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chapter
34
Endocrine Metabolism V: Reproductive System
Endometrium
Estrogen stimulates proliferation of the
epithelial and stromal cells of the endometrium and is
essential for its repair (regeneration) following menstru-
ation. Estrogen induces the synthesis of progesterone
receptors in the endometrium and thereby permits the en-
dometrium to respond to progesterone during the luteal
phase. This permissive effect of estrogen decays rapidly
and requires the continued presence of low levels of es-
trogen for maintenance; this explains why the production
of estradiol during the luteal phase and during pregnancy
is important. In pathological states, the endometrial tissue
may grow at ectopic sites of the body, and has been found
in the fallopian tube, abdominal cavity, ovary, and other
sites, including the lung. This condition (endometriosis)
is dependent on estrogenic stimulation but is not caused
by estrogen; treatment with either an estrogen antagonist
or with an androgen is effective. The stimulatory effect of
estrogen on endometrial growth also explains why estro-
gen treatment of postmenopausal women carries with it an
increased risk of developing endometrial hyperplasia and
cancer; however, when combined with progesterone, the
risk is markedly reduced.
Myometrium
Estrogen decreases the resting membrane
potential of the myometrium and increases ciliary activity
of the endometrial epithelium. Rising levels of estradiol
prior to ovulation cause the smooth muscle of the fallopian
tubes to become increasingly contractile at about the time
of ovulation. This and the increased activity of cilia on the
endometrial lining facilitate entry of the oocyte-cumulus
complex into the lumen of the fallopian tube at the time of
ovulation. In the pregnant uterus shortly before parturition,
estradiol stimulates the formation of gap junctions and the
production of myometrial receptors for oxytocin, PGF, and
PGE, and thereby promotes the myometrial contractions
that facilitate parturition.
Mammary Gland
Estrogen, in the presence of pro-
lactin (PRL), stimulates ductal proliferation and thereby
increases the area occupied by the branching ductules.
This effect also occurs in males if the level of estrogen
is sufficiently high to overcome the inhibitory effect of
androgens. Estrogen induces synthesis of progesterone re-
ceptors in the ductal epithelium and probably induces oxy-
tocin receptor sites in the myoepithelial cells that surround
the alveoli and ductules. The stimulatory effect of estro-
gen on mammary gland growth continues in the presence
of progesterone, such that mitotic growth of the mammary
gland peaks during the luteal phase, in contrast to the en-
dometrium, in which mitotic growth peaks in the follicular
phase and is inhibited by luteal progesterone. This ex-
plains why the risk of breast cancer is approximately the
same (~ 32-41%) whether or not estrogen treatment is
supplemented with progesterone. Estradiol inhibits the re-
lease of GnRH by reducing the amount of GnRH released
per pulse (reduces pulse height) without affecting the
pulse frequency. This results in a corresponding reduction
in the pulse height of LH and FSH that reduces their plasma
concentrations. Estradiol also directly inhibits FSH release
by reducing the production of FSH-/I subunits but has
no inhibitory effect on either LH-/1 or the
a
subunit. In
addition to its effect on GnRH and the pituitary go-
nadotropins, estrogen stimulates growth hormone (GH)
synthesis and promotes an increase in the GH response
to provocative stimuli. Estrogen decreases hypothala-
mic somatastatin content, increases somatotrope number,
GH mRNA levels, and GH content.
Bone
At puberty, estrogen promotes height gain and ac-
counts for the peak height velocity in girls. As in pubertal
boys, the pubertal growth spurt in girls leads to cessation
of linear growth due to ossification of the epiphyseal plate
of long bone. In the adult, estrogen has an overall protec-
tive effect on bone tissue that results from its action on
osteoblasts and osteoclasts in both cancellous (trabecular)
and cortical bone. This explains why estrogen replace-
ment therapy begun at the time of menopause effectively
prevents the loss of bone mass (osteoporosis) associated
with the postmenopausal state, if begun prior to the onset
of osteoporotic changes. The molecular mechanism of es-
trogen action on bone mass may partially occur through
the regulation of the gene for transforming growth factor
ft
(TGF-/3). Of the number of specific effects estrogen has
been found to have on bone, the two most important are
as follows:
1. Estrogen inhibits osteoclast-mediated resorption of
cancellous and cortical bone by a direct effect on the
osteoclasts; and
2. Estrogen inhibits the bone-mobilizing effect of
parathyroid hormone (PTH) by a direct effect on the
osteoblasts (Chapter 37).
Liver
Estrogen has an overall trophic effect on the liver
and opposes some of the hepatic effects of androgens,
while promoting the hepatotropic actions of glucocorti-
coids. Thus, estrogen increases circulating levels of TeBG
and thereby reduces the percentage of bioactive androgen
in plasma. Estrogen stimulates the hepatic production of
corticosteroid-binding globulin and angiotensinogen, and
provides support for glucocorticoids in an additive fashion.
Estrogen promotes blood clotting by stimulating hepatic
production of some of the clotting factors (VII-X), while
inhibiting formation of antithrombin (Chapter 36). These
and possibly other effects are believed to contribute to
the increased incidence of
thromboembolism
and
throm-
bophlebitis
in women on estrogen treatment alone or in
combination with progestin.
Skin
Estrogen inhibits the stimulatory effect of andro-
gen (DHT) on pilosebaceous activity, and thereby reduces
