RESEARCH ARTICLE

Male sexual dysfunction in obesity: The role of

sex hormones and small fibre neuropathy
Jan Hoong Ho1,2, Safwaan Adam ID1,2, Shazli Azmi2, Maryam Ferdousi ID2, Yifen Liu2,
Alise Kalteniece2, Shaishav S. Dhage1,2, Brian G. Keevil ID3, Akheel A. Syed ID4, Basil
J. Ammori5, Tomás Ahern6, Rachelle Donn2, Rayaz A. Malik2,7, Handrean Soran ID1,2*
1 Department of Medicine, Manchester University NHS Foundation Trust, Manchester, United Kingdom,
2 Cardiovascular Research Group, The University of Manchester, Manchester, United Kingdom,
3 Department of Biochemistry, Wythenshawe Hospital, Manchester University NHS Foundation Trust,
Manchester, United Kingdom, 4 Department of Diabetes & Endocrinology, Salford Royal NHS Foundation
a1111111111 Trust, Salford, United Kingdom, 5 Department of Surgery, Salford Royal NHS Foundation Trust, Salford,
a1111111111 United Kingdom, 6 Department of Endocrinology, Our Lady of Lourdes Hospital, RCSI Hospital Group,
a1111111111 Drogheda, Ireland, 7 Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
a1111111111
* hsoran@aol.com, Handrean.Soran@mft.nhs.uk
a1111111111

Abstract
OPEN ACCESS

Citation: Ho JH, Adam S, Azmi S, Ferdousi M, Liu

Context
Y, Kalteniece A, et al. (2019) Male sexual Multiple factors contribute to sexual dysfunction in men with obesity. Sex hormone levels
dysfunction in obesity: The role of sex hormones
are commonly abnormal in men with obesity and this abnormality is often the focus of man-
and small fibre neuropathy. PLoS ONE 14(9):
e0221992. https://doi.org/10.1371/journal. agement in clinical practice. The role of small fibre neuropathy in obesity-related sexual dys-
pone.0221992 function is not well established.
Editor: Marco Aurélio Gouveia Alves, University of
Porto, PORTUGAL Objective
Received: July 17, 2018 We aimed to investigate the relationship between sexual function, sex hormone levels and
Accepted: July 30, 2019
small nerve fibre morphology in men with severe obesity.

Published: September 11, 2019

Materials and methods
Copyright: © 2019 Ho et al. This is an open access
A prospective study of 29 men with severe obesity was undertaken. Sexual function was
article distributed under the terms of the Creative
Commons Attribution License, which permits assessed using the European Male Ageing Study Sexual Function Questionnaire. Small
unrestricted use, distribution, and reproduction in nerve fibre morphology was quantified using corneal confocal microscopy. Sex hormone
any medium, provided the original author and levels were measured by mass spectrophotometry.
source are credited.

Data Availability Statement: All relevant data are Results

within the paper and its Supporting Information
files.
Erectile dysfunction was present in 72% of the cohort with a higher prevalence of diabetes
among the symptomatic group (88% vs 38%, p = 0.006). Corneal nerve fibre length (CNFL)
Funding: This work was supported by the National
Institute for Health Research/Wellcome Trust
and corneal nerve fibre density (CNFD) were both significantly lower in participants with
Clinical Research Facility at Manchester University erectile dysfunction compared to those without (p = 0.039 and p = 0.048 respectively). The
NHS Foundation Trust, Greater Manchester Clinical erectile function score correlated with CNFL (r = -0.418, p = 0.034) and CNFD (r = -0.411, p
Research Network and research donation from
= 0.037). Total testosterone and calculated free testosterone levels did not differ significantly
AMGEN. The funders had no role in study design,
data collection and analysis, decision to publish, or between men with or without erectile dysfunction (median 8.8 nmol/L vs 9.0 nmol/L, p =
preparation of the manuscript. 0.914; and median 176 pmol/L vs 179 pmol/L, p = 0.351 respectively), infrequent sexual

PLOS ONE | https://doi.org/10.1371/journal.pone.0221992 September 11, 2019 1 / 11

 Male sexual dysfunction in obesity

Competing interests: This study was partially thoughts (median 8.1 nmol/L vs 9.2 nmol/L, p = 0.650; and median 184 pmol/L, vs 176 pmol/
funded by a research donation from AMGEN. This L, p = 0.619 respectively) and decreased morning erections (median 9.0 nmol/L vs 8.8
does not alter our adherence to PLOS ONE policies
on sharing data and materials. There are no
nmol/L, p = 0.655; and median 170 pmol/L vs 193 pmol/L, p = 0.278 respectively).
patents, products in development or marketed
products associated with this research to declare. Conclusion
Sexual dysfunction is highly prevalent in men with severe obesity. We found an association
between small fibre neuropathy with erectile dysfunction with presence of diabetes a likely a
significant contributing factor. We found no associations between testosterone levels with
sexual symptoms (including frequency of sexual thoughts). The influence of small nerve fibre
neuropathy on response to therapeutic interventions and whether interventions that improve
small fibre neuropathy can improve erectile function in this population merits further study.

Introduction
Sexual dysfunction is common in men with obesity [1]. Normal sexual functioning is depen-
dent on complex vascular, neural, hormonal and psychological factors, all of which are poten-
tially affected by obesity [2, 3]. Low testosterone level, in particular, is thought to have a
bidirectional relationship with obesity [4, 5] and is common in men with obesity [6] and is
very common in men with severe obesity [7, 8]. Current guidelines recommend testosterone
replacement in men with symptomatic androgen deficiency to improve general well-being,
bone mineral density and sexual function [9]. Whilst testosterone therapy may improve sexual
symptoms in hypogonadal men [9], evidence that it benefits sexual function in men with obe-
sity and low levels of testosterone is inconsistent [10–13].
Erectile dysfunction is associated with diminished small and large nerve fibre sensory
thresholds [14]. Peripheral neuropathy, especially small fibre neuropathy, occurs more com-
monly in people with obesity than in those without [15, 16]. Corneal confocal microscopy is a
rapid, validated and non-invasive technique that assesses small nerve fibre integrity [17, 18]
with comparable diagnostic efficiency to intraepidermal nerve fibre density in diabetic periph-
eral neuropathy [19]. We have recently shown that small fiber neuropathy, quantified using
corneal confocal microscopy, is associated with erectile dysfunction in men with type 1 diabe-
tes [20].
We aimed to assess, for the first time, whether relationships exist between sexual symptoms
with small fibre neuropathy and/or with sex hormone levels in men with severe obesity.

Materials and methods

Participants
Twenty-nine male patients with severe obesity were recruited from the weight management
clinic at Salford Royal National Health Service Foundation Trust (Salford, United Kingdom).
Severe obesity is defined as BMI above 40 which is equivalent to obesity class III using the BMI
classification set out by the World Health Organisation (WHO) [21]. Patients known to have
cardiovascular disease, disease of the pituitary, testes or adrenal glands, or taking therapy for
erectile dysfunction or known to affect androgen levels or cause erectile dysfunction and lutei-
nising hormone >9.4 U/L (primary hypogonadism), were excluded [22]. Further exclusion
criteria included: other causes of peripheral neuropathy apart from diabetes; cancer, radiother-
apy or chemotherapy; previous eye surgery and corneal disease. Presence of comorbidities

PLOS ONE | https://doi.org/10.1371/journal.pone.0221992 September 11, 2019 2 / 11

 Male sexual dysfunction in obesity

such as hypertension and type 2 diabetes were determined on medical history. A HbA1c mea-
surement at baseline was used in addition to identify patients with undiagnosed type 2 diabetes
(HbA1c � 48 mmol/mol) and pre-diabetes (HbA1c 42–47 mmol/mol) [23]. This study has
approval from the Greater Manchester Central Research and Ethics Committee. Written
informed consent was obtained from all individuals prior to participation.

Sexual function assessment

Sexual function was assessed using the European Male Ageing Study Sexual Function Question-
naire [24]. Three sexual symptoms were used for assessment of sexual function: erectile func-
tion, frequency of sexual thoughts, and frequency of morning erections. Participants were
divided into symptomatic and asymptomatic groups using previously established cut-offs based
on validated scores for each individual question relating to the three sexual symptoms [25, 26].

Neuropathy assessment
Symptoms of peripheral neuropathy was assessed using the neuropathy symptom profile
(NSP). Cold (CT) and warm (WT) perception thresholds were assessed on the dorsolateral
aspect of the left foot (S1) using the TSA-II NeuroSensory Analyser (Medoc, Ramat-Yishai,
Israel). Electrodiagnostic studies were undertaken using a Dantec Keypoint system (Dantec
Dynamics, Bristol, UK). Vibration perception threshold (VPT) was established using a Hor-
well Neurothesiometer (Scientific Laboratory Supplies, Wilfrod, Nottingham, UK). Deep
breathing heart rate variability (DB-HRV) was established using an ANX 3.0 autonomic ner-
vous system monitoring device (ANSAR Medical Technologies, Philadelphia, PA, USA).

Corneal confocal microscopy

Corneal nerve morphology was assessed using corneal confocal microscopy [17, 27]. Corneal
confocal microscopy (Heidelberg Retinal Tomograph III Rostock Cornea Module; Heidelberg
Engineering, Heidelberg, Germany) was performed using our established protocol [27]. Six
non-overlapping images from the centre of the cornea were selected per patient (three per eye)
[28]. Automated image analysis was performed using ACCMetrics software (The University of
Manchester, United Kingdom). Corneal nerve fibre length (total length of nerves in mm per
mm2), corneal nerve fibre density (CNFD) (number of major nerves per mm2) and corneal
nerve branch density (CNBD) (number of nerve branches per mm2) were quantified [29].

Laboratory measurements
Venous blood samples were obtained between the hours of 0800 and 1100 after an overnight
fast of at least 12 hours. Apart from glycosylated haemoglobin (HbA1c) which was measured
using standard laboratory methods in the Department of Biochemistry, Manchester University
NHS Foundation Trust on the day of collection, all other laboratory measurements were per-
formed at the end of the study. Serum or plasma, isolated within 2 hours of collection, was
stored at 4˚C or -20˚C until analysed. Each serum aliquot was stored for a maximum of two
years and underwent one freeze-thaw cycle only. Serum total testosterone, dihydrotestoster-
one, dehydroepiandrosterone sulphate and androstenendione levels were determined using
liquid chromatography–tandem mass spectrometry in a validated clinical laboratory [30, 31].
Sex hormone-binding globulin, luteinising hormone and follicle-stimulating hormone levels
were measured electrochemiluminescence immunoassay (Roche Diagnostics) using Roche1
automated analysers (E170 platform). Serum free testosterone levels were calculated using the
mass action equation described by Vermeulen [32] and participant-specific total testosterone,

PLOS ONE | https://doi.org/10.1371/journal.pone.0221992 September 11, 2019 3 / 11

 Male sexual dysfunction in obesity

sex hormone-binding globulin and albumin levels. A participant was considered to have a low
testosterone level if either; his total testosterone level was less than 8 nmol/L; or his total testos-
terone level was between 8 and 11 nmol/L and his calculated free testosterone level was less
than 220 pmol/L [25].

Statistical analyses
All statistical analyses were performed using SPSS for Windows (Version 23.0, IBM SPSS Sta-
tistics, Armonk, NY). Continuous variables were compared between groups using the inde-
pendent samples t-test or, in the case of non-parametrically distributed data, the Mann-
Whitney U test. Normality of data distribution was assessed for all continuous variables using
the Shapiro-Wilk test. The chi-squared test was used for analysis of categorical data. Correla-
tions between variables were assessed using Spearman’s analyses. Results are expressed as
mean with standard deviation (SD) for parametric data and as median with interquartile range
(IQR) for non-parametric data. No attempt was made to adjust for missing data. The level of
statistical significance was set at less than 0.05 for all analyses.

Results
Sixteen (55%) of the participants had erectile dysfunction of whom 34% had severe erectile
dysfunction. Infrequent sexual thoughts and decreased morning erections were reported in 13
(45%) and 23 (79%) of the participants respectively. The median overall satisfaction score cor-
responded with moderate dissatisfaction.
The median total testosterone was 9.0 nmol/L, 95% confidence interval ranged between 7.4
nmol/L and 11.1 nmol/L. The total testosterone level was less than 8 nmol/L in 12 (41%) par-
ticipants, between 8 and 11 nmol/L in ten (34%) participants, of whom 4 (14%) had a calcu-
lated free testosterone level below 220 pmol/L.

Erectile dysfunction
When participants were divided into symptomatic and asymptomatic groups based on their
erectile function scores, age was higher and body mass index was lower in the symptomatic
group (Table 1). The prevalence of type 2 diabetes mellitus and hypertension were higher in
those with erectile dysfunction. The HbA1c, however, did not differ significantly between the
groups. The prevalence of dysglycaemia (pre-diabetes and type 2 diabetes mellitus) also did
not differ between symptomatic and asymptomatic groups.
Both CNFL and CNFD were lower in participants with erectile dysfunction compared to
those without (Table 2 and Fig 1). Erectile function score correlated with both CNFL (Spear-
man’s r = -0.418, p = 0.034) and CNFD (Spearman’s r = -0.411, p = 0.037).
The level of total testosterone, free testosterone, sex hormone-binding globulin, dihydrotes-
tosterone, dehydroepiandrosterone sulphate and androstenendione did not differ between
participants with and without erectile dysfunction (Table 1 and Fig 1). There was no difference
in the prevalence of low testosterone between these two groups. Total and free testosterone did
not correlate with erectile function (Spearman’s r = -0.083, p = 0.667 and Spearman’s r =
-0.255, p = 0.181 respectively).
There were no difference in lipid profile between the two groups.

Infrequent sexual thoughts and decreased morning erections

Clinical, corneal nerve or hormone parameters did not differ between those with and without
infrequent sexual thoughts (S2 Table) or in those with and without decreased morning

PLOS ONE | https://doi.org/10.1371/journal.pone.0221992 September 11, 2019 4 / 11

 Male sexual dysfunction in obesity

Table 1. Comparison of demographics, clinical characteristics, and sex hormone levels between asymptomatic and symptomatic patients divided based on erectile
function.
Asymptomatic based on erectile function Symptomatic based on erectile function p-value
(n = 13) (n = 16)
Clinical characteristics
Age, years 44.4 ±8.4 52.1 ±10.9 0.045
BMI, kg/mm2 54.8 ±12.4 46.9 ±7.3 0.041
Type 2 diabetes, n (%) 5 (38%) 14 (88%) 0.006
Duration of diabetes, years 5±3 6±5 0.787
Pre-diabetes and type 2 diabetes, n (%) 10 (77%) 14 (88%) 0.453
Hypertension, n (%) 4 (30%) 11 (68%) 0.042
Antihypertensives, n 0 (0–1) 1 (0–2) 0.092
Biochemistry
HbA1c, mmol/mol 52±13 55±15 0.591
Total cholesterol, mmol/l 3.8±1.2 4.0±1.0 0.796
Triglyceride, mmol/l 1.0±0.5 1.3±0.5 0.206
HDL-C, mmol/l 1.01±0.38 0.95±0.22 0.702
LDL-C, mmol/l 2.5±1.0 2.4±0.8 0.808
Sex hormones
Low testosterone, n (%) 7 (54) 10 (63) 0.638
Total testosterone, nmol/L 9.0 (6.4–12.3) 8.8 (6.4–11.0) 0.914
Free testosterone, pmol/L 179 (132–311) 176 (120–216) 0.351
Sex hormone-binding globulin, nmol/L 29.2 (21.7–35.5) 32.1 (21.7–38.3) 0.559
Luteinising hormone, mIU/Ml 2.3±1.2 3.5±1.9 0.059
Follicle-stimulating hormone, mIU/L 4.2 (2.9–4.7) 3.5 (2.4–4.9) 0.779
Dihydrotestosterone, nmol/L 0.60 (0.34–0.98) 0.62 (0.50–0.99) 0.914
Dehydroepiandrosterone sulphate, nmol/L 2.2 (1.1–3.4) 1.3 (0.9–3.6) 0.537
Androstenedione, nmol/L 2.3 (1.6–3.0) 1.6 (1.3–2.4) 0.170

Notes: Data are presented as mean and standard deviation for normally-distributed variables and median and interquartile range for non-parametric variables.
Independent t-test was performed for normally-distributed variables, Mann-Whitney U test for non-parametric variables, and chi-squared test for categorical variables
when comparing asymptomatic and symptomatic groups. p<0.05 is considered statistically significant.
Abbreviations: BMI, body mass index; HbA1c, glycosylated haemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

https://doi.org/10.1371/journal.pone.0221992.t001

erections (S3 Table). Total and free testosterone did not correlate with frequency of sexual
thoughts (Spearman’s r = 0.236, p = 0.218 and Spearman’s r = 0.179, p = 0.352 respectively) or
with frequency of morning erections (Spearman’s r = 0.079, p = 0.682 and Spearman’s
r = 0.186, p = 0.333 respectively). The HbA1c and lipid profile did not differ between patients
with and without infrequent sexual thoughts and patients with and without decreased morning
erections (S2 and S3 Tables).

Low testosterone
There was no difference in sexual symptom frequency between men with and without a low
testosterone level (S4 Table).

Discussion
This is the first study to assess sexual function, small fibre neuropathy, sex hormone levels and
their relationships simultaneously in men with severe obesity. Male sexual dysfunction was

PLOS ONE | https://doi.org/10.1371/journal.pone.0221992 September 11, 2019 5 / 11

 Male sexual dysfunction in obesity

Table 2. Comparison of measures of neuropathy between asymptomatic and symptomatic patients divided based on erectile function.
Asymptomatic based on erectile function Symptomatic based on erectile function p-value
(n = 13) (n = 16)
NSP, /38 0 (0–5) 4 (0–15) 0.131
VPT, V 13.3±5.6 16.3±7.2 0.296
CT, ˚C 22.6±5.9 20.6±8.2 0.528
WT, ˚C 41.0±2.3 41.9±3.3 0.437
CNFL, mm/mm2 20.29±3.21 16.74±4.45 0.039
CNFD, no./mm2 30.21 (27.34–33.59) 27.60 (22.50–29.17) 0.048
CNBD, no./mm2 60.75±33.53 45.70±24.86 0.201
DB-HRV, beats/min 35 (24–44) 14 (12–23) 0.016

Notes: Data are presented as mean and standard deviation for normally-distributed variables and median and interquartile range for non-parametric variables.
Independent t-test was performed for normally-distributed variables, Mann-Whitney U test for non-parametric variables, and chi-squared test for categorical variables
when comparing asymptomatic and symptomatic groups. p<0.05 is considered statistically significant.
Abbreviations: CNFD, corneal nerve fibre density; CNBD, corneal nerve branch density; CNFL, corneal nerve fibre length; CT, cold perception threshold; DB-HRV,
deep breathing heart rate variability; NSP, neuropathy symptom profile; VPT, vibration perception threshold; WT, warm perception threshold.

https://doi.org/10.1371/journal.pone.0221992.t002

highly prevalent in our study population with symptomatic erectile dysfunction and reduction
in frequency of sexual thoughts being present in 55% and 45% of patients, respectively. The
vast majority of patients had overall sexual function scores below the mean value found in the
European Male Ageing Study, despite being ten years younger (mean age of 49 compared to

Fig 1. Comparison of corneal nerve parameters in asymptomatic and symptomatic patients based on erectile function score (a & b) and comparison of total
and free testosterone levels between asymptomatic and symptomatic patients based on erectile function (c & d), frequency of sexual thoughts (e & f), and
frequency of morning erections (g & h). CNFL and CNFD are both significantly lower in symptomatic compared to asymptomatic patients with erectile
dysfunction (a & b). Data are presented as mean and standard deviation for normally-distributed variables and median and interquartile range for non-parametric
variables. Erectile function questionnaire response categories: 1: always able to keep erection good enough for sexual intercourse, 2: usually able, 3: sometimes able, 4:
never able. Abbreviations: CNFD, corneal nerve fibre density; CNFL, corneal nerve fibre length. p<0.05 is considered statistically significant.
https://doi.org/10.1371/journal.pone.0221992.g001

PLOS ONE | https://doi.org/10.1371/journal.pone.0221992 September 11, 2019 6 / 11

 Male sexual dysfunction in obesity

59 years) [24]. The level of distress related to sexual functioning was also higher compared to
that observed in the European Male Ageing Study cohort.
We have demonstrated, for the first-time, that reduction in small nerve fibre indices occur
in patients with severe obesity and erectile dysfunction. In particular, corneal nerve fibre den-
sity and length were significantly lower in patients with symptomatic erectile dysfunction and
they correlated with erectile function. There was, however, no difference between corneal
nerve branch density and the severity of erectile dysfunction. We hypothesise that this could
be a result of constant changes in this parameter secondary to nerve regeneration. There was
also evidence of autonomic dysfunction in patients with erectile dysfunction. Older age, obe-
sity and a higher prevalence of diabetes and hypertension in the cohort with erectile dysfunc-
tion are likely to be the major contributors of corneal nerve loss in accord with our previous
studies [33, 34] and our recent study in type 1 diabetes.
Although somatic and autonomic neuropathy are associated with erectile dysfunction
[35], patients continue to have assessment of sex hormones and cardiovascular risk factors,
but not neuropathy. Our study emphasizes the importance of assessing small fibre neuropa-
thy as it plays an important role in the neurovascular regulation of erectile function [36, 37].
Although phosphodiesterase type 5 inhibitors (PDE5i) are used in the management of erec-
tile dysfunction, they are less effective in people with nerve damage [38, 39]. Based on our
study findings, we therefore suggest that assessment of small fibre neuropathy prior to initia-
tion of PDE5i may help identify patients who are more likely to respond to treatment and
corneal confocal microscopy provides a rapid, objective and clinically feasible method to
assess small fibre damage and repair [17–19]. Larger studies will be required to prove this
further.
In keeping with previously published studies, we found a high prevalence of low testoster-
one levels in this cohort of men with severe obesity [8]. However, testosterone levels were not
associated with sexual symptoms and sexual symptom frequency did not differ between those
with low and normal testosterone levels. This perhaps suggests that low testosterone might not
be a major determinant of presence of sexual symptoms in severe obesity.
The limitations of this study are the cross-sectional design which limits the inference of
cause and effect between small fibre neuropathy and erectile dysfunction. A larger sample
size would have allowed adjustment of confounding factors for small fibre damage in rela-
tion to erectile dysfunction. A single sample to determine sex hormone levels may also be
seen as a limitation, however, several studies have confirmed that testosterone levels do
not fluctuate significantly when measured serially in a timed sample over several months
[40–42].

Conclusion
We conclude that erectile dysfunction is common among men with severe obesity and is asso-
ciated with small fibre neuropathy, likely to be further driven by older age, diabetes and cardio-
vascular risk factors. Corneal confocal microscopy is a rapid, non-invasive technique to
quantify of small nerve fibre degeneration and regeneration. Prospective studies are required
to assess the impact of small fibre neuropathy on the effectiveness of therapies for erectile dys-
function and whether interventions that improve small fibre neuropathy can improve erectile
dysfunction in men with severe obesity.

Supporting information
S1 Table. Questions regarding sexual symptoms within the EMAS sexual function ques-
tionnaire and definitions of asymptomatic and symptomatic response categories. The

PLOS ONE | https://doi.org/10.1371/journal.pone.0221992 September 11, 2019 7 / 11

 Male sexual dysfunction in obesity

definitions of asymptomatic and symptomatic response categories are based on validated pub-
lished criteria [25, 26].
(DOCX)
S2 Table. Comparison of sex hormone levels between asymptomatic and symptomatic
patients divided based on frequency of sexual thoughts. Notes: Data are presented as mean
and standard deviation for normally-distributed variables and median and interquartile range
for non-parametric variables. Independent t-test was performed for normally-distributed vari-
ables, Mann-Whitney U test for non-parametric variables, and chi-squared test for categorical
variables. p<0.05 is considered statistically significant. Abbreviations: CNFD, corneal nerve
fibre density; CNBD, corneal nerve branch density; CNFL, corneal nerve fibre length.
(DOCX)
S3 Table. Comparison of sex hormone levels between symptomatic and asymptomatic
patients divided based on frequency of morning erections. Notes: Data are presented as
mean and standard deviation for normally-distributed variables and median and interquartile
range for non-parametric variables. Independent t-test was performed for normally-distrib-
uted variables, Mann-Whitney U test for non-parametric variables, and chi-squared test for
categorical variables. p<0.05 is considered statistically significant. Abbreviations: CNFD, cor-
neal nerve fibre density; CNBD, corneal nerve branch density; CNFL, corneal nerve fibre
length.
(DOCX)
S4 Table. Comparison of sexual symptoms between groups with low testosterone and nor-
mal testosterone. Data are presented as median and interquartile range for non-parametric
variables. Mann-Whitney U test was performed for non-parametric variables. Questionnaire
response categories: erectile function: 1: always able to keep erection good enough for sexual
intercourse, 2: usually able, 3: sometimes able, 4: never able; frequency of sexual thoughts and
morning erection frequency: 1: none or once in the past month, 2: 2–3 times/month and 1
time/week, 3: 2–6 times/week, 4: �1/day; overall satisfaction: 0: very dissatisfied, 1: moderately
dissatisfied, 2: equally satisfied and dissatisfied, 3: moderately satisfied, 4: very satisfied. Overall
sexual function score ranges from 0 to 33 with higher scores corresponding with higher level
of sexual functioning. Sexual functioning-related distress ranges from 0 to 20, with higher
scores corresponding with higher level of distress. p<0.05 is considered statistically significant.
(DOCX)

Acknowledgments
This work was supported by the National Institute for Health Research/Wellcome Trust Clini-
cal Research Facility at Manchester University NHS Foundation Trust, Greater Manchester
Clinical Research Network and research donation from AMGEN.

Author Contributions
Conceptualization: Jan Hoong Ho, Safwaan Adam, Handrean Soran.
Data curation: Jan Hoong Ho, Safwaan Adam, Shazli Azmi, Akheel A. Syed, Basil J. Ammori.
Formal analysis: Jan Hoong Ho, Safwaan Adam.
Investigation: Jan Hoong Ho, Maryam Ferdousi, Yifen Liu, Alise Kalteniece, Brian G. Keevil.
Methodology: Jan Hoong Ho, Safwaan Adam, Handrean Soran.

PLOS ONE | https://doi.org/10.1371/journal.pone.0221992 September 11, 2019 8 / 11

 Male sexual dysfunction in obesity

Project administration: Jan Hoong Ho, Safwaan Adam.

Supervision: Akheel A. Syed, Basil J. Ammori, Rachelle Donn, Rayaz A. Malik, Handrean
Soran.
Writing – original draft: Jan Hoong Ho, Safwaan Adam.
Writing – review & editing: Jan Hoong Ho, Safwaan Adam, Shazli Azmi, Maryam Ferdousi,
Yifen Liu, Alise Kalteniece, Shaishav S. Dhage, Brian G. Keevil, Akheel A. Syed, Basil J.
Ammori, Tomás Ahern, Rachelle Donn, Rayaz A. Malik, Handrean Soran.

References
1. Steffen KJ, King WC, White GE, Subak LL, Mitchell JE, Courcoulas AP, et al. Sexual functioning of men
and women with severe obesity before bariatric surgery. Surg Obes Relat Dis. 2016. Epub Sep 16.
https://doi.org/10.1016/j.soard.2016.09.022 PMID: 27986585
2. Kandeel FR, Koussa VK, Swerdloff RS. Male sexual function and its disorders: physiology, pathophysi-
ology, clinical investigation, and treatment. Endocr Rev. 2001; 22(3):342–88. Epub 2001/06/16. https://
doi.org/10.1210/edrv.22.3.0430 PMID: 11399748.
3. Soran H, Wu FC. Endocrine causes of erectile dysfunction. Int J Androl. 2005; 28 Suppl 2:28–34. Epub
2005/10/21. https://doi.org/10.1111/j.1365-2605.2005.00596.x PMID: 16236061.
4. Wang C, Jackson G, Jones TH, Matsumoto AM, Nehra A, Perelman MA, et al. Low testosterone associ-
ated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular dis-
ease risk in men with type 2 diabetes. Diabetes Care. 2011; 34(7):1669–75. Epub 2011/06/29. https://
doi.org/10.2337/dc10-2339 PMID: 21709300.
5. Diaz-Arjonilla M, Schwarcz M, Swerdloff RS, Wang C. Obesity, low testosterone levels and erectile dys-
function. Int J Impot Res. 2009; 21(2):89–98. Epub 2008/10/10. https://doi.org/10.1038/ijir.2008.42
PMID: 18843273.
6. Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, O’Neill TW, et al. Hypothalamic-pituitary-testicular axis
disruptions in older men are differentially linked to age and modifiable risk factors: the European Male
Aging Study. J Clin Endocrinol Metab. 2008; 93(7):2737–45. Epub 2008/02/14. https://doi.org/10.1210/
jc.2007-1972 PMID: 18270261.
7. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males
aged at least 45 years: the HIM study. Int J Clin Pract. 2006; 60(7):762–9. Epub 2006/07/19. https://doi.
org/10.1111/j.1742-1241.2006.00992.x PMID: 16846397.
8. Hofstra J, Loves S, van Wageningen B, Ruinemans-Koerts J, Jansen I, de Boer H. High prevalence of
hypogonadotropic hypogonadism in men referred for obesity treatment. Neth J Med. 2008; 66(3):103–
9. Epub 2008/03/20. PMID: 18349465.
9. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone
therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J
Clin Endocrinol Metab. 2010; 95(6):2536–59. Epub 2010/06/09. https://doi.org/10.1210/jc.2009-2354
PMID: 20525905.
10. Giltay EJ, Tishova YA, Mskhalaya GJ, Gooren LJ, Saad F, Kalinchenko SY. Effects of testosterone sup-
plementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic
syndrome. J Sex Med. 2010; 7(7):2572–82. Epub 2010/06/08. https://doi.org/10.1111/j.1743-6109.
2010.01859.x PMID: 20524974.
11. Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, et al. Testosterone replacement in
hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care.
2011; 34(4):828–37. Epub 2011/03/10. https://doi.org/10.2337/dc10-1233 PMID: 21386088.
12. Gianatti EJ, Dupuis P, Hoermann R, Zajac JD, Grossmann M. Effect of testosterone treatment on con-
stitutional and sexual symptoms in men with type 2 diabetes in a randomized, placebo-controlled clinical
trial. J Clin Endocrinol Metab. 2014; 99(10):3821–8. Epub 2014/07/01. https://doi.org/10.1210/jc.2014-
1872 PMID: 24978674.
13. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, et al. Effects
of Testosterone Treatment in Older Men. N Engl J Med. 2016; 374(7):611–24. Epub 2016/02/18.
https://doi.org/10.1056/NEJMoa1506119 PMID: 26886521.
14. Bleustein CB, Arezzo JC, Eckholdt H, Melman A. The neuropathy of erectile dysfunction. Int J Impot
Res. 2002; 14(6):433–9. Epub 2002/12/21. https://doi.org/10.1038/sj.ijir.3900907 PMID: 12494274.

PLOS ONE | https://doi.org/10.1371/journal.pone.0221992 September 11, 2019 9 / 11

 Male sexual dysfunction in obesity

15. Miscio G, Guastamacchia G, Brunani A, Priano L, Baudo S, Mauro A. Obesity and peripheral neuropa-
thy risk: a dangerous liaison. J Peripher Nerv Syst. 2005; 10(4):354–8. Epub 2005/11/11. https://doi.
org/10.1111/j.1085-9489.2005.00047.x PMID: 16279984.
16. Herman RM, Brower JB, Stoddard DG, Casano AR, Targovnik JH, Herman JH, et al. Prevalence of
somatic small fiber neuropathy in obesity. Int J Obes (Lond). 2007; 31(2):226–35. Epub 2006/06/14.
https://doi.org/10.1038/sj.ijo.0803418 PMID: 16770330.
17. Malik RA, Kallinikos P, Abbott CA, van Schie CH, Morgan P, Efron N, et al. Corneal confocal micros-
copy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia.
2003; 46(5):683–8. Epub 2003/05/10. https://doi.org/10.1007/s00125-003-1086-8 PMID: 12739016.
18. Pritchard N, Edwards K, Russell AW, Perkins BA, Malik RA, Efron N. Corneal confocal microscopy pre-
dicts 4-year incident peripheral neuropathy in type 1 diabetes. Diabetes Care. 2015; 38(4):671–5. Epub
2015/01/13. https://doi.org/10.2337/dc14-2114 PMID: 25573881.
19. Chen X, Graham J, Dabbah MA, Petropoulos IN, Ponirakis G, Asghar O, et al. Small nerve fiber quantifi-
cation in the diagnosis of diabetic sensorimotor polyneuropathy: comparing corneal confocal micros-
copy with intraepidermal nerve fiber density. Diabetes Care. 2015; 38(6):1138–44. Epub 2015/03/22.
https://doi.org/10.2337/dc14-2422 PMID: 25795415.
20. Azmi S, Ferdousi M, Alam U, Petropoulos IN, Ponirakis G, Marshall A, et al. Small-fibre neuropathy in
men with type 1 diabetes and erectile dysfunction: a cross-sectional study. Diabetologia. 2017; 60
(6):1094–101. Epub 2017/03/31. https://doi.org/10.1007/s00125-017-4245-z PMID: 28357503.
21. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health
Organ Tech Rep Ser. 2000; 894:i–xii, 1–253. Epub 2001/03/10. PMID: 11234459.
22. Tajar A, Forti G, O’Neill TW, Lee DM, Silman AJ, Finn JD, et al. Characteristics of secondary, primary,
and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin
Endocrinol Metab. 2010; 95(4):1810–8. Epub 2010/02/23. https://doi.org/10.1210/jc.2009-1796 PMID:
20173018.
23. (NICE) NIfHaCE. NICE Public Health Guideline 38. Type 2 diabetes: prevention in people at high risk.
2012.
24. O’Connor DB, Corona G, Forti G, Tajar A, Lee DM, Finn JD, et al. Assessment of sexual health in aging
men in Europe: development and validation of the European Male Ageing Study sexual function ques-
tionnaire. The journal of sexual medicine. 2008; 5(6):1374–85. Epub 2008/03/12. https://doi.org/10.
1111/j.1743-6109.2008.00781.x PMID: 18331267.
25. Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, et al. Identification of late-onset hypogonad-
ism in middle-aged and elderly men. N Engl J Med. 2010; 363(2):123–35. Epub 2010/06/18. https://doi.
org/10.1056/NEJMoa0911101 PMID: 20554979.
26. Derby CA, Araujo AB, Johannes CB, Feldman HA, McKinlay JB. Measurement of erectile dysfunction in
population-based studies: the use of a single question self-assessment in the Massachusetts Male
Aging Study. Int J Impot Res. 2000; 12(4):197–204. Epub 2000/11/18. PMID: 11079360.
27. Tavakoli M, Malik RA. Corneal confocal microscopy: a novel non-invasive technique to quantify small
fibre pathology in peripheral neuropathies. Journal of visualized experiments: JoVE. 2011;(47). Epub
2011/01/21. https://doi.org/10.3791/2194 PMID: 21248693.
28. Kalteniece A, Ferdousi M, Adam S, Schofield J, Azmi S, Petropoulos I, et al. Corneal confocal micros-
copy is a rapid reproducible ophthalmic technique for quantifying corneal nerve abnormalities. PLoS
One. 2017; 12(8):e0183040. Epub 2017/08/18. https://doi.org/10.1371/journal.pone.0183040 PMID:
28817609.
29. Tavakoli M, Quattrini C, Abbott C, Kallinikos P, Marshall A, Finnigan J, et al. Corneal confocal micros-
copy: a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy. Dia-
betes Care. 2010; 33(8):1792–7. Epub 2010/05/04. https://doi.org/10.2337/dc10-0253 PMID:
20435796.
30. Gallagher LM, Owen LJ, Keevil BG. Simultaneous determination of androstenedione and testosterone
in human serum by liquid chromatography-tandem mass spectrometry. Ann Clin Biochem. 2007; 44(Pt
1):48–56. Epub 2007/02/03. https://doi.org/10.1258/000456307779595922 PMID: 17270092.
31. Owen LJ, Wu FC, Buttler RM, Keevil BG. A direct assay for the routine measurement of testosterone,
androstenedione, dihydrotestosterone and dehydroepiandrosterone by liquid chromatography tandem
mass spectrometry. Ann Clin Biochem. 2016; 53(Pt 5):580–7. Epub 2015/11/22. https://doi.org/10.
1177/0004563215621096 PMID: 26589631.
32. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of
free testosterone in serum. J Clin Endocrinol Metab. 1999; 84(10):3666–72. Epub 1999/10/16. https://
doi.org/10.1210/jcem.84.10.6079 PMID: 10523012.
33. Dehghani C, Pritchard N, Edwards K, Russell AW, Malik RA, Efron N. Risk Factors Associated With
Corneal Nerve Alteration in Type 1 Diabetes in the Absence of Neuropathy: A Longitudinal In Vivo

PLOS ONE | https://doi.org/10.1371/journal.pone.0221992 September 11, 2019 10 / 11

 Male sexual dysfunction in obesity

Corneal Confocal Microscopy Study. Cornea. 2016; 35(6):847–52. Epub 2016/02/05. https://doi.org/10.
1097/ICO.0000000000000760 PMID: 26845318.
34. Dehghani C, Pritchard N, Edwards K, Vagenas D, Russell AW, Malik RA, et al. Morphometric stability of
the corneal subbasal nerve plexus in healthy individuals: a 3-year longitudinal study using corneal con-
focal microscopy. Invest Ophthalmol Vis Sci. 2014; 55(5):3195–9. Epub 2014/04/26. https://doi.org/10.
1167/iovs.14-13959 PMID: 24764058.
35. Klein R, Klein BE, Lee KE, Moss SE, Cruickshanks KJ. Prevalence of self-reported erectile dysfunction
in people with long-term IDDM. Diabetes Care. 1996; 19(2):135–41. Epub 1996/02/01. PMID: 8718433.
36. Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med. 2009; 6(5):1232–47. Epub
2009/02/13. https://doi.org/10.1111/j.1743-6109.2008.01168.x PMID: 19210706.
37. Kim N, Azadzoi KM, Goldstein I, Saenz de Tejada I. A nitric oxide-like factor mediates nonadrenergic-
noncholinergic neurogenic relaxation of penile corpus cavernosum smooth muscle. J Clin Invest. 1991;
88(1):112–8. Epub 1991/07/01. https://doi.org/10.1172/JCI115266 PMID: 1647413.
38. de Tejada IS. Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dys-
function considered difficult or challenging to treat. Int J Impot Res. 2004; 16 Suppl 1:S40–2. Epub
2004/06/30. https://doi.org/10.1038/sj.ijir.3901215 PMID: 15224136.
39. Hatzimouratidis K, Burnett AL, Hatzichristou D, McCullough AR, Montorsi F, Mulhall JP. Phosphodies-
terase type 5 inhibitors in postprostatectomy erectile dysfunction: a critical analysis of the basic science
rationale and clinical application. Eur Urol. 2009; 55(2):334–47. Epub 2008/11/07. https://doi.org/10.
1016/j.eururo.2008.10.028 PMID: 18986755.
40. Srinivas-Shankar U, Roberts SA, Connolly MJ, O’Connell MD, Adams JE, Oldham JA, et al. Effects of
testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-
frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol
Metab. 2010; 95(2):639–50. Epub 2010/01/12. https://doi.org/10.1210/jc.2009-1251 PMID: 20061435.
41. Keevil BG, MacDonald P, Macdowall W, Lee DM, Wu FC, Team N. Salivary testosterone measurement
by liquid chromatography tandem mass spectrometry in adult males and females. Ann Clin Biochem.
2014; 51(Pt 3):368–78. https://doi.org/10.1177/0004563213506412 PMID: 24194586.
42. Vermeulen A, Verdonck G. Representativeness of a single point plasma testosterone level for the long
term hormonal milieu in men. J Clin Endocrinol Metab. 1992; 74(4):939–42. https://doi.org/10.1210/
jcem.74.4.1548361 PMID: 1548361.

PLOS ONE | https://doi.org/10.1371/journal.pone.0221992 September 11, 2019 11 / 11