The combinations of estrogens and progestins exert their contra-ceptive effect largely through selective inhibition of pituitary func-tion that results in inhibition of ovulation. The combination agents also produce a change in the cervical mucus, in the uterine endo-metrium, and in motility and secretion in the uterine tubes, all of which decrease the likelihood of conception and implantation. The continuous use of progestins alone does not always inhibit ovula-tion. The other factors mentioned, therefore, play a major role in the prevention of pregnancy when these agents are used.
Chronic use of combination agents depresses ovarian function. Follicular development is minimal, and corpora lutea, larger fol-licles, stromal edema, and other morphologic features normally seen in ovulating women are absent. The ovaries usually become smaller even when enlarged before therapy.
The great majority of patients return to normal menstrual pat-terns when these drugs are discontinued. About 75% will ovulate in the first posttreatment cycle and 97% by the third posttreat-ment cycle. About 2% of patients remain amenorrheic for periods of up to several years after administration is stopped.
The cytologic findings on vaginal smears vary depending on the preparation used. However, with almost all of the combined drugs, a low maturation index is found because of the presence of progestational agents.
After prolonged use, the cervix may show some hypertrophy and polyp formation. There are also important effects on the cervical mucus, making it more like postovulation mucus, ie, thicker and less copious.
Agents containing both estrogens and progestins produce fur-ther morphologic and biochemical changes of the endometrial stroma under the influence of the progestin, which also stimulates glandular secretion throughout the luteal phase. The agents con-taining “19-nor” progestins—particularly those with the smaller amounts of estrogen—tend to produce more glandular atrophy and usually less bleeding.
Stimulation of the breasts occurs in most patients receiving estrogen-containing agents. Some enlargement is generally noted. The administration of estrogens and combinations of estrogens and progestins tends to suppress lactation. When the doses are small, the effects on breast-feeding are not appreciable. Studies of the transport of the oral contraceptives into breast milk suggest that only small amounts of these compounds cross into the milk, and they have not been considered to be of importance.
1. Effects on the central nervous system—The centralnervous system effects of the oral contraceptives have not been well studied in humans. A variety of effects of estrogen and pro-gesterone have been noted in animals. Estrogens tend to increase excitability in the brain, whereas progesterone tends to decrease it. The thermogenic action of progesterone and some of the synthetic progestins is also thought to occur in the central nervous system.
It is very difficult to evaluate any behavioral or emotional effects of these compounds in humans. Although the incidence of pro-nounced changes in mood, affect, and behavior appears to be low, milder changes are commonly reported, and estrogens are being successfully employed in the therapy of premenstrual tension syn-drome, postpartum depression, and climacteric depression.
2. Effects on endocrine function— The inhibition of pitu-itary gonadotropin secretion has been mentioned. Estrogens also alter adrenal structure and function. Estrogens given orally or at high doses increase the plasma concentration of the α2 globulin that binds cortisol (corticosteroid-binding globulin). Plasma con-centrations may be more than double the levels found in untreated individuals, and urinary excretion of free cortisol is elevated.
These preparations cause alterations in the renin-angiotensin-aldosterone system. Plasma renin activity has been found to increase, and there is an increase in aldosterone secretion.
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 estro-gen may decrease androgens by gonadotropin suppression.
3. Effects on blood—Serious thromboembolic phenomenaoccurring in women taking oral contraceptives gave rise to a great many studies of the effects of these compounds on blood coagula-tion. 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 profoundeffects on the function of the liver. Some of these effects are delete-rious and will be considered below in the section on adverseeffects. The effects on serum proteins result from the effects of the estrogens on the synthesis of the various α2 globulins and fibrino-gen. Serum haptoglobins produced in the liver are depressed rather than increased by estrogen. Some of the effects on carbohy-drate and lipid metabolism are probably influenced by changes in liver metabolism .
Important alterations in hepatic drug excretion and metabo-lism also occur. Estrogens in the amounts seen during pregnancy or used in oral contraceptive agents delay the clearance of sulfo-bromophthalein and reduce the flow of bile. The proportion of cholic acid in bile acids is increased while the proportion of chen-odeoxycholic 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, estrogensincrease 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 administra-tion 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 causesmall increases in cardiac output associated with higher systolic and diastolic blood pressure and heart rate. The pressure returns to normal 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. Effects on the skin— The oral contraceptives have beennoted to increase pigmentation of the skin (chloasma). This effect seems to be enhanced in women with dark complexions and by exposure to ultraviolet light. Some of the androgen-like progestins might increase the production of sebum, causing acne in some patients. However, since ovarian androgen is suppressed, many patients note decreased sebum production, acne, and terminal hair growth. The sequential oral contraceptive preparations as well as estrogens alone often decrease sebum production.