of myosin heavy chain. The extent to which skeletal mus-
cle mass can be increased is limited by the concentration
of androgen receptors in the muscle that can be activated.
In normal adult males, the androgen receptors in most tis-
sues are nearly saturated, and further increases in plasma
androgens do not produce significant increases in tissue
responsiveness. This explains why androgen treatment of
boys, girls, and women results in increased skeletal muscle
mass, whereas similar treatment of men does not; however,
pharmacologic doses of potent synthetic androgens report-
edly promoted skeletal muscle mass by a mechanism that
is unclear. Conversion of the exogenous testosterone to es-
trogen may result in a stimulation of AR synthesis in mus-
cle, since AR concentration in skeletal muscle is increased
by estrogen and decreased (downregulated) by androgen.
Bone
Androgens promote skeletal growth and matura-
tion by a direct effect on bone tissue and by an indirect
effect on growth hormone (GH) release. At puberty, the
increasing levels of androgens stimulate the release of GH
and result in accelerated endochondral growth of the epi-
physes of long bones, which causes a doubling of height
gain that is maximal at about mid- to late puberty. This
peak height velocity (PHV) or pubertal growth spurt is
dependent on the increased secretion of androgens (estro-
gen in girls) and GH at this time. By mechanisms that are
not yet understood, androgens also increase bone mass
and accelerate the ossification of the epiphyseal growth
plate, and thereby reduce the rate of linear growth during
late puberty. Ultimately, androgens bring about the fusion
of the epiphysis with the diaphysis (i.e., complete endo-
chondral ossification of the growth plate), resulting in the
irreversible cessation of linear growth, at about age 19 in
boys and age 17 in girls. Even after epiphyseal closure, an-
drogens continue to promote an increase in cortical bone
mass, a process that continues to age 30 years. Testicular
failure (or any other cause of androgen deficiency through
childhood) allows the epiphyseal growth plate to grow for
several additional years, resulting in eunuchoidal propor-
tions, as indicated by a reduction in the upper-to-lower
body ratio due to longer legs, and an arm span that is
greater than the height due to longer arms. In addition, the
absence of pubertal androgen results in osteopenia due to
inadequate cortical bone mass.
Blood Volume
Testosterone acts on the proximal tubule
of the nephron to promote the reabsorption of K+, Na+,
and CU, which, along with stimulated erythropoiesis (see
below), contributes to the androgen-associated increase in
blood volume. Athletes treated with synthetic androgens
experience a weight gain that can largely be explained by
an increase in blood volume, and men who undergo an-
drogen treatment as a means of contraception also exhibit
blood volume expansion and weight gain.
788
Erythropoiesis
Androgens stimulate the production of
erythropoietin (Chapter 28) by the kidney and, in part,
cause an increase in hematocrit by this mechanism. This
may explain why males have a higher hematocrit than
females.
Adipose Tissue
Androgens promote truncal-abdominal
fat deposition and favor development of upper body obe-
sity. In contrast to gluteofemoral (lower body) fat, upper
body fat accumulation, particularly visceral fat, is charac-
terized by an increase in fat cell size, increased lipoprotein
lipase (LPL) activity, enhanced lipolysis, and reduced re-
sponse to the antilipolytic effect of insulin. This explains
why androgen-dominated states favor insulin resistance.
Liver
Androgens cause a reduction in the plasma levels
of testosterone-estradiol-binding globulin (TeBG), which
results in an increased percentage of testosterone that
is accessible for tissue uptake. This leads to a greater
androgenic response by the tissues but also results in
accelerated clearance of testosterone from circulation.
Ultimately, the outcome of a reduced TeBG level will be
a reduction in total plasma androgen concentration due
to increased negative feedback suppression of LH release
and a reduction of testosterone synthesis. Androgens also
modify the production of other hepatic proteins such as fib-
rinogen (decreased), transferrin (decreased), haptoglobin
(increased),
a
i -antitrypsin
(increased),
and
hepatic
triglyceride lipase (increased). Synthetic steroids exhibit-
ing enhanced anabolic activity and reduced androgenic-
ity (anabolic steroids) have been developed (Figure 34-3).
Athletes who use these steroids to increase their strength
and durability often consume high doses, which can have
adverse effects. The anabolic steroids exert their effects by
binding to cytosolic androgen receptors, and the neuroen-
docrine system responds by reducing secretion of LH and
FSH. This response leads to diminished Leydig and Sertoli
cell function and to a reduction of endogenous testosterone
production and of spermatogenesis. Testicular atrophy and
reduced sperm counts are documented consequences of
excessive anabolic steroid treatment. Most of the orally
active androgenic steroids contain a 17a-alkyl group
(17o!-methyl or 17a-ethynyl) that makes the steroid re-
sistant to liver inactivation. This explains why these
steroids are orally active; however, long-term usage of
these steroids is associated with hepatic disorders with
varying severity (from abnormal liver function tests to
jaundice to hepatic carcinoma). The probable cause of hep-
atic damage is the chronic demand on the liver to continue
increasing its microsomal P450 redox activity, which is
incapable of oxidizing 17a-alkyl-substituted steroids.
Structure-Function Relation
The 17-hydroxyl group
of testosterone and DHT appears to be important for
androgenic activity, since testosterone enanthate and
chapter
34
Endocrine Metabolism V: Reproductive System
