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

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SECTION V
HORMONES AND HORMONE ANTAGONISTS
Table 40–1
Structural Formulas of Selected Estrogens
STEROIDAL ESTROGENS
Derivative R 1
R 2
R 3
Estradiol —H —H —H
O
Estradiol valerate —H —H
C(CH 2 ) 3 CH 3
Ethinyl estradiol —H —CæCH —H
Mestranol —CH 3
—CæCH —H
Estrone sulfate —SO 3
H — a ÁO a
Equilin b —H — a ÁO a
a
Designates C17 Ketone.
b
Also contains 7, 8 double bond.
2
3
R 1 O
1
A
4
9
10
5
11
B
6
R 3
18 O
12 CH 3
R 2
17
13 16
C D
14
15
8
7
NONSTEROIDAL COMPOUNDS WITH
ESTROGENIC ACTIVITY
Diethylstilbestrol
CH 3 OH
HO
CH 3
Bisphenol A
CH 3
HO
C
OH
CH 3
Genistein
HO O
OH O
OH
humans, for both ERα- and ERβ-mediated actions, is 17β-estradiol,
followed by estrone and estriol. Each contains a phenolic A ring
with a hydroxyl group at carbon 3, and a β-OH or ketone in position
17 of ring D.
The phenolic A ring is the principal structural feature responsible
for selective high-affinity binding to both receptors. Most alkyl
substitutions on the A ring impair binding, but substitutions on ring
C or D may be tolerated. Ethinyl substitutions at the C17 position
greatly increase oral potency by inhibiting first-pass hepatic metabolism.
Models for the ligand-binding sites of both estrogen receptors
have been determined from structure–activity relationships
(Harrington et al., 2003) and structural analysis (Pike et al., 2000).
Diethylstilbestrol (DES), which is structurally similar to
estradiol when viewed in the trans conformation, binds with high
affinity to both estrogen receptors and it is as potent as estradiol in
most assays but has a much longer t 1/2
. DES no longer has widespread
use, but it was important historically as an inexpensive orally
active estrogen.
Selective ligands for ERα and ERβ are available for experimental
studies but are not yet used therapeutically (Harrington
et al., 2003).
Nonsteroidal compounds with estrogenic or anti-estrogenic
activity—including flavones, isoflavones (e.g., genistein), and
coumestan derivatives—occur in plants and fungi. Synthetic agents—
including pesticides (e.g., p,p′-DDT), plasticizers (e.g., bisphenol A),
and a variety of other industrial chemicals (e.g., polychlorinated
biphenyls)—also have hormonal or antihormonal activity. Although
their affinity is relatively weak, their large number, bioaccumulation,
and persistence in the environment have raised concerns about their
potential toxicity in humans and wildlife. Over-the-counter and prescription
preparations containing naturally occurring estrogenlike
compounds from plants (i.e., phytoestrogens) now are available
(Fitzpatrick, 2003).
Biosynthesis. Steroidal estrogens arise from androstenedione or
testosterone (Figure 40–1) by aromatization of the A ring. The reaction
is catalyzed by aromatase (CYP19) that uses nicotinamide adenine
dinucleotide phosphate (NADPH) and molecular oxygen as
co-substrates. A ubiquitous flavoprotein, NADPH–cytochrome P450
reductase, also is essential. Both proteins are localized in the endoplasmic
reticulum of ovarian granulosa cells, testicular Sertoli and
Leydig cells, adipose stroma, placental syncytiotrophoblasts, preimplantation
blastocysts, bone, various brain regions, and many other
tissues (Simpson et al., 2002).
The ovaries are the principal source of circulating estrogen in
premenopausal women, with estradiol the main secretory product.