METHODS

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

ﬂ

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

value

.05 was

considered statistically signi

cant.

RESULTS

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,

.001),

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.

COMMENT

In evaluating men with suspected hypogonadism, some

clinicians start by evaluating T levels; others evaluate FT or

bioavailable testosterone levels, which can also identify

hypogonadism.

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

studies.

The

Veterans

Administration

researchers

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.

About

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

ciency.

Of the 32 symptoms,

signi

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

231)

Age

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.

288

UROLOGY 86 (2), 2015