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

ERα (Hewitt and Korach, 2003) and the progesterone receptor PR-
A (Conneely et al., 2002) mediate the major actions of estrogens and
progestins, respectively, on the hypothalamic-pituitary axis.
In males, testosterone regulates the hypothalamic-pituitarygonadal
axis at both the hypothalamic and pituitary levels, and its
negative feedback effect is mediated to a substantial degree by estrogen
formed via aromatization. Thus, exogenous estrogen administration
decreases LH and testosterone levels in men, and anti-estrogens
such as clomiphene cause an elevation of serum LH, which can be
used to evaluate the male reproductive axis.
When the ovaries are removed or cease to function, there is
overproduction of FSH and LH, which are excreted in the urine.
Measurement of urinary or plasma LH is valuable to assess pituitary
function and the effectiveness of therapeutic doses of estrogen.
Although FSH levels will also decline upon estrogen administration,
they do not return to normal, secondary to production of inhibin by
the ovary (Chapter 38). Consequently, the measurement of FSH levels
as a means to monitor the effectiveness of hormone therapy is not
clinically useful. Additional features of the regulation of gonadotropin
secretion and actions are discussed in Chapters 38 and 66.
Effects of Cyclical Gonadal Steroids on the Reproductive Tract.
The cyclical changes in estrogen and progesterone production by the
ovaries regulate corresponding events in the fallopian tubes, uterus,
cervix, and vagina. Physiologically, these changes prepare the uterus
for implantation, and the proper timing of events in these tissues is
essential for pregnancy. If pregnancy does not occur, the endometrium
is shed as the menstrual discharge.
The uterus is composed of an endometrium and a
myometrium. The endometrium contains an epithelium lining the
uterine cavity and an underlying stroma; the myometrium is the
smooth muscle component responsible for uterine contractions.
These cell layers, the fallopian tubes, cervix, and vagina display a
characteristic set of responses to both estrogens and progestins. The
changes typically associated with menstruation occur largely in the
endometrium (Figure 40–3).
The luminal surface of the endometrium is a layer of simple
columnar epithelial secretory and ciliated cells that is continuous
with the openings of numerous glands that extend through the
underlying stroma to the myometrial border. Fertilization normally
occurs in the fallopian tubes, so ovulation, transport of the fertilized
ovum through the fallopian tube, and preparation of the
endometrial surface must be temporally coordinated for successful
implantation.
The endometrial stroma is a highly cellular connective-tissue
layer containing a variety of blood vessels that undergo cyclic
changes associated with menstruation. The predominant cells are
fibroblasts, but macrophages, lymphocytes, and other resident and
migratory cell types also are present.
Menstruation marks the start of the menstrual cycle. During
the follicular (or proliferative) phase of the cycle, estrogen begins
the rebuilding of the endometrium by stimulating proliferation and
differentiation. Numerous mitoses become visible, the thickness of
the layer increases, and characteristic changes occur in the glands
and blood vessels. In rodent models, ERα mediates the uterotrophic
effects of estrogens (Hewitt and Korach, 2003). The overall endometrial
response involves estrogen- and progesterone-mediated expression
of peptide growth factors and receptors, cell cycle genes, and
other regulatory signals. An important response to estrogen in the
endometrium and other tissues is induction of the progesterone
receptor (PR), which enables cells to respond to this hormone during
the second half of the cycle.
In the luteal (or secretory) phase of the cycle, elevated progesterone
limits the proliferative effect of estrogens on the
endometrium by stimulating differentiation. Major effects include
stimulation of epithelial secretions important for implantation of the
blastocyst and the characteristic growth of the endometrial blood
vessels seen at this time. These effects are mediated by PR-A in
animal models (Conneely et al., 2002). Progesterone is thus important
in preparation for implantation and for the changes that take
place in the uterus at the implantation site (i.e., the decidual
response). There is a narrow “window of implantation,” spanning
days 19-24 of the endometrial cycle, when the epithelial cells of the
endometrium are receptive to blastocyst implantation. Because
endometrial status is regulated by estrogens and progestins, the efficacy
of some contraceptives may be due in part to production of an
endometrial surface that is not receptive to implantation. If pregnancy
does not occur, the corpus luteum regresses due to lack of continued
LH secretion, estrogen and progesterone levels fall, and the
endometrium is shed (Figure 40–3).
If implantation occurs, human chorionic gonadotropin (hCG)
(Chapter 38), produced initially by the trophoblast and later by the
placenta, interacts with the LH receptor of the corpus luteum to
maintain steroid hormone synthesis during the early stages of pregnancy.
In later stages the placenta itself becomes the major site of
estrogen and progesterone synthesis.
Estrogens and progesterone have important effects on the fallopian
tube, myometrium, and cervix. In the fallopian tube, estrogens
stimulate proliferation and differentiation, whereas progesterone
inhibits these processes. Also, estrogens increase and progesterone
decreases tubal muscular contractility, which affects transit time of
the ovum to the uterus. Estrogens increase the amount of cervical
mucus and its water content to facilitate sperm penetration of the
cervix, whereas progesterone generally has opposite effects.
Estrogens favor rhythmic contractions of the uterine myometrium,
and progesterone diminishes contractions. These effects are physiologically
important and may also play a role in the action of some
contraceptives.
Metabolic Effects. Estrogens affect many tissues and
have many metabolic actions in humans and animals. It
is not clear in all cases if effects result directly from
hormone actions on the tissue in question or secondarily
from actions at other sites. Many nonreproductive
tissues, including bone, vascular endothelium, liver,
CNS, immune system, gastrointestinal (GI) tract, and
heart, express low levels of both estrogen receptors, and
the ratio of ERα to ERβ varies in a cell-specific manner.
Many metabolic effects of estrogens result directly
from receptor-mediated events in affected organs. The
effects of estrogens on selected aspects of mineral,
lipid, carbohydrate, and protein metabolism are particularly
important for understanding their pharmacological
actions.
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CHAPTER 40
ESTROGENS AND PROGESTINS