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L
ate
-
onset
hypogonadism
or
ADAM:
diagnosis
R
ev
A
ssoc
M
ed
B
ras
2014; 60(4):286-294
289
normal, while TT below 200 ng/dL (6.9 nM) is diagnosed
as hypogonadism, though there is controversy in the TT
range between 320 and 200 ng/dL (6.9 -11.1 nM). These
ranges established by the laboratory cover all adult men
while not taking into account the variation of age groups.
The standard for laboratory diagnosis of late-onset hypogo-
nadism, in this study, was defined as a patient having two
free testosterone values calculated as less than 6.5 ng/dL
obtained using the Vermeulen formula, with a minimum
interval of one month between measurements
28
(
A
). The
laboratory definition of late-onset hypogonadism has not
yet been established. Thus, the diagnosis of late-onset
hypogonadism is usually based on the clinical features of
hypogonadism and a demonstration of morning serum
testosterone level below the minimum reference value for
young adults
18
(
A
).
A major problem occurs when the reference texts for
physicians describe a reference value for adult men that
does not correspond to the values cited by many laborato-
ries. The reference values supplied by the manufacturer are
significantly lower than the reference values to whichmany
publications refer, based on traditional RIAmethods
18
(
A
).
According to the recommendations of many scienti-
fic societies, there is no lower limit for TT universally ac-
cepted for the diagnosis of male hypogonadism. There is
a general consensus that total TT levels above 12 nmol/L
(350 ng/dL) do not require testosterone replacement.
Similarly, based on data from young men, there is a
consensus that patients with total serum testosterone be-
low 8 nmol/L (230 ng/nL) would be hypogonadic. There
is controversy in the range between 8 and 12 nmol/L
30
(
B
).
Free testosterone levels, whether verified through equi-
librium dialysis, calculation of bioavailable testosterone
or calculation of the total testosterone coefficient and
SHBG, are dependent on the exact level of total testoste-
rone, and the result of the study has implications on the
determination of free testosterone
18
(
A
).
There are various assays available to measure free
and bioavailable testosterone in blood serum. There is
the gold standard dosing method for these values, but
as they take time and are technically more complicated,
they are only used by reference laboratories. FT can be
measured through direct method with RIA using a com-
mercial kit, which is the method used in many laborato-
ries in the country, with the values obtained being lower
than those in the reference methods.
Both free and bioavailable testosterone can be calcu-
lated based on the level of SHBG and total testosterone,
using the formula published by Vermeulen. The values
obtained correlate significantly with the values obtained
(testosterone) with high affinity. SHBG-bound T would
not be available for dissociation in target tissues via the
classical androgen receptor mechanism. Contrarily, albu-
min binds to testosterone with low affinity, and the dis-
sociation of albumin-bound T is quick. Therefore, both
albumin-bound T and free T are referred to as bioavaila-
ble T (BAT). Based on these physiological facts, this small
free fraction is the most biologically active T circulating,
owing to its accessibility to tissues. For clinical purposes,
this simplified paradigm of fractions of circulating tes-
tosterone and its actions is reasonable
29
(
A
).
Thus, TT (total testosterone) would not be the ideal
scale for measuring late-onset hypogonadism, as the in-
crease of SHBG associated with aging results in an in-
crease in testosterone binding. The FT or BAT, fraction
of T available, during male aging would be a more preci-
se marker of hypogonadism. It has been demonstrated
that there is a fall in testosterone and BAT levels at 1.1%/
year and 2.3%/year
27
(
A
).
As free testosterone levels, whether verified through
equilibrium dialysis, calculation of bioavailable testoste-
rone or calculation of the total testosterone coefficient
and SHBG, are dependent on the exact level of total tes-
tosterone, the result of the TT level has implications on
the determination of free testosterone
18
(
A
).
Recommendation
Free testosterone, the fraction of testosterone that is bioavai-
lable, is amore precisemarker of hypogonadism. As the levels
of free testosterone are dependent on the exact level of total
testosterone, the result of the total testosterone level has im-
plications on the determination of free testosterone.
W
hat
are
the
reference
values
for
the
serum
levels
of
total
and
free
testosterone
used
in
the
diagnosis
of
late
-
onset
hypogonadism
?
For the level of TT (total testosterone), clinical laborato-
ries use commercial RIA kits and competitive-type immu-
noassays that use chemiluminescence technology. These
TT tests use standard and reference levels provided by the
manufacturer
18
(
A
). For example, in São Paulo, the labo-
ratory studied uses electrochemiluminescence testing and
liquid chromatography coupled with mass spectrometry
in tandem. At this laboratory, the reference values for to-
tal testosterone in males for both methods are 240 to 816
ng/dL. Another laboratory, whose data were used in a
Brazilian study with good evidence, established the fol-
lowing reference data for total testosterone: total testos-
terone values above 320 ng/dL (11.1 nM) are considered
SCIELO.indb 289
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