Estrogens have been used extensively for replacement therapy in estrogen-deficient patients. The estrogen deficiency may be due to primary failure of development of the ovaries, premature meno-pause, castration, or menopause.
Treatment of primary hypogonadism is usually begun at 11–13 years of age in order to stimulate the development of secondary sex characteristics and menses, to stimulate optimal growth, to prevent osteoporosis and to avoid the psychological consequences of delayed puberty and estrogen deficiency. Treatment attempts to mimic the physiology of puberty. It is initi-ated with small doses of estrogen (0.3 mg conjugated estrogens or 5–10 mcg ethinyl estradiol) on days 1–21 each month and is slowly increased to adult doses and then maintained until the age of menopause (approximately 51 years of age). A progestin is added after the first uterine bleeding. When growth is completed, chronic therapy consists mainly of the administration of adult doses of both estrogens and progestins, as described below.
In addition to the signs and symptoms that follow closely upon the cessation of normal ovarian function—such as loss of menstrual peri-ods, vasomotor symptoms, sleep disturbances, and genital atro-phy—there are longer-lasting changes that influence the health and well-being of postmenopausal women. These include an accel-eration of bone loss, which in susceptible women may lead to ver-tebral, hip, and wrist fractures; and lipid changes, which may contribute to the acceleration of atherosclerotic cardiovascular dis-ease noted in postmenopausal women. The effects of estrogens on bone have been extensively studied, and the effects of hormone withdrawal have been well-characterized. However, the role of estro-gens and progestins in the cause and prevention of cardiovascular disease, which is responsible for 350,000 deaths per year, and breast cancer, which causes 35,000 deaths per year, is less well understood.
When normal ovulatory function ceases and the estrogen levels fall after menopause, oophorectomy, or premature ovarian failure, there is an accelerated rise in plasma cholesterol and LDL concen-trations, while LDL receptors decline. HDL is not much affected, and levels remain higher than in men. Very-low-density lipopro-tein and triglyceride levels are also relatively unaffected. Since cardiovascular disorders account for most deaths in this age group, the risk for these disorders constitutes a major consideration in deciding whether or not hormonal “replacement” therapy (HRT, also correctly called HT) is indicated and influences the selection of hormones to be administered. Estrogen replacement therapy has a beneficial effect on circulating lipids and lipoproteins, and this was earlier thought to be accompanied by a reduction in myo-cardial infarction by about 50% and of fatal strokes by as much as 40%. These findings, however, have been disputed by the results of a large study from the Women’s Health Initiative (WHI) project showing no cardiovascular benefit from estrogen plus progestin replacement therapy in perimenopausal or older postmenopausal patients. In fact, there may be a small increase in cardiovascular problems as well as breast cancer in women who received the replacement therapy. Interestingly, a small protective effect against colon cancer was observed. Although current clinical guidelines do not recommend routine hormone therapy in postmenopausal women, the validity of the WHI report has been questioned. In any case, there is no increased risk for breast cancer if therapy is given immediately after menopause and for the first 7 years, while the cardiovascular risk depends on the degree of atherosclerosis at the onset of therapy. Transdermal or vaginal administration of estrogen may be associated with decreased cardiovascular risk because it bypasses the liver circulation. Women with premature menopause should definitely receive hormone therapy.
In some studies, a protective effect of estrogen replacement therapy against Alzheimer’s disease was observed. However, several other studies have not supported these results.
Progestins antagonize estrogen’s effects on LDL and HDL to a variable extent. However, one large study has shown that the addi-tion of a progestin to estrogen replacement therapy does not influ-ence the cardiovascular risk.
Optimal management of the postmenopausal patient requires careful assessment of her symptoms as well as consideration of her age and the presence of (or risks for) cardiovascular disease, osteo-porosis, breast cancer, and endometrial cancer. Bearing in mind the effects of the gonadal hormones on each of these disorders, the goals of therapy can then be defined and the risks of therapy assessed and discussed with the patient.
If the main indication for therapy is hot flushes and sleep distur-bances, therapy with the lowest dose of estrogen required for symp-tomatic relief is recommended. Treatment may be required for only a limited period of time and the possible increased risk for breast cancer avoided. In women who have undergone hysterectomy, estrogens alone can be given 5 days per week or continuously, since progestins are not required to reduce the risk for endometrial hyper-plasia and cancer. Hot flushes, sweating, insomnia, and atrophicvaginitis are generally relieved by estrogens; many patients experi-ence some increased sense of well-being; and climacteric depression and other psychopathologic states are improved.The role of estrogens in the prevention and treatment of osteo-porosis has been carefully studied . The amount of bone present in the body is maximal in the young active adult in the third decade of life and begins to decline more rapidly in middle age in both men and women. The development of osteoporosis also depends on the amount of bone present at the start of this process, on vitamin D and calcium intake, and on the degree of physical activity. The risk of osteoporosis is highest in smokers who are thin, Caucasian, and inactive and have a low calcium intake and a strong family history of osteoporosis. Depression also is a major risk factor for development of osteoporosis in women.
Estrogens should be used in the smallest dosage consistent with relief of symptoms. In women who have not undergone hysterec-tomy, it is most convenient to prescribe estrogen on the first 21–25 days of each month. The recommended dosages of estrogen are 0.3–1.25 mg/d of conjugated estrogen or 0.01–0.02 mg/d of ethinyl estradiol. Dosages in the middle of these ranges have been shown to be maximally effective in preventing the decrease in bone density occurring at menopause. From this point of view, it is important to begin therapy as soon as possible after the meno-pause for maximum effect. In these patients and others not taking estrogen, calcium supplements that bring the total daily calcium intake up to 1500 mg are useful.
Patients at low risk of developing osteoporosis who manifest only mild atrophic vaginitis can be treated with topical prepara-tions. The vaginal route of application is also useful in the treat-ment of urinary tract symptoms in these patients. It is important to realize, however, that although locally administered estrogens escape the first-pass effect (so that some undesirable hepatic effects are reduced), they are almost completely absorbed into the circula-tion, and these preparations should be given cyclically.
As noted below, the administration of estrogen is associated with an increased risk of endometrial carcinoma. The administra-tion of a progestational agent with the estrogen prevents endome-trial hyperplasia and markedly reduces the risk of this cancer. When estrogen is given for the first 25 days of the month and the progestin medroxyprogesterone (10 mg/d) is added during the last 10–14 days, the risk is only half of that in women not receiving hormone replacement therapy. On this regimen, some women will experience a return of symptoms during the period off estrogen administration. In these patients, the estrogen can be given con-tinuously. If the progestin produces sedation or other undesirable effects, its dose can be reduced to 2.5–5 mg for the last 10 days of the cycle with a slight increase in the risk for endometrial hyperpla-sia. These regimens are usually accompanied by bleeding at the end of each cycle. Some women experience migraine headaches during the last few days of the cycle. The use of a continuous estrogen regimen will often prevent their occurrence. Women who object to the cyclic bleeding associated with sequential therapy can also con-sider continuous therapy. Daily therapy with 0.625 mg of conju-gated equine estrogens and 2.5–5 mg of medroxyprogesterone will eliminate cyclic bleeding, control vasomotor symptoms, prevent genital atrophy, maintain bone density, and show a favorable lipidprofile with a small decrease in LDL and an increase in HDL con-centrations. These women have endometrial atrophy on biopsy. About half of these patients experience breakthrough bleeding during the first few months of therapy. Seventy to 80 percent become amenorrheic after the first 4 months, and most remain so. The main disadvantage of continuous therapy is the need for uter-ine biopsy if bleeding occurs after the first few months.
As noted above, estrogens may also be administered vaginally or transdermally. When estrogens are given by these routes, the liver is bypassed on the first circulation, and the ratio of the liver effects to peripheral effects is reduced.
In patients in whom estrogen replacement therapy is contrain-dicated, such as those with estrogen-sensitive tumors, relief of vasomotor symptoms may be obtained by the use of clonidine.
Estrogens combined with progestins can be used to suppress ovu-lation in patients with intractable dysmenorrhea or when suppres-sion of ovarian function is used in the treatment of hirsutism and amenorrhea due to excessive secretion of androgens by the ovary. Under these circumstances, greater suppression may be needed, and oral contraceptives containing 50 mcg of estrogen or a com-bination of a low estrogen pill with GnRH suppression may be required.