Male Sexual Dysfunction
Association of Free Testosterone With
Hypogonadal Symptoms in Men With
Near-normal Total Testosterone Levels
Ranjith Ramasamy, Ron Golan, Nathan Wilken, Jason M. Scovell, and Larry I. Lipshultz
To investigate the association between hypogonadal symptoms and free testosterone (FT) levels
in men with near-normal total testosterone (T) levels (250-350 ng/dL) and to determine whether
a discriminatory threshold for FT exists below which hypogonadal symptoms become more
We reviewed the charts of 3167 men who presented to an outpatient men
s health clinic. Two
hundred thirty-one men had symptoms of
and serum testosterone levels between
250 and 350 ng/dL. We evaluated hypogonadal symptoms using the Androgen De
ciency in the
Adult Male (ADAM) and quantitative ADAM (qADAM) questionnaires. Serum levels of T and sex
binding globulin were collected on the same day that men completed their questionnaires.
We used linear regression to determine whether a threshold of FT exists for hypogonadal symptoms.
We performed univariate and multivariable analyses to evaluate factors that predicted a low FT level.
The median age was 43.5 years, and the median testosterone and FT levels were 303 ng/dL and
6.3 ng/dL, respectively. Prevalence and severity of hypogonadal symptoms (ADAM and
qADAM) were similar between men with low (
6.4 ng/mL) and normal FT levels. There was an
association between age and 3 of the 10 hypogonadal symptoms (decreased enjoyment in life,
sadness, and deterioration of work performance) with a low FT on a univariate analysis. Only
younger age was positively associated with FT on multivariable analysis.
We did not observe a relationship between hypogonadal symptoms and FT in men with
near-normal testosterone levels. Symptom-speci
c FT thresholds could not be de
ned, as age
remains an important confounder.
2015 Elsevier Inc.
ree testosterone (FT) is the fraction of the total
testosterone (T) that is readily available to the cells
and is dependent on the levels of sex hormone
binding globulin (SHBG) and albumin.
testosterone remains in the circulation with no binding
function in this form. Higher T and lower SHBG levels
can increase FT. FT can be diagnostically useful when T
does not correspond with the clinical presentation of
hypogonadism, especially in aging men with borderline
low levels of T and men in whom levels of SHBG are
suspected to be altered.
FT can be calculated by the
Vermeulen formula using serum T, SHBG, and albumin
levels. The use of FT is complicated by the wide range of
assays used to determine FT levels and the lack of a
standard threshold value.
Previous studies have analyzed the association of FT with
the symptoms of hypogonadism and concluded that FT is
associated with hypogonadism at a low level of speci
In a multicenter study, more than 3000 men aged 40 to
79 years answered questionnaires assessing 32 physical,
psychological, and sexual symptoms.
Of the 32 symptoms,
association with FT was observed
for only 3 sexual symptoms, namely decreased sexual
thoughts, weak morning erections, and erectile dysfunc-
tion. Unfortunately, the FT threshold associated with these
3 symptoms varied widely from 4.5 to 8.0 ng/mL.
The Endocrine Guidelines suggest measurement of FT
or bioavailable testosterone levels in men in whom T
concentrations are near the lower limit of the normal
Therefore, we restricted our analysis to men with
near-normal T levels (250-350 ng/dL) and hypogonadal
symptoms. In the present study, we evaluated the asso-
ciation between FT and hypogonadal symptoms and
attempted to determine whether there exists a clear-cut
discriminatory threshold of FT below which hypo-
gonadal symptoms become more prevalent.
Larry I. Lipshultz was a clinical trial investigator, consultant,
and speaker to Endo. Ranjith Ramasamy, Ron Golan, Nathan Wilken, and Jason
Scovell have no relevant
Ranjith Ramasamy is a K12 scholar supported by a Male Repro-
ductive Health Research (MRHR) Career Development Physician-Scientist Award
(Grant # HD073917-01) from the Eunice Kennedy Shriver National Institute of Child
Health and Human Development (NICHD) Program.
From the Department of Urology, Baylor College of Medicine, Houston, TX; and the
Department of Urology, Weill Cornell Medical College, New York, NY
Address correspondence to: Ranjith Ramasamy, M.D., 6624 Fannin Street, #1700,
Houston, TX 77030. E-mail:
Submitted: March 25, 2015, accepted (with revisions): May 8, 2015
2015 Elsevier Inc.
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