Page 747 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 40 The Gonadal Hormones & Inhibitors 733

drugs, a low maturation index is found because of the presence of androgens by increasing their binding; large amounts of estrogen
progestational agents. may decrease androgens by gonadotropin suppression.
C. Effects on the Uterus 3. Effects on blood—Serious thromboembolic phenomena
After prolonged use, the cervix may show some hypertrophy and occurring in women taking oral contraceptives gave rise to a great
polyp formation. There are also important effects on the cervical many studies of the effects of these compounds on blood coagula-
mucus, making it more like postovulation mucus, ie, thicker and tion. A clear picture of such effects has not yet emerged. The oral
less copious. contraceptives do not consistently alter bleeding or clotting times.
Agents containing both estrogens and progestins produce The changes that have been observed are similar to those reported
further morphologic and biochemical changes of the endometrial in pregnancy. There is an increase in factors VII, VIII, IX, and X
stroma under the influence of the progestin, which also stimulates and a decrease in antithrombin III. Increased amounts of couma-
glandular secretion throughout the luteal phase. The agents con- rin anticoagulants may be required to prolong prothrombin time
taining “19-nor” progestins—particularly those with the smaller in patients taking oral contraceptives.
amounts of estrogen—tend to produce more glandular atrophy There is an increase in serum iron and total iron-binding
and usually less bleeding. capacity similar to that reported in patients with hepatitis.
Significant alterations in the cellular components of blood have
D. Effects on the Breast not been reported with any consistency. A number of patients
Stimulation of the breasts occurs in most patients receiving have been reported to develop folic acid deficiency anemias.
estrogen-containing agents. Some enlargement is generally noted. 4. Effects on the liver—These hormones also have profound
The administration of estrogens and combinations of estrogens effects on the function of the liver. Some of these effects are del-
and progestins tends to suppress lactation, but when the doses are eterious and will be considered below in the section on adverse
small, the effects on breast-feeding are not appreciable. Studies of effects. The effects on serum proteins result from the effects of the
the transport of the oral contraceptives into breast milk suggest estrogens on the synthesis of the various α globulins and fibrino-
2
that only small amounts of these compounds cross into the milk, gen. Serum haptoglobins produced in the liver are depressed
and they have not been considered to be of importance.
rather than increased by estrogen. Some of the effects on carbohy-
E. Other Effects of Oral Contraceptives drate and lipid metabolism are probably influenced by changes in
liver metabolism (see below).
1. Effects on the central nervous system—The central Important alterations in hepatic drug excretion and metab-
nervous system effects of the oral contraceptives have not been olism also occur. Estrogens in the amounts seen during
well studied in humans. A variety of effects of estrogen and pro- pregnancy or used in oral contraceptive agents delay the clear-
gesterone have been noted in animals. Estrogens tend to increase ance of sulfobromophthalein and reduce the flow of bile. The
excitability in the brain, whereas progesterone tends to decrease it. proportion of cholic acid in bile acids is increased while the pro-
The thermogenic action of progesterone and some of the synthetic portion of chenodeoxycholic acid is decreased. These changes may
progestins is also thought to occur in the central nervous system. be responsible for the observed increase in cholelithiasis associated
It is very difficult to evaluate any behavioral or emotional effects with the use of these agents.
of these compounds in humans. Although the incidence of pro-
nounced changes in mood, affect, and behavior appears to be low, 5. Effects on lipid metabolism—As noted above, estrogens
milder changes are commonly reported, and estrogens are being increase serum triglycerides and free and esterified cholesterol.
successfully employed in the therapy of premenstrual tension syn- Phospholipids are also increased, as are HDL; levels of LDL usu-
drome, postpartum depression, and climacteric depression. ally decrease. Although the effects are marked with doses of 100
mcg of mestranol or ethinyl estradiol, doses of 50 mcg or less have
2. Effects on endocrine function—The inhibition of pituitary minimal effects. The progestins (particularly the “19-nortestos-
gonadotropin secretion has been mentioned. Estrogens also alter terone” derivatives) tend to antagonize these effects of estrogen.
adrenal structure and function. Estrogens given orally or at high Preparations containing small amounts of estrogen and a proges-
globulin that
doses increase the plasma concentration of the α 2 tin may slightly decrease triglycerides and HDL.
binds cortisol (corticosteroid-binding globulin). Plasma concen-
trations may be more than double the levels found in untreated 6. Effects on carbohydrate metabolism—The administra-
individuals, and urinary excretion of free cortisol is elevated. tion of oral contraceptives produces alterations in carbohydrate
These preparations cause alterations in the renin-angiotensin- metabolism similar to those observed in pregnancy. There is a
aldosterone system. Plasma renin activity has been found to reduction in the rate of absorption of carbohydrates from the
increase, and there is an increase in aldosterone secretion. gastrointestinal tract. Progesterone increases the basal insulin
Thyroxine-binding globulin is increased. As a result, total level and the rise in insulin induced by carbohydrate ingestion.
plasma thyroxine (T ) levels are increased to those commonly seen Preparations with more potent progestins such as norgestrel may
4
during pregnancy. Since more of the thyroxine is bound, the free cause progressive decreases in carbohydrate tolerance over several
thyroxine level in these patients is normal. Estrogens also increase years. However, the changes in glucose tolerance are reversible on
the plasma level of SHBG and decrease plasma levels of free discontinuing medication.