Androgens in Health and Disease.pdf - E Library

Chapter 1/Testosterone Synthesis, Transport, and Metabolism 13
implying that the nocturnal increase in testosterone is only partly LH controlled. Fragmented
sleep disrupts the diurnal testosterone rhythm (105), but the link between sleep
and testosterone secretion is thus far unknown. Moreover, this rhythm is blunted with
aging (106) and in men with testicular failure (107).
SHBG AND TESTOSTERONE TRANSPORT
After its release from the testis, testosterone is bound by plasma proteins in the
circulation. About 45% of the plasma testosterone in adult men is bound with high
affinity to sex hormone-binding globulin (SHBG), 50% is loosely bound to albumin,
1–2% to cortisol-binding globulin, and less than 4% is free (not protein bound) (108).
SHBG is a carbohydrate-rich -globulin produced by the liver. SHBG is a 100,000-kDa
dimer, with protomers of 48–52 kDa that convert to a single 39-kDa species after
deglycosylation (109). Androgen-binding protein (ABP) is a product of the SHBG gene
in testicular Sertoli cells. Expression utilizes a 5' alternative exon to produce a protein
with an identical AA sequence but variant glycosylation.
Sex hormone-binding globulin binds testosterone and other steroids and prolongs
their metabolic clearance; however, the function of SHBG remains controversial (110).
The general view, however, is that SHBG-bound testosterone is not biologically active.
SHBG reduces cellular uptake of testosterone in vitro (111) as well as testosterone
bioactivity (112), implying that SHBG regulates testosterone availability to target cells.
SHBG is seemingly absent in rats, mice, and pigs, although there is an SHBG in fetal rats,
suggesting that the role of SHBG could be species-specific. ABP is thought to maintain
a high level of testosterone in the extracellular space of the male reproductive tract for
androgen-dependent sperm maturation. The finding of membrane binding sites for SHBG
in the testis, prostate, and other tissues (113) and for ABP in the caput epididymis (114)
and germ cells (115) suggest, however, that ligand activation of these binding proteins
could directly influence androgen action.
The SHBG levels decrease from infancy to puberty in both sexes (116,117) and are
lower in adult men than in women. SHBG levels rise as men grow older (118). SHBG
levels are reduced in obesity (119), especially with abdominal obesity (120). A high-fat
diet decreased SHBG in normal men, whereas a weight-reducing high-protein diet
increased SHBG levels (121). Metabolic effects on SHBG are partly mediated by insulin,
because insulin levels are increased with visceral obesity (122) and with a high-fat
diet, and insulin decreases SHBG mRNA (123). Moreover, lowering insulin levels using
diazoxide increased plasma SHBG levels (124). However, imperfect correlations
between insulin levels and SHBG suggest that other factors related to insulin resistance,
including GH and insulin-like growth factors and their binding proteins, or glucorticoids,
may contribute to low SHBG as well. Table 1 lists the hormonal factors that are known
to influence SHBG concentrations. A low level of SHBG is a marker for visceral obesity,
insulin resistance, and hyperinsulinemia and is associated with increased risk for developing
diabetes and cardiovascular disease.
Because of its function to bind testosterone with high affinity, the level of SHBG in
plasma is a strong predictor of the total testosterone concentration among normal men (see
Fig. 5). As such, the factors that increase or decrease SHBG levels similarly influence the
total testosterone concentration. For example, both SHBG and total testosterone levels
tend to be low in obese men (120) and increased in men with hyperthyroidism (118).
Because the portion of circulating testosterone that is not bound to SHBG is thought
to represent the biologically active fraction, many methods for determining non-SHBGbound
or free testosterone have been developed. Of these methods, there is a high
positive correlation between the level of free-testosterone by equilibrium dialysis, non-