Page 738 - Basic _ Clinical Pharmacology ( PDFDrive )

724 SECTION VII Endocrine Drugs

TABLE 40–1 Commonly used estrogens. actions of selective estrogen receptor modulators (SERMs, see
below). The receptor may also bind to other transcription factors
Preparation Average Replacement Dosage to influence the effects of these factors on their responsive genes.
Ethinyl estradiol 0.005–0.02 mg/d Interestingly, although ERβ has its own separate actions from
ERα, it also acts as a dominant negative inhibitor of ERα. Thus,
Micronized estradiol 1–2 mg/d
while ERα has many growth-promoting properties, ERβ has anti-
Estradiol cypionate 2–5 mg every 3–4 weeks
growth effects. Many phytoestrogens act via the ERβ protecting
Estradiol valerate 2–20 mg every other week cells from the pro-growth effects of ERα.
Estropipate 1.25–2.5 mg/d The relative concentrations and types of receptors, receptor
Conjugated, esterified, or mixed estrogenic substances: coregulators, and transcription factors confer the cell specificity
Oral 0.3–1.25 mg/d of the hormone’s actions. The genomic effects of estrogens are
mainly due to proteins synthesized by translation of RNA tran-
Injectable 0.2–2 mg/d
scribed from a responsive gene. Some of the effects of estrogens
Transdermal Patch
are indirect, mediated by the autocrine and paracrine actions of
Quinestrol 0.1–0.2 mg/week autacoids such as growth factors, lipids, glycolipids, and cytokines
Chlorotrianisene 12–25 mg/d produced by the target cells in response to estrogen.
2+
Methallenestril 3–9 mg/d Rapid estrogen-induced effects such as granulosa cell Ca
uptake and increased uterine blood flow do not require gene
activation. These appear to be mediated by nongenomic effects of
However, the conjugates may be hydrolyzed in the intestine to the classic estrogen receptor-estrogen complex, influencing several
active, reabsorbable compounds. Estrogens are also excreted in intracellular signaling pathways.
small amounts in the breast milk of nursing mothers. Recently, all steroid receptors except the mineralocorticoid
Because significant amounts of estrogens and their active receptors were shown to have palmitoylation motifs that allow
metabolites are excreted in the bile and reabsorbed from the enzymatic addition of palmitate and increased localization of the
intestine, the resulting enterohepatic circulation ensures that receptors in the vicinity of plasma membranes. Such receptors
orally administered estrogens will have a high ratio of hepatic to are available for direct interactions with, and effects on, various
peripheral effects. As noted below, the hepatic effects are thought membrane-associated or cytoplasmic proteins without the need
to be responsible for some undesirable actions such as synthesis of for entry into the nucleus and induction of transcriptional actions.
increased clotting factors and plasma renin substrate. The hepatic
effects of estrogen can be minimized by routes that avoid first-pass B. Female Maturation
liver exposure, ie, vaginal, transdermal, or by injection. Estrogens are required for the normal sexual maturation and
growth of the female. They stimulate the development of the
Physiologic Effects vagina, uterus, and uterine tubes as well as the secondary sex
characteristics. They stimulate stromal development and ductal
A. Mechanism growth in the breast and are responsible for the accelerated growth
Estrogens in the blood and interstitial fluid are bound to SHBG, phase and the closing of the epiphyses of the long bones that
from which they dissociate to cross the cell membrane, enter occur at puberty. They contribute to the growth of axillary and
the nucleus, and bind to their receptor. Two genes code for two pubic hair and alter the distribution of body fat to produce typical
estrogen receptor isoforms, α and β, which are members of the female body contours. Larger quantities also stimulate develop-
superfamily of steroid, sterol, retinoic acid, and thyroid receptors. ment of pigmentation in the skin, most prominent in the region
Unlike glucocorticoid receptors, estrogen receptors are found pre- of the nipples and areolae and in the genital region.
dominantly in the nucleus, where they are bound to heat shock
proteins that stabilize them (see Figure 39–4). C. Endometrial Effects
Binding of the hormone to its receptor alters the recep-
tor’s conformation and releases it from the stabilizing proteins In addition to its growth effects on uterine muscle, estrogen plays
(predominantly Hsp90). The receptor-hormone complex forms an important role in the development of the endometrial lin-
dimers (usually ERα-ERα, ERβ-ERβ, or ERα-ERβ) that bind ing. When estrogen production is properly coordinated with the
to a specific sequence of nucleotides, called estrogen response production of progesterone during the normal human menstrual
elements (EREs), in the regulatory regions of various genes cycle, regular periodic bleeding and shedding of the endometrial
and regulate their transcription. The ERE is composed of two lining occur. Continuous exposure to estrogens for prolonged
half-sites arranged as a palindrome separated by a small group of periods leads to hyperplasia of the endometrium that is usually
nucleotides called the spacer. The interaction of a receptor dimer associated with abnormal bleeding patterns.
with the ERE also involves a number of nuclear proteins, the
coregulators, as well as components of the transcription machin- D. Metabolic and Cardiovascular Effects
ery. Complex interactions with various coregulators appear to be Estrogens have a number of important metabolic and cardiovascu-
responsible for some of the tissue-specific effects that govern the lar effects. They seem to be partially responsible for maintenance