptor and farnesoid X receptor [200] . Several and other environmental contaminants should be gathered by
xeno-PPAR-γ ligands have been identified, including phthalate occupation and lifestyle questionnaires and it may help explain
monoesters [201] , such as di(2-ethylhexyl) phthalate [202] and its idiopathic forms of male infertility. In general, it is anticipated
metabolite mono(2-ethylhexyl)phthalate [198] , organotin com- that the obese man is likely to exhibit hypogonadism and is
pounds triphenyltin and tributyltin [200,203–206] , dioxins [207] and hyperestrogenic, conditions that would cause the greatest risk
phytoestrogen genistein [208] , many of which have established to male infertility.
toxicity to the reproductive system [178,209] . Studies performed in
laboratory and wildlife animals provide additional evidence for Five-year view
crosstalks between endocrine and adipogenic pathways, further The issue of infertility in the obese male is critical in the context
implicating that environmental contaminants, which can be of the obesity epidemic in the Western world. Within the next
endocrine disrupters, probably also modulate adipocyte differen- 5 years, the obesity epidemic will begin to evolve into the Type 2
tiation and contribute to reproductive pathologies (Figure 13C & D) . diabetes epidemic, with an explosion of men and women devel-
oping insulin resistance. As we learn more about the molecular
Conclusion biology underlying insulin resistance, the intriguing findings of
Three main biological mechanisms can be used to explain the concomitant suppression of Leydig cell testosterone production
relationship between obesity and male infertility: hypogonad- may be further elucidated. Certainly, there is a need for more
ism; testicular heat-stress-/hypoxia-induced apoptosis and robust studies examining semen quality in insulin-resistant
endocrine disruption by obesogens (Figure 14) . Obesity-induced men. Adipocytokines are hormones released from adipocytes,
hypogonadism appears to be present in most morbidly obese including leptin (reviewed here), resistin and adiponectin.
men, driven by peripheral conversion of androgens to estrogens Investigation of the physiological roles of these adipocytokines
and leptin/insulin resistance. Obese men diagnosed with hypo- is in its infancy, although links between adipocytokines and
gonadism may have several treatment options, including weight insulin resistance have already been postulated. Kisspeptins
loss and short-term aromatase inhibitor treatment. Similarly, and their modulation of the hypothalamic–pituitary–gonadal
testicular heat stress, although difficult to ascertain medically, axis in both men and women is a field that is developing at a
could be anticipated following gradation of the pannus (supra- rapid pace. Understanding the neuroendocrine modulation of
pubic/abdominal fat overhang). Testicular heat stress may be the reproductive system and its potential sensitivity to endocrine
alleviated through increased activity, weight loss and use of disrupters and nutritional stressors will contribute significantly
air-cooling devices during sleep. Future areas for investigation to this field. The contribution of environmental stressors (nutri-
include the roles of adipocytokines and endocrine disrupters tion, endocrine disrupters and infectious agents) to fetal devel-
in male fertility and obesity. Prenatal exposures to endocrine opment, and ultimately adult-onset diseases, including obesity
disrupters may reprogram not only reproductive and endocrine and infertility, will be investigated using molecular approaches.
pathways but also molecular modulation of adipocytes. Obesity Although this review has focused on male infertility, the poten-
is, therefore, a causal factor in male infertility, and for some tial for environmental stressors to create epigenetic changes
individuals, prenatal exposures may confer additional risk via to the germ line will have important implications for future
intersecting endocrine and adipogenic signaling pathways. generations. Endocrine disrupters, particularly environmental
estrogens, are well-established reproductive toxicants and target
Expert commentary steroid hormone signaling pathways associated with nuclear
Clinical knowledge in the identification and treatment of obe- receptor superfamily members. The recent characterization
sity‑induced male infertility is still lacking. The assessment of of nongenomic steroid hormone receptors has the potential to
male infertility relies on numbers of sperm and morphological revolutionize the field of endocrinology. Chemicals with the
abnormalities, with little functional analysis beyond estimates capacity to perturb adipose physiology have only recently been
of motility. Subfertility is undoubtedly underestimated, simply identified and termed obesogens or metabolic disrupters. The
because clinics lack tools to provide functional semen analysis, importance of these chemicals to obesity, diabetes and male
including sperm–egg binding and acrosome/capacitation assays. infertility remains to be elucidated.
Screening for insulin resistance and hypogonadism should be
considered as part of infertility diagnostics for overweight and Financial & competing interests disclosure
obese male patients. As the age of onset for Type 2 diabetes is Nongnuj Tanphaichitr is supported by grants from the Canadian
declining, men under the age of 40 years should be included in Institutes of Health Research (CIHR) and the Natural Sciences and
this screening. BMI and waist:hip ratio data should be collected Engineering Research Council of Canada (NSERC). The authors have
for male infertility patients along with standard endocrine pro- no other relevant affiliations or financial involvement with any organiza-
files to identify who would benefit from weight loss or treatment tion or entity with a financial interest in or financial conflict with the
with hormone therapies. Medications used to treat Type 2 dia- subject matter or materials discussed in the manuscript apart from
betes (sulfonylureas, biguanides, e.g., metformin and thiazoli- those disclosed.
dinediones) have not been well examined for their impacts on No writing assistance was utilized in the production of this manuscript.

Key issues
• BMI is negatively correlated with subfertility.
• Metabolic syndrome, including obesity and diabetes, intersects with male infertility due to hypogonadism.
• Adipose tissue secretes leptin and estrogen, both of which modulate male reproduction.
• Leptin has central effects at the hypothalamus, which indirectly stimulates release of gonadotropins.
• Leptin has local testicular effects, negatively regulating spermatogenesis and steroidogenesis.
• Testicular temperature elevations in obese, sedentary men may be sufficient to impair spermatogenesis.
• Fetal period represents a critical window of development, wherein environmental stressors (nutrition, chemical exposures) may
contribute to adult onset diabetes, obesity or infertility.
• Obesogens, or metabolic disrupters, are chemicals in the environment that modulate adipogenic pathways and may also
impair reproduction.
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206 Nakanishi T. Endocrine disruption 209 Phillips KP, Foster WG. Key developments • Nongnuj Tanphaichitr, PhD
induced by organotin compounds: in endocrine disrupter research and human Senior Scientist, Ottawa Hospital Research
organotin’s function as a powerful agonist health. J. Toxicol. Environ. Health B Crit. Institute, and Professor in Obstetrics and
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Sciences, Principal Scientist, Institute of
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Population Health, University of Ottawa,
Boutin JA, Lowik CW. Peroxisome
43 Templeton Street, Room 215, Ottawa,
proliferator-activated receptor g (PPAR g)
ON K1N 6N5, Canada
as a molecular target for the soy
Tel.: +1 613 562 5800 ext. 8678
phytoestrogen genistein. J. Biol. Chem.
[email protected]
278, 962–967 (2003).

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Keywords : endocrine disrupters • estrogen • hypogonadism • leptin • obesity • obesogens • semen

www.expert-reviews.com 10.1586/EEM.09.65 © 2010 Expert Reviews Ltd ISSN 1744-6651 229

density, this technology differentiates between absorption of

– GnRH Reproductive parameters in obese men

230 Expert Rev. Endocrinol. Metab. 5(2), (2010)

radiation or chemotherapy [1] , testicular

Expert Rev. Endocrinol. Metab. 5(2), (2010)

hyperinsulimia, somehow directly suppressed Leydig cell testos-

234 Expert Rev. Endocrinol. Metab. 5(2), (2010)

Cholesterol contrast to the hypogonadism featured in

was first considered following reports that the ratios of cerebro-

236 Expert Rev. Endocrinol. Metab. 5(2), (2010)

however, in the event of central leptin insuf-

238 Expert Rev. Endocrinol. Metab. 5(2), (2010)

reported seminal plasma leptin levels in LH

Research studies using animals provide

240 Expert Rev. Endocrinol. Metab. 5(2), (2010)

apoptosis as mouse spermatocytes with constitutive expression

apoptosis of actively dividing germ cells

Figure 12. Fetal origins of adult-onset diseases. Endocrine disruption

A B Fatty acids, ‘obesogens’

C D Fatty acids, ‘obesogens’

Expert Rev. Endocrinol. Metab. © Future Science Group (2010)

242 Expert Rev. Endocrinol. Metab. 5(2), (2010)

activity [179–181] . Male infertility and obes-

244 Expert Rev. Endocrinol. Metab. 5(2), (2010)

246 Expert Rev. Endocrinol. Metab. 5(2), (2010)

248 Expert Rev. Endocrinol. Metab. 5(2), (2010)

250 Expert Rev. Endocrinol. Metab. 5(2), (2010)

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