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

1170 Estrogens have positive effects on bone mass
(reviewed by Riggs et al., 2002). Bone is continuously
remodeled at sites called bone-remodeling units by the
resorptive action of osteoclasts and the bone-forming
action of osteoblasts (Chapter 61). Maintenance of total
bone mass requires equal rates of formation and resorption
as occurs in early adulthood (ages 18-40 years);
thereafter resorption predominates. Osteoclasts and
osteoblasts express both ERα and ERβ, with the former
apparently playing a greater role. Bone also expresses
both androgen and progesterone receptors. Based on animal
models, the actions of ERα predominate in bone.
Estrogens directly regulate osteoblasts and increase the
synthesis of type I collagen, osteocalcin, osteopontin,
osteonectin, alkaline phosphatase, and other markers of
differentiated osteoblasts. Estrogens also increase osteocyte
survival by inhibiting apoptosis. However, the major
effect of estrogens is to decrease the number and activity
of osteoclasts. Much of the action of estrogens on
osteoclasts appears to be mediated by altering cytokine
(both paracrine and autocrine) signals from osteoblasts.
Estrogens decrease osteoblast and stromal cell production
of the osteoclast-stimulating cytokines interleukin
(IL)-1, IL-6, and tumor necrosis factor (TNF)-α and
increase the production of IGF-1, bone morphogenic
protein (BMP)-6, and transforming growth factor (TGF)-
β, which are anti-resorptive (reviewed by Spelsberg et
al., 1999). Estrogens also increase osteoblast production
of the cytokine osteoprotegerin (OPG), a soluble
non–membrane-bound member of the TNF superfamily
(Chapter 44). OPG acts as a “decoy” receptor that antagonizes
the binding of OPG-ligand (OPG-L) to its receptor
(termed RANK, or receptor activator of NF-κB) and
prevents the differentiation of osteoclast precursors to
mature osteoclasts. Estrogens increase osteoclast apoptosis,
either directly or by increasing OPG. Estrogens have
anti-apoptotic effects on both osteoblasts and osteocytes
in animal models, and this action may be mediated by
rapid signal transduction mechanisms (Kousteni et al.,
2002; Levin, 2008). Estrogens affect bone growth and
epiphyseal closure in both sexes. The importance of
estrogen in the male skeleton is illustrated by a man with
a completely defective ER who had osteoporosis,
unfused epiphyses, increased bone turnover, and delayed
bone age (Smith et al., 1994), and by the observation that
male idiopathic osteoporosis is associated with reduced
ERα expression in both osteocytes and osteoblasts
(Braidman et al., 2000).
Estrogens have many effects on lipid metabolism;
of major interest are their effects on serum lipoprotein
and triglyceride levels (Walsh et al., 1994). In general,
SECTION V
HORMONES AND HORMONE ANTAGONISTS
estrogens slightly elevate serum triglycerides and
slightly reduce total serum cholesterol levels. More
important, they increase high-density lipoprotein
(HDL) levels and decrease the levels of low-density
lipoprotein (LDL) and lipoprotein A (LPA) (Chapter 31).
This beneficial alteration of the ratio of HDL to LDL is
an attractive effect of estrogen therapy in postmenopausal
women. The initial conclusions from two
large clinical trials—the Heart and Estrogen/Progestin
Replacement Study, or HERS (Hulley et al., 1998), and
the Women’s Health Initiative, or WHI (Anderson et al.,
2004; Rossouw et al., 2002)—were that estrogenprogestin
or estrogen-only regimens do not provide any
protection from cardiovascular disease. However,
re-examination of the data in women who took hormone
replacement within 10 years of the menopause showed
a 32% reduction in myocardial infarction (heart attack).
At relatively high concentrations, estrogens have antioxidant
activity and may inhibit the oxidation of LDL by affecting superoxide
dismutase. Long-term administration of estrogen is associated
with decreased plasma renin, angiotensin-converting enzyme, and
endothelin-1; expression of the AT 1
receptor for angiotensin II is also
decreased. Estrogen actions on the vascular wall include increased
production of nitric oxide (NO), which occurs within minutes via a
mechanism involving activation of Akt (protein kinase B) (Simoncini
et al., 2000), induction of NO synthase, and increased production of
prostacyclin. All of these changes promote vasodilation and retard
atherogenesis. Estrogens also promote endothelial cell growth while
inhibiting the proliferation of vascular smooth muscle cells.
The presence of estrogen receptors in the liver suggests that
the beneficial effects of estrogen on lipoprotein metabolism are due
partly to direct hepatic actions, but other sites of action cannot be
excluded. Estrogens also alter bile composition by increasing cholesterol
secretion and decreasing bile acid secretion. This leads to
increased saturation of bile with cholesterol and appears to be the
basis for increased gallstone formation in some women receiving
estrogens. The decline in bile acid biosynthesis may contribute to
the decreased incidence of colon cancer in women receiving combined
estrogen-progestin treatment. In general, estrogens increase
plasma levels of cortisol-binding globulin, thyroxine-binding globulin,
and sex hormone-binding globulin (SHBG), which binds both
androgens and estrogens. ERα deficiency or aromatase enzyme deficiency
in mice is associated with impaired glucose tolerance and
other elements of the metabolic syndrome due to increased insulin
resistance (Simpson, 2003).
Estrogens alter a number of metabolic pathways that affect
the clotting cascade (Mendelsohn and Karas, 1999). Systemic effects
include changes in hepatic production of plasma proteins. Estrogens
cause a small increase in coagulation factors II, VII, IX, X, and XII,
and they decrease the anticoagulation factors protein C, protein S,
and antithrombin III (Chapter 30). Fibrinolytic pathways also are
affected, and several studies of women treated with estrogen alone
or estrogen with a progestin have demonstrated decreased levels of
plasminogen-activator inhibitor 1 (PAI-1) protein with a concomitant
increase in fibrinolysis (Koh et al., 1997). Thus, estrogens increase