the incidence of acne vulgaris. There is no evidence that
estrogen can prevent the androgen-sensitive conversion of
terminal to vellus hair in male pattern baldness.
Adipose Tissue
Estrogenic states favor subcutaneous
fat deposition in the gluteofemoral region (lower body)
and promote lower body obesity. Current evidence sug-
gests that a lower body fat pattern, or a low upper-lower
body circumference ratio (referred to as “gynoid”), is as-
sociated with a lower incidence of coronary heart disease
and may be due to the effect of estrogen on lipoprotein
Cardiovascular System
In women, estrogen protects
against cardiovascular disease. The protective cardiovas-
cular effects of estrogen include decreased serum LDL
cholesterol and increased HDL cholesterol levels, va-
sodilatory effect, and antioxidation of LDL cholesterol
(Chapter 20). Extensive clinical trials have shown that
estrogen replacement therapy of postmenopausal women
reduces the risk of heart disease.
Estrogen mediates learning and memory func-
tions and also enhances cognitive processes. The brain
can produce significant levels of estrogen, and brain tis-
sues possess ER-/3.
Metabolism of Estrogen
The liver is the principal site of estrogen inactivation
although target tissues are equipped with a means of
controlling their estrogen microenvironment. The major
route of estradiol metabolism is by way of estrone for-
mation, which is essentially an inactivation process that
converts an active estrogen (estradiol =
1 0 0
% activity)
into a less active one (estrone = 30% activity). Peripheral
17/3HSD converts estradiol to estrone (15%) to a greater
extent than the reverse reaction (5%). Estrone is metab-
olized by three independent pathways in the liver but is
present in other tissues as well. The three pathways are
as follows:
1. Estriol formation;
2. Catecholestrogen formation; and
3. Sulfotransferase reaction.
The estriol route is the most significant, judging from
the fact that estriol is the major urinary estrogen in
humans. As its name suggests, estriol contains three
hydroxyl groups, two of which are identical to those
of estradiol (3/1, 17/3), but the third is unique to es-
triol, a 16a-hydroxyl group that is attached to either
estrone or estradiol. Estriol formation is increased in
obesity and hypothyroidism, and is decreased in hy-
perthyroidism. Catecholestrogen formation is catalyzed
by a
-hydroxylase that is present in the liver, nerve
cells, and other tissues, and both estrone and estradiol
are converted to their respective
-hydroxylated metabo-
lites. As the name suggests, the A ring of the catechole-
strogens has a catechol structure; this makes for their
rapid processing by COMT, which is present in many
tissues, including the erythrocytes. Thus, catecholestro-
gens are rapidly O-methylated at position 2 and ex-
creted as such. Catecholestrogen formation is increased
in hyperthyroidism and decreased in hypothyroidism.
A potentially mutagenic and carcinogenic metabolite
of estradiol is 4-hydroxyestradiol, which is also a cat-
echolestrogen. The hydroxylation of estradiol at the
(CYP1B1). The activated 4-hydroxyestradiol gives rise
to reactive, free-radical semiquinone / quinone interme-
diates that can damage DNA. Finally, estrone is con-
verted to estrone sulfate by sulfotransferase, present
in the liver and other tissues such as the uterus. Es-
trone sulfate is the most abundant estrogen in plasma,
with peak concentrations about
2 - 1 0
times higher than
these of unconjugated estrogens, probably due to its
long half-life in circulation. Estrone sulfate is biologi-
cally inactive and can be metabolized to estriol and cat-
echolestrone, but it is usually excreted as such by the
Selective Estrogen Receptor Modulators (SERM)
As discussed earlier, estrogens have tissue selectivity in
part, based on the type of the estrogen receptor and DNA-
bound transcription complex present in the target cells.
Drugs are being developed to mimic (agonist) or antag-
onize (antagonist) the effect of estrogen (Figure 34-7).
An example of a synthetic estrogen is diethylstilbestrol.
Tamoxifen and raloxifene are mixed agonists and antag-
onists of estrogen activity and are named SERMs (also
known as designer estrogens). Tamoxifen antagonizes the
action of estrogen in breast tissue and is used in the treat-
ment of ER-positive breast cancer. However, tamoxifen
is an estrogen agonist in the uterus and increases the risk
for endometrial cancer. In bone and in the cardiovascular
system, tamoxifen has beneficial effects similar to those
of estrogen. Raloxifene is used in the treatment of os-
teoporosis as an antiresorptive agent in postmenopausal
women but does not exhibit estrogen-related adverse ef-
fects on the endometrium. Raloxifene has a similar effect
on the serum lipid profile compared to estrogen; how-
ever, neither tamoxifen or raloxifene increases the serum
concentration of HDL-cholesterol. Many phytoestrogens
contain nonsteroidal precursors of estrogenic substances
(Figure 34-8), which may affect estrogen sensitive tis-
sues if ingested in significant amounts. However, indi-
cations are that the intake must be very high for this to
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