wileyonlinelibrary.com/journal/cen Clinical Endocrinology. 2018;88:538–540.
© 2018 John Wiley & Sons Ltd
Male hypogonadism is a clinical diagnosis confirmed by consistent bio-
chemical findings. Clinical guidelines agree that the initial diagnostic
test to confirm clinically suspected androgen deficiency should be a
fasting morning total testosterone concentration by a reliable assay.
They also agree that a diagnosis of androgen deficiency should only be
made in men with consistent symptoms and signs, and unequivocally
and repeatedly low serum testosterone concentrations.
However, what should be done when the total testosterone is near
the lower limit of the reference range, but not clearly low? Most guide-
lines suggest that obtaining a free testosterone concentration either by
equilibrium dialysis or by calculation with a validated algorithm should be
the next step.
Because serum sex hormone binding globulin (SHBG)
concentrations affect total testosterone concentrations and their inter-
pretation (Figure 1), a free testosterone measurement is also recom-
mended if a condition associated with alterations in circulating SHBG is
In practice, however, equilibrium dialysis is usually not avail-
able, and some formulae used to calculate free testosterone have not
been fully validated.
Moreover, while recent progress has been made
towards standardization of reference intervals for total testosterone,
normal ranges for free testosterone remain currently less well defined.
Recently, Australian guidelines have proposed that, rather than re-
lying on free testosterone measured by suboptimal methodology, at
high and low ends of the reference interval, serum total testosterone
should primarily be interpreted in relation to SHBG concentrations.
However, there has been relatively little evidence that SHBG pro-
vides information in the assessment of male androgen status addi-
tional to that of total testosterone, a gap that is addressed by Rastrelli
in this issue of Clinical Endocrinology.
Previous epidemiological studies trying to identify the best bio-
chemical measure of androgen status have compared total to free
testosterone. These studies reported that free and
bioavailable testosterone are better predictors of clinical androgen
status than total testosterone with respect to symptoms,
as well as
with respect to end- organ deficits compatible with androgen defi-
ciency such as low muscle strength, bone density or haemoglobin.
In these studies, free and bioavailable testosterone were calculated
rather than measured directly. Given that the formulae used to calcu-
late free and bioavailable testosterone incorporate SHBG, the differ-
ential associations of calculated vs total testosterone with androgen
deficiency- like features might reflect possible, unaccounted for roles
of SHBG. There is evidence that SHBG may not be just a passive car-
rier for sex steroids, and epidemiological studies suggest that SHBG
may predict health outcomes such as diabetes
pendently of circulating testosterone.
Rastrelli et al
report results of a cross- sectional study among a
cohort of 2622 middle- aged men referred to a single academic cen-
tre in Italy for sexual dysfunction. Most men had normal total tes-
tosterone concentrations (mean 15.3 nmol/L), suggesting that sexual
dysfunction was not due to androgen deficiency in a substantial
proportion. This study tested the hypothesis that circulating SHBG
concentrations are associated with markers of androgen status inde-
pendently of total testosterone. Rastrelli et al
report the interesting
and novel observation that in this large cohort, higher SHBG con-
centrations were independently associated with both subjective and
objective markers of androgen deficiency. Higher SHBG was associ-
ated with a higher frequency of androgen deficiency- like symptoms
by self- reported questionnaire, and with lower frequency of sexual
intercourse, independent of confounders such as age or body mass
index. Higher SHBG was also associated with lower prostate- specific
antigen and haemoglobin, which are nonspecific markers of androgen
action. These associations remained significant after adjustment for
Received: 21 December 2017
Accepted: 12 January 2018
Biochemical evaluation of male androgen status: Beyond total
Department of Medicine Austin Health, University of Melbourne, Heidelberg, Vic., Australia
Department of Endocrinology, Austin Health, Heidelberg, Vic., Australia
Mathis Grossmann, Department of Medicine Austin Health, The University of Melbourne, Heidelberg, Vic., Australia.
Bayer Pharma; Novartis; Weight Watchers; Lilly; Besins Healthcare
Please see related paper on pages [556–564] of this issue.