Estrogens

Pharmacology

Nonsynthetic (natural) estrogens: Nonsynthetic estrogens may be given orally, vaginally, transdermally, or subcutaneously. In general, conjugated estrogens are twice as potent as estrone preparations (eg, estropipate) because they also contain equine estrogens, which are very potent. In particular, they have a long half-life, in part as a result of their storage in and slow release from adipose tissue.

Conjugated estrogens given orally at 0.3 or 0.625 mg, estropipate 0.625 or 1.25 mg, or micronized estradiol-17 0.5 or 1 mg is most commonly prescribed. These doses maintain the mean peak serum estradiol level at about 30 to 40 pg/mL (110 to 150 pmol/L), similar to that during the early follicular phase of the menstrual cycle, and the estrone level at 150 to 250 pg/mL (555 to 925 pmol/L). These doses are generally effective in relieving menopausal symptoms and preventing osteoporosis. The lowest dose may be used for women who experience adverse effects. However, whether lower doses confer maximal therapeutic benefit is unknown.

Enterohepatic circulation contributes to the prolonged effect of oral estrogens. Thus, patients with altered gut flora (eg, due to antibiotic use) may not sufficiently hydrolyze these conjugates, thereby preventing reabsorption, and may need higher doses. Also, patients given long-term phenytoin have enhanced glucuronidation and therefore excrete estrogens more rapidly; they too may need higher doses.

Because the concentration of oral estrogen is 4 to 5 times higher in the portal than in the general circulation, more estrogen is presented to hepatocytes than to cells of other organs. Thus, the liver is more affected by estrogens given orally than by those given parenterally. Although many of these effects on the liver may be deleterious (eg, stimulating renin-substrate and coagulation factors), some effects may be beneficial (eg, increasing high-density lipoprotein [HDL] cholesterol levels, decreasing low-density lipoprotein [LDL] cholesterol levels).

Vaginally applied estrogens are absorbed and enter the systemic circulation, achieving about one fourth the circulatory level of an equal oral dose. Specifically, vaginal estrogens exert a potent local effect; 0.3 mg of conjugated estrogens given vaginally produces the same degree of epithelial maturation as does 1.25 mg po. Continued use of vaginal estrogen increases blood estrogen levels because of enhanced transfer across a healthier, better vascularized epithelium.

Silastic rings containing estradiol may be placed in the vagina and changed every 3 months; these rings introduce negligible quantities of estradiol into the systemic circulation.

Transdermal estradiol patches 50 µg/24 hours twice weekly provide constant serum levels of estradiol 60 pg/mL (220 pmol/L) and estrone 50 pg/mL (185 pmol/L), which usually reduce menopausal symptoms and prevent osteoporosis. Occasionally, higher doses (eg, 75 µg/24 hours, 100 µg/24 hours) may be needed to control symptoms.

Synthetic estrogens: These chemical derivatives of estradiol are 100 times more potent, on a per-weight basis, than nonsynthetic estrogens in stimulating the production of hepatic proteins. Synthetic estrogens have not been routinely used postmenopausally.

Adverse Effects

Estrogens may cause nausea, mastalgia, headache, and mood changes. They may also cause or aggravate serious disorders.

Endometrial hyperplasia and cancer: Only unopposed estrogen use (ie, without the addition of a progestin) induces endometrial hyperplasia. Unopposed estrogen also increases the risk of endometrial cancer (adenocarcinoma) about fourfold, from 1/1000 to 4/1000 women per year, depending on the dose and duration (minimum, 1 to 2 years). Prescribing estrogen in a reduced dose in a cyclic fashion reduces but does not completely eliminate the increased risk of cancer. Thus, concomitant use of progestins is advised for a patient with an intact uterus.

Progestins can prevent and reverse endometrial hyperplasia; use for 7 days/month significantly reduces the incidence of hyperplasia, and use for 10 to 13 days/month offers even greater protection. Progestins also reduce the incidence of endometrial cancer to below that of women not using estrogen replacement therapy.

Ovarian cancer: Estrogen replacement therapy may increase the risk of endometrioid cancer of the ovary (which accounts for 10 to 20% of all ovarian cancers), although this effect has not been proved. The effect of progestin use on this risk is unknown.

Breast cancer: Estrogen use may theoretically increase the risk of breast cancer, because breast tumors can be estrogen sensitive, estrogens can induce breast tumors in rats, and women with prolonged endogenous estrogen exposure (eg, due to early menarche, late menopause, or nulliparity) are at increased risk of breast cancer. However, the association between estrogen replacement therapy and breast cancer is unclear, except for a possible modest increase in risk with use for 10 years or more. Nonetheless, estrogen replacement therapy may not be appropriate for menopausal women at particularly high risk of breast cancer. Adding a progestin may also increase the risk of breast cancer. The mitotic activity of the breast increases during the luteal phase, when maximum progestin secretion occurs (peak endometrial mitosis occurs during the follicular phase, when progesterone secretion is minimal). Moreover, progestins induce mammary ductal growth in rats. Therefore, the use of progestins in women without an intact uterus is unnecessary and possibly detrimental.

Cholelithiasis: During the first year of use, oral estrogen replacement therapy increases the risk of cholelithiasis by 20%. Cholelithiasis probably occurs because estrogens increase the hepatic excretion of LDL cholesterol and reduce the amount of chenodeoxycholic acid in bile.

Thromboembolic disease: Postmenopausal use of estrogen replacement therapy appears to increase the risk of deep vein thrombosis and pulmonary embolism by about 2.5-fold. Thus, oral estrogen replacement therapy should not be given to a patient with a history of thromboembolic disorders.

Hypertension: Oral estrogen replacement therapy may increase the hepatic production of renin substrate or may stimulate the production of an aberrant form. Estrogen replacement therapy does not usually induce or exacerbate hypertension and may actually lower blood pressure in some women. Moreover, estrogen replacement therapy is not associated with an increased risk of stroke. When blood pressure is increased due to estrogen replacement therapy, it is usually reversible when therapy is discontinued.

Impaired glucose tolerance: Although oral contraceptives can impair carbohydrate metabolism, the doses of estrogen replacement therapy used to treat postmenopausal symptoms do not appear to do so. Postmenopausal women with diabetes who take estrogen replacement therapy show no change, lower glucose levels, or reduced insulin requirements. Indeed, estrogen replacement therapy appears to increase the binding of insulin to its receptor, and in animal models, estrogen replacement therapy improves experimentally induced hyperglycemia.