Prevalence of male secondary hypogonadism in moderate to severe obesity and its relationship with insulin resistance and excess body weight

Abstract

To study the prevalence of male obesity-secondary hypogonadism (MOSH) in patients with moderate to severe obesity, we performed a prospective prevalence study including 100 male patients with moderate to severe obesity at a university tertiary hospital. Total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations among others were assayed in all patients. Serum-free testosterone (FT) concentration was calculated from TT and SHBG levels. Semen analysis was conducted in 31 patients. We found a prevalence of 45% (95% CI: 35-55%) when considering decreased TT and/or FT concentrations. Serum concentrations of TT were correlated negatively with glucose (r = -0.328, p < 0.001) and insulin resistance (r = -0.261, p = 0.011). The same occurred with FT and glucose (r = -0.340, p < 0.001) and insulin resistance (r = -0.246, p = 0.016). Sixty-two percent (95% CI: 39-85%) of the patients with seminogram also presented abnormal results in semen analysis. The frequencies of low TT or low FT values were similar in patients with abnormal or normal semen analysis (p = 0.646 and p = 0.346, respectively). Ejaculate volume inversely correlated with BMI (ρ = -0.400, p = 0.029) and with excess body weight (ρ = -0.464, p = 0.010). Our data show the prevalence of MOSH in patients with moderate to severe obesity is high. Low circulating testosterone is associated with insulin resistance and low ejaculate volume with higher BMI and excess body weight. Semen analysis must be performed in these patients when considering fertility whether or not presenting low circulating testosterone.

Full text

ORIGINAL ARTICLE
Correspondence:
Jos
e I. Botella-Carretero, MD, PhD, MBA,
Department of Endocrinology and Nutrition,
IRYCIS, CIBERobn, Hospital Universitario Ram
on y
Cajal, Carretera de Colmenar Km. 9.1, 28034
Madrid, Spain.
E-mail: joseignacio.botella@salud.madrid.org
Keywords:
insulin resistance, male hypogonadism, male
infertility, obesity, testosterone
Received: 15-Sep-2015
Revised: 13-Oct-2015
Accepted: 23-Oct-2015
doi: 10.1111/andr.12135
Prevalence of male obesity-
secondary hypogonadism in
moderate to severe obesity and its
relationship with insulin resistance
and excess body weight
1
Berniza Calder
on,
1
Jes
us M. G
omez-Mart
ın,
1
Bel
en Vega-Pi~
nero,
2,3
Antonia Mart

ın-Hidalgo,
4
Julio Galindo,
1,5
Manuel Luque-Ram

ırez,
1,5
H
ector F. Escobar-Morreale and
1,3
Jos
e I. Botella-Carretero
1
Department of Endocrinology and Nutrition, Hospital Universitario Ram
on y Cajal & Instituto
Ram
on y Cajal de Investigaci
on Sanitaria (IRYCIS), Madrid, Spain,
2
Department of Biochemistry-
Research, Hospital Universitario Ram
on y Cajal & Instituto Ram
on y Cajal de Investigaci
on Sanitaria
(IRYCIS), Madrid, Spain,
3
Centro de Investigaci
on Biom
edica en Red-Fisiopatolog

ıa de Obesidad y
Nutrici
on (CIBERobn), Madrid, Spain,
4
Department of General Surgery, Hospital Universitario Ram
on
y Cajal, Madrid, Spain, and
5
Centro de Investigaci
on Biom
edica en Red Diabetes y Enfermedades
Metab
olicas Asociadas (CIBERDEM), Madrid, Spain
SUMMARY
To study the prevalence of male obesity-secondary hypogonadism (MOSH) in patients with moderate to severe obesity, we per-
formed a prospective prevalence study including 100 male patients with moderate to severe obesity at a university tertiary hospital.
Total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations among others were assayed in all patients. Serum-
free testosterone (FT) concentration was calculated from TT and SHBG levels. Semen analysis was conducted in 31 patients. We
found a prevalence of 45% (95% CI: 35–55%) when considering decreased TT and/or FT concentrations. Serum concentrations of TT
were correlated negatively with glucose (r=0.328, p<0.001) and insulin resistance (r=0.261, p=0.011). The same occurred
with FT and glucose (r=0.340, p<0.001) and insulin resistance (r=0.246, p=0.016). Sixty-two percent (95% CI: 39–85%) of the
patients with seminogram also presented abnormal results in semen analysis. The frequencies of low TT or low FT values were simi-
lar in patients with abnormal or normal semen analysis (p=0.646 and p=0.346, respectively). Ejaculate volume inversely correlated
with BMI (q=0.400, p=0.029) and with excess body weight (q=0.464, p=0.010). Our data show the prevalence of MOSH in
patients with moderate to severe obesity is high. Low circulating testosterone is associated with insulin resistance and low ejaculate
volume with higher BMI and excess body weight. Semen analysis must be performed in these patients when considering fertility
whether or not presenting low circulating testosterone.
INTRODUCTION
The prevalence of overweight and obesity have increased
markedly during the past decades, reaching epidemic figures
(Finucane et al., 2011). Obesity is a significant risk factor for
increased mortality, mainly because of its association with dia-
betes, cardiovascular disease and cancer (Berrington de Gonza-
lez et al., 2010). Obesity is also associated with gonadal
dysfunction, including polycystic ovary syndrome (PCOS) and
male obesity-associated secondary hypogonadism (MOSH)
(Alvarez-Blasco et al., 2006; Saboor Aftab et al., 2013).
PCOS and MOSH have been found in approximately 50% and
60% of severely obese female and male patients submitted to
bariatric surgical procedures (Escobar-Morreale et al., 2005;
Calderon et al., 2014). Of note, the marked weight loss that
occurs after bariatric surgery results into remission of the hor-
monal derangements present in PCOS (Escobar-Morreale et al.,
2005) and MOSH (Botella-Carretero et al., 2013; Calderon et al.,
2014; Samavat et al., 2014) in almost all patients. The latter has
been confirmed by a recent meta-analysis showing that bariatric
surgery induces an increase in both total testosterone (TT) and
free testosterone (FT), the normalization of serum sex hormone-
binding globulin (SHBG), and the remission of MOSH in a large
proportion of patients (Corona et al., 2013). Therefore, it is not
surprising why MOSH have been recently proposed as an indica-
tion for bariatric surgery (Lucchese & Maggi, 2013; Samavat
et al., 2014).
©2015 American Society of Andrology and European Academy of Andrology Andrology, 1–6 1
ISSN: 2047-2919 ANDROLOGY

However, there are still some controversies regarding how
obesity affects gonadal function and fertility in men and what
are the best options for treatment (Stokes et al., 2015). First,
MOSH has been normally defined as low circulating testosterone
levels with normal or reduced gonadotropins in the majority of
the studies, without evaluating semen quality (Hofstra et al.,
2008; Dhindsa et al., 2010). These studies demonstrated a high
prevalence of MOSH, when defined by low serum testosterone
levels, in patients presenting with obesity, from grade one to
morbid obesity. Several mechanisms have been proposed to
explain low circulating testosterone levels in obese men includ-
ing, among others, increased aromatase activity and production
of estradiol in adipose tissue, decreased SHBG levels thereby
reducing TT concentrations, central leptin resistance, insulin
resistance, and the direct effects of several adipokines (Zumoff,
1988; Gautier et al., 2013; Landry et al., 2013).
Whether infertility and semen abnormalities are directly
related to the low androgens levels present in MOSH or to other
factors related to obesity is unclear, but it is known that
increased body weight is associated with abnormalities in semen
parameters, and the percentage of men with abnormalities in
sperm volume, concentration and total counts, increases with
increasing body size (Eisenberg et al., 2014).
We here aimed to assess the prevalence of MOSH and the
presence of semen abnormalities in a series of moderate to sev-
ere obese men focusing on the anthropometric and biochemical
parameters associated with these alterations.
SUBJECTS AND METHODS
Subjects
We studied 100 consecutive male patients with moderate
to severe obesity referred to our Obesity Surgery Unit for
counseling about metabolic surgery. Inclusion criteria
required a body mass index (BMI) of at least 35 kg/m
2
and
the compromise to attend the scheduled visits, irrespective of
whether or not the patients finally underwent a bariatric pro-
cedure. Exclusion criteria included previous diagnoses of
hypogonadism, thyroid disease, heart disease, kidney or liver
failure and hyperprolactinemia or treatment for sexual dys-
function or drugs that could interfere with normal gonadal
function. Thirty-one patients gave consent for semen analysis
and completed the simplified International Index of Erectile
Function test, in which a value equal or less than 21 is con-
sidered abnormal (Rosen et al., 1997; Rhoden et al., 2002).
Twenty healthy controls were matched with patients in terms
of age for establishing reference ranges for calculated FT
concentrations and insulin resistance. Written informed con-
sent was obtained and the study was approved by the Insti-
tutional Review Board of our Hospital, and according to the
Declaration of Helsinki.
Anthropometric parameters were recorded. BMI was calcu-
lated as weight in kilograms divided by the square of height in
meters. Waist circumference was measured as the smallest
perimeter between the costal border and the anterior suprailiac
spines. Ideal body weight was calculated as the weight corre-
sponding for a BMI of 25, given previous lack of consensus for
the precise definition (Shah et al., 2006; Montero et al., 2011).
Excess body weight (EBW) was calculated as the difference
between body weight and ideal weight.
Analytical procedures and reference ranges
Serum creatinine, alanine aminotransferase, aspartate amino-
transferase, and serum glucose concentrations were measured
by standard colorimetric methods, using the Architect ci8200
analyzer (Abbot Diagnostics, Berkshire, UK). Levels of HDL
cholesterol were measured in supernatant after plasma precipi-
tation with phosphotungstic acid and Mg
2+
(Boehringer Man-
nheim GmbH, Mannheim, Germany). Levels of total cholesterol
and triglycerides were measured by enzymatic methods (Menar-
ini Diagnostica, Florence, Italy). The LDL cholesterol concentra-
tion was calculated by using Friedewald’s formula.
Fasting insulin, TT, SHBG, ferritin, luteinizing hormone (LH),
follicle-stimulating hormone (FSH), and estradiol were also
assayed (Escobar-Morreale et al., 2005). Briefly, TT was mea-
sured by radioimmunoassay (Spectria; Orion Diagnostica,
Espoo, Finland). FT concentration was calculated from total
testosterone and SHBG concentrations (Vermeulen et al., 1999).
Serum ferritin, LH, FSH, estradiol, and insulin were measured by
immunochemoluminescence (Immulite 2000; Siemens Health-
care Diagnostics Inc., Gwynedd, UK). Insulin resistance in the
fasting state was estimated by the homeostasis model assess-
ment method (HOMAIR). A commercial enzyme-linked
immunosorbent assay (ELISA) was employed for the measure-
ment of 25-hydroxyvitamin D concentrations (IDS Ltd., Boldon,
UK). The specificity of this assay is 100% for 25-hydroxyvitamin
D
3
and 75% for 25-hydroxyvitamin D
2
, with negligible cross-
reactivities with vitamin D
3
and vitamin D
2
(<0.01% and <0.30%,
respectively). All the assays had a coefficient of variation <10%.
Normal ranges were 10.4–31.2 nmol/L for TT, and 13–71
nmol/L for SHBG as provided by the Central Laboratory of
Hospital Universitario Ram
on y Cajal. We used the 95% confi-
dence interval of the mean of a group of 20 healthy men to obtain
the reference range for FT, which was set at 225–635 pmol/L.
Semen parameters and reference ranges
Sperm samples were produced by masturbation and ejacu-
lated into a clean wide-mouthed container, following a stan-
dardized 4-day sexual abstinence period. Sperm concentration
was determined in a B€
urker hemocytometer. The number of
motile spermatozoa was analyzed using a Sperm Class Analyzer
â
SCA 2002 (Microptic Inc., Barcelona, Spain). For semen analy-
sis, we used the reference values proposed by the World Health
Organization (Cooper et al., 2010).
Statistics
We used the Ene 3.0 software (http://www.e-biometria.com)
for a priori power analysis. Ninety-six patients were required to
identify correctly a putative 50% prevalence of MOSH in moder-
ately to severely obese men, with a confidence interval of 95%
and a precision error (omega) of 10%. Results are expressed as
means SD unless otherwise stated. The Kolmogorov–Smirnov
statistic was applied to continuous variables. Logarithmic trans-
formation was applied as needed to ensure normal distribution
of the variables. Unpaired t-test or Mann–Whitney U-test were
used to compare the central tendencies of the different
groups as needed. To evaluate the association between dis-
continuous variables, we used the v
2
test and Fisher’s exact
test as appropriate. Bivariate correlation was employed to
study lineal association between two quantitative variables
2Andrology, 1–6 ©2015 American Society of Andrology and European Academy of Andrology
B. Calder
on et al. ANDROLOGY

using Pearson’s or Spearman’s tests as appropriate. Finally, a
backwards multiple linear regression model was applied to
evaluate the effects of several dependent variables on the
changes of serum TT and FT concentration. Analyses were
performed using SPSS 18 (SPSS Inc, Chicago, IL, USA).
p<0.05 was considered statistically significant.
RESULTS
Prevalence of MOSH
The prevalence of MOSH was 45% (95% CI: 35–55%) when
considering decreased TT and/or FT concentrations. One patient
presented normal TT with reduced FT, 11 patients presented
reduced TT with normal FT, and 33 patients presented both
reduced TT and FT concentrations. Hence, when considering
only decreased TT concentrations for defining MOSH a 44%
(95% CI: 34–54%) prevalence of this condition was found, and
when taking decreased values of FT, the prevalence of MOSH
diminished to 34% (95% CI: 25–44%). None of the patients
reported a decrease in beard or body hair growth, gynecomastia,
or loss of strength. Forty-five patients had symptoms of fatigue,
but all of them had sleep apnea or were active smokers. Fourteen
patients also reported a decreased sex drive.
Characteristics of men diagnosed as having MOSH
Patients with or without MOSH had similar BMI, but patients
with MOSH were older and had higher serum FSH, estradiol/TT
ratio and fasting glucose concentrations (Table 1). There were
no differences depending on the presence or absence of MOSH
in the percentages of active smokers (16 vs. 20 in patients with
or without MOSH, respectively, p=0.817), diagnosis of sleep
apnea (12 vs. 9, p=0.295), or use of non-invasive mechanical
ventilation (4 vs. 2, p=0.416), and of patients reporting fatigue
(23 vs. 22, p=0.547) or decreased sex drive (7 vs. 7, p=0.808).
When defining MOSH only by decreased TT or only by decreased
calculated FT similar results were obtained (data not shown).
Serum concentrations of TT and FT correlated inversely with
glucose (r=0.328 and r=0.340, respectively, p<0.001) and
HOMAIR (r=0.261, p=0.011 and r=0.246, p=0.016,
respectively). A multivariate linear regression model, introducing
TT as dependent variable and age, BMI, EBW, fasting glucose,
and insulin as independent variables, retained glucose as the
only variable explaining the variability in TT levels (Table 2).A
similar model introducing FT as dependent variable retained
glucose and age as the only variables associated with the vari-
ability in FT values (Table 2).
Semen analysis
Thirty-one patients gave consent for semen analysis. This sub-
group of patients was representative of the whole sample of
obese men in terms of age (39.9 6.6 year) and BMI
(48.01 8.45 Kg/m
2
). Fifteen patients (48%, 95% CI: 29–68%)
presented abnormal semen results, but one patient was finally
excluded from the statistical analysis because of azoospermia.
The hormonal profile of patients with or without abnormal
semen did not differ, including TT and FT (Table 3).
These 31 patients completed the simplified International
Index of Erectile Function test, with 19 men (62%, 95% CI:
43–81%) scoring below normal. There were no differences in the
results of this test when comparing patients with or without
abnormal semen (Mann–Whitney U =86.000, p=0.324), or
when comparing them with or without MOSH (Mann–Whitney
U=94.000, p=0.674).
We found that ejaculate volume inversely correlated with
BMI (q=0.400, p=0.029) and with excess body weight
(q=0.464, p=0.010). Furthermore, we found that serum
estradiol inversely correlated with sperm counts (q=0.411,
p=0.027), total mobility (q=0.404, p=0.030), and normal
morphology (q=0.433, p=0.024). No other variable corre-
lated with abnormal semen parameters (data not shown).
DISCUSSION
Our present results show a large prevalence of MOSH in
patients with moderate to severe obesity and that semen
Table 1 Comparison of clinical and biochemical characteristics of patients
with and without MOSH
With MOSH
(n=45)
Without MOSH
(n=55)
p
Age (years) 44 11 37 8<0.001
Weight (kg) 144 23 140 21 0.459
Height (cm) 174 7 174 7 0.931
Body mass index (kg/m
2
) 47.2 7.2 46.2 6.6 0.484
Excess body weight (kg) 68 22 64 20 0.450
Waist circumference (cm) 140 16 139 13 0.888
Systolic blood pressure (mmHg) 141 16 142 17 0.768
Diastolic blood pressure (mmHg) 87 11 85 12 0.415
Serum creatinine (lmol/L) 80 18 80 18 0.419
Aspartate aminotransferase (U/L) 27 14 23 9 0.118
Alanine aminotransferase (U/L) 49 38 43 23 0.330
Total cholesterol (nmol/L) 5.0 0.9 5.1 1.1 0.489
High-density lipoprotein
cholesterol (nmol/L)
1.0 0.2 1.0 0.2 0.297
Low-density lipoprotein
cholesterol (nmol/L)
3.1 0.8 3.2 0.8 0.650
Triglycerides (nmol/L) 1.9 0.8 1.8 1.0 0.518
Total testosterone (nmol/L) 8.0 1.8 15.3 4.2 <0.001
Sex hormone binding globulin
(nmol/L)
2.2 0.9 2.7 0.9 0.072
Free testosterone (pmol/L) 200 45 367 105 <0.001
Luteinizing hormone (U/L) 3.2 1.5 3.4 1.2 0.507
Follicle-stimulating hormone (U/L) 4.2 2.0 3.2 1.5 0.022
Estradiol (pmol/L) 121 40 125 48 0.896
Estradiol/total testosterone ratio 0.15 0.05 0.08 0.03 <0.001
Fasting Insulin (pmol/L) 215 167 174 139 0.178
Fasting glucose (mmol/L) 7.2 3.1 5.9 1.7 0.011
Homeostasis model assessment
of insulin resistance
9.5 6.9 7.2 7.9 0.131
Data are means SD.
Table 2 Multivariate linear regression analysis
R
2
Fbp
Model I 0.164 6.161 0.001
Dependent variable
Total Testosterone
Retained independent variables
Glucose 0.261 0.010
Model II 0.211 6.221 <0.001
Dependent variable
Free testosterone
Retained independent variables
Age 0.296 0.003
Glucose 0.222 0.024
Age, BMI, EBW, glycemia, and insulinemia were introduced as independent
variables in both backwards stepwise linear regression models.
©2015 American Society of Andrology and European Academy of Andrology Andrology, 1–6 3
PREVALENCE OF MOSH ANDROLOGY

abnormalities are also very frequent. However, there is a dissoci-
ation between circulating concentrations of testosterone and
semen abnormalities in these men, the former being mainly
associated with age, glycemia, and insulin resistance, and the
latter being associated with BMI, EBW, and circulating estradiol.
Moreover, considering that clinical symptoms did not serve to
discriminate patients with MOSH from those showing normal
androgen levels, the identification of this disorder would require
universal screening by measuring serum androgens in all male
patients with moderate or severe obesity, even if asymptomatic.
Semen analysis should also be performed in those seeking fertil-
ity, whether or not presenting with low testosterone, given the
potential need for specific therapies such as exogenous gonado-
tropins with the aim of improving spermatogenesis.
Male hypogonadism is a condition characterized by inade-
quate testicular production of sex steroids and spermatozoa;
however, the term is more commonly used to identify testos-
terone deficiency (Bhasin et al., 2010). When considering andro-
gens alone, the prevalence of MOSH was studied in the past in a
cross-sectional study in the Netherlands (Hofstra et al., 2008).
The authors of this study involving 160 patients showed that TT
was subnormal in 57.5% and FT in 35.6% of the subjects, similar
to our results, and both were inversely related to BMI. They also
found decreased libido and more erectile dysfunction in these
patients, yet semen analysis was not investigated (Hofstra et al.,
2008). Recent studies performed in patients before and after
metabolic surgery have yielded even higher proportion of
MOSH, up to 79% when using TT as the diagnostic criteria (Pel-
litero et al., 2012; Corona et al., 2013). However, this very large
figure of MOSH may represent a selection bias overestimating
the prevalence of MOSH because this study included only
patients who underwent bariatric procedures, and obesity-asso-
ciated comorbidities are an indication for surgery.
Semen abnormalities are associated with increased body
weigh as the percentage of men with abnormal sperm volume,
concentration, and total sperm counts increased with increasing
body size (Eisenberg et al., 2014). In contrast, a recent meta-ana-
lysis pooling five studies has found no relationship between BMI
and semen parameters (MacDonald et al., 2010). However, the
main limitation of this meta-analysis was that data from most
studies could not be aggregated, and the authors concluded that
population-based studies with larger sample sizes and longitudi-
nal studies were required (MacDonald et al., 2010).
The precise physiopathology of MOSH is not completely
understood, but the increased estrogen production by enhanced
conversion of testosterone to estradiol by the enzyme aromatase
cytochrome P450 that is abundantly present in the adipocyte
(Zumoff, 1988) has been proposed as one of the factors involved.
Serum estradiol exerts a negative feedback on pituitary LH secre-
tion (Hofstra et al., 2008) and may also down-regulate GLUT4 by
an augmentation of the estrogen receptor beta expression with a
resultant increase in insulin resistance (Cohen, 2008). The role of
increase aromatization in MOSH has also been supported by the
efficacy of the aromatase inhibitor letrozole to treat this condi-
tion (Loves et al., 2008). Although we could not find differences
in serum estradiol between patients with or without MOSH, we
found a higher estradiol/TT ratio in patients with MOSH, and
also that serum estradiol concentrations inversely correlated
with sperm counts and indexes of sperm health.
Other factors associated with obesity such as central leptin
resistance and the increase in some adipokines (Fischer-
Posovszky et al., 2007; Gautier et al., 2013; Landry et al., 2013)
may also participate in the physiopathology of MOSH by inhibit-
ing gonadotropin pulses and/or secretion. In our study, we
found negative correlations with glucose and insulin resistance
in agreement with previous data showing that glycemia and
insulin resistance are clearly associated with secondary hypogo-
nadism in men: first, testosterone concentrations have been
shown to be diminished not only in obese men but also in those
with type 2 diabetes (Yeap et al., 2009; Zitzmann, 2009); second,
an association with other features of the metabolic syndrome (in
which insulin resistance is a hallmark) has also been observed
(Dandona et al., 2008); third, we have recently shown that cor-
rection of MOSH after metabolic surgery is accompanied by a
reduction in both glucose concentrations and insulin resistance
(Botella-Carretero et al., 2013; Calderon et al., 2014); and fourth,
it has been recently shown that hyperinsulinism induces DAX-1
in Leydig cells of mice which in turn inhibits testicular steroido-
genesis (Ahn et al., 2013).
It has been shown that testosterone therapy is effective in
achieving sustained weight loss in obese hypogonadal men, irre-
spective of the severity of obesity (Saad et al., 2015). Therefore,
testosterone therapy might be advocated as a valid treatment for
MOSH –such as other weight loss strategies and aromatase inhi-
bitors –when fertility is not an issue, although MOSH is still not
considered a ‘classic’ form of hypogonadism (Nguyen et al.,
2015). Long-term cardiovascular adverse effects in the long term
have to be balanced against, and the uncertainties about how
long testosterone therapy might be needed are still not solved
yet (Nguyen et al., 2015). On other hand, when patients have an
indication for metabolic surgery, this has been proved to be a
highly effective treatment for reversing MOSH (Samavat et al.,
2014).
The physiopathology of the relationship between abnormal
sperm production and adiposity is uncertain and complex. Alter-
ations in the hypothalamic–pituitary–gonadal axis, as mentioned
Table 3 Sperm analysis
a
Subnormal semen
(n=14)
Normal semen
(n=16)
p
Age (years) 42 (15) 40 (8) 0.382
Body mass index (kg/m
2
) 46.0 (7.0) 45.4 (15.0) 0.589
Excess body weight (kg) 68.3 (26.6) 66.7 (34.0) 0.901
Total testosterone (nmol/L) 11.4 (6.8) 12.0 (8.3) 0.835
Sex hormone binding
globulin (nmol/L)
2.7 (1.6) 3.0 (1.8) 0.819
Free testosterone (pmol/L) 282 (190) 265 (211) 0.708
Luteinizing hormone (U/L) 3.6 (2.7) 2.9 (1.2) 0.280
Follicle-stimulating
hormone (U/L)
3.3 (2.3) 2.9 (1.9) 0.318
Estradiol (pmol/L) 128 (77) 114 (51) 0.382
Estradiol/total testosterone ratio 0.1 (0.06) 0.1 (0.07) 0.694
Fasting insulin (pmol/L) 151 (150) 174 (125) 0.467
Fasting glucose (mmol/L) 5.3 (1.5) 5.4 (1.9) 0.394
Volume (mL) 2.0 (2.0) 2.5 (2.0) 0.314
Sperm concentration (10
6
/mL) 9.5 (28) 53 (41) 0.001
Progressive motility (%) 18 (26) 43 (5) 0.001
Liabilities (%) 5 (5) 10 (10) 0.001
Immobile (%) 75 (30) 50 (8) 0.131
Normal form (%) 29 (8) 37 (17) 0.382
One patient was excluded from the statistical analysis because of complete
azoospermia. Data are shown as median (interquartile range). SHBG, sex
hormone binding globulin.
a
Classified according to WHO criteria.
4Andrology, 1–6 ©2015 American Society of Andrology and European Academy of Andrology
B. Calder
on et al. ANDROLOGY

above, can lead to relative declines in gonadotropin levels (Hofs-
tra et al., 2008; Michalakis et al., 2013). However, in our study
we could not find low levels of gonadotropins in patients with
subnormal semen parameters, but we found that serum estra-
diol inversely correlated with the number of spermatozoa. We
also found that the alterations in the semen parameters were
associated with BMI and excess body weight, in agreement with
a recent study (Eisenberg et al., 2014). It is possible that other
factors may play a role in the physiopathology of semen alter-
ations beyond that of gonadotropins in the obese patient,
including a putative increase in testicular temperature, and
other lifestyle, nutritional or environmental factors among
others (Sharpe & Franks, 2002).
Our study have several limitations: first, it is possible that the
small sample size of the subgroup used for semen analysis in our
study may have precluded us from finding any significant differ-
ence in the aforementioned nutritional factors. Second, not all
patients consented in having their spermatozoa analyzed, so the
net effect of multiple positive and negative biases on sperm con-
centration is difficult to estimate in our study (Handelsman,
1997). This possibility is further supported by the fact that, in
our study, all patients reporting a decreased sex drive consented
for semen analysis. Third, patients with MOSH were significantly
older than those without MOSH, and a previous study demon-
strated that free testosterone had a curvilinear relationship with
weight change in the same direction, as those patients who
gained or lost >15% of weight showed this significant change
(Camacho et al., 2013). Unfortunately data on when patients
started being obese and longitudinal changes in weight were not
available in our study, so we were not able to analyze this issue.
In conclusion, the prevalence of MOSH in patients with mod-
erate or severe obesity is high and, because clinical symptoms of
gonadal dysfunction were not useful for its detection, routine
screening for this condition is warranted before obesity surgery,
even in asymptomatic men. Also, regardless of the testosterone
concentrations, a semen analysis should be performed in mod-
erate or severely obese patients considering fertility since sperm
abnormalities are also prevalent in these men.
ACKNOWLEDGMENTS
This study was supported by Grant PI1100357 from Instituto
de Salud Carlos III, Spanish Ministry of Economy and Competi-
tiveness. CIBERDEM and CIBERobn are also initiatives of Insti-
tuto de Salud Carlos III. Supported in part by the Fondo Europeo
de Desarrollo Regional (FEDER) from the European Union. We
thank the nurses of the Department of Endocrinology and Nutri-
tion for their help with the anthropometric and blood sampling
of the patients.
CONFLICT OF INTEREST
The Authors declare that they have no conflict of interest.
AUTHORS CONTRIBUTIONS
B.C., J.G.-M., B.V.-P., and J.I.B.-C. contributed to data acquisi-
tion and revision. B.C. and J.I.B.-C. wrote the manuscript. J.I.B.-
C and H.F.E.-M. designed the study. All authors contributed to
data interpretation, drafted and revised critically the article for
important intellectual content, and approved the final version of
the manuscript.
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