Update on Hormone Replacement: Sorting Out the Options for Preventing Coronary Artery Disease and Osteoporosis

, Ohio State University

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In This Article

Considerations When Instituting and Continuing HRT

Measuring estradiol levels. It may be helpful to measure blood estradiol (E2) levels in patients receiving any of the oral or transdermal preparations; minimum target levels are approximately 60pg/mL. Since estrone (E1) and estradiol (E2) equilibrate in the plasma, it is not necessary to measure E1 as long as the E2 level is known. Measuring an estradiol level can be particularly helpful for women who are taking estrogen daily and who continue to experience vasomotor symptoms. Adequate estradiol levels (100-150pg/mL) indicate that continued vasomotor symptoms may have another etiology.[17] Conversely, the patient may have increased estrogen receptors in the hypothalamus. In women with estradiol levels greater than 100pg/mL and mastalgia, it may be necessary to reduce the estrogen dose. In women receiving estrogen replacement for established osteoporosis, blood levels of estradiol should also be measured to ensure adequate estrogen levels.

Therapeutic estrogen dosages. Oral or transdermal estrogens are the preferred routes of administration. Vaginally applied estrogen such as estradiol (Estrace) vaginal cream (2g daily for 2 weeks, then 1-3 times per week) is an excellent option for women who still have mild residual genitourinary atrophy while they are receiving standard doses of systemic estrogens. There may be some initial systemic absorption of vaginal estrogen through the thin, atrophic mucosa; once mucosal integrity is restored with local therapy, however, systemic absorption of estradiol is generally not a concern. Treatment with vaginal estrogen alone is therefore an option for women who only need treatment of urogenital atrophy. However, periodic assessment of the endometrium may be needed if this vaginal estrogen is not opposed with progestin treatment.

For women with a uterus (and therefore an endometrial lining), progestin-estrogen replacement therapy (PERT) with cyclic or continuous progestin is needed to prevent endometrial hyperplasia associated with estrogen therapy.[16] Cyclic therapy with estrogen alone does not protect against endometrial hyperplasia; therefore, either cyclic or continuous progestin is needed. Although cyclic estrogen may decrease the incidence of mastalgia in some women, it is not routinely advocated, especially when cardiovascular protection and osteoporosis prevention are the intended treatment goals.

Androgen replacement. Young women who have undergone surgical menopause as a result of a radical hysterectomy usually need androgen as well as higher-dose estrogen replacement. A bilateral oophorectomy removes almost half of the circulating testosterone; replacing this sex hormone can help maintain a woman's sense of well-being and libido. Twice the usual minimum estrogen dose (conjugated equine estrogen 1.25mg, transdermal estradiol 0.10mg, or micronized 17-B estradiol 1mg bid) may initially be needed to suppress the vasomotor symptoms that can ensue from the precipitous drop in estrogens after surgical menopause. To supply the combination of hormones required, methyltestosterone combined with esterified estrogen (Estratest), available at full strength (1.5mg estrogen/2.5mg methyltestosterone) or half strength (0.625mg estrogen/2.5mg methyltestosterone) is particularly appropriate for these women.

Oral androgens have been associated with abnormal liver function, however, and periodic monitoring of liver function tests is recommended for women taking oral androgen replacement. Rarely, a woman taking methyltestosterone combined with estrogen may experience acne, hirsutism, or other virilizing effects.

Some women undergoing a natural menopausal experience such symptoms of androgen deficiency as lowered libido and decreased sense of well being and should have free-testosterone levels tested prior to instituting any androgen replacement.

Progestins. For PERT in women going through natural menopause with an intact uterus, the standard progestin is medroxyprogesterone acetate (Provera, Cycrin, Amen) added to the daily estrogen in doses of 5-10mg on days 1 through 12 of every calendar month. Other cyclic regimens of progestin, such as 14 days every third month (4 times per year total), are being investigated and look promising, but they are not standard treatments.[18] In recent years, conjugated equine estrogen and medroxyprogesterone acetate have been combined in a 28-day pill pack. Sometimes called the menopause pill, each day's dose consists of one tablet that contains 0.625mg conjugated estrogen and one tablet with medroxyprogesterone acetate (MPA) in either a 2.5-mg (Prempro) or 5.0-mg (Premphase) dose.

For women who prefer not to continue monthly menses after menopause, a continuous combined regimen of daily estrogen and daily progestin can be offered; however, there is much less published information regarding the cardiovascular benefit ofcontinuous, combined PERT regimen. This regimen may be an appropriate option for older women who have not had a menstrual period in several years and wish to avoid regular, cyclic withdrawal bleeding.

The continuous, combined regimen potentially produces complete amenorrhea within 6 to 9 months; however, this is achieved in only 50% to 75% of women on continuous PERT.[19] To hasten the onset of amenorrhea with continuous, combined daily PERT, some clinicians prescribe progestin using the 5-mg dose daily for the first few months followed by the 2.5-mg dose.[20] Because this regimen is not a cycled program, it is impossible to tell whether uterine bleeding that may occur beyond the first 6 months is normal. Therefore, one of the disadvantages of acontinuous PERT regimen is the potential for irregular bleeding that may lead to the need for outpatient endometrial biopsy. The American College of Physicians recommends that an endometrial biopsy be done if on initiating this continuous, combined program of PERT, there is any prolonged (more than 10 days) bleeding heavier than that for previous menses, or any bleeding persists beyond 6 months.[21]

Alternatives to MPA are norethindrone (available as low-dose progestin birth control pills) or micronized progesterone. The oral micronized progesterone used in the PEPI trial is generally not commercially available, but it can be prepared by a few pharmacies across the country. Because of the lack of standardization of pharmacy-prepared oral micronized progesterone, there is concern regarding bioavailability of the progesterone and subsequent endometrial protection. Transdermal norethindrone and transdermal norethisterone acetate (in combination with transdermal estrogen) are currently under investigation, and may be promising as a combination, sequential menopause patch causing less undesirable metabolic and psychological side effects.

In general, progestins are not recommended after hysterectomy. Progestins may exhibit androgenic effects depending on the agent, dose, and route of administration. Combined estrogen/progestins may be associated with premenstrual-like syndrome side effects, the most common limiting factor in the choice of this therapy. Current epidemiological studies do not support the addition of progestins to estrogen for the purpose of bone or breast protection.

Bleeding patterns on PERT. On the cycled program of MPA for the first 12 days of the calendar month, mild to moderate uterine bleeding generally occurs mid-month, usually beginning between days 10 and 15. In the absence of cervical os stenosis/occlusion, the absence of withdrawal bleeding indicates there is no endometrial lining to be shed. Any abnormal bleeding should be investigated. Bleeding is generally considered normal if it occurs on or after the 10th day of the calendar month, but a recent study challenged this assumption.[22]

Some women object to the resumption of monthly uterine bleeding on cyclic HRT; others accept the inconvenience because of the relief of vasomotor symptoms, reversal of urogenital atrophy, prevention of accelerated bone loss associated with estrogen deficiency, as well as reduction of cardiovascular risk.[23] Thus, the options should be fully discussed with the patient.

Endometrial biopsy. Endometrial biopsy is indicated for women who have been treated with unopposed ERT. It is also indicated for any menopausal woman not on HRT who has any postmenopausal bleeding more than 6 months after natural cessation of the menses. Biopsies are also indicated in women who are on HRT and have bleeding that is off schedule. Contraindications to outpatient endometrial biopsies include pregnancy and any cervical, uterine, or pelvic infections. Cervical os (internal and/or external) stenosis is a relative contraindication and does require cervical dilation.

Women should be referred to a gynecologist for surgical dilation and curettage and possible hysteroscopy if abnormal endometrial tissue is detected by the endometrial sampling. Furthermore, women who continue to have abnormal bleeding in the presence of a normal Pipelle biopsy or in whom the Pipelle biopsy is unsuccessful should be referred to a gynecologist.

Postmenopausal endometrial thicknesses of 5mm or less on sonography suggest a benign endometrium.[24] Sonographic endometrial assessment alone is investigational and cannot be recommended as the only means to evaluate abnormal bleeding. However, information regarding thickness of the endometrium obtained on standard pelvic ultrasound can provide additional information for managing postmenopausal women. Abnormal fluid collections in the endometrial canal should be investigated with biopsy regardless of the menstrual bleeding history.

Length of treatment. If systemic HRT is prescribed solely for the benefit of treating menopausal symptoms, the treatment duration is generally for 2-3 years and then is gradually tapered off. If the intended treatment goal is to provide cardiac protection and osteoporosis prophylaxis, then long-term treatment is needed, possibly over a lifetime. For most menopausal women, the benefits of HRT generally outweigh the risks (Table III).

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