J C E M
O N L I N E
Hot Topics in Translational Endocrinology—Endocrine Research
The Relationships between Sex Hormones and Sexual
Function in Middle-Aged and Older European Men
Daryl B. O’Connor, David M. Lee, Giovanni Corona, Gianni Forti, Abdelouahid Tajar,
Terence W. O’Neill, Neil Pendleton, Gyorgy Bartfai, Steven Boonen,
Felipe F. Casanueva, Joseph D. Finn, Aleksander Giwercman, Thang S. Han,
Ilpo T. Huhtaniemi, Krzysztof Kula, Fernand Labrie, Michael E. J. Lean,
Margus Punab, Alan J. Silman, Dirk Vanderschueren, Frederick C. W. Wu, and the
European Male Ageing Study Group*
Context: Limited data are available exploring the associations between sex hormones, multiple
domains of sexual functioning, and sexual function-related distress in nonpatient samples in
Europe.
Objectives: The aim of the study was to investigate the relationships between serum testosterone
(T), estradiol (E2), and dihydrotestosterone (DHT) and sexual function in a multicenter populationbased study of aging in men.
Design: Using stratified random sampling, 2838 men aged 40 –79 yr completed the European Male
Ageing Study-Sexual Function Questionnaire and provided a blood sample for hormone measurements. T, E2, and DHT were measured using gas chromatography-mass spectrometry.
Setting: We conducted a community-based population survey in eight European centers.
Main Outcome Measures: Self-reported sexual function (overall sexual function, sexual functionrelated distress, erectile dysfunction, masturbation) was measured.
Results: Total and free T, but not E2 or DHT, was associated with overall sexual function in middleaged and older men. E2 was the only hormone associated with sexual function-related distress such
that higher levels were related to greater distress. Free T levels were associated with masturbation
frequency and erectile dysfunction in the fully adjusted models, such that higher T was associated
with less dysfunction and greater frequency. Moreover, there was a T threshold for the relationship
between total T, sexual function, and erectile dysfunction. At T concentrations of 8 nmol/liter or
less, T was associated with worse sexual functioning, whereas at T levels over 8 nmol/liter, the
relationship came to a plateau.
Conclusions: These findings suggest that different hormonal mechanisms may regulate sexual
functioning (T) vs. the psychological aspects (E2) of male sexual behavior. Moreover, there was
a T threshold for overall sexual function such that at levels greater than 8 nmol/liter the
relationship between T and sexual function did not become stronger. (J Clin Endocrinol Metab
96: E1577–E1587, 2011)
he importance of testosterone (T) for the maintenance
of normal sexual function is well established in young
eugonadal and hypogonadal men (1). However, its role in
the sexual function of aging men remains controversial
T
(2–5). Thus, a recent meta-analysis demonstrated a sizable
and significant impact of T replacement therapy on libido
but a moderate, nonsignificant, and inconsistent effect on
erectile function in older patients (mean age, ⬎50 yr) (6).
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2011 by The Endocrine Society
doi: 10.1210/jc.2010-2216 Received September 20, 2010. Accepted July 11, 2011.
First Published Online August 17, 2011
* Author affiliations are shown at the bottom of the next page.
Abbreviations: BDI, Beck Depression Inventory; BMI, body mass index; CI, confidence
interval; CV, coefficient of variation; DHT, dihydrotestosterone; E2, estradiol; ED, erectile
dysfunction; GC-MS, gas chromatography-mass spectrometry; LLOQ, lower limit of quantification; LOWESS, locally weighted scatterplot smoothing; Overall SF, overall sexual functioning; SF Distress, sexual function-related distress; T, testosterone.
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The bulk of previous research has been conducted in the
United States and focused on patients with erectile dysfunction (ED) using either the International Index of Erectile Dysfunction (IIED) or the single item measure from the
Massachusetts Male Aging Study (5, 7–9). Moreover, few
of the existing instruments have been specifically developed for administration in large, population-based studies
of nonpatient samples, and none of these measures assessed all aspects of sexual functioning [e.g. the IIED (7),
Brief Sexual Function Inventory (10), and the Male Sexual
Health Questionnaire (11) do not assess frequency of sexual intercourse or masturbation]. In addition, many of the
items included in the existing instruments are not appropriate for use in elderly men from the general population,
as opposed to patients seeking medical attention for sexual
or genitourinary complaints.
Recent work has explored the association between a
number of sex hormones, broader aspects of sexual function, and psychological symptoms of male aging (2–5, 12–
14). This has been prompted by the worldwide increase in
the number of men over 65 yr of age, which is predicted to
double between 1980 and 2025 (15), and the appreciation
that sexual function remains a significant part of life in the
elderly population (16, 17). Furthermore, ED has become
a more prevalent disorder, possibly related to the rise in
obesity and vascular diseases (17–19). Because circulating
T declines with aging, androgen deficiency may affect a
number of men at the lower extreme end of the physiological distribution. Although T deficiency is found in patients presenting with ED alone, it is commonly not the
principal cause. Nevertheless, there is an increasing tendency to consider T treatment, especially in those patients
unresponsive to phosphodiesterase type 5 inhibitors (5,
20 –22). Moreover, the practice of using T in the management of ED is currently not supported by an adequate
evidence base. The causal relationship between low T and
ED, unlike loss of sexual interest and spontaneous erection, has not been firmly established, although there is
some preliminary animal experimental evidence that T
may regulate nitric oxide-mediated vasodilation in ex vivo
penile vasculature (5, 17, 23). It is, therefore, important to
further investigate the relationships between T (and other
J Clin Endocrinol Metab, October 2011, 96(10):E1577–E1587
sex hormones) and various domains of sexual function in
a general population sample of men without the substantial biases inherent in patient samples.
Little research has explored the associations between
sex hormones other than T and broader domains of sexual
function such as sexual function-related distress (SF Distress). Recent work has been mixed, but some evidence has
suggested that T metabolites such as estradiol (E2) and
dihydrotestosterone (DHT) may be implicated in the agerelated decline of sexual function (13, 17, 24 –27). For
example, in a randomized, double-blind, placebo-controlled trial, Amory et al. (25) demonstrated that suppression of circulating serum DHT (by 5␣-reductase inhibitors) resulted in modest, but reversible, reduction in sexual
function in men. In addition, to the best of our knowledge,
no previous studies have used mass spectrometry-based
methods [e.g. gas chromatography-mass spectrometry
(GC-MS)] with improved accuracy and precision in serum
T, DHT, and E2 measurements, as recommended by The
Endocrine Society (28), in studies of male sexual function.
Using baseline data from the European Male Ageing
Study (EMAS), an ongoing epidemiological study of aging
in middle-aged and older men, Wu et al. (16) recently
showed that low T was associated with three sexual symptoms (e.g. decreased morning erection, ED, and decreased
frequency of sexual thoughts). However, this work was
focused on developing evidence-based criteria for identifying late-onset hypogonadism in the general population.
In contrast, the current study aimed to examine the relationships between multiple sex hormones (T, E2, and
DHT) measured by GC-MS and all the principal domains
of sexual function [i.e. overall sexual functioning (Overall
SF), SF Distress, masturbation, and ED (29)] in men with
a current sexual partner. A secondary aim was to investigate whether any observed associations could be explained by lifestyle, health, and psychological factors.
Subjects and Methods
Participants and design
Our analyses are based on baseline data from the EMAS, a
prospective, noninterventional cohort study of male aging in
Institute of Psychological Sciences (D.B.O.), University of Leeds, Leeds LS2 9JT, United Kingdom; Arthritis Research UK Epidemiology Unit (D.M.L., A.T., T.W.O., A.J.S.), The University of Manchester,
Manchester M13 9PL, United Kingdom; Andrology Unit (G.C., G.F.), Department of Clinical Physiopathology, University of Florence, 50121 Florence, Italy; School of Community-Based Medicine
(N.P.), The University of Manchester, Hope Hospital, Salford M6 8, United Kingdom; Department of Obstetrics, Gynaecology and Andrology (G.B.), Albert Szent-Gyorgy Medical University, H-6720
Szeged, Hungary; Division of Gerontology and Geriatrics and Center for Musculoskeletal Research (S.B.), Department of Experimental Medicine, Katholieke Universiteit Leuven, 3000 Leuven,
Belgium; Department of Medicine (F.F.C.), Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago, CIBER de Fisiopatología Obesidad y Nutricion (CB06/03), Instituto
Salud Carlos III, 15705 Santiago de Compostela, Spain; Andrology Research Unit (J.D.F., F.C.W.W.), Developmental and Regenerative Biomedicine Research Group, Manchester Royal Infirmary,
The University of Manchester, Manchester M13 9PL, United Kingdom; Reproductive Medicine Center (A.G.), Malmö University Hospital, University of Lund, 221 00 Lund, Sweden; Department
of Endocrinology (T.S.H.), Royal Free and University College Hospital Medical School, Royal Free Hospital, Hampstead, London NW3 2QG, United Kingdom; Department of Reproductive Biology
(I.T.H.), Imperial College London, Hammersmith Campus, London SW7, United Kingdom; Department of Andrology and Reproductive Endocrinology (K.K.), Medical University of Łódź, 90-419
Łódź, Poland; Laboratory of Molecular Endocrinology and Oncology (F.L.), Laval University, Québec, Canada G1V 0A6; Department of Human Nutrition (M.E.J.L.), University of Glasgow, Glasgow
G12 8QQ, United Kingdom; Andrology Unit (M.P.), United Laboratories of Tartu University Clinics, 50406 Tartu, Estonia; and Department of Andrology and Endocrinology (D.V.), Katholieke
Universiteit Leuven, 3000 Leuven, Belgium
J Clin Endocrinol Metab, October 2011, 96(10):E1577–E1587
Europe. Details regarding recruitment, response rates, and assessments have been described elsewhere (30). Briefly, noninstitutionalized men aged 40 –79 yr were recruited from municipal
or population registers in eight centers: Florence, Italy; Leuven,
Belgium; Łódź, Poland; Malmö, Sweden; Manchester, UK; Santiago de Compostela, Spain; Szeged, Hungary; and Tartu, Estonia. For the baseline survey, stratified random sampling was used
with the aim of recruiting equal numbers of men into each of four
age bands (40 – 49, 50 –59, 60 – 69, and 70 –79 yr). Participants
were invited by letter to complete a short postal questionnaire
and to attend a screening at a local clinic. Overall, the mean
response rate for full participation in the study was 41%. The
study was funded by the European Union, and ethical approval
was obtained in accordance with local institutional requirements
in each center, with written informed consent obtained from all
participants. The current analyses focused only on men who
reported having a current sexual partner to explore the relationships between hormone levels and all aspects of sexual function.
Measures
Participants completed a postal questionnaire at baseline that
included information about self-reported health, employment,
education, smoking, and alcohol consumption as well as the
presence of concomitant morbidities (30). The participants also
attended a research clinic to complete an interviewer-assisted
questionnaire and undergo clinical assessments. The questionnaire included the Beck Depression Inventory (BDI)-II (31) and
the EMAS-Sexual Function Questionnaire (EMAS-SFQ) (29).
The latter was completed in private and then placed in a sealable
envelope by the participants without scrutiny by the researchers.
The EMAS-SFQ has been found to exhibit excellent internal and
test-retest reliability, as well as convergent, divergent, and discriminant validity in psychometric analyses (29). It consists of 16
items assessing sexual functioning, SF Distress, and change in
sexual functioning compared with 1 yr ago. Measurements of
height and weight were carried out as described previously (30).
Four of the five domains from the EMAS-SFQ were used in
the present analysis and are summarized in Supplemental Table
1 (published on The Endocrine Society’s Journals Online web site
at http://jcem.endojournals.org). These were: Overall SF, SF Distress, frequency of masturbation, and ED. The change in sexual
functioning domain results was not reported in the current crosssectional study because it was felt that responses to these items
were potentially heavily influenced by retrospective bias and inaccurate recall. The Overall SF and SF Distress scores are all
derived from five self-report items. Items in the Overall SF score
were: frequency of sexual thoughts, sexual intercourse, petting,
morning erection, and orgasm. SF Distress items were worrying
about: frequency of desire, sexual intercourse, erection, morning
erection, and orgasm. Low scores on the Overall SF and higher
scores on the SF Distress scales represent worse sexual functioning. Single item scores were used for frequency of masturbation
and ED (see Supplemental Data).
Hormone measurements
A single fasting morning (before 1000 h) venous blood sample
was obtained, and processed serum was stored at ⫺80 C. A
validated GC-MS system (32) was used to analyze T [1.7 nmol/
liter; lower limit of quantification (LLOQ), 0.17 nmol/liter; in1
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traassay coefficient of variation (CV), 2.9%; interassay CV,
3.4%], E2 (70 pmol/liter; LLOQ, 7.3 pmol/liter; intraassay CV,
3.5%; interassay CV, 3.7%), and DHT (LLOQ, 0.07 nmol/liter;
intraassay CV, 3.1%; interassay CV, 4.1%). All GC-MS analyses
were performed in the Laboratory of Molecular Endocrinology,
Laval University, Quebec. SHBG was measured by the Modular
E170 platform electrochemiluminescence immunoassay (Roche
Diagnostics, Mannheim, Germany) as previously described (33),
with a detection limit of 0.35 nmol/liter and intra- and interassay
CV of 1.7 and 3.2%, respectively. Free T levels were derived from
total hormone, SHBG, and albumin concentrations and using
mass action equations and association constants from Vermeulen et al. (34).1
Statistical analysis
Statistical analyses were performed using Intercooled Stata
version 9.2 (StataCorp, College Station, TX). Subjects without a
sexual partner, with prevalent pituitary or testicular disease, or
those using medications that could directly impact upon pituitary/testicular function (33) were excluded from this analysis.
Hormone levels, age, the BDI, body mass index (BMI), and the
Overall SF score were treated as continuous variables. The SF
Distress scores, frequency of masturbation, and ED were examined as ordinal variables. Bivariate associations of the four
EMAS-SFQ domains with other covariates were examined using
Pearson (rp) or Spearman (rs) correlation.
Linear regression was used to determine the association of
hormones (independent variables) with the Overall SF score (dependent variable) because the Overall SF variable approximated
a normal distribution. Adjustments were made for age, BMI,
center, smoking, alcohol consumption, depression, and number
of morbidities. Results are expressed as ␤-coefficients (␤) and
95% confidence intervals (CI). Because the SF Distress scores,
frequency of masturbation, and ED variables were not normally
distributed, the associations between hormones and these outcomes were explored using ordinal logistic regression (proportional odds models). Ordinal logistic regression is an extension
of logistic regression, and the resulting coefficient for a given
predictor represents the odds of being in a higher outcome category associated with a unit increase in the value of that variable
(35). The SF Distress scores and frequency of masturbation were
each reduced into a three-item ordered response outcome,
whereas the ED variable was retained as a four-item outcome.
Nonviolation of the parallel slope assumption of the ordinal
logistic models was assessed using the Brant test in Stata. A full
summary of EMAS-SFQ variable recoding for the ordinal logistic
regressions is shown in Supplemental Table 2. The ordinal models were also adjusted for the same independent variables used in
the linear regression models, and the results were expressed as
odds ratios and 95% CI. Where significant, independent associations between hormones and sexual function were observed in
the multiple linear regressions or multiple ordinal logistic regressions; an additional model also included the standardized
z-scored hormone. This provided a comparative measure of the
magnitude of the association between each hormone (per SD
change) and the sexual function outcome, independent of the
units of concentration.
In addition, where significant associations were observed between either T or E2 and the Overall SF or SF Distress domains
Note that our results remained unchanged when free T was calculated using the Sartorius formula (47).
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TABLE 1. Baseline characteristics: men with a sexual
partner (n ⫽ 2963)
Age (yr)
BDI-II
BMI (kg/m2)
No. of morbidities
Overall SF
SF distress
Total T (nmol/liter)
Free T (pmol/liter)
Total E2 (pmol/liter)
DHT (nmol/liter)
SHBG (nmol/liter)
Mean (SD)
59.4 (10.9)
6.6 (6.3)
27.6 (4.0)
0.9 (1.1)
19.5 (8.1)
6.7 (3.4)
16.6 (5.9)
293 (87)
73.9 (25.1)
1.3 (0.6)
42.7 (19.8)
Masturbation (ⱖonce/wk)
EDa
Worried about erectile functionb
Current smoker
Alcohol (ⱖ1 d/wk)
Obese (BMI ⱖ30 kg/m2)
Depressionc
Living arrangement
Living with wife
Living with partner
Partner, living apart
Percentiles
(2.5, 97.5)
(6, 33)
(7.4, 30.4)
(145, 485)
(36.2, 133)
(0.4, 2.8)
(16.8, 91.8)
n (%)
471 (17)
802 (28)
931 (33)
629 (21)
1683 (57)
700 (24)
104 (4)
2467 (86)
198 (7)
195 (7)
⬙Sometimes able⬙ to ⬙Never able⬙ to attain an erection good enough
for sexual intercourse.
a
b
⬙A little bit⬙ to ⬙extremely⬙ worried or distressed.
c
BDI-II score ⱖ13 and/or using antidepressant medications.
after multivariable adjustment, the analyses were extended to
explore the relationships between hormone levels (z-scored) and
the individual items making up each domain using ordinal logistic regression.
Results
Participants
A total of 406 participants who had no current sexual
partner, had known pituitary or testicular diseases, or
used medications that could affect pituitary/testicular
functions or sex steroid clearance (33) were excluded from
this analysis. The baseline characteristics of the remaining
2963 men are shown in Table 1. Complete data concerning frequency of sexual activities and erectile function
were available in 2838 and 2830 subjects, respectively.
Among those reporting one or more morbidities (n ⫽
1429), the four most common conditions were hypertension (56%), heart condition (31%), prostate disease
(20%), and diabetes (15%) (see Supplemental Table 3 for
the associations between main morbidities and SF domains). The Overall SF score (rp ⫽ ⫺0.51; P ⬍ 0.001) and
frequency of masturbation (rs ⫽ ⫺0.27; P ⬍ 0.001) were
negatively associated with age, whereas ED (rs ⫽ 0.48; P ⬍
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0.001) was positively associated. Total T (rp ⫽ ⫺0.04; P ⫽
0.04) and free T (rp ⫽ ⫺0.37; P ⬍ 0.001) showed negative,
and total E2 (rp ⫽ 0.12; P ⬍ 0.001), DHT (rp ⫽ 0.05; P ⫽
0.01), and SHBG (rp ⫽ 0.36; P ⬍ 0.001) showed positive
cross-sectional relationships with age. Using a multilevel
regression model, we found that the majority of the hormone variance was due to interindividual variation, and
only around 5% was attributable to contextual effects, i.e.
center, such that 94, 95, and 97% of the variance in T, E2,
and DHT, respectively, was due to interindividual variation. Having shown that the center effect was relatively
minor, we chose to adjust for center in our statistical models, rather than stratify analyses by center.
Hormones and Overall SF
Relationships between Overall SF and T, free T, E2, and
DHT are shown in Table 2. Models are presented unadjusted and adjusted for age, smoking, alcohol consumption, depression, BMI, number of morbidities, and center.
Significant univariate associations were observed between
the Overall SF score and free T (␤ ⫽ 0.02; P ⬍ 0.001) and
total E2 (␤ ⫽ ⫺0.02; P ⬍ 0.01) only. After multivariable
adjustment (model a), higher levels of total T, free T, and
total E2 were significantly associated with a higher Overall SF score. To facilitate comparisons between regression
models, hormones were also z-scored to provide a measure
of the relative magnitude of the association between each
hormone and the Overall SF score, independent of the
units of concentration (model b). For each SD change in
hormone, the association with the Overall SF score was
greatest for free T (␤ ⫽ 0.55; P ⬍ 0.001), and then for total
T (␤ ⫽ 0.37; P ⬍ 0.01) and total E2 (␤ ⫽ 0.25; P ⬍ 0.05).
When the T models were additionally adjusted for total
E2, the results were broadly unchanged (model c). However, when the E2 model was additionally adjusted for
total T, the association was no longer significant. There
was no significant association between the Overall SF
score and DHT. In view of the observed associations between the Overall SF score and higher total and free T, we
also examined the relationship between the five individual
items making up the Overall SF score and z-scored T. The
results of these additional multiple ordinal logistic regressions are summarized in Fig. 1 and show that of the items
making up the Overall SF score, only frequency of petting/
kissing was not associated with T.
Locally weighted scatterplot smoothing (LOWESS)
and spline regression analysis were used to explore whether
there were any obvious threshold effects for the association
of total T with the Overall SF score. The LOWESS plot suggested that there was an inflection point around 8 nmol/
liter total T (Fig. 2). When modeled separately with two
slopes (breakpoint ⫽ 8 nmol/liter) in an age-adjusted
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TABLE 2. Association between hormones and Overall SF: linear regressions
Model
Unadjusted
Total T (nmol/liter)
0.021 (⫺0.026, 0.067)
Free T (pmol/liter)
0.019 (0.016, 0.022)***
Total E2 (pmol/liter) ⫺0.019 (⫺0.030, ⫺0.008)**
DHT (nmol/liter)
⫺0.340 (⫺0.790, 0.110)
Age, lifestyle, healtha
0.063 (0.019, 0.106)**
0.006 (0.003, 0.009)***
0.010 (0.000, 0.020)*
0.385 (⫺0.036, 0.806)
Age, lifestyle, healthb
0.374 (0.115, 0.633)**
0.553 (0.285, 0.821)***
0.252 (0.012, 0.492)*
Age, lifestyle, healthc
0.325 (0.014, 0.637)*
0.557 (0.246, 0.868)***
0.104 (⫺0.185, 0.392)
Data are expressed as ␤ coefficient (95% CI). Analysis excludes subjects without a sexual partner, but with complete item response for Overall SF
domain (n ⫽ 2838).
Adjusted for age, smoking (nonsmoker vs. current smoker), alcohol consumption (⬍1 d/wk vs. ⱖ1 d/wk), depression (BDI score), BMI, number of
morbidities, and center.
a
b
Adjusted for all variables above: hormones z-scored to report Overall SF change per SD change in hormone.
c
T model additionally adjusted for total E2; E2 model additionally adjusted for total T (all hormones z-scored).
*, P ⬍ 0.05; **, P ⬍ 0.01; ***, P ⬍ 0.001.
spline regression, there was a significant difference between the models (P ⬍ 0.001; see Fig. 2 and Supplemental Table 4).
Hormones and SF Distress
Relationships between SF Distress and sex hormones
(ordinal logistic regressions) are summarized in Table 3. A
significant univariate association was observed between
SF Distress and higher total E2 only, which remained after
multivariable adjustment (model a). Using z-scored hormones (model b), the adjusted odds for being in a “higher
distress” group, compared with the reference group (no
distress), increased approximately 10% for each SD increase in total E2. This relationship was unchanged after
additional adjustment for total T (model c). We additionally examined the associations between the five items making up the SF Distress domain and z-scored total E2. Figure
3 summarizes the results of these multiple ordinal logistic
regressions and shows that only distress about the orgasmic experience was not associated with total E2.
LOWESS and spline regression analysis were used
again to explore whether there were any obvious threshold
effects for the association of total E2 with the SF Distress
score. The LOWESS plot suggested that there was no inflection point (data not shown).
FIG. 1. Association of T with Overall SF items. **, P ⬍ 0.01; ***, P ⬍
0.001.
Hormones and masturbation frequency
Relationships between frequency of masturbation and
sex hormones are shown in Table 4. Significant univariate
associations were observed between masturbation frequency and total T and free T, which remained significant
after multivariable adjustment (model a). Using z-scored
hormones (model b), the adjusted odds for being in an
“infrequent masturbation” group compared with the reference group (frequent), decreased between approximately 9 and 16% for each SD increase in total T or free T.
After additional adjustment for total E2, the relationship
between total T and masturbation frequency was no longer significant (model c), whereas the relationship with
free T remained unchanged. There was no relationship
between DHT and frequency of masturbation.
Hormones and ED
Relationships between ED and sex hormones are shown
in Table 5. Significant univariate associations were observed
FIG. 2. Relationship between total T and Overall SF score with
evidence of a T threshold at 8 nmol/liter. LOWESS plot adjusted for
age.
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TABLE 3. Association between hormones and overall SF Distress (3 category variable): ordinal logistic regressions
Model
Total T (nmol/liter)
Free T (pmol/liter)
Total E2 (pmol/liter)
DHT (nmol/liter)
Unadjusted
1.008 (0.996, 1.021)
1.000 (0.999, 1.001)
1.005 (1.002, 1.008)***
1.055 (0.935, 1.189)
Age, lifestyle,
healtha
1.003 (0.988, 1.018)
1.000 (0.999, 1.001)
1.004 (1.001, 1.007)*
1.032 (0.895, 1.189)
Age, lifestyle,
healthb
Age, lifestyle,
healthc
1.098 (1.013, 1.191)*
1.125 (1.021, 1.239)*
Data are expressed as odds ratio (95% CI), with odds ratio of being in a ⬙higher distress⬙ group. Analysis excludes subjects without a sexual
partner, but with complete item response for SF Distress domain (n ⫽ 2717).
a
Adjusted for age, smoking (nonsmokers vs. current smokers), alcohol consumption (⬍1 d/wk vs. ⱖ1 d/wk), depression (BDI score), BMI, number
of morbidities, and center.
b
Adjusted for all variables above: hormones z-scored to report odds ratio per SD change in hormone.
c
E2 model additionally adjusted for total T (all hormones z-scored).
*, P ⬍ 0.05; ***, P ⬍ 0.001.
only between free T (P ⬍ 0.001) and a decreased likelihood
of ED, and between total E2 and an increased likelihood of
ED (P ⬍ 0.001). Only free T and a decreased likelihood of
ED remained significant after multivariable adjustment
(model a). Using z-scored hormones (model b), the adjusted odds for being in the ED group compared with the
reference group (normal erection) decreased approximately 9% for each SD increase in free T. Additional adjustment for total E2 did not change the magnitude of the
association between free T and ED (data not shown).
In keeping with our earlier work reported by Wu et al.
(16), we examined whether there were any obvious threshold effects for the association of total T and likelihood of
ED using spline regression analysis. The results showed
that there was a significant relationship between T and
likelihood of ED at total T concentrations less than or
equal to 8 nmol/liter (P ⬍ 0.01) and that the relationship
came to a plateau at total T levels over 8 nmol/liter.
FIG. 3. Association of total E2 with SF Distress items. Ordinal logistic
regression models adjusted for age, smoking (nonsmoking vs. current),
alcohol consumption (⬍1 d/wk vs. ⱖ1 d/wk), depression (BDI score),
BMI, number of morbidities, and center. Hormones z-scored to report
odds ratio per SD change in hormone. *, P ⬍ 0.05; **, P ⬍ 0.01;
***, P ⬍ 0.001. Analysis excludes subjects without a sexual partner;
hormones z-scored.
Discussion
Three main findings emerged from the current study. First,
T, and not E2 or DHT, was found to be related to Overall
SF in middle-aged and older European men. Second, there
was a T threshold for the relationship between total T,
Overall SF, and ED. Third, E2 was the only hormone associated with SF Distress. Moreover, this is the first study
to simultaneously explore, in community-dwelling men,
all aspects of sexual function including frequency of sexual
behavior activities (pertinent to the wide age range under
study) including libido, masturbation, ED, and distress
while controlling for lifestyle factors (e.g. smoking, alcohol consumption), the presence of morbidities (e.g. heart
disease, diabetes), and the availability of a sexual partner.
To the best of our knowledge, this is also the first study
using a mass spectrometry-based method to measure T,
DHT, and E2 simultaneously in an aging male cohort. We
were able to demonstrate that total T levels were positively
associated with Overall SF but not directly related to masturbation frequency or ED (in our fully adjusted models)
in the entire sample. Importantly, the former finding remained statistically significant after adjusting for total E2
levels, suggesting that T is directly (independent of aromatization or estrogen receptor activation) associated
with sexual function in older men (across the entire physiological range). In terms of other previous communitybased surveys, the Olmsted County study showed that
age-related decline in sexual function was not associated
with reductions in total T (2). Similarly, Ahn et al. (36) in
a sample of aging men reported that total T was not associated with ED, whereas consistent with the current
study, free T levels were related to ED. A likely explanation for these inconsistencies is that the two earlier studies
were underpowered (n ⫽ 294 and 213, respectively) to
detect the relatively small associations observed in the
J Clin Endocrinol Metab, October 2011, 96(10):E1577–E1587
jcem.endojournals.org
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TABLE 4. Association between hormones and frequency of masturbation (3 category variable): ordinal logistic
regressions
Model
Total T (nmol/liter)
Free T (pmol/liter)
Total E2 (pmol/liter)
DHT (nmol/liter)
Unadjusted
0.969 (0.958, 0.981)***
0.995 (0.994, 0.996)***
0.999 (0.996, 1.002)
0.907 (0.804, 1.022)
Age, lifestyle,
healtha
0.983 (0.968, 0.998)*
0.998 (0.997, 0.999)***
0.997 (0.994, 1.001)
0.925 (0.797, 1.073)
Age, lifestyle,
healthb
0.902 (0.825, 0.987)*
0.841 (0.766, 0.922)***
Age, lifestyle,
healthc
0.911 (0.818, 1.015)
0.829 (0.744, 0.923)**
Data are expressed as odds ratio (95% CI), with odds ratio of being in a ⬙lower frequency⬙ group. Analysis excludes subjects without a sexual
partner, but who answered the frequency of masturbation question (n ⫽ 2839).
a
Adjusted for age, smoking (nonsmoker vs. current smoker), alcohol consumption (⬍1 d/wk vs. ⱖ1 d/wk), depression (BDI score), BMI, number of
morbidities and center.
b
Adjusted for all variables above: hormones z-scored to report odds ratio per SD change in hormone.
c
T model additionally adjusted for total E2 (all hormones z-scored).
*, P ⬍ 0.05; **, P ⬍ 0.01; ***, P ⬍ 0.001.
EMAS cohort. Moreover, it is critical to highlight that
although the relationship between total T and Overall SF
was statistically significant in the current investigation, the
magnitude of this association was modest.
However, we also found evidence of a threshold for the
relationship between total T levels and Overall SF and ED
such that at levels less than or equal to 8 nmol/liter, lower
levels of T were associated with worse sexual functioning
(see Supplemental Table 5 for a summary of recent evidence and Refs. 5 and 6 for related reviews). At levels
above 8 nmol/liter, the relationship came to a plateau and
importantly did not become stronger at higher levels of T.
These results are in keeping with our earlier work on the
identification of late-onset hypogonadism (16), whereby
low levels of T were found to be associated with measures
of Overall SF assessed using the EMAS-SFQ. Moreover,
they are in keeping with previous research by Bhasin and
colleagues (37, 38). For example, in an experimental
study, Gray et al. (37) found evidence of a T dose-response
relationship, consistent with the existence of a T threshold
effect, in a sample of older men following suppression of
endogenous T by a long-acting GnRH agonist. In contrast,
an earlier investigation in healthy younger men by the
same group, using a similar experimental design, failed to
show a dose-response relationship between T and sexual
function. Similarly, O’Connor et al. (4) also failed to show
any effects of exogenous T on sexual function in a sample
of healthy young men. Therefore, these findings taken together suggest that: 1) T supplementation will not have
additional beneficial effects on sexual function once T
levels are restored to the normal male range; 2) a T
threshold exists for Overall SF and ED (but not for
petting/kissing) in older men; and 3) the relationship
between T and sexual function may be different in older
compared with younger men. Future research ought to
use well-designed, experimental trials to explore the
precise nature of the relationship between T and sexual
functioning in older and younger men.
We also found that total E2 was the only sex hormone
associated with SF Distress, even after adjusting for T levels, such that higher E2 levels were related to greater distress. This suggests that the observed effects of E2 are
independent of T. Thus, different hormonal mechanisms
may regulate the behavioral (T) vs. the psychological/state
TABLE 5. Association between hormones and ED (4 category variable): ordinal logistic regressions
Model
Total T (nmol/liter)
Free T (pmol/liter)
Total E2 (pmol/liter)
DHT (nmol/liter)
Unadjusted
0.999 (0.988, 1.010)
0.995 (0.994, 0.996)***
1.009 (1.006, 1.012)***
1.111 (0.994, 1.242)
Age, lifestyle, healtha
0.998 (0.984, 1.012)
0.999 (0.998, 1.000)*
1.003 (0.999, 1.006)
1.053 (0.923, 1.202)
Age, lifestyle, healthb
0.910 (0.833, 0.993)*
Data are expressed as odds ratio (95% CI). Analysis excludes subjects without a sexual partner, but who answered the erectile function question
(n ⫽ 2830).
a
Adjusted for age, smoking (nonsmoker vs. current smoker), alcohol consumption (⬍1 d/wk vs. ⱖ1 d/wk), depression (BDI score), BMI, number of
morbidities and center.
b
Adjusted for all variables above: hormones z-scored to report odds ratio per SD change in hormone.
*, P ⬍ 0.05; ***, P ⬍ 0.001.
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O’Connor et al.
Sex Hormones and Sexual Function
(E2) aspects of male sexual functioning, implying that T
treatment is unlikely to provide beneficial effects for SF
Distress. A possible explanation for our findings is that
increasing levels of E2 may be associated with the development of depressed mood related to declining sexual
function in aging men. Some evidence in women has
shown clear associations between estrogen levels, depression, and dysphoric mood (39, 40), albeit in the opposite
direction. However, the importance of E2 in depression in
women remains controversial, and it is acknowledged that
the findings are not uniform (41). To the best of our
knowledge, no studies have provided evidence of either a
positive or negative relationship between total E2 and depression in aging men (42). For example, in a sample of
community-dwelling older men, Barrett-Connor et al.
(42) showed that total E2 was not associated with depressed mood (measured using the BDI), whereas low T
was associated with depression. This null finding may reflect that, similar to women, the relationship between E2
and depression is also not uniform in men and/or highlights that other mechanisms might explain the current
observed relationship. Age-related increases in E2 may
lead to subtle changes in global assessments of sexual function such as satisfaction (not measured in the current
study), which may have knock-on effects on the psychological aspects of sexual functioning.
Nonetheless, our finding is consistent with that of
Basar et al. (13) who showed that low total (and free) T
was associated with sexual symptoms of aging (e.g. impaired potency, ED), whereas E2 was positively correlated with the psychological symptoms (e.g. depressed,
irritable, anxious) of male aging. It is also noteworthy
in the current analyses that the association between E2
and SF Distress persisted after controlling for depression levels (assessed using the BDI) and that E2 levels
were not associated with BDI scores (data not shown).
Therefore, the current data cannot rule out the possibility
that higher E2 levels are associated with the development
of subclinical levels of depression (not measured by the
BDI) or negative mood related to declining sexual function. Previous studies on E2 in men using immunoassays
were potentially hampered by assay imprecision and variability so that data, particularly in aging men, may not
always be reliable. Our current results using GC-MS are
less likely to suffer from these potential assay problems.
Future research should employ mass spectrometry measurements to further explore the relationships between E2
and SF Distress and measures of clinical and subclinical
depression [e.g. the profile of mood states has been used
successfully in older populations (43)].
In terms of clinical studies, evidence from case studies
of men with aromatase deficiency suggests that E2 may
J Clin Endocrinol Metab, October 2011, 96(10):E1577–E1587
play a role in male sexual activity. Carani et al. (44) have
observed that normal sexual function was restored in an
aromatase-deficient man only after estrogen (and not T)
treatment. More recently, the same group reported that
sex drive was returned to normal levels in another man
with aromatase deficiency and hypogonadism when both
T and E levels (and not T alone) were returned to the
normal range (45). Therefore, in addition to T, it is possible that optimal levels of E2 are also required to maintain
different aspects of sexual function in aging men (similar
to components of cognitive function; see Ref. 46). If this is
the case, then it is feasible that higher and lower levels of
E2 would be associated with negative effects on sexual
activities and experience.
The findings in relation to free T require further comment. We found that free T levels were associated with ED
and masturbation frequency, such that high T was related
to less dysfunction and greater frequency in the fully adjusted models. We recognize that the use of calculated
hormones such as free T is controversial and that recent
studies have demonstrated that empirical formulae (such
as the Vermeulen method) overestimate free T relative to
laboratory measurement by equilibrium dialysis [e.g. Sartorius et al. (47); Ly et al. (48)]. For example, Ly and
colleagues, comparing the accuracy of five different methods, showed that the two empirical equations used by Sartorius et al. (47) and Ly et al. (48) consistently performed
better than the equilibrium-binding methods used by Vermeulen et al. (34) and Södergård et al. (49) as well as
another empirical formula published by Nanjee and
Wheeler (50). These issues notwithstanding, in the current
study, we have presented our results using the Vermeulen
method to allow direct comparisons with our previous
findings and other published studies. Moreover, it is important to note that our results remained unchanged when
free T was calculated using the Sartorius formula. It is also
possible that the calculation of free T is confounded by
age, given that SHBG is itself largely age dependent, and
as a result, the free hormone represents age in a covert
form. A number of factors indicate that this is not the
case. In our preliminary analyses, collinearity diagnostics between the predictor variables (e.g. age, hormones)
were found to be low (i.e. all variance inflation factors
were around 1.5), indicating an absence of multicollinearity. In addition, the ␤-coefficient between SHBG and age
was also small, signifying that although the relationship
was statistically significant, only 14% of the variance in
SHBG was explained by age. Nevertheless, we cannot
completely rule out the possible confounding by age of the
observed relationship between free T, masturbation, and
ED, and future researchers ought to be mindful of the
potential limitation.
J Clin Endocrinol Metab, October 2011, 96(10):E1577–E1587
The main strengths of our study are that it was based on
a large sample of community-dwelling men and used uniform methods to assess sexual function, hormone levels,
and putative confounders. In addition, it employed a stateof-the-art GC-MS methodology for measuring serum T,
E2, and DHT levels simultaneously. Practical limitations
inherent to the EMAS have been described previously (30),
although a number of specific factors need to be considered here. The overall response rate for participation in the
study was 41%. Those who participated may have differed, with respect to levels of sexual function/distress and
also sex hormone status, from those who did not participate, and some caution is therefore needed in interpreting
these data. The main findings, however, were based on
internal association among responders, which reduces the
risk that selection factors had any important effect on
these results. The cross-sectional data cannot offer any
explanation for the observed associations or the temporal
nature of these relationships. There remains the possibility
that some of our findings may be due to unmeasured factors, residual confounding, and/or misclassification bias
from self-reported lifestyle factors (e.g. smoking status). In
addition, we recognize that the EMAS-SFQ is a self-report
instrument, and therefore responses to its questions may
be influenced by extraneous variables (e.g. quality of the
sexual relationship with the man’s partner), and it may not
capture all the subtleties of a man’s sexual relationship
with his partner. We are also mindful that the Overall SF
domain may not always be sensitive to detecting sexual
dysfunction; however, the EMAS-SFQ does include an established measure of ED. These potential shortcomings
notwithstanding, it is important to bear in mind that the
instrument has excellent psychometric properties, is sensitive to variations in sex hormones, and was specifically
developed to assess all aspects of sexual functioning in
community-dwelling middle-aged and older men.
In conclusion, using GC-MS, this study showed that T,
and not E2 or DHT, was associated with Overall SF in
middle-aged and older European men. E2 was the only sex
hormone related to SF Distress. Free T, but not total T, was
associated with ED or masturbation frequency in the fully
adjusted models. Moreover, there was a T threshold for
the relationship between total T, sexual function, and ED.
At total T concentrations less than or equal to 8 nmol/liter,
T was associated with worse sexual functioning, whereas
at total T levels over 8 nmol/liter, the relationship came to
a plateau. The magnitude of the observed associations was
modest, and the relationship between T and Overall SF did
not become stronger at higher levels of T. Prospective data
may well provide clues to the directionality of these associations, although cause and effect can only be satisfacto-
jcem.endojournals.org
E1585
rily addressed with well-designed and sufficiently powered interventional trials.
Appendix
The EMAS Study Group: Florence—Gianni Forti, Luisa
Petrone, and Giovanni Corona; Leuven—Dirk Vanderschueren, Steven Boonen, and Herman Borghs; Łódź—
Krzysztof Kula, Jolanta Slowikowska-Hilczer, and Renata Walczak-Jedrzejowska; London—Ilpo Huhtaniemi;
Malmö—Aleksander Giwercman; Manchester—Frederick Wu, Alan Silman, Neil Pendleton, Terence O’Neill,
Joseph Finn, Philip Steer, Abdelouahid Tajar, David Lee,
and Stephen Pye; Santiago—Felipe Casanueva, and Mary
Lage; Szeged—Gyorgy Bartfai, Imre Földesi, and Imre
Fejes; Tartu—Margus Punab, and Paul Korrovitz; and
Turku—Min Jiang.
The authors thank the men who participated in the
eight countries and the research/nursing staff in the eight
centers: C. Pott (Manchester), E. Wouters (Leuven), M.
Nilsson (Malmö), M. del Mar Fernandez (Santiago de
Compostela), M. Jedrzejowska (Łódź), H.-M. Tabo
(Tartu), and A. Heredi (Szeged) for their data collection;
and C. Moseley (Manchester) for data entry and project
coordination.
Acknowledgments
Address all correspondence and requests for reprints to: Daryl
B. O’Connor, Institute of Psychological Sciences, University
of Leeds, Leeds LS2 9JT, United Kingdom. E-mail:
d.b.o’[email protected].
The European Male Aging Study is funded by the Commission of the European Communities Fifth Framework Program
“Quality of Life and Management of Living Resources” Grant
QLK6-CT-2001-00258. Additional support was also provided
by Arthritis Research UK. The sponsor had no role in the study.
S.B. is senior clinical investigator of the Fund for Scientific
Research, Flanders, Belgium (F.W.O.–Vlaanderen). D.V. is a senior clinical investigator supported by the Clinical Research
Fund of the University Hospitals Leuven, Belgium.
Disclosure Summary: The authors have nothing to disclose.
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