Other Potential Untoward Effects

Nausea and vomiting occur in some women but often disappear with time and may be minimized by taking estrogens with food or just prior to sleeping. Breast fullness and tenderness and edema may occur, which may be diminished by lowering the dose. A more serious concern is that estrogens may cause severe migraine in some women. Estrogens also may reactivate or exacerbate endometriosis.

Therapeutic Uses

The two major uses of estrogens are as components of combination oral contraceptives (see below) and for MHT. Historically, conjugated estrogens have been the most common agents for postmenopausal use (typically 0.625 mg/day). In contrast, most combination oral contraceptives in current use employ 20-35 ,ug/day of ethinyl estradiol. The "effective" dose of estrogen used for MHT is less than that in oral contraceptives when one considers potency. The doses of estrogens employed in both settings have decreased substantially in recent years and untoward effects have a lower incidence and severity than those reported in older studies.

menopausal hormone therapy Established benefits of estrogen therapy in postmenopausal women include amelioration of vasomotor symptoms and the prevention of bone fractures and urogenital atrophy.

Vasomotor Symptoms

The decline in ovarian function at menopause is associated with vasomotor symptoms, typically hot flashes. Treatment of vasomotor symptoms with estrogen is specific and is the most efficacious pharmacotherapy.

Osteoporosis

Osteoporosis is associated with the loss of bone mass and an increased incidence of fractures. Estrogen therapy clearly is efficacious in decreasing the incidence of fractures, although bone loss resumes when treatment is discontinued. However, because of potential risks associated with estrogen use, first-line use of other drugs should be carefully considered (see Chapter 61). Estrogens are more effective at preventing than restoring bone loss and are most effective if initiated before significant bone loss occurs.

Vaginal Dryness and Urogenital Atrophy

Loss of tissue lining the vagina or bladder in postmenopausal women leads to a variety of symptoms, including dryness and itching of the vagina, dyspareunia, swelling of tissues in the genital region, pain during urination, a need to urinate urgently or often, and sudden or unexpected urinary incontinence. When estrogens are being used solely for relief of vulvar and vaginal atrophy, local administration as a vaginal cream, ring device, or tablets may be considered.

Cardiovascular Disease

Prospective studies unexpectedly indicated that the incidence of heart disease and stroke in older postmenopausal women treated with conjugated estrogens and a progestin was initially increased, although the trend reversed with time. While it is not clear if similar results would occur with different drugs/doses or in different patient populations, estrogens (alone or in combination with a progestin) should not be used for the treatment or prevention of cardiovascular disease.

MENOPAUSAL HORMONE REGIMENS Estrogen-replacement therapy, or ERT (i.e., estrogens alone), in postmenopausal women was associated with an increased incidence of endometrial carcinoma; this led to the use of hormone-replacement therapy, or HRT, which includes a progestin to limit estrogen-related endometrial hyperplasia. "Hormone-replacement" therapy (now generally referred to as "menopausal hormone" therapy) with both an estrogen and progestin now is recommended for postmenopausal women with a uterus. For women who have undergone a hysterectomy, estrogen alone avoids the possible deleterious effects of progestins. Regardless of the specific agent or regimen, MHT with estrogens should use the lowest dose and shortest duration necessary to achieve an appropriate therapeutic goal.

Conjugated estrogens and MPA have been used most commonly in menopausal hormone regimens, although estradiol, estrone, and estriol have been used as estrogens, and norethindrone, norgestimate, levonorgestrel, norethisterone, and progesterone also have been widely used (especially in Europe). Various "continuous" or "cyclic" regimens that include drug-free days have been used. An example of a cyclic regimen is: (1) administration of an estrogen for 25 days, (2) the addition of MPA for the last 12—14 days of estrogen treatment, and (3) 5-6 days with no hormone treatment, during which withdrawal bleeding normally occurs due to breakdown and shedding of the endometrium. Continuous administration of combined estrogen plus progestin does not lead to regular, recurrent endometrial shedding, but may cause intermittent spotting or bleeding. Other regimens include a progestin intermittently (e.g., every third month), but the long-term endometrial safety of these regimens remains to be firmly established. PREMPRO (conjugated estrogens plus MPA given as a fixed dose daily) and PREMPHASE (conjugated estrogens given for 28 days plus MPA given for 14 out of 28 days) are widely used combinations. Other combination products available in the U.S. are FEMHRT (ethinyl estradiol plus norethindrone acetate), ACTIVELLA (estradiol plus norethindrone), and PREFEST (estradiol and norgestimate).

Another pharmacological consideration is the route of administration. Oral administration exposes the liver to higher concentrations of estrogens than transdermal administration and may increase SHBG, other binding globulins, angiotensinogen; and the cholesterol content of bile. Transdermal estrogen appears to cause smaller beneficial changes in LDL and HDL profiles but may be preferred in women with hypertriglyceridemia.

Tibolone (LIVIAL) is widely used in Europe for treatment of vasomotor symptoms and prevention of osteoporosis but is not approved in the U.S. The parent compound is metabolized in a tissue-selective manner to metabolites that have predominantly estrogenic, progestogenic, and androgenic activities. The drug increases bone mineral density and decreases vasomotor symptoms without stimulating the endometrium, but its effects on fractures, breast cancer, and long-term outcomes remain to be established.

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