Following approval by the institutional review board, we retro-
spectively reviewed the charts of a total of 3167 men seen
consecutively between May 2013 and July 2014 who complained
of symptoms of
low testosterone.
Men using testosterone or
other androgenic anabolic steroids within 6 months of the time of
the survey were excluded. We also excluded men who had pre-
sented with a primary diagnosis of infertility, Klinefelter syn-
drome, or secondary hypogonadism after appropriate assessment
of history and endocrine evaluation with gonadotropins.
All men answered the Androgen De
ciency in the Adult Male
(ADAM) and quantitative ADAM (qADAM) questionnaires,
and their testosterone levels were measured on the same day. The
ADAM questionnaire consists of 10 yes/no questions regarding
hypogonadal symptoms. The qADAM questionnaire quanti
the severity of the symptoms on a 1-5 scale (range from 10 to 50).
All venous blood samples were obtained under standardized
conditions before 10AM from fasting patients. Serum or plasma was
separated at 800
. T and SHBG measurements were taken using
the enzyme immunoassay Beckman Access II platform (Beckman
Coulter, Fullerton, CA). FT was calculated on the basis of T and
SHBG using the Vermeulen formula.
FT levels were
tted on a
scatter plot to determine in
ection points and threshold levels.
Data were analyzed using Microsoft Excel (Microsoft, Red-
mond, WA) and SPSS. A Q-Q test was performed to verify that
the variables were normally distributed. Univariate and multi-
variable analyses were performed for age, T, and the 10 symp-
toms identi
ed on the ADAM questionnaire. Variables that
were statistically signi
cant on the univariate analysis were
included in the multivariable analysis. All values were reported
as median
interquartile range, and
tests were used to eval-
uate differences in means between groups. A
.05 was
considered statistically signi
Of the 3167 men, 231 men had a T value between 250 and
350 ng/dL. The median age of the 231 men was 43.5 years.
The median T level was 303 ng/dL, and the median FT
level was 6.3 ng/dL (
Table 1
). As expected, men with a
higher FT (
6.3 ng/dL) were younger (37 vs 51,
had a higher T (307 vs 295,
.02), and lower SHBG (21
vs 36,
.001). Interestingly, regardless of whether men
had low (
6.3) or normal FT levels, they reported similar
hypogonadal symptoms (
Table 2
; as evaluated using
ADAM and qADAM scores). Similarly, there was no as-
sociation between T levels and hypogonadal symptoms.
Age and 3 of the 10 hypogonadal symptoms (the prob-
ability of having decreased enjoyment in life, sadness, and
deterioration of work performance) were associated with a
low FT on a univariate analysis. However, on multivariable
analysis, only younger age, and none of the hypogonadal
symptoms, was positively associated with higher FT
Table 3
). We used locally weighted linear regression to
attempt to identify threshold levels of FT below which the
probability of a symptom increased above the background
prevalence in the overall study population. Unfortunately,
no signi
cant threshold could be established.
In evaluating men with suspected hypogonadism, some
clinicians start by evaluating T levels; others evaluate FT or
bioavailable testosterone levels, which can also identify
Many factors (including obesity, drugs,
comorbidities, assay variability, and time of day) affect T
and FT levels.
Most testosterone circulates tightly bound
to SHBG or weakly bound to albumin. A minor amount
circulates as FT, and it is believed that this combined with
the fraction bound to albumin is the metabolically active
fraction as opposed to the fraction tightly bound to SHBG.
FT has been evaluated in 2 large population-based
analyzed data from 3700 men (mean age, 60; nearly half
obese) in whom evaluation for hypogonadism included
measurement of both T and calculated FT levels.
15% had low FT levels (
34 pg/mL) and thus were
considered to have biochemical hypogonadism. The Eu-
ropean Male Aging Study (EMAS) study was a multicenter
study of more than 3000 men aged 40 to 79 years who were
administered questionnaires assessing 32 physical, psycho-
logical, and sexual symptoms suggested by previous studies
to be related to androgen de
Of the 32 symptoms,
cant syndromic association was observed for only 3
sexual symptoms, namely decreased sexual thoughts, weak
morning erections, and erectile dysfunction. The authors
concluded that a diagnosis of syndromic late-onset hypo-
gonadism can be made in a man with these 3 sexual
symptoms and serum T level
230 ng/dL or serum T level
between 230 and 317 ng/dL and FT level
7 ng/mL (220
pmol/L). In fact, FT thresholds for the 3 sexual symptoms
(decreased frequency of morning erection, decreased fre-
quency of sexual thoughts, and erectile dysfunction) were
160, 280, and 280 pmol/L (46, 81, and 81 pg/mL), respec-
tively. No thresholds were identi
ed for either psychologi-
cal or physical symptoms associated with FT.
Like the EMAS study, we wanted to determine whether
there exists a threshold for FT at which symptoms of
hypogonadism would become more prevalent. In addition,
we wanted to identify a cluster of symptoms that would be
more prevalent in men with low FT. However, we identi-
ed neither a threshold nor a cluster of symptoms that were
more prevalent in men with low FT. This
nding is not
Table 1.
Baseline characteristics of hypogonadal men with
serum total testosterone between 250 and 350 ng/dL
Baseline characteristics
Total (N
43.5 (34.96-57.60)
Total testosterone (ng/dL)
303 (269.5-323.75)
Free testosterone
6.3 (5.27-7.395)
Estradiol (ng/dL)
2 (2-3)
SHBG (nmol/L)
27 (21-36)
qADAM (range 10-50)
32 (29-37)
ADAM (range 1-5)
4 (1-7)
ADAM, Androgen De
ciency in the Adult Male Questionnaire;
qADAM, quantitative Androgen De
ciency in the Adult Male
Questionnaire; SHBG, sex hormone-binding globulin.
Values represented are median
interquartile range.
UROLOGY 86 (2), 2015