CLINICAL PHARMACOLOGY
Estrogen drug products act by regulating the transcription
of a limited number of genes. Estrogens diffuse through
cell membranes, distribute themselves throughout the cell,
and bind to and activate the nuclear estrogen receptor,
a DNA-binding protein which is found in estrogen-responsive
tissues. The activated estrogen receptor binds to specific
DNA sequences, or hormone-response elements, which enhance
the transcription of adjacent genes and in turn lead to
the observed effects. Estrogen receptors have been identified
in tissues of the reproductive tract, breast, pituitary,
hypothalamus, liver, and bone of women.
Estrogens are important in the development and maintenance
of the female reproductive system and secondary sex characteristics.
By a direct action, they cause growth and development
of the uterus, fallopian tubes, and vagina. With other
hormones, such as pituitary hormones and progesterone,
they cause enlargement of the breasts through promotion
of ductal growth, stromal development, and the accretion
of fat. Estrogens are intricately involved with other
hormones, especially progesterone, in the processes of
the ovulatory menstrual cycle and pregnancy, and affect
the release of pituitary gonadotropins. They also contribute
to the shaping of the skeleton, maintenance of tone and
elasticity of urogenital structures, changes in the epiphyses
of the long bones that allow for the pubertal growth spurt
and its termination, and pigmentation of the nipples and
genitals.
Estrogens occur naturally in several forms. The primary
source of estrogen in normally cycling adult women is
the ovarian follicle, which secretes 70 to 500 mcg of
estradiol daily, depending on the phase of the menstrual
cycle. This is converted primarily to estrone, which circulates
in roughly equal proportion to estradiol, and to small
amounts of estriol. After menopause, most endogenous estrogen
is produced by conversion of androstenedione, secreted
by the adrenal cortex, to estrone by peripheral tissues.
Thus, estrone¾especially in its sulfate ester form¾is
the most abundant circulating estrogen in postmenopausal
women. Although circulating estrogens exist in a dynamic
equilibrium of metabolic interconversions, estradiol is
the principal intracellular human estrogen and is substantially
more potent than estrone or estriol at the receptor.
Estrogens used in therapy are well absorbed through the
skin, mucous membranes, and gastrointestinal tract. When
applied for a local action, absorption is usually sufficient
to cause systemic effects. When conjugated with aryl and
alkyl groups for parenteral administration, the rate of
absorption of oily preparations is slowed with a prolonged
duration of action, such that a single intramuscular injection
of estradiol valerate or estradiol cypionate is absorbed
over several weeks.
Administered estrogens and their esters are handled within
the body essentially the same as endogenous hormones.
Metabolic conversion of estrogens occurs primarily in
the liver (first pass effect), but also at local target
tissue sites. Complex metabolic processes result in a
dynamic equilibrium of circulating conjugated and unconjugated
estrogenic forms which are continually interconverted,
especially between estrone and estradiol and between esterified
and unesterified forms. Although naturally-occurring estrogens
circulate in the blood largely bound to sex hormone-binding
globulin and albumin, only unbound estrogens enter target
tissue cells. A significant proportion of the circulating
estrogen exists as sulfate conjugates, especially estrone
sulfate, which serves as a circulating reservoir for the
formation of more active estrogenic species. A certain
proportion of the estrogen is excreted into the bile and
then reabsorbed from the intestine. During this enterohepatic
recirculation, estrogens are desulfated and resulfated
and undergo degradation through conversion to less active
estrogens (estriol and other estrogens), oxidation to
nonestrogenic substances (catecholestrogens, which interact
with catecholamine metabolism, especially in the central
nervous system), and conjugation with glucuronic acids
(which are then rapidly excreted in the urine).
When given orally, naturally-occurring estrogens and
their esters are extensively metabolized (first pass effect)
and circulate primarily as estrone sulfate, with smaller
amounts of other conjugated and unconjugated estrogenic
species. This results in limited oral potency. By contrast,
synthetic estrogens, such as ethinyl estradiol and the
nonsteroidal estrogens, are degraded very slowly in the
liver and other tissues, which results in their high intrinsic
potency. Estrogen drug products administered by non-oral
routes are not subject to first-pass metabolism, but also
undergo significant hepatic uptake, metabolism, and enterohepatic
recycling.
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