Thyroxine-binding globulin is increased. As a result, total plasma thyroxine (T4) levels are increased to those commonly seen during pregnancy. Since more of the thyroxine is bound, the free thyroxine level in these patients is normal. Estrogens also increase the plasma level of SHBG and decrease plasma levels of free androgens by increasing their binding; large amounts of estrogen may decrease androgens by gonadotropin suppression.
3. Effects on blood—Serious thromboembolic phenomena occurring in women taking oral contraceptives gave rise to a great many studies of the effects of these compounds on blood coagulation. A clear picture of such effects has not yet emerged. The oral contraceptives do not consistently alter bleeding or clotting times. The changes that have been observed are similar to those reported in pregnancy. There is an increase in factors VII, VIII, IX, and X and a decrease in antithrombin III. Increased amounts of coumarin anticoagulants may be required to prolong prothrombin time in patients taking oral contraceptives.
There is an increase in serum iron and total iron-binding capacity similar to that reported in patients with hepatitis.
Significant alterations in the cellular components of blood have not been reported with any consistency. A number of patients have been reported to develop folic acid deficiency anemias.
4.
Effects on the liver—These hormones also have profound effects on the function of the liver. Some of these effects are deleterious and will be considered below in the section on adverse effects. The effects on serum proteins result from the effects of the estrogens on the synthesis of the various α2 globulins and fibrinogen. Serum haptoglobins produced in the liver are depressed rather than increased by estrogen. Some of the effects on carbohydrate and lipid metabolism are probably influenced by changes in liver metabolism (see below).
Important alterations in hepatic drug excretion and metabolism also occur. Estrogens in the amounts seen during pregnancy or used in oral contraceptive agents delay the clearance of sulfobromophthalein and reduce the flow of bile. The proportion of cholic acid in bile acids is increased while the proportion of chenodeoxycholic acid is decreased. These changes may be responsible for the observed increase in cholelithiasis associated with the use of these agents.
5.
Effects on lipid metabolism—As noted above, estrogens increase serum triglycerides and free and esterified cholesterol. Phospholipids are also increased, as are HDL; levels of LDL usually decrease. Although the effects are marked with doses of 100 mcg of mestranol or ethinyl estradiol, doses of 50 mcg or less have minimal effects. The progestins (particularly the “19-nortestosterone” derivatives) tend to antagonize these effects of estrogen. Preparations containing small amounts of estrogen and a progestin may slightly decrease triglycerides and HDL.
6.
Effects on carbohydrate metabolism—The administration of oral contraceptives produces alterations in carbohydrate metabolism similar to those observed in pregnancy. There is a reduction in the rate of absorption of carbohydrates from the gastrointestinal tract. Progesterone increases the basal insulin level and the rise in insulin induced by carbohydrate ingestion. Preparations with more potent progestins such as norgestrel may cause progressive decreases in carbohydrate tolerance over several years. However, the changes in glucose tolerance are reversible on discontinuing medication.
7.
Effects on the cardiovascular system—These agents cause small increases in cardiac output associated with higher systolic and diastolic blood pressure and heart rate. The pressure returns to pretreatment levels when treatment is terminated. Although the magnitude of the pressure change is small in most patients, it is marked in a few. It is important that blood pressure be followed in each patient. An increase in blood pressure has been reported to occur in a few postmenopausal women treated with estrogens alone.
8.