Testosterone is associated with erectile dysfunction: a cross-sectional study in Chinese men.

Abstract

Testosterone is essential for the regulation of erectile physiology, but the relationship between low testosterone and erectile dysfunction (ED) has not been firmly established.
To examine the association between serum total, free and bio-available testosterone and ED in a population-based sample.
A consecutive series of 1776 men aged 20-77 participated in the routine physical examination from September 2009 to December 2009 in Guangxi, China. ED was assessed using the five-item International Index of Erectile Function (IIEF-5) questionnaire. Total testosterone (TT), sex hormone binding globulin (SHBG) and other biochemical profiles were measured. Free testosterone (FT) and bio-available testosterone (BT) were calculated based on Vermeulen's formula. Data were collected with regard to smoking, alcoholic drinking, physical activity and metabolic syndrome.
The prevalence of ED (IIEF-5<22) was 47.6%. Men with ED were significantly older, and more prone to smoke cigarettes (≥20 cigarettes/day) or drink alcohol (≥3 drinks/week), and more likely to have elevated blood pressure (P = 0.036) or hyperglycemia (P<0.001) compared with those without ED. The significant increase in SHBG with age was parallel to its increase with increasing severity of ED (P<0.001). The obscure increase in TT across the ED status was detected without significance (P = 0.418), but TT was positively associated with ED after adjustment for age [odds ratio (OR)  = 1.02, 95% CI (confidence internal): 1.00-1.04]. FT and BT were inversely associated with ED (OR = 0.14, 95%CI: 0.06-0.33; OR = 0.92 (95%CI: 0.89-0.96, respectively) in the univariate analysis, and this inverse association appeared to be independent of smoking status, alcoholic drinking, physical activity, hyper-triglyceridemia and hyperglycemia.
FT and BT are inversely related to worsening ED, whereas the positive association between TT and ED is most likely due to the increase in SHBG.

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Testosterone Is Associated with Erectile Dysfunction: A
Cross-Sectional Study in Chinese Men
Ming Liao1,2., Xianghua Huang7,2., Yong Gao1,2,6, Aihua Tan2,3, Zheng Lu1,2, Chunlei Wu1,2,
Youjie Zhang1,2, Xiaobo Yang2,4, Haiying Zhang2,4, Xue Qin2,5, Zengnan Mo1,2*
1Institute of Urology and Nephrology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China,
2Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China, 3Center for
Metabolic Disease and Diabetes, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China,
4Department of Occupational Health and Environmental Health, School of Public Health of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region,
People’s Republic of China, 5Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region,
People’s Republic of China, 6Fudan-VARI Center for Genetic Epidemiology, School of Life Science, Fudan University, Shanghai, People’s Republic of China, 7Urology
Department, Guigang People’s Hospital, Guigang, Guangxi Zhuang Autonomous Region, People’s Republic of China
Abstract
Background: Testosterone is essential for the regulation of erectile physiology, but the relationship between low
testosterone and erectile dysfunction (ED) has not been firmly established.
Purpose: To examine the association between serum total, free and bio-available testosterone and ED in a population-
based sample.
Methods: A consecutive series of 1776 men aged 20–77 participated in the routine physical examination from September
2009 to December 2009 in Guangxi, China. ED was assessed using the five-item International Index of Erectile Function (IIEF-
5) questionnaire. Total testosterone (TT), sex hormone binding globulin (SHBG) and other biochemical profiles were
measured. Free testosterone (FT) and bio-available testosterone (BT) were calculated based on Vermeulen’s formula. Data
were collected with regard to smoking, alcoholic drinking, physical activity and metabolic syndrome.
Results: The prevalence of ED (IIEF-5,22) was 47.6%. Men with ED were significantly older, and more prone to smoke
cigarettes ($20 cigarettes/day) or drink alcohol ($3 drinks/week), and more likely to have elevated blood pressure
(P=0.036) or hyperglycemia (P,0.001) compared with those without ED. The significant increase in SHBG with age was
parallel to its increase with increasing severity of ED (P,0.001). The obscure increase in TT across the ED status was detected
without significance (P=0.418), but TT was positively associated with ED after adjustment for age [odds ratio (OR) =1.02,
95% CI (confidence internal): 1.00–1.04]. FT and BT were inversely associated with ED (OR=0.14, 95%CI: 0.06–0.33; OR=0.92
(95%CI: 0.89–0.96, respectively) in the univariate analysis, and this inverse association appeared to be independent of
smoking status, alcoholic drinking, physical activity, hyper-triglyceridemia and hyperglycemia.
Conclusions: FT and BT are inversely related to worsening ED, whereas the positive association between TT and ED is most
likely due to the increase in SHBG.
Citation: Liao M, Huang X, Gao Y, Tan A, Lu Z, et al. (2012) Testosterone Is Associated with Erectile Dysfunction: A Cross-Sectional Study in Chinese Men. PLoS
ONE 7(6): e39234. doi:10.1371/journal.pone.0039234
Editor: Moray Campbell, Roswell Park Cancer Institute, United States of America
Received February 8, 2012; Accepted May 17, 2012; Published June 21, 2012
Copyright: ? 2012 Liao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The work described in this article is supported by grants from the National Natural Science Foundation of China (Grant No. 30945204) and the
Provincial departments of Finance and Education, Guangxi Zhuang Autonomous Region, China (Grant No. 2009GJCJ150). The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: zengnanmo@hotmail.com
. These authors contributed equally to this work.
Introduction
Erectile dysfunction (ED) is a highly prevalent disorder among
men all around the world [1–3], and possibly related to the rise in
diabetes and vascular diseases [4]. Its incidence increases with age,
and the ageing process in men is accompanied by a progressive
decline in serum testosterone levels. Although testosterone
deficiency is often found in patients presenting with ED alone, it
is commonly not the principal cause [5]. Nevertheless, testosterone
is increasingly considered in the clinical setting to treat ED [6],
especially in those patients unresponsive to phosphodiesterase type
5 inhibitors, and often results in an improvement in sexual
function [7]. Although there is some preliminary animal exper-
imental evidence that testosterone is essential for the regulation of
erectile physiology by multiple mechanisms [8], the causal
relationship between low testosterone and ED has not been firmly
established [5]. It is, therefore, important to further investigate the
relationships between testosterone and erectile function, especially
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in a general population without the substantial biases inherent in
patient samples.
Previously in a sample of Korean men with lower urinary tract
symptoms [9], free testosterone (FT) was correlated with erectile
function,consistent with the later
testosterone (TT) was not correlated with any of the five
domains of the international Index of Erectile Function (IIEF). In
terms of other previous surveys, neither correlation between TT
and ED risk nor with ED severity was demonstrated in studies of
Brazil [11,12], Turkey [13,14] and Italy [15], though low TT
was associated with sexual dysfunction more often in the oldest
subjects [16]. With respect to bio-available testosterone (BT), it
was correlated well with the erectile function assessed by IIEF-5
score in the sample of 130 outpatients from Japan [17]. And it
was reported in the Olmsted County study, the age-related
decline in sexual function was due to age-related declines in
levels of BT rather than TT levels [18]. It is only fairly recently
that testosterone threshold for the relationship between TT and
ED has been found in European Male Ageing Study (EMAS) [5].
We conclude that the frustration to clarify the relationship
between testosterone and ED in previous studies is probably due
to the different provenances of studied population or the
underpowered sample size. Moreover, to best of our knowledge,
unhealthy lifestyles such as cigarette smoking, alcoholic drinking
and physical activity [19], as well as the metabolic syndrome
consisting of a myriad of abnormalities including central obesity,
glucose intolerance, dyslipidemia, and hypertension [20] have
been associated with ED, but few studies considered these
factors. It is, therefore, in order to further evaluate the
relationship between testosterone and ED with the consideration
of these confounders of ED, that we conducted this cross-
sectional study in a large series of Chinese men from general
population.
study [10], but total
Materials and Methods
Study Population
Our analyses are based on the Fangchenggang Area Male
Health and Examination Survey (FAMHES), which was designed
to investigate the effects of environmental and genetic factors and
their interaction with the development of age-related chronic
diseases [21–23]. Briefly, the FAMHES was a population-based
study conducted among non-institutionalized Chinese men aging
from 17 to 88 years old in Guangxi, China. A comprehensive
demographic and health survey was conducted among a
consecutive series of 4303 men participating in the routine
physical examination at the Medical Centre in Fangchenggang
First People’s Hospital from September 2009 to December 2009.
A total of 3,593 people completed the data collection interviews.
There were no significant differences between these people and
those who did not complete the interviews. The response rate was
83.5% [23], and all the participants provided written informed
consents. The survey received the approval from ethics committee
in Guangxi Medical University.
In the current cross-sectional study, participants were excluded
based on the following criteria: (1) currently diagnosed with
myocardial infarction, congestive heart failure, stroke, hyperthy-
roidism, rheumatoid arthritis, acquired immune deficiency
syndrome and any kind of cancer, or with a history of pelvic
trauma/surgery or suffering significant urinary tract infection; (2)
in current treatment with herbal remedies, or with medication
including psychotropic drugs, non-steroidal anti-inflammatory
drugs, antibiotics, spironolactone, cimetidine, glucocorticoids or
other steroidal drugs which might affect the testosterone level or
drugs with effect on erectile physiology, such as dopamine-
antagonists, diuretics and so on; (3) men without regular sexual
experiences during six months preceding completion of the
International Index of Erectile Function (IIEF-5) questionnaire
or men with absence of sex hormones measurements; (4) who
drank beer, wine or hard liquor the day before serologic
examination. A flow chart indicating the process of enrolling
was showed in Figure 1. We finally enrolled 1,776 men aged 20–
77 years in the present study.
Data Collection
ED was defined using the IIEF-5, a self-administered and
validated instrument widely used in both clinical and epidemi-
ologic studies [24]. The five items assess erection confidence,
erection firmness, maintenance ability, maintenance frequency,
and satisfaction. Each item is scored on a 5-point ordinal scale
where lower values represent poorer sexual function. The IIEF-5
score ranges between 5 and 25 with lower scores indicating
increased severity of ED. ED status was classified into five
categories as none (IIEF-5 score 22–25), mild (17–21), moderate
(12–16), and severe (5–11). Additionally, ED was defined as a
dichotomous variable using a cut-off point of IIEF-5,22 (mild,
moderate, and severe). This approach is similar to the definition
Figure 1. Flow chart of recruitment in the present study.
doi:10.1371/journal.pone.0039234.g001
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of ED used in the Boston Area Community Health (BACH)
Survey [25].
A complete physical examination including the measurement of
waist circumference and blood pressure (BP) was performed on
each subject. Waist circumference was measured at the midpoint
between the inferior costal margin and the superior border of iliac
crest on midaxillary line. BP was measured twice after resting for
more than 15 min, with the mercury sphygmomanometer by well-
trained nurses, and the average values were taken. Metabolic
syndrome was defined based upon the updated report of National
Cholesterol Education Program Adult Treatment Panel III (NCEP
ATPIII criteria) for Asian Americans as having three or more of
the following components: (1) waist circumference at least 90 cm,
(2) triglycerides at least 1.7 mmol/L, (3) high-density lipoprotein
cholesterol (HDL-C) less than 1.03 mmol/L, (4) BP at least 130/
85 mm Hg, (5)fasting glucose at least 5.6 mmol/l [26]. Smoking
status was defined as never smoker, former smoker (cessation of
smoking .6 months) and current smoker (daily smoking .6
moths) [27]. Current smokers were further divided into two groups
(,20 cigarettes/day and $20 cigarettes/day) [28]. Physical
activities were measured by weekly total activities; men with
regular exercise $2 h/week were considered physically active
[29]. Alcoholic drinkers were defined as those who had ever
consumed three or more drinks (beer, wine, and hard liquor)
weekly and done so for six consecutive months [30].
Serum Assay
The description of the laboratory test has been previously
reported in detail [21,22]. Briefly, about 10 ml overnight fasting
venous blood specimens were collected between 8:00 and 11:00 in
the morning and were transported frozen to the testing center of
Department of Clinical Laboratory at the First Affiliated Hospital
of Guangxi Medical University in Nanning in two hours, which
were centrifuged within 15 to 25 minutes and stored at 280C until
analysis. Triglycerides, HDL-c, and serum glucose were measured
enzymatically on a Dimension-RxL Chemistry Analyzer (Dade
Behring, Newark, DE) in the Department of Clinical Laboratory
at the Fangchenggang First People’s Hospital. Serum TT and sex
hormone binding globulin (SHBG) were measured with electro-
chemiluminescence immunoassay on COBAS 6000 system
E601(Elecsys module) immunoassay analyzer (Roche Diagnostics,
GmbH, Mannheim, Germany) with the same batch of reagents,
and the inter-assay coefficient of variation was 3.6% and 4.4%,
respectively. BT and FT were calculated from a validated formula
based on equilibrium-binding theory suggesting good agreement
with laboratory assay [31,32].
Statistical Analysis
All statistical analyses were performed using SPSS version 18.0
software (SPSS Inc., Chicago, IL, USA). The continuous
variables were examined by Shapiro-Wilks test. Sex hormones
including TT, FT, BT and SHBG, not conforming to a normal
distribution, were logarithmically transformed in the following
analysis, whereas the back-transformed values were reported.
Categorical variables were presented with frequencies and
proportions. Baseline characteristics were compared between
cases (ED) and controls (non-ED) with Mann–Whitney u-test and
x2 test where appropriate. The sample was divided into four
groups according to each decade of age: 20–30 (N=540), 31–40
(N=682), 41–50 (N=346), $51–60 (N=198). ED status was
classified into four categories as none (N=931), mild (N=621),
moderate (N=169), and severe (N=55). Changes of testosterone
and SHBG levels across the four age groups or ED status were
evaluated by one-way analysis of variance (ANOVA), thus
Student-Newman-Keuls test was used for multiple comparisons.
Correlations of age with sex hormones including TT, FT, BT
and SHBG were examined via Spearman correlation analyses.
When IIEF-5 score was used as a continuous variable to indicate
the increased severity of ED, the linear regression models were
used to assess the association between testosterone and IIEF-5.
Analyses were repeated in the binary logistic regression models
when ED was defined as a dichotomous variable using a cut-off
point of IIEF-5,22. Both the linear regression and the binary
logistic regression were constructed in unadjusted, age-adjusted
and multivariate adjusted models. The multivariate adjusted
model included the following covariates: age, smoking status,
alcoholic drinking, physical activity, hypertriglyceridemia, hyper-
glycemia, elevated BP, low HDL-C and central obesity.
Statistical tests were two-tailed, and a P value,0.05 was
considered statistically significant.
Table 1. Characteristics of the analysis sample at baseline in
FAMHES*.
Erectile Dysfunction
YesNoP
Number845 931
Age{- year40 (31–47)35(28–40)
,0.001
Race Han - % 760 (89.9)820 (88.1)0.72
TT{- nmol/l20.561.4 20.061.40.212
FT{- nmol/l0.3960.10.4160.10.006
BT{- nmol/l 9.361.3 9.761.30.007
SHBG{-nmol/l38.961.3634.961.6
,0.001
Cigarette smoking - %0.05
Never smoker 388 (45.9)422 (45.3)
Former smoker44 (5.2)27 (2.9)
,20 cigarettes per day 178 (21.1)225 (24.2)
$20 cigarettes per day 235 (27.8) 257 (27.6)
Alcoholic drinking - %0.022
Never drinker 134(15.9) 107 (11.9)
,3 drinks per week 567 (67.1)668 (74.1)
$3 drinks per week 144 (17.0) 156 (17.3)
Physical activities - % 0.922
,2 hours per week 630 (74.6)696 (74.8)
$2 hours per week 215 (25.4)235 (25.2)
Metabolic Syndrome - %104 (12.4)97 (10.5) 0.207
Hypertriglyceridemia 232 (27.5)271 (29.2)0.407
Hyperglycemia248 (29.3) 199 (21.4)
,0.001
Elevated BP189 (22.4) 171 (18.4)0.036
Low HDL-C57 (6.7) 74 (8.0)0.32
Central obesity 148 (17.7)167(18.0)0.855
{Age was present as median values (25–75th percentile); sex hormones
including TT, BT and SHBG were logarithmically transformed in the following
analysis and reported as back-transformed arithmetic mean values 6 SD
(standard deviation).
*FAMHES= the Fangchenggang Area Male Health and Examination Survey,
TT=total testosterone, FT=free testosterone, BT=bioavailable testosterone,
SHBG=sex hormone-binding globulin, BP=blood pressure, HDL-C=high-
density lipoprotein cholesterol. TT and FT values divide by 3.467 can be
converted to ng/ml.
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Figure 2. Prevalence of ED increases with age.
doi:10.1371/journal.pone.0039234.g002
Figure 3. Testosterone and SHBG levels across ages and ED status. Panels A and B. Changes of TT, SHBG, FT, BT by each decade of age;
Panels C and D. Association of TT, SHBG, FT, BT with ED status. P value is obtained by one-way analysis of variance (ANOVA). Student-Newman-Keuls
test is used for multiple comparisons; asterisk in panels A and B stands for P,0.05 compared with the 20–30 yr age group, whereas in panels C and D
stands for P,0.05 compared with the none-ED group. Dots represent median values of sex hormones, while bars represent the 25–75th percentiles.
Abbreviations: ED, erectile dysfunction; SHBG, sex hormone-binding globulin; TT, total testosterone; FT, free testosterone; BT, bioavailable
testosterone. Testosterone value.
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Results
General Characteristics of the Studied Sample
Characteristics of the 1,776 men in our study were presented in
Table 1. There were 47.6% of men with ED (IIEF-5,22).
Between the ages of 20 and 77, the prevalence of mild ED
increased from 28.7% to 42.3%, moderate ED increased from
6.5% to 24.2%, and severe ED increased from 1.7% to 10.1%. As
showed in Figure 2, prevalence of ED increased with age.
The median age of ED group was 40 (Table 1). Men in ED
group were significantly older than men in non-ED group
(P,0.001). The proportion of men with smoking or drinking
showed very little differences between ED group and non-ED
group (P=0.050, P=0.018). The proportion of men with regular
exercise $2 h/week did not show significant difference between
ED group and non-ED group (P=0.922). Regarding the
components of metabolic syndrome, men with ED were more
prone to have elevated BP (P=0.036) and hyperglycemia
(P,0.001).
Both FT and BT were inversely correlated with age (both
r=20.482, P,0.001). Although TT was inversely correlated with
age as well (r=20.169, P,0.001), its reduction across the age
groups was relatively small in absolute terms (Figure 3). Both FT
and BT gradually increased with advancing age (P,0.001),
parallel to its decrease with increasing severity of ED (P,0.0
01). Similarly, SHBG gradually increased with advancing age
(P,0.001), parallel to its increase with increasing severity of ED
(P,0.0 01). However, the significant decrease of TT across the age
(P,0.0 01) groups was not parallel with its obscure increase across
the ED status (P=0.418).
Association between Testosterone and ED
Table 2 presented the unadjusted, age-adjusted, and multivar-
iate adjusted association between TT, FT, BT and ED. TT was
inversely associated with IIEF-5 after adjusting for age [b=20.05;
95% confidence interval (CI): 20.08, 20.03], and it was
associated with a risk of ED in the age-adjusted model [odds
ratio (OR) =1.02, 95% CI: 1.00–1.04]. After adjusting the
following variables including smoking status, alcoholic drinking,
physical activity, hypertriglyceridemia, hyperglycemia, elevated
BP, low HDL-C and central obesity, the positive association
between ED and TT remained significant.
FT and BT were positively associated with IIEF-5 scores
(b=3.81 and 95%CI: 2.29–5.34, b=0.16 and 95%CI: 0.09–0.22,
respectively), however, the positive associations were not statisti-
cally significant after adjusting for age (Table 3). In the unadjusted
model of binary logistic regression analysis, FT was associated with
ED with an OR of 0.14 (95%CI: 0.06–0.33), and BT was
associated with ED with an OR of 0.92 (95%CI: 0.89–0.96). The
inverse associations between FT, BT and ED were still observed in
subgroup analysis (Table 3); however, in men with elevated BP,
low HDL-C or central obesity, the association was detected
without statistical significance.
Discussion
The present study in a large series of Chinese men from general
population reveals that serum levels of FT and BT are decreased
with age, whereas TT do not change much with age presumably
because the SHBG increases as well. FT and BT are inversely
related to worsening ED, whereas the positive association between
TT and ED is most likely due to the increase in SHBG.
The ED prevalence of our studied sample was 47.6%, closed to
the prevalence of 49.4% in the primary care setting [4], 52% in
Massachusetts Male Aging Study (MMAS) [33] and 47% in
BACH Survey [25]. The IIEF-5 instrument was previously used in
China [34], and it was reported that among Chinese men above
40 the prevalence of ED was 40.2% [3]. Additionally, the BACH
survey has demonstrated the contribution of modifiable lifestyle
factors (physical activity, smoking, and alcohol consumption) to the
prevalence of ED [25]. Consistent with the results from BACH
[28], we have reported that heavy smokers ($20 cigarettes/day)
had a significantly increased risk of ED than never smokers [23],
which had some implications in the present study. Moreover,
previous studies have reported that current smokers, alcoholic
drinkers had a higher level of FT, and physical activity was
positively associated with FT [27], however, in the subgroup
analysis of our study, the effect of these lifestyles did not attenuate
the inverse association between ED and FT or BT. Similarly, the
inverse association between ED and FT or BT appeared to be
independent of hypertriglyceridemia and hyperglycemia, whereas
in groups with elevated BP, low HDL-C or central obesity, it
might be underpowered to detect the relatively small associations
observed in other groups.
Table 2. Association between testosterone and ED in the multivariate regression analysis{.
IIEF-5 scores
UnadjustedAge-adjustedMultivariate adjusted{
TT
20.03(20.51, 0.00); P=0.065
20.05(20.08, 20.03); P,0.001
20.04(20.07, 20.01); P=0.006
FT3.81 (2.29, 5.34); P,0.001
20.88(22.48, 0.72); P=0.283
20.78(22.38, 0.83); P=0.344
BT 0.16(0.09, 0.22); P,0.001
20.04(20.10, 0.03); P=0.276
20.03(20.10, 0.03); P=0.347
Erectile dysfunction
UnadjustedAge-adjusted Multivariate adjusted{
TT1.01(1.00, 1.03); P=0.1511.02(1.01, 1.04); P=0.0021.02(1.00, 1.04); P=0.021
FT0.14 (0.06, 0.33); P,0.0011.05(0.41, 2.68); P=0.9210.98(0.38, 2.55); P=0.988
BT0.92 (0.89, 0.96); P,0.0011 (0.96, 1.04); P=0.9031 (0.96, 1.04); P=0.992
{Multivariate adjusted for age, smoking status, alcoholic drinking, hypertriglyceridemia, hyperglycemia, elevated BP, low HDL-C and central obesity. Linear regression is
conducted using the IIEF-5 score as a continuous variable, whereas the binary logistic regression is conducted using ED defined as a dichotomous variable using a cut-
off point of IIEF-5,22. ED=erectile dysfunction; IIEF-5=5-item International Index of Erectile Function; TT=total testosterone; FT=free testosterone; BT=bioavailable
testosterone; BP=blood pressure, HDL-C=high-density lipoprotein cholesterol.
doi:10.1371/journal.pone.0039234.t002
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