Page 739 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 40 The Gonadal Hormones & Inhibitors 725

of the normal structure and function of the skin and blood vessels Treatment of primary hypogonadism is usually begun at
in women. Estrogens also decrease the rate of resorption of bone 11–13 years of age in order to stimulate the development of
by promoting the apoptosis of osteoclasts and by antagonizing secondary sex characteristics and menses, to stimulate optimal
the osteoclastogenic and pro-osteoclastic effects of parathyroid growth, to prevent osteoporosis, and to avoid the psychologi-
hormone and interleukin 6. Estrogens also stimulate adipose tis- cal consequences of delayed puberty and estrogen deficiency.
sue production of leptin and are in part responsible for the higher Treatment attempts to mimic the physiology of puberty. It is ini-
levels of this hormone in women than in men. tiated with small doses of estrogen (0.3 mg conjugated estrogens
In addition to stimulating the synthesis of enzymes and growth or 5–10 mcg ethinyl estradiol) on days 1–21 each month and
factors leading to uterine and breast growth and differentiation, is slowly increased to adult doses and then maintained until the
estrogens alter the production and activity of many other proteins age of menopause (approximately 51 years of age). A progestin is
in the body. Metabolic alterations in the liver are especially impor- added after the first uterine bleeding. When growth is completed,
tant, so that there is a higher circulating level of proteins such as chronic therapy consists mainly of the administration of adult
transcortin (corticosteroid-binding globulin [CBG]), thyroxine- doses of both estrogens and progestins, as described below.
binding globulin (TBG), SHBG, transferrin, renin substrate, and
fibrinogen. This leads to increased circulating levels of thyroxine, B. Postmenopausal Hormonal Therapy
estrogen, testosterone, iron, copper, and other substances. In addition to the signs and symptoms that follow closely
Alterations in the composition of the plasma lipids caused by upon the cessation of normal ovarian function—such as loss of
estrogens are characterized by an increase in the high-density lipo- menstrual periods, vasomotor symptoms, sleep disturbances, and
proteins (HDL), a slight reduction in the low-density lipoproteins genital atrophy—there are longer-lasting changes that influence
(LDL), and a reduction in total plasma cholesterol levels. Plasma the health and well-being of postmenopausal women. These
triglyceride levels are increased. Estrogens decrease hepatic oxida- include an acceleration of bone loss, which in susceptible women
tion of adipose tissue lipid to ketones and increase synthesis of may lead to vertebral, hip, and wrist fractures; and lipid changes,
triglycerides. which may contribute to the acceleration of atherosclerotic cardio-
vascular disease noted in postmenopausal women. The effects of
E. Effects on Blood Coagulation estrogens on bone have been extensively studied, and the effects
Estrogens enhance the coagulability of blood. Many changes of hormone withdrawal have been well-characterized. However,
in factors influencing coagulation have been reported, includ- the role of estrogens and progestins in the cause and prevention
ing increased circulating levels of factors II, VII, IX, and X of cardiovascular disease, which is responsible for 350,000 deaths
and decreased antithrombin III, partially as a result of the per year, and breast cancer, which causes 35,000 deaths per year,
hepatic effects mentioned above. Increased plasminogen levels is less well understood.
and decreased platelet adhesiveness have also been found (see When normal ovulatory function ceases and the estrogen
Hormonal Contraception, below). levels fall after menopause, oophorectomy, or premature ovarian
failure, there is an accelerated rise in plasma cholesterol and LDL
F. Other Effects concentrations, while LDL receptors decline. HDL is not much
Estrogens induce the synthesis of progesterone receptors. They affected, and levels remain higher than in men. Very-low-density
are responsible for estrous behavior in animals and may influ- lipoprotein and triglyceride levels are also relatively unaffected.
ence behavior and libido in humans. Administration of estrogens Since cardiovascular disorders account for most deaths in this age
stimulates central components of the stress system, including the group, the risk for these disorders constitutes a major consider-
production of corticotropin-releasing hormone and the activity ation in deciding whether hormonal “replacement” therapy (HRT,
of the sympathetic system, and promotes a sense of well-being also correctly called HT) is indicated and influences the selection
when given to women who are estrogen-deficient. They also of hormones to be administered. Estrogen replacement therapy
facilitate the loss of intravascular fluid into the extracellular space, has a beneficial effect on circulating lipids and lipoproteins, and
producing edema. The resulting decrease in plasma volume causes this was earlier thought to be accompanied by a reduction in myo-
a compensatory retention of sodium and water by the kidney. cardial infarction by about 50% and of fatal strokes by as much as
Estrogens also modulate sympathetic nervous system control of 40%. These findings, however, have been disputed by the results
smooth muscle function. of a large study from the Women’s Health Initiative (WHI) project
showing no cardiovascular benefit from estrogen plus progestin
Clinical Uses * replacement therapy in perimenopausal or older postmenopausal
patients. In fact, there may be a small increase in cardiovascular
A. Primary Hypogonadism problems as well as breast cancer in women who received the
Estrogens have been used extensively for replacement therapy replacement therapy. Interestingly, a small protective effect against
in estrogen-deficient patients. The estrogen deficiency may be colon cancer was observed. Although current clinical guidelines
due to primary failure of development of the ovaries, premature do not recommend routine hormone therapy in postmenopausal
menopause, castration, or menopause. women, the validity of the WHI report has been questioned. In
any case, there is no increased risk for breast cancer if therapy is
* The use of estrogens in contraception is discussed later in this chapter. given immediately after menopause and for the first 7 years, while