Androgens in Health and Disease.pdf - E Library

10 Winters and Clark
-subunit mRNA levels (72,73). When administered as pulses, but not continuously,
GnRH also increases GnRH-receptor gene expression (74). In addition, gonadotropin
glycosylation is increased by GnRH, and this modification influences circulating halflife
and receptor-binding activity.
The importance of the LH pulse to normal testicular function is less clear. Although
Leydig cells respond to pulses of LH with bursts of testosterone secretion, continuous
infusion of LH (into rams rendered gonadotropin deficient by GnRH immunization) also
stimulated testosterone secretion and had little effect on the subsequent response to LH
(75). Likewise, treatment of men with hCG (with a much longer circulating half-life than
LH and therefore little pulsatile variation) also effectively increases testosterone secretion.
The action of hCG in gonadotropin-deficient men is biphasic with peaks at 4 h and
72 h (76), which may represent an acute steroidogenic response followed by upregulation
of the genes for the steroidogenic enzymes. Very large doses of LH/hCG desensitize rat
Leydig cells and downregulate LH receptors (77) by decreasing receptor mRNA levels
(78). This effect may be applicable to men treated with hCG and to men with hCGproducing
tumors among whom testosterone levels are generally not elevated.
Testosterone regulates is own production by negative feedback inhibition of LH
secretion. Otherwise, unchecked LH drive would stimulate testosterone production maximally,
and undesirable side effects would occur. Testosterone exerts negative feedback
effects by suppressing LH secretion within a few hours (79) and by downregulating
gonadotropin subunit gene expression (80). Most of the testosterone feedback inhibition
of LH in men appears to be via GnRH. For example, testosterone and dihydrotestosterone
(DHT) decrease LH (and presumably GnRH) pulse frequency in adult men (79,81), and
LH pulse frequency is increased in patients with androgen insensitivity (82). Moreover,
testosterone inhibition of LH secretion is less effective in men with congenital gonadotropin
deficiency treated with pulsatile GnRH than in normal men (in whom testosterone
can reduce GnRH production) (83). Experiments in the nonhuman adult male primate
rendered gonadotropin deficient by a hypothalamic lesion and reactivated with pulses of
GnRH further demonstrate the importance of the GnRH pulse generator in the testosterone
control of LH secretion. In that model, removal of the testes produced little change
in circulating LH levels until the frequency of the applied GnRH pulses was increased
(84). Furthermore, testosterone fails to suppress GnRH-stimulated LH secretion or
-subunit mRNA levels in GnRH-stimulated primate pituitary cell cultures, although
these effects are demonstrable using pituitary cell cultures from adult male rats (85).
Estradiol is also an important feedback regulator of LH and, thereby, testosterone
secretion in men. In fact, much of feedback inhibition of LH secretion by testosterone
can be accounted for by its bioconversion to estradiol (79,86). Recent findings in men
with mutations of ER- (87) or the aromatase gene (88) reveal that LH levels are increased
even though testosterone levels are elevated. The importance of estradiol in the testicular
control of LH secretion was predicted some years ago with the findings that the
antiestrogen clomiphene (89) and the aromatase inhibitor testolactone (90) increased LH
secretion in men. Furthermore, LH pulse frequency accelerated during clomiphene treatment,
indicating that a portion of the estradiol effect is on the GnRH pulse generator (91).
Aromatase is expressed in the hypothalamus, and estradiol produced in the brain from
testosterone may suppress GnRH secretion by a genomic or transmembrane effects. The
importance of central nervous system (CNS) production of estradiol is evident in rams
in which intracerebral ventricular (icv) infusion of the aromatase inhibitor fadrozole
increased LH pulse frequency with no effect on plasma estradiol concentrations (92).