Androgens in Health and Disease.pdf - E Library

8 Winters and Clark
These enzymes are increased by transcriptional and posttranscriptional mechanisms, but
the best characterized response to LH so far is the cAMP-dependent transcriptional activation
of P450scc and P450c17. Perhaps the most striking observation from this research
is the apparent lack of coordination for regulation of these two genes; both are responsive
to cAMP, but distinct promoter elements and transcription factors are required for gene
activation (42).
OTHER FACTORS THAT INFLUENCE TESTOSTERONE SYNTHESIS
The concept that testosterone biosynthesis and secretion are under LH control is well
established and is underscored by the prepubertal levels of circulating testosterone in
men with the complete form of congenital hypogonadotropic hypogonadism (43). The
phenotype in these men is that of a normal male presumably because placental hCG
stimulates testosterone synthesis in the human male fetus. In support of this view, inactivating
mutations of the LH receptor produce XY infants with Leydig cell agenesis and
female external genitalia (44). On the other hand, in mice expressing a functionless LH
receptor, males are phenotypically normal yet are hypogonadal as adults, implying that
other factors activate testicular steroidogensis in fetal rodents but play a lesser role in
adulthood (45). One candidate activator of fetal testosterone biosynthesis is pituitary
adenylate cyclase-activating polypeptide (PACAP) (46).
Early studies with purified follicle-stimulating hormone (FSH) preparations suggested
that FSH enhanced Leydig cell responsiveness to LH. From studies using recombinant
gonadotropins (which do not contain other hormones), however, recombinant
human (rh)-FSH is now known (47) to have a negligible effect on testosterone production
in vitro (1 : 100,000 the potency of LH). Moreover, neither treating GnRH-primed
juvenile monkeys with rh-FSH (48) nor adding rh-FSH to rh-LH treated gonadotropindeficient
men (49) increased circulating testosterone levels further. Thus, FSH appears
to have little or no direct effect on testosterone production.
Many studies have proposed that prolactin (PRL) affects testosterone production, but
the function of PRL in males remains controversial. PRL receptors are found on Leydig
cells (50), and PRL may increase LH-stimulated testosterone production by increasing
LH binding (51). However, PRL has a dose-dependent biphasic effect on Leydig cell
steroidogenesis (52), and PRL knockout mice have normal circulating levels of testosterone
and are fertile (53). Men with prolactin-producing pituitary microadenomas
have low plasma testosterone levels primarily because pulsatile LH secretion is suppressed
(54).
Growth hormone (GH) has been proposed to stimulate testosterone biosynthesis
directly, or via testicular insulin-like growth factor-1 (IGF-1) and IGF-1 receptors on
Leydig cells (55). In rodents, testicular IGF-1 is upregulated by gonadotropins and may
play a role in the differentiation of immature into adult Leydig cells (56). In IGF-1deficient
mice, testosterone levels are 18% of normal, although this may be the result of
gonadotropin deficiency (57). The testes are smaller than normal in men with childhoodonset
GH deficiency; however, circulating testosterone levels are generally normal (58).
In adult men with isolated GH deficiency as a result of hypothalamic–pituitary disease,
plasma testosterone levels increased slightly following 6–12 mo of human GH (hGH)
therapy, and the testosterone response to hCG stimulation was increased by 20% (59).
Thus, GH may play a minor role in testosterone production. There is a direct stimulatory
effect of T3 on the production of testosterone and estradiol by Leydig cells, in part, by
increasing StAR expression (60).