Page 740 - Basic _ Clinical Pharmacology ( PDFDrive )

726 SECTION VII Endocrine Drugs

the cardiovascular risk depends on the degree of atherosclerosis treatment of urinary tract symptoms in these patients. It is impor-
at the onset of therapy. Transdermal or vaginal administration tant to realize, however, that although locally administered estro-
of estrogen may be associated with decreased cardiovascular risk gens escape the first-pass effect (so that some undesirable hepatic
because it bypasses the liver circulation. Women with premature effects are reduced), they are almost completely absorbed into the
menopause should definitely receive hormone therapy. circulation, and these preparations should be given cyclically.
In some studies, a protective effect of estrogen replacement As noted below, the administration of estrogen is associated
therapy against Alzheimer’s disease was observed. However, several with an increased risk of endometrial carcinoma. The administra-
other studies have not supported these results. tion of a progestational agent with the estrogen prevents endo-
Progestins antagonize estrogen’s effects on LDL and HDL to metrial hyperplasia and markedly reduces the risk of this cancer.
a variable extent. However, one large study has shown that the When estrogen is given for the first 25 days of the month and the
addition of a progestin to estrogen replacement therapy does not progestin medroxyprogesterone (10 mg/d) is added during the last
influence the cardiovascular risk. 10–14 days, the risk is only half of that in women not receiving
Optimal management of the postmenopausal patient requires hormone replacement therapy. On this regimen, some women will
careful assessment of her symptoms as well as consideration of her experience a return of symptoms during the period off estrogen
age and the presence of (or risks for) cardiovascular disease, osteo- administration. In these patients, the estrogen can be given con-
porosis, breast cancer, and endometrial cancer. Bearing in mind tinuously. If the progestin produces sedation or other undesirable
the effects of the gonadal hormones on each of these disorders, effects, its dose can be reduced to 2.5–5 mg for the last 10 days of
the goals of therapy can then be defined and the risks of therapy the cycle with a slight increase in the risk for endometrial hyper-
assessed and discussed with the patient. plasia. These regimens are usually accompanied by bleeding at the
If the main indication for therapy is hot flushes and sleep distur- end of each cycle. Some women experience migraine headaches
bances, therapy with the lowest dose of estrogen required for symp- during the last few days of the cycle. The use of a continuous
tomatic relief is recommended. Treatment may be required for only estrogen regimen will often prevent their occurrence. Women who
a limited period of time and the possible increased risk for breast object to the cyclic bleeding associated with sequential therapy can
cancer avoided. In women who have undergone hysterectomy, also consider continuous therapy. Daily therapy with 0.625 mg of
estrogens alone can be given 5 days per week or continuously, since conjugated equine estrogens and 2.5–5 mg of medroxyprogester-
progestins are not required to reduce the risk for endometrial hyper- one will eliminate cyclic bleeding, control vasomotor symptoms,
plasia and cancer. Hot flushes, sweating, insomnia, and atrophic prevent genital atrophy, maintain bone density, and show a favor-
vaginitis are generally relieved by estrogens; many patients experi- able lipid profile with a small decrease in LDL and an increase in
ence some increased sense of well-being; and climacteric depression HDL concentrations. These women have endometrial atrophy
and other psychopathologic states are improved. on biopsy. About half of these patients experience breakthrough
The role of estrogens in the prevention and treatment of osteo- bleeding during the first few months of therapy. About 70–80%
porosis has been carefully studied (see Chapter 42). The amount become amenorrheic after the first 4 months, and most remain
of bone present in the body is maximal in the young active adult so. The main disadvantage of continuous therapy is the need for
in the third decade of life and begins to decline more rapidly in uterine biopsy if bleeding occurs after the first few months.
middle age in both men and women. The development of osteo- As noted above, estrogens may also be administered vaginally
porosis also depends on the amount of bone present at the start of or transdermally. When estrogens are given by these routes, the
this process, on vitamin D and calcium intake, and on the degree liver is bypassed on the first circulation, and the ratio of the liver
of physical activity. The risk of osteoporosis is highest in smokers effects to peripheral effects is reduced.
who are thin, Caucasian, and inactive and have a low calcium In patients in whom estrogen replacement therapy is contra-
intake and a strong family history of osteoporosis. Depression also indicated, such as those with estrogen-sensitive tumors, relief of
is a major risk factor for development of osteoporosis in women. vasomotor symptoms may be obtained by the use of clonidine.
Estrogens should be used in the smallest dosage consistent
with relief of symptoms. In women who have not undergone hys- C. Other Uses
terectomy, it is most convenient to prescribe estrogen on the first Estrogens combined with progestins can be used to suppress
21–25 days of each month. The recommended dosages of estro- ovulation in patients with intractable dysmenorrhea or when sup-
gen are 0.3–1.25 mg/d of conjugated estrogen or 0.01–0.02 mg/d pression of ovarian function is used in the treatment of hirsutism
of ethinyl estradiol. Dosages in the middle of these ranges have and amenorrhea due to excessive secretion of androgens by the
been shown to be maximally effective in preventing the decrease ovary. Under these circumstances, greater suppression may be
in bone density occurring at menopause. From this point of view, needed, and oral contraceptives containing 50 mcg of estrogen
it is important to begin therapy as soon as possible after the meno- or a combination of a low-estrogen pill with GnRH suppression
pause for maximum effect. In these patients and others not taking may be required.
estrogen, calcium supplements that bring the total daily calcium
intake up to 1500 mg are useful. Adverse Effects
Patients at low risk of developing osteoporosis who mani-
fest only mild atrophic vaginitis can be treated with topical Adverse effects of variable severity have been reported with the
preparations. The vaginal route of application is also useful in the therapeutic use of estrogens. Many other effects reported in