DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

H 3 C
H 3 C O
16α-OHase
H 3 C
H 3 C O
OH
3β-OH-SDH
H 3 C
H 3 C O
OH
1165
HO
Dehydroepiandrosterone
HO
16α-Hydroxydehydroepiandrosterone
O
16α-Hydroxyandrostenedione
3β-OH-SDH
17-OH-SDH,
aromatase
H 3 C O
H 3 C
O
Androstenedione
aromatase
HO
Estrone
H 3 C O
17-OH-SDH
16α-OHase
HO
Estriol
H 3 C OH
OH
CHAPTER 40
16α-OHase
17-OH-SDH
17-OH-SDH
H 3 C OH
H 3 C OH
17
H
C D 16
3 C
aromatase
A B
O 3
HO
Testosterone
Estradiol
Figure 40–1. The biosynthetic pathway for the estrogens.
3β-OH-SDH
3β-Hydroxysteroid
dehydrogenase
17-OH-SDH
17-Hydroxysteroid
dehydrogenase
16α-OHase
16α-Hydroxylase
ESTROGENS AND PROGESTINS
Gonadotropins, acting via receptors that couple to the G s
-adenylyl
cyclase–cyclic AMP pathway, increase the activities of aromatase
and the cholesterol side-chain cleavage enzyme and facilitate the
transport of cholesterol (the precursor of all steroids) into the mitochondria
of cells that synthesize steroids. The ovary contains a form
of 17β-hydroxysteroid dehydrogenase (type I) that favors the production
of testosterone and estradiol from androstenedione and
estrone, respectively. However, in the liver, another form of this
enzyme (type II) favors oxidation of circulating estradiol to estrone
(Peltoketo et al., 1999), and both of these steroids are then converted
to estriol (Figure 40–1). All three of these estrogens are excreted in
the urine along with their glucuronide and sulfate conjugates.
In postmenopausal women, the principal source of circulating
estrogen is adipose tissue stroma, where estrone is synthesized
from dehydroepiandrosterone secreted by the adrenals. In men,
estrogens are produced by the testes, but extragonadal production
by aromatization of circulating C19 steroids (e.g., androstenedione
and dehydroepiandrosterone) accounts for most circulating estrogens.
Thus, the level of estrogens is regulated in part by the availability
of androgenic precursors (Simpson, 2003).
Estrogenic effects most often have been attributed to circulating
hormones, but locally produced estrogens also may have important
actions (Simpson et al., 2002). For example, estrogens may be
produced from androgens by the actions of aromatase or from estrogen
conjugates by hydrolysis. Such local production of estrogens
could play a causal or promotional role in the development of certain
diseases such as breast cancer because mammary tumors contain
both aromatase and hydrolytic enzymes. Estrogens also may be produced
from androgens via aromatase in the central nervous system
(CNS) and other tissues and exert local effects near their production
site (e.g., in bone they affect bone mineral density).
The placenta uses fetal dehydroepiandrosterone and its 16αhydroxyl
derivative to produce large amounts of estrone and estriol.
Human urine during pregnancy is thus an abundant source of natural
estrogens, and pregnant mare’s urine is the source of conjugated
equine estrogens, which have been widely used therapeutically for
many years.
Physiological and Pharmacological Actions
Developmental Actions. Estrogens are largely responsible
for pubertal changes in girls and secondary sexual
characteristics. They cause growth and development of
the vagina, uterus, and fallopian tubes, and contribute to
breast enlargement. They also contribute to molding the
body contours, shaping the skeleton, and causing the
pubertal growth spurt of the long bones and epiphyseal
closure. Growth of axillary and pubic hair, pigmentation
of the genital region, and the regional pigmentation
of the nipples and areolae that occur after the first
trimester of pregnancy are also estrogenic actions.
Androgens may also play a secondary role in female
sexual development (Chapter 41).