SECTION 34.1
Testes
785
in the testes. Leydig cells are steroidogenic cells, con-
verting cholesterol to pregnenolone under regulation by
LH. The major steroid product of the Leydig cells is
testosterone, which accounts for most of the steroid out-
put by the adult testes. The preferred pathway is the
A
4
pathway, although detectable amounts of A
5
steroids
(dehydroepiandrosterone, androstenediol) are secreted
(Figure 34-1). LH acts at the cholesterol side chain
cleavage step. LH release is held in check by the level
of non-TeBG-bound testosterone in the circulation, al-
though the principal inhibitor is DHT. Because the anterior
pituitary contains
5a
-reductase activity, it converts testos-
terone to DHT and responds to DHT by diminishing output
of LH. LH release is also inhibited by testosterone via in-
hibition of GnRH release. In the preoptic hypothalamus,
testosterone can be converted to DHT or estradiol, and may
thereby inhibit the pulse frequency (DHT) or pulse height
(estradiol) of GnRH released at the median eminence.
Secretion of testosterone is fairly constant and consis-
tent in adult men, although higher levels occur in the morn-
ing and lower levels in late evening. This circadian rhythm
is not accompanied by changes in the levels of LH; thus, it
appears to be an intrinsic testicular rhythm. Testosterone
levels decline by 10-15% between the ages of 30 and
70 years, accompanied by reduction in tissue responsive-
ness to androgenic stimulation.
Metabolism of Testosterone
Testosterone in plasma exists in two fractions: TeBG-
bound (44%) and non-TeBG-bound (56%). The plasma
level of TeBG in adult males is ~25 nM, which ap-
proximates the normal testosterone level in adult men
(~22 nM); thus, an increase in testosterone production
or a decrease in TeBG level will result in a higher level of
testosterone available for tissue uptake.
In androgen target tissues that lack 5a-reductase, testos-
terone activates the androgen receptor (AR)-androgen
response element (ARE) mechanism directly and induces
the expression of androgen-dependent genes (Chapter 30).
After dissociating from the AR, testosterone may be me-
tabolized by the target cell or make its way to the liver for
inactivation. The liver modifies three parts of the testos-
terone structure that are important for hormonal activity:
oxidation of the 17/3-OH group (to produce a 17-keto
derivative), saturation of the A
4
in ring A (to produce an
androstane derivative), and reduction of the 3-keto- group
(to produce a 3a-hydroxylated derivative (Figure 34-2).
In androgen target tissues that contain 5a-reductase,
testosterone is converted to DHT, which activates the
AR-ARE sequence leading to an androgenic response.
DHT undergoes inactivation when it dissociates from
the AR; the major metabolites (except in the liver and
kidney)
are
the
reduced,
hydroxylated
metabolites,
3a-androstenediol
and
3/3-androstenediol,
which
are
then conjugated to glucuronic acid for renal excretion
(Figure 34-2). These and other polar compounds account
for about 30-50% of the testosterone metabolites excreted
daily.
In tissues that contain aromatase (CYP 19), testosterone
can be converted to estradiol, which may exert an effect
in situ
if the tissue is an estrogen-responsive one, and/or
may return to plasma for distribution to estrogen target tis-
sues. Unlike the androgenic steroids, the only major site
of estrogen inactivation appears to be the liver; therefore,
estrogen theoretically can be recycled until being trans-
ported to the liver, which itself is an estrogen-responsive
tissue. Testosterone-derived estradiol accounts for a small
percentage (0.3%) of the testosterone metabolized.
Testosterone is known to exert some important biolog-
ical effects in the liver and kidney, which are the ma-
jor testosterone-inactivating tissues in the body. About
50% of the testosterone is removed from plasma with
each passage through the liver. The major metabolites
of testosterone in the liver are etiocholanolone, andros-
terone, and epiandrosterone, collectively referred to as
the 17-ketosteroids (17KS), all of which are released as
glucuronide conjugates for excretion by the kidney (Fig-
ure 34-2). This route accounts for 50-70% of the total
testosterone metabolized daily.
An epimer of testosterone, epitestosterone (17a-hydro-
xylated testosterone), is produced by the testes and
excreted as such in the urine in amounts approximately
equal to that of testosterone(T:epiT ~1:1). Epitestos-
terone is biologically inactive, but it is not a metabolite,
and is believed to be produced only by the gonads; thus,
it is used as a gonadal steroid marker. In women, the
ratio of T to epiT is also normally 1:1. Urinary T:epiT
is useful in monitoring abuse of anabolic steroids by
athletes because the ratio increases when any exogenous
testosterone derivative is used.
Biological Effects of Androgens
The biological effects of androgenic hormones can be of
two types: (a) reproductive (androgenic), i.e., promoting
the primary and secondary sexual characteristics of a male;
and (b) nonreproductive, which includes anabolic effects.
Both types of effects are mediated by the same AR; there-
fore, testosterone and DHT are capable of exerting either
types of effect; however, under physiologic conditions, a
critical factor that determines what hormone is active in
a given tissue is the presence or absence of 5a-reductase.
As underscored above, pharmacological treatment with
