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

Estrogens and Progestins
Ellis R. Levin
and Stephen R. Hammes
Estrogens and progestins are endogenous hormones
that produce numerous physiological actions. In
women, these include developmental effects, neuroendocrine
actions involved in the control of ovulation, the
cyclical preparation of the reproductive tract for fertilization
and implantation, and major actions on mineral,
carbohydrate, protein, and lipid metabolism. Estrogens
also have important actions in males, including effects
on bone, spermatogenesis, and behavior. The biosynthesis,
biotransformation, and disposition of estrogens
and progestins are well established. Two well-characterized
receptors are present for each hormone, and there is
evidence that the receptors mediate biological actions in
both the unliganded and steroid hormone-liganded
states.
The therapeutic use of estrogens and progestins
largely reflects extensions of their physiological activities.
The most common uses of these agents are
menopausal hormone therapy and contraception in
women, but the specific compounds and dosages used
in these two settings differ substantially. Estrogen- and
progesterone-receptor antagonists also are available.
The main uses of anti-estrogens are treatment of
hormone-responsive breast cancer and infertility.
Selective estrogen receptor modulators (SERMs) that
display tissue-selective agonist or antagonist activities
are useful to prevent breast cancer and osteoporosis.
The main use of anti-progestins has been for medical
abortion, but other uses are theoretically possible.
A number of naturally occurring and synthetic
environmental chemicals mimic, antagonize, or otherwise
affect the actions of estrogens in experimental test
systems. The precise effect of these agents on humans
is unknown, but this is an area of active investigation.
Cancer chemotherapeutic strategies based on blockade
of estrogen- and/or progesterone-receptor functions
are considered in further detail in Chapter 63.
Complementary therapeutic strategies based on suppression
of gonadotropin secretion by long-acting
gonadotropin-releasing hormone agonists are also discussed
in Chapter 63.
History. The hormonal nature of the ovarian control of the female
reproductive system was firmly established in 1900 by Knauer when
he found that ovarian transplants prevented the symptoms of
gonadectomy, and by Halban, who showed that normal sexual development
and function occurred when glands were transplanted. In
1923, Allen and Doisy devised a bioassay for ovarian extracts based
on the vaginal smear of the rat. Frank and associates in 1925 detected
an active sex principle in the blood of sows in estrus, and Loewe and
Lange discovered in 1926 that a female sex hormone varied in the
urine of women throughout the menstrual cycle. The excretion of
estrogen in the urine during pregnancy also was reported by Zondek
in 1928 and enabled Butenandt and Doisy in 1929 to crystallize an
active substance.
Early investigations indicated that the ovary secretes two substances.
Beard had postulated in 1897 that the corpus luteum serves
a necessary function during pregnancy, and Fraenkel showed in 1903
that destruction of the corpora lutea in pregnant rabbits caused abortion.
Several groups then isolated progesterone from mammalian
corpora lutea in the 1930s.
In the early 1960s, pioneering studies by Jensen and colleagues
suggested the presence of intracellular receptors for estrogens
in target tissues. This was the first demonstration of receptors
of the steroid/thyroid superfamily and provided techniques to identify
receptors for the other steroid hormones. A second estrogen
receptor was identified in 1996 and termed estrogen receptor β
(ERβ) to distinguish it from the receptor identified by Jensen and
others, termed estrogen receptor α (ERα). Two protein isoforms, A
and B, of the progesterone receptor arise from a single gene by transcription
initiation from different promoters. For the primary literature
references about the history of this subject, consult the ninth
and tenth editions of this text.
ESTROGENS
Chemistry. Many steroidal and nonsteroidal compounds, some of
which are shown in Table 40–1 and Figure 40–1, possess estrogenic
activity. The most potent naturally occurring estrogen in