Page 749 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 40 The Gonadal Hormones & Inhibitors 735

6. Ureteral dilation similar to that observed in pregnancy has been among women 40–44 who smoke heavily. The association with
reported, and bacteriuria is more frequent. myocardial infarction is thought to involve acceleration of athero-
7. Vaginal infections are more common and more difficult to treat genesis because of decreased glucose tolerance, decreased levels of
in patients who are using oral contraceptives. HDL, increased levels of LDL, and increased platelet aggregation.
8. Amenorrhea occurs in some patients. Following cessation of In addition, facilitation of coronary arterial spasm may play a role
administration of oral contraceptives, 95% of patients with in some of these patients. The progestational component of oral
normal menstrual histories resume normal periods and all but contraceptives decreases HDL cholesterol levels, in proportion to
a few resume normal cycles during the next few months. How- the androgenic activity of the progestin. The net effect, therefore,
ever, some patients remain amenorrheic for several years. Many will depend on the specific composition of the pill used and the
of these patients also have galactorrhea. Patients who have had patient’s susceptibility to the particular effects. Recent studies sug-
menstrual irregularities before taking oral contraceptives are gest that risk of infarction is not increased in past users who have
particularly susceptible to prolonged amenorrhea when the discontinued oral contraceptives.
agents are discontinued. Prolactin levels should be measured in c. Cerebrovascular disease—The risk of stroke is concen-
these patients, since many have prolactinomas.
trated in women over age 35. It is increased in current users of
C. Severe Adverse Effects oral contraceptives but not in past users. However, subarachnoid
1. Vascular disorders—Thromboembolism was one of the hemorrhages have been found to be increased among both current
and past users and may increase with time. The risk of thrombotic
earliest of the serious unanticipated effects to be reported and has or hemorrhagic stroke attributable to oral contraceptives (based
been the most thoroughly studied.
on older, higher-dose preparations) has been estimated at about
a. Venous thromboembolic disease—Superficial or deep 37 cases per 100,000 users per year.
thromboembolic disease in women not taking oral contraceptives In summary, available data indicate that oral contraceptives
occurs in about 1 patient per 1000 woman years. The overall inci- increase the risk of various cardiovascular disorders at all ages and
dence of these disorders in patients taking low-dose oral contracep- among both smokers and nonsmokers. However, this risk appears
tives is about threefold higher. The risk for this disorder is increased to be concentrated in women 35 years of age or older who are
during the first month of contraceptive use and remains constant heavy smokers. It is clear that these risk factors must be considered
for several years or more. The risk returns to normal within a in each individual patient for whom oral contraceptives are being
month when use is discontinued. The risk of venous thrombosis or considered. Some experts have suggested that screening for coagu-
pulmonary embolism is increased among women with predisposing lopathy should be performed before starting oral contraception.
conditions such as stasis, altered clotting factors such as antithrom- 2. Gastrointestinal disorders—Many cases of cholestatic jaun-
bin III, increased levels of homocysteine, or injury. Genetic disor- dice have been reported in patients taking progestin-containing
ders, including mutations in the genes governing the production drugs. The differences in incidence of these disorders from one
of protein C (factor V Leiden), protein S, hepatic cofactor II, and population to another suggest that genetic factors may be involved.
others, markedly increase the risk of venous thromboembolism. The The jaundice caused by these agents is similar to that produced by
incidence of these disorders is too low for cost-effective screening other 17-alkyl-substituted steroids. It is most often observed in the
by current methods, but prior episodes or a family history may be first three cycles and is particularly common in women with a his-
helpful in identifying patients with increased risk. tory of cholestatic jaundice during pregnancy. Jaundice and pruritus
The incidence of venous thromboembolism appears to be
related to the estrogen but not the progestin content of oral disappear 1–8 weeks after the drug is discontinued.
These agents have also been found to increase the incidence of
contraceptives and is not related to age, parity, mild obesity, or symptomatic gallbladder disease, including cholecystitis and chol-
cigarette smoking. Decreased venous blood flow, endothelial angitis. This is probably the result of the alterations responsible for
proliferation in veins and arteries, and increased coagulability of jaundice and bile acid changes described above.
blood resulting from changes in platelet functions and fibrinolytic It also appears that the incidence of hepatic adenomas is
systems contribute to the increased incidence of thrombosis. The increased in women taking oral contraceptives. Ischemic bowel
major plasma inhibitor of thrombin, antithrombin III, is substan- disease secondary to thrombosis of the celiac and superior and
tially decreased during oral contraceptive use. This change occurs inferior mesenteric arteries and veins has also been reported in
in the first month of treatment and lasts as long as treatment women using these drugs.
persists, reversing within a month thereafter.
3. Depression—Depression of sufficient degree to require cessa-
b. Myocardial infarction—The use of oral contraceptives is asso- tion of therapy occurs in about 6% of patients treated with some
ciated with a slightly higher risk of myocardial infarction in women preparations.
who are obese, have a history of preeclampsia or hypertension, or
have hyperlipoproteinemia or diabetes. There is a much higher risk 4. Cancer—The occurrence of malignant tumors in patients tak-
in women who smoke. The risk attributable to oral contraceptives ing oral contraceptives has been studied extensively. It is now clear
in women 30–40 years of age who do not smoke is about 4 cases that these compounds reduce the risk of endometrial and ovarian
per 100,000 users per year, as compared with 185 cases per 100,000 cancer. The lifetime risk of breast cancer in the population as