Page 741 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 40 The Gonadal Hormones & Inhibitors 727

conjunction with hormonal contraceptives may be related to their known whether other estrogens have a similar effect or whether the
estrogen content. These are discussed below. observed phenomena are peculiar to diethylstilbestrol. This agent
should be used only in the treatment of cancer (eg, of the prostate)
A. Uterine Bleeding or as a “morning after” contraceptive (see page 736).
Estrogen therapy is a major cause of postmenopausal uterine
bleeding. Unfortunately, vaginal bleeding at this time of life may C. Other Effects
also be due to carcinoma of the endometrium. To avoid confusion, Nausea and breast tenderness are common and can be minimized
patients should be treated with the smallest amount of estrogen by using the smallest effective dose of estrogen. Hyperpigmenta-
possible. It should be given cyclically so that bleeding, if it occurs, tion also occurs. Estrogen therapy is associated with an increase in
will be more likely to occur during the withdrawal period. As frequency of migraine headaches as well as cholestasis, gallbladder
noted above, endometrial hyperplasia can be prevented by admin- disease, and hypertension.
istration of a progestational agent with estrogen in each cycle.
Contraindications
B. Cancer
The relation of estrogen therapy to cancer continues to be the Estrogens should not be used in patients with estrogen-dependent
subject of active investigation. Although no adverse effect of short- neoplasms such as carcinoma of the endometrium or in those
term estrogen therapy on the incidence of breast cancer has been with—or at high risk for—carcinoma of the breast. They
demonstrated, a small increase in the incidence of this tumor may should be avoided in patients with undiagnosed genital bleeding,
occur with prolonged therapy. Although the risk factor is small liver disease, or a history of thromboembolic disorder. In addition,
(1.25), the impact may be great since this tumor occurs in 10% of the use of estrogens should be avoided by heavy smokers.
women, and addition of progesterone does not confer a protective
effect. Studies indicate that following unilateral excision of breast Preparations & Dosages
cancer, women receiving tamoxifen (an estrogen partial agonist, The dosages of commonly used natural and synthetic preparations
see below) show a 35% decrease in contralateral breast cancer are listed in Table 40–1. Although all of the estrogens produce
compared with controls. These studies also demonstrate that almost the same hormonal effects, their potencies vary both
tamoxifen is well tolerated by most patients, produces estrogen- between agents and depending on the route of administration. As
like alterations in plasma lipid levels, and stabilizes bone mineral noted above, estradiol is the most active endogenous estrogen, and
loss. Studies bearing on the possible efficacy of tamoxifen and it has the highest affinity for the estrogen receptor. However, its
raloxifene in postmenopausal women at high risk for breast cancer metabolites estrone and estriol have weak uterine effects.
show decreases of risk for at least 5 years, but of unknown further For a given level of gonadotropin suppression, oral estrogen prepa-
duration. Another study showed that postmenopausal hormone rations have more effect on the circulating levels of CBG, SHBG,
replacement therapy with estrogens plus progestins was associated and a host of other liver proteins, including angiotensinogen, than
with greater breast epithelial cell proliferation and breast epithe- do transdermal preparations. The oral route of administration allows
lial cell density than estrogens alone or no replacement therapy. greater concentrations of hormone to reach the liver, thus increas-
Furthermore, with estrogens plus progestins, breast proliferation ing the synthesis of these proteins. Transdermal preparations were
was localized to the terminal duct-lobular unit of the breast, which developed to avoid this effect. When administered transdermally,
is the main site of development of breast cancer. Thus, further 50–100 mcg of estradiol has effects similar to those of 0.625–1.25 mg
studies are needed to conclusively assess the possible association of conjugated oral estrogens on gonadotropin concentrations, endo-
between progestins and breast cancer risk. metrium, and vaginal epithelium. Furthermore, the transdermal
Many studies show an increased risk of endometrial carcinoma estrogen preparations do not significantly increase the concentrations
in patients taking estrogens alone. The risk seems to vary with the of renin substrate, CBG, and TBG and do not produce the character-
dose and duration of treatment: 15 times greater in patients taking istic changes in serum lipids. Combined oral preparations containing
large doses of estrogen for 5 or more years, in contrast with two to 0.625 mg of conjugated estrogens and 2.5 mg of medroxyprogester-
four times greater in patients receiving lower doses for short peri- one acetate are available for menopausal replacement therapy. Tablets
ods. However, as noted above, the concomitant use of a progestin containing 0.625 mg of conjugated estrogens and 5 mg of medroxy-
prevents this increased risk and may in fact reduce the incidence progesterone acetate are available to be used in conjunction with con-
of endometrial cancer to less than that in the general population. jugated estrogens in a sequential fashion. Estrogens alone are taken on
There have been a number of reports of adenocarcinoma of the days 1–14 and the combination on days 15–28.
vagina in young women whose mothers were treated with large
doses of diethylstilbestrol early in pregnancy. These cancers are most
common in young women (ages 14–44). The incidence is less than THE PROGESTINS
1 per 1000 women exposed—too low to establish a cause-and- Natural Progestins: Progesterone
effect relationship with certainty. However, the risks for infertility,
ectopic pregnancy, and premature delivery also are increased. It is Progesterone is the most important progestin in humans. In addi-
now recognized that there is no indication for the use of dieth- tion to having important hormonal effects, it serves as a precur-
ylstilbestrol during pregnancy, and it should be avoided. It is not sor to the estrogens, androgens, and adrenocortical steroids. It is