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SEX HORMONE BINDING GLOBULIN: INDICATOR OF A FUNCTIONAL HPG AXIS
IN MEN?
de Ronde, W.
Department of Internal Medicine, Erasmus Medical Center, PO Box 1738,
3000 DR Rotterdam, The Netherlands
Sex-Hormone Binding Globulin (SHBG), corticosteroid binding globulin
(CBG) and albumin are important steroid hormone binding
proteins in human plasma. Although recent evidence
shows that SHBG can participate in signal transduction
via its own membrane receptor (1) it is best known
for its role as a binding protein of sex hormones
in human plasma. In normal men between 20 and 65%
of circulating testosterone (T) and between 10 and
50% of circulating estradiol (E2) is bound to SHBG
(2). Binding of T to SHBG decreases its metabolic
clearance rate and its conversion rate to androstenedione
(3). In vitro experiments show that with increasing
levels of SHBG and stable levels of T and E2 the ratio
of unbound E2 to unbound T increases (4). In healthy
males there is a wide variation in SHBG concentrations.
Binding to SHBG also prevents bound hormone from diffusing
out of the bloodstream thereby preventing hormone
binding to the intracellular androgen or estrogen
receptors. The non-SHBG bound fraction of hormone
is, therefore, considered to be bioactive (free hormone
hypothesis as reviewed in (5)). In cross sectional
studies the plasma concentrations of T and SHBG are
positively correlated (2;6). This correlation not
only reflects the high binding affinity of SHBG for
T, resulting in increased storage of the steroid,
but may also be explained by the effect of SHBG levels
on the bioavailability of T. Higher SHBG levels would
then lead to lower levels of bioactive T, a decreased
feedback signal on GnRH and thereby on LH secretion
by the pituitary and a subsequent increase of T levels
until a new set-point is reached. The dependence of
total T on variations in SHBG in men in vivo differs
from the stable T levels in in vitro experiments described
above. Therefore, the conclusions drawn from these
in vitro experiments do not apply to the in vivo situation.
The question is whether the observed positive relationship
between SHBG and testosterone in men can be explained
by effects of SHBG on testosterone production rate
or the metabolic clearance rate. To clarify this issue
we investigated the relationship between SHBG and
testosterone levels in a group of subjects in which
the HPG axis is clearly dysfunctional. In this group
there was no significant relationship between SHBG
and testosterone levels indicating that such a relation
can only exist if the HPG axis is functional. Furthermore,
if the relationship between SHBG and testosterone
can be primarily explained by the effect of SHBG on
the testosterone production rate, then a negative
association of SHBG levels with bioavailable testosterone
levels in a group of men can be considered indicative
of a dysfunctional HPG-axis. Therefore we studied
the relationship between testosterone and SHBG levels
in aging men and in male newborns in order to evaluate
the functionality of the HPG axis in these subjects.
We found that in both these groups SHBG and testosterone
are associated, indicative of a normally functioning
HPG axis.
1. Kahn SM, Hryb DJ, Nakhla AM, Romas NA, Rosner
W 2002 Sex hormone-binding globulin is synthesized
in target cells. J Endocrinol 175:113-120
2. de Ronde W, van der Schouw YT, Muller M, Grobbee
DE, Gooren LJ, Pols HA, de Jong FH 2004 Associations
of sex hormone binding globulin with non-SHBG bound
levels of testosterone and estradiol in independently
living men. J Clin Endocrinol Metab
3. Vermeulen A, Ando S 1979 Metabolic clearance
rate and interconversion of androgens and the influence
of the free androgen fraction. J Clin Endocrinol Metab
48:320-326
4. Burke CW, Anderson DC 1972 Sex-hormone-binding
globulin is an oestrogen amplifier. Nature 240:38-40
5. Mendel CM 1989 The free hormone hypothesis:
a physiologically based mathematical model. Endocr
Rev 10:232-274
6. Vermeulen A, Kaufman JM, Giagulli VA 1996
Influence of some biological indexes on sex hormone-binding
globulin and androgen levels in aging or obese males.
J Clin Endocrinol Metab 81:1821-1826
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