Hormonal Replacement Therapy:
A Clinician's Guide To Use In Menopausal Women

Andrew M. Kaunitz, M.D.
Andrew M. Kaunitz, M.D. is Professor and Assistant Chairman
of the Department of Obstetrics and Gynecology at the
University of Florida Health Science Center/Jacksonville.

Indications For Hormonal Replacement Therapy

Vasomotor and Other Central Nervous System Symptoms

Vasomotor symptoms, often described as "hot flashes" or "hot flushes" and associated sleep disturbances commonly occur during the perimenopausal transition and represent a common bothersome symptom for women during their post-menopausal years. Estrogen replacement therapy (ERT) represents a highly effective treatment for these vasomotor symptoms. In women for whom use for ERT is inappropriate, high doses of progestins can also effectively reduce vasomotor symptoms. The non-hormonal medication clonidine hydrochloride (0.1 - 0.3-mg patch) can also be used to treat hot flashes.¹

Mood disorders, particularly depression, commonly occur in menopausal women. The effectiveness of ERT in treating depression in menopausal women, however, has not been well documented. In some women receiving combination estrogen/progestin HRT, the progestin component may in fact lead to irritability and emotional lability.

Some menopausal women experience a decline in their libido. Although sexual desire represents a complex multi-fortorial phenomenon, androgen replacement may represent a therapeutic consideration in highly selected well-monitored menopausal women (see later section on estrogen/androgen regimens).

Recent observational studies have lead clinicians and women to become hopeful that ERT might reduce the progression of dementia in elderly women. Although this hypothesis is being addressed by a randomized trial within the Women's Health Initiative study (described later), currently available data does not support prescribing ERT specifically to address dementia.²

Osteoporosis

Peak bone mineral density (BMD) is reached in women in their late 20s or early 30s. At the onset of menopause, BMD declines at a rate of approximately 3% annually for the first five years and 1% annually thereafter. Hip fractures, which occur in more than 300,000 U.S. women annually, carry an overall mortality rate of 30% within one year of fracture. Other fractures associated with menopausal osteoporosis include fractures of the vertebrae, distal forearm, and proximal humerus. These fractures characteristically occur 15 - 25 years after menopause, resulting from the combination of severely reduced BMD and falls.

The cessation of ovarian estrogen production in menopausal women is associated with increased bone resorption, which exceeds the rate of bone formation. Osteopenia, or abnormally low bone density, is diagnosed when BMD decreases to one standard deviation or more below the young adult peak mean (T < -1.0). Osteoporosis is diagnosed when the BMD has declined to more than 2.5 standard deviations below the young adult peak mean (T < - 2.5). Dual energy x-ray absorptiometry (DEXA) represents a standardized technology for assessing BMD. Indications for BMD assessment are listed in Table 1.

ERT has been found to be effective in preventing loss of BMD by inhibiting bone resorption. Formulations and doses of estrogen effective in preventing loss of BMD include conjugated equine estrogen 0.625 mg, micronized estradiol 0.5 mg, transdermal estradiol 0.5 mg and esterified estrogen 0.3 mg. Other medications useful in preventing loss of BMD include alendronate, calcitonin, raloxifene, and possibly androgens.

Adequate calcium and vitamin D intake are important in preventing loss of BMD. Current guidelines recommend that postmenopausal women consume 1,200 - 1,500 mg daily elemental calcium.³

Unfortunately, menopausal women on the average are currently consuming only half this amount. A glass of milk or a portion of another dairy product will provide about 300 mg of calcium. If insufficient calcium is obtained from the diet, calcium supplementation is appropriate. Vitamin D plays an important role in facilitating intestinal absorption of calcium. Although many menopausal women living in Florida receive sun exposure, vitamin D supplementation (as included in a one-a-day multivitamin) will help menopausal women reach the recommended level of at least 400 I.U. daily.

Genital Urinary Symptoms

The tissues of the urethra and vagina are highly estrogen-responsive. Accordingly, the cessation of ovarian estradiol production in menopausal women results in a reduction in mitotic activity in these mucosal surfaces, reduced tissue vascularity, and thinning of the mucosa. The vaginal and urethral mucosa becomes pale, dry and lacking in normal texture. These hypoestrogenic changes in the vaginal mucosa cause patients to experience dryness, painful sexual relations and in some women an unpleasant vaginal discharge (atrophic vaginitis). Atrophy of the urethra mucosa is associated with an increased incidence of urethritis and possibly, urinary incontinence.

Use of systemic or local ERT can reverse many of these changes. Physicians should be aware that estrogen cream applied to the vaginal mucosa is readily absorbed and can lead to significant increases in circulating estrogen levels. A three-month estrogen - releasing ring can relieve vaginal and urinary tract symptoms without increasing systemic estradiol levels (Table 2).

Cardiovascular Disease

Coronary heart disease is the leading cause of death in women. The incidence of coronary heart disease increases dramatically after the onset of menopause, resulting in approximately 400,000 annual deaths in the United States. Many observational studies have found that coronary heart disease occurs less often in women who use ERT or HRT. Investigators have speculated that a mechanism of cardio- protection is the lowered LDL cholesterol and increased HDL cholesterol associated with oral ERT use. Although progestin therapy added to estrogen attenuates these beneficial lipoprotein changes, overall, HDL cholesterol levels improve even in combination estrogen/progestin HRT users.⁴

If the ability of ERT and HRT to prevent coronary heart disease is confirmed, this would represent the most important potential indication for use of hormonal replacement. No large randomized trial has assessed the ability of HRT to prevent coronary heart disease in healthy menopausal women. However, a randomized placebo - controlled study recently evaluated the risks and benefits of hormonal replacement therapy as investigators followed over 2,700 women with known heart disease. After a mean follow-up of four years, no significant differences in coronary events occurred in HRT vs. placebo users. Venous thromboembolism occurred almost three times more frequently in women assigned to the HRT arm of the study.⁵ When the results of the Women's Health Initiative are published in the first decade of the next century, menopausal women and their physicians will finally know whether use of HRT prevents heart disease in healthy menopausal women. At its combined Jacksonville/Gainesville clinical site, the University of Florida is participating in this massive and important study of the health of menopausal women. Based on currently available information, treatment of established coronary artery disease or prevention of coronary artery disease do not in themselves represent appropriate indications for prescribing HRT.

Hormonal Replacement Therapy Risks

Breast Cancer

Concerns that use of HRT might increase the risk of breast cancer being diagnosed deter many women from using menopausal hormones. Although some studies have suggested that HRT is linked to an increased risk of breast cancer in post menopausal women,⁶ others have shown little or no such relationship.^7,8 Although more than 50 epidemiologic studies have been published on this topic, no consistent link between HRT use and breast cancer has been confirmed. This suggests that either there is no increased risk or that the risk is too small to be demonstrated clearly or consistently by existing studies. The randomized placebo-controlled HRT trial component of the Women's Health Initiative should help, early next century, to determine whether any increased breast cancer risk is indeed associated with ERT or HRT. As with all menopause age women, regular breast self-examination and annual mammography are appropriate for HRT users.

Package labeling for all estrogens, progestins and androgens indicates that a personal history of breast cancer contraindicates hormone use. However, no studies support the concern that HRT use might increase recurrence risk or decrease survival in such women. Preliminary observational studies suggest HRT in this setting may indeed be safe.⁹ Breast cancer survivors motivated to initiate HRT need extensive and individualized counseling, including input from the treating medical or surgical oncologist.

Endometrial Neoplasia

Long-term of ERT increases the risk of endometrial hyperplasia and adenocarcinoma. Women taking combined estrogen/progestin HRT, however, experience a risk of developing endometrial hyperplasia comparable to women using no hormones.⁴ In women taking conjugated estrogen 0.625 mg daily or it's equivalent, continuous therapy with 2.5 - 5 mg of medroxyprogesterone acetate daily or 5 - 10 mg of medroxyprogesterone acetate for 14 days each month prevents the development of endometrial hyperplasia. Micronized progesterone (100 mg daily continuously or 200 mg daily cyclically) and norethindrone, although not as well studied as medroxyprogesterone acetate, can also be used to prevent endometrial hyperplasia during use of HRT. Progesterone gel applied vaginally can also be used to prevent endometrial hyperplasia (Table 5). Use of progesterone gel as part of HRT is currently being evaluated.

Thromboembolic Disease

Use of HRT appears to increase the risk of thromboembolic disease approximately threefold.⁵ Because the absolute baseline risk of thromboembolic disease is low in most healthy HRT candidates, the absolute risk of blood clot disease developing during HRT use is small in most circumstances. However, when risk factors for thromboembolism, including family history, gross obesity, previous thromboembolism or illness associated with immobilization is present, the risks as well as benefits of HRT need to be carefully individualized. Some physicians feel that transdermal ERT may increase thrombosis risk less than oral ERT.

Hypertension and Weight Gain

A large randomized prospective placebo-controlled trial of HRT found no significant differences in blood pressure between HRT and placebo users. During this same three-year trial, women in the placebo group gained more weight than those assigned to active HRT.⁴

HRT Choices

Indications for HRT include vasomotor symptoms, prevention/treatment of osteoporosis and genital urinary tract atrophy. Several studies have suggested that HRT use reduces the risk of colon cancer.^10,11

Estrogen Treatment

A variety of oral and transdermal estrogen formulations are available. The lowest dose that will relieve symptoms while preventing loss of BMD therapy represents an appropriate starting dose for most candidates (Tables 3 & 4). Because oral estrogen formulations are initially transported to the liver via portal circulation, oral estrogens have more impact on lipid and lipoprotein metabolism than transdermal estrogen. Accordingly, total cholesterol may be noted to be elevated in women taking oral ERT. However, analysis of lipoprotein subfractions in such women characteristically reveals that the HDL subfraction is increased, indicating that risk of cardiovascular disease may be lower than average. Because use of oral ERT increases triglyceride levels, women with overt hypertri-glyceridemia at baseline are not appropriate oral ERT candidates. Use of transdermal estrogen, with individualized monitoring, however, may be appropriate in such women. Because hypertriglyceridemia is prevalent in diabetic women, a baseline lipid profile should be obtained prior to starting HRT in diabetics. Monitoring serum estradiol levels has not been found to be useful in women taking oral estrogen. Likewise, because levels of follicle-stimulating hormone remain elevated in the postmenopausal range during use of ERT, monitoring gonadotropins is not useful during HRT use. A common side effect associated with ERT use is breast tenderness or a sense of breast heaviness. Often, this diminishes during ERT use.

Progestins

Several types of progestins can be used in HRT (Table 5). Some women note the occurrence of breast, abdominal wall or lower extremity bloating during progestin use. More distressing for some women is the occurrence of mood changes including irritability, depression and emotional lability.

Therapeutic Considerations

As with other women, annual physical examinations including breast and pelvic examinations, and blood pressure evaluation are appropriate for women choosing to initiate HRT and during HRT use. In women with a uterus, a progestin should be given along with ERT in a continuous or cyclical fashion (Table 6). Because the baseline prevalence of endometrial neoplasia is low in menopausal women,¹² a baseline endometrial biopsy is not necessary unless factors associated with an increased risk of endometrial disease are present (Table 7). Likewise, endometrial evaluation during use of HRT should be reserved for specific situations (Table 7).

Bleeding Issues

Women taking continuous estrogen with cyclical progestin therapy often experience predictable uterine withdrawal bleeding. No predictable bleeding pattern occurs in women using continuous estrogen/progestin HRT. After one year of continuous combination HRT use, most individuals will experience amenorrhea or only occasional spotting or bleeding. However, the desirable outcome of becoming amenorrheic is not entirely predictable, with some continuous HRT users experiencing persistent spotting or bleeding.

Estrogen/Androgen Regimens

Two estrogen/methyltestosterone oral formulations are available (Table 8). Although the addition of an androgen to ERT does not appear to offer any advantages in treating vasomotor symptoms, a positive impact on libido, mood and BMD may occur.¹³ Because the use of even low doses of androgens can cause undesirable lipoprotein changes as well as acne and hirsutism, careful monitoring is appropriate during use of estrogen/androgen combination HRT therapy. Because androgen therapy does not prevent endometrial hyperplasia during ERT use, menopausal women with a uterus using estrogen / androgen therapy should also be treated with a progestin.

Selective Estrogen Receptor Modulators

Tamoxifen and raloxifene are nonsteroidal compounds that act as estrogen agonists in certain tissues. Currently, tamoxifen is indicated as adjunctive treatment for breast cancer and for chemoprevention of breast cancer in high-risk women. Because tamoxifen has estrogen agonist effects on the endometrium, some authorities recommend routine endometrial monitoring in women taking tamoxifen.

Raloxifene use increases bone mineral density in menopausal women without having an estrogen agonist impact on the endometrium or causing uterine bleeding. Raloxifene's positive impact on BMD is not as great as that of estrogen or alendronate. Raloxifene causes leg cramps in some women, and does not suppress vasomotor symptoms (in fact, use of raloxifene may precipitate hot flashes).¹⁴ Although the long-term impact of raloxifene use on breast cancer risk is unknown, it's use is not contraindicated in breast cancer survivors. Accordingly, one appropriate use for raloxifene may be in breast cancer survivors with osteopenia or osteoporosis who can not tolerate use of alendronate.

Summary And Conclusion

Hormonal replacement therapy effectively treats vasomotor symptoms, prevents osteoporosis and improves symptoms of genital urinary atrophy in menopausal women. Whether ERT or HRT prevents heart disease or dementia remains unknown. Concerns that HRT might increase breast cancer risk remain the biggest concern preventing many menopausal candidates from choosing to use hormones. Among menopausal women with a uterus, the occurrence of uterine bleeding represents an important and undesirable side effect. For some women, progestin-induced mood changes are bothersome. Because long-term HRT use can have an important positive impact on quality of life for menopausal women, physicians should be prepared to help their menopausal patients make appropriate, individualized decisions regarding HRT use. Once women have made a thoughtful decision to begin HRT, measures to facilitate long-term treatment compliance can maximize the chance that women can realize HRT's long-term benefits.

References

1. American College of Obstetricians and Gynecologists. Hormone Replacement Therapy. ACOG Educational Bulletin. No. 247, 1998, Washington, D.C.
2. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women _ Effects on cognitive function and dementia. JAMA. 1998; 279:688-695.
3. NIH Consensus Conference. Optimal calcium intake. JAMA. 1994; 272:1942-1947.
4. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA. 1996; 275;370-375.
5. Hulley S, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998; 280:605-613.
6. Colditz GA, Stampfer MJ., Willett WC, et al. Use of postmenopausal estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med. 1995; 332:1589-1593.
7. Stanford JL, Weiss NS, Voigt LF, et al. Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA. 1995; 274:137-142.
8. Newcomb PA, Longnecker LP, Storer BE, et al. Long-term hormone replacement therapy and risk of breast cancer in postmenopausal women. Am J Epidemiol. 1995; 142:788-795.
9. Eden JA, Bush T, Nand S, Wren BG. A case-control study of combined continuous estrogen-progestin replacement therapy among women with a personal history of breast cancer. J North American Menopause Soc. 1995; 2:67-72.
10. Fernandez E, et al. Hormone replacement therapy and risk of colon and rectal cancer. Cancer Epidemiol Biomarkers Prev. 198; 7:329-333.
11. Grodstein F, et al. Postmenopausal hormone use and risk for colorectal cancer an adenoma. Ann Intern Med. 1998; 128:705-712.
12. Archer DF, McIntyre-Seltman K, Wilborn WW, et al. Endometrial morphology in asymptomatic postmenopausal women. Am J Obstet Gynecol. 1991; 165:317-322.
13. Kaunitz AM. The role of androgens in menopausal hormonal replacement. Endocrinology and Metabolism Clinics of North America. 1997; 26:391-397.
14. Delmas PD, et al. Effects of Raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med. 1997; 337: 1641-1647.

January, 1999/ Jacksonville Medicine

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