Androgens in Health and Disease.pdf - E Library

4 Winters and Clark
chorionic gonadotropin) receptors and steroidogenic enzymes. Testosterone production
peaks toward the end of the first trimester of fetal life and then declines to about 10% of
peak values for the remainder of gestation. This temporal pattern is readily superimposed
upon the levels of hCG in maternal blood. Following birth, there is a second peak in
testosterone secretion that lasts up to 4–6 mo and results from transient activation of
gonadotropin-releasing hormone (GnRH) production. Then, there is sharp decline in testosterone
production that is associated with a considerable loss of mature Leydig cells.
GnRH secretion increases markedly at puberty, at which time Leydig cell differentiation
and testosterone production parallel activation of the spermatogenesis process (2).
TESTOSTERONE BIOSYNTHETIC PATHWAY
All mammalian steroid hormones are synthesized from cholesterol by sequential
cytochrome P450- and dehydrogenase-dependent enzymatic reactions. Testosterone is
a C19 3-keto, 17-hydroxy 4 steroid. Figure 1 illustrates the biosynthetic pathway for
testosterone synthesis in Leydig cells. The cyclopentanophenanthrene ring structure of
the cholesterol nucleus is retained, and the distinct biological function of the end-product
steroid hormone is the result of the stereo-specific modifications of the ring carbons. The
first reaction, the conversion of cholesterol to pregnenolone, occurs within mitochondria
and is catalyzed by the cytochrome P450 side-chain cleavage enzyme, P450scc (3,4).
P450scc is encoded by the CYP11A gene located in the q23-q24 region of chromosome
15 (5,6). P450scc is translated with an amino-terminal signal sequence that
targets the protein to the mitochondria, where it is localized in the inner membrane
(7). The enzyme is part of an electron-transport complex that includes adrenodoxin
reductase and adrenodoxin, an FAD-containing flavoprotein and iron–sulfur protein,
respectively, that are required to transfer reducing equivalents from NADPH to P450scc
for the mixed-function oxidase reactions (8). P450scc catalyzes two sequential hydroxylations
of the cholesterol side chain at C22 and C20, producing 22R-hydroxycholesterol
and 20,22-dihydroxycholesterol intermediates (9,10). Subsequent cleavage of the bond
between C20 and C22 by P450scc produces pregnenolone and releases isocaproaldehyde.
Pregnenolone diffuses out of the mitochondria and can be converted to testosterone
by two alternative routes referred to as the 4 pathway or the 5 pathway, based on
whether the steroid intermediates are 3-keto, 4 steroids ( 4 ) or 3-hydroxy, 5 steroids
( 5 ). In the 4 pathway, which predominates in rodents, pregnenolone is metabolized to
progesterone by 3-hydroxysteroid dehydrogenase/ 5 - 4 isomerase (3HSD) that catalyzes
both the oxidation of the 3-hydroxyl group to a 3-keto group and the isomerization
of the double bond between C5 and C6 to a double bond between C4 and C5 position in
an NAD+/–dependent reaction (11). 3HSD is a member of a family of short-chain
dehydrogenases (SDR) of which the type II human enzyme, 3HSD-II, is the gonadspecific
form encoded by the HSD3B2 gene on chromosome 1p13 (12–15). Progesterone
is then hydroxylated at C17 to form 17-hydroxyprogesterone, followed by cleavage
of the bond between C17 and C20 to produce androstenedione. Both reactions are catalyzed
by cytochrome P450 17-hydroxylase/C17,20 lyase, an enzyme encoded by the
CYP17 gene on chromosome 10q24.3 (16,17). CYP17 is a microsomal enzyme that
utilizes a ubiquitous flavoprotein, NADPH–cytochrome P450 reductase, to transfer
reducing equivalents from NADPH to the enzyme. Finally, the C17 keto group of
androstenedione is reduced to a hydroxyl group to produce testosterone. This reaction
is catalyzed by 17-hydroxysteroid dehydrogenase (17HSD), and the reaction can be
reversible in vitro. Activity in vivo is typically unidirectional, however, and depends on