Henry Burger, MD: Estradiol levels are well preserved until the onset of the menopausal transition—a phase in a woman’s life marked by physiologic changes that indicate the approach of menopause. During that transition, hormone levels may fluctuate widely and symptoms begin to occur. Concentrations of estradiol fall by about 90% during the time when the final menses are experienced, although the lowest levels are not usually reached until 1 to 3 years later.
Interestingly, despite that very marked fall in estradiol, the impact of menopause may vary from woman to woman in the same community and among women in different communities and different countries. Community surveys indicate that the impact of menopause is not very great for the majority of women but is very great for a minority.
Hormone replacement therapy (HRT) may be used for both short-term symptom control and for the long-term prevention of a number of disorders resulting directly or indirectly from menopause (Table 1). Short-term symptom control may be required for hot flashes; symptoms that result from lower genital tract atrophy, such as difficulty with intercourse or urination; sleep disturbances; or mood disturbances.
For long-term disease prevention, a number of indications for systemic hormone therapy are generally accepted. Apart from the preservation of postmenopausal quality of life, however, none of these indications has been rigorously established. The consensus view is that established indications include a reduction in the risk of osteoporotic fracture, treatment of established osteoporosis, and a reduction in atherosclerotic cardiovascular disease risk, particularly myocardial infarction.
Reducing Osteoporotic Fracture and Treating Osteoporosis
Osteoporosis is a major cause of morbidity, mortality, and health expenditure but with variable prevalence worldwide. About 75 million women in the United States, Europe, and Japan are affected. One in three postmenopausal women will suffer from the consequences of this disease, the majority being elderly. In US women, about 1.3 million osteoporotic fractures occur annually, at a cost of $10 billion to the health-care system. Most significant is hip fracture, which may result in a 1-year mortality of 12% to 20% and frequently leads to a loss of the woman’s independence.
Estrogen deficiency increases bone remodeling and leads to bone loss. Estrogen administration reverses that process, although all of the mechanisms involved are still unclear. The effect ceases when therapy is discontinued.
Many believe that the greatest benefit of estrogen is seen when treatment is initiated within 5 years of menopause, although there is no consensus on when treatment should be initiated or for how long it should be continued. No controlled clinical trials have shown a reduction in hip fracture in women given estrogen replacement therapy. In placebo-controlled studies, only a small number of patients have shown actual reductions in fractures, such as vertebral fractures.
The dose of estrogen is important, while the route is probably not. The effects of progestins on bone mineral density are variable.
Reducing Cardiovascular Disease
The impact of HRT on cardiovascular disease is generally regarded as a major focus of research. Mortality data from Australia in 1993 showed that 47.5% of all deaths in women were due to cardiovascular disease and 23.8% were due to coronary heart disease. In contrast, breast cancer accounted for 4.7% of deaths, which is approximately one-fifth of total coronary heart disease mortality.
Mortality from breast cancer, when compared to mortality from heart disease, varies as a function of the age group in which that comparison is made. Rather old US data on age-specific death rates indicate that breast cancer mortality never reaches the figure for heart disease. However, more recent data suggest that the prevalence rates may converge, particularly in the 50- to 60-year-old age bracket.
To demonstrate an effect of estrogen in the prevention of coronary heart disease, randomized, controlled clinical trials are required. Observational and case-controlled studies show that estrogen probably reduces the risk of heart disease, and the general consensus favors that conclusion. Rigorous proof will be lacking, however, until the proper studies are reported.
Primary Prevention—With respect to primary prevention, a variety of observational epidemiologic studies have shown that estrogen users have a reduced risk of developing heart disease; generally, the magnitude of this reduction is approximately 50%. Estrogen administration has demonstrated acute and chronic effects in both human and animal studies that are consistent with such a protective effect. The mechanisms of estrogen’s effects are large in number and include favorable effects on serum lipids, as well as a wide variety of direct effects on the vasculature. Despite figures to the contrary, the more recently published major studies suggest that progestins do not exert a major influence on the beneficial effects of estrogen.
Secondary Prevention—With respect to secondary prevention, a number of observational studies show that estrogen therapy produces an even greater risk reduction of up to 80% in subsequent disease or death among women who have already had a heart attack or who have clear clinical evidence of coronary artery disease. A number of prospective studies focusing on secondary prevention are underway. One of these trials, the Heart and Estrogen-Progestin Replacement (HERS) trial, was recently reported. [Editors’ Note: Although the HERS trial was reported after the 1997 conference, its results were considered important enough to be added to the published proceedings.]
This study examined the effect of conjugated estrogens (Premarin) plus continuous medroxyprogesterone acetate in the secondary prevention of heart disease. Of interest was the observation of an increase in new cardiac events during the first year of the study when estrogen-medroxyprogesterone was compared with placebo. During the third to fifth years of observation, a reduction in new coronary events occurred. These results suggested an initial prothrombotic effect of estrogen and a longer-term beneficial effect. However, no overall effect of estrogen was documented. Longer-term studies that rigorously control for all possible variables are now needed and should be forthcoming.
Other Possible Indications
Several other conditions can be considered as possible indications for hormone replacement therapy. One that has arisen recently is the possibility of reducing the risks of and even treating Alzheimer’s disease. A number of studies also suggest that HRT may reduce the risk of colon cancer and some forms of arthritis. Although there are very little data, estrogens also may be beneficial in treating a number of complications related to macrovascular disease in diabetics.
Alzheimer’s disease is an idiopathic degenerative disease of the brain, the risk of which increases progressively beginning at 40 years of age. Its prevalence may be as high as 5% in people over the age of 65 and is much higher in those over age 85. Alzheimer’s disease is probably more frequent in women, although this has not been established with certainty, and men may have more vascular dementia then women.
A number of symptoms characterize Alzheimer's disease. These initially include memory loss and a number of other clear-cut neurologic disorders; personality and emotional changes occur later. Progression of Alzheimer’s disease leads to incontinence, gait disturbance, mutism, and dependency, typically over a 6- to 12-year period.
There are several theories relating estrogens to Alzheimer’s disease. Evidence exists that women with a history of myocardial infarction and menopausal women, who, by implication, have lower estrogen levels or lower estrogen exposure, have an increased likelihood of developing Alzheimer’s disease. Most women with Alzheimer’s disease are thinner and, as a result, would have lower estrogen levels. They are also more likely to sustain hip fractures, which suggests an association with estrogen deficiency.
Oophorectomy may lead to rather specific deficits in some aspects of cognitive function, such as verbal recall, which are corrected by giving estrogen. Experimental evidence shows that estrogen has direct trophic effects on the basal forebrain cholinergic neurons. The degeneration and loss of the synapses of these neurons are believed to be major factors in the pathogenesis of Alzheimer’s dementia. Estrogen, which may maintain the levels of nerve growth factor and brain-derived growth factor, may thus be relevant to the disease.
Several observational epidemiologic studies have shown a 25% to 50% reduction in the relative risk of Alzheimer’s disease with the use of estrogens. A relationship to duration of use is apparent in some studies but not in others. A number of very small treatment studies suggest that estradiol itself and estrone sulfate may improve both cognitive and affective function in women with probable or relatively early-stage Alzheimer’s disease.
Thus, a decreased risk of Alzheimer’s disease may be a reason to consider postmenopausal hormone therapy. There is considerable debate over whether progesterone may reverse the beneficial effects of estrogens on Alzheimer’s disease.
Perhaps one of the more striking studies on the effect of estrogen is a paper by Tang and colleagues published in 1996. This community-based study of aging in New York City involved 1,282 nondemented elderly women who, at the beginning of the study, were 74 years old on average. Estrogen use was associated with a statistically significant, 40% reduction in the risk of developing Alzheimer’s disease: 6% of estrogen users vs 16% of nonusers developed the disease. The age of onset of the disease was later in estrogen users, and none of the 23 women who were taking estrogens at the outset of the study actually developed Alzheimer’s disease.
In 1996, Kuller published a very useful critical review of the data regarding estrogens. He argued that, of the possible benefits of estrogen use in Alzheimer’s disease, only its vascular effects on the pathogenesis of the disease are solidly based. According to Kuller, there is little evidence of a major gender difference in the prevalence or incidence of Alzheimer’s disease. He contended that the data on estrogen’s effects on cognitive function are equivocal. There is also the paradox of individuals with higher estrogen levels having greater longevity and, hence, a higher risk of developing Alzheimer’s disease.
In Kuller’s view, clinical trials, although very expensive, are essential and probably worth the cost. His overall conclusion is that the possibility that estrogen therapy may prevent Alzheimer’s disease is a hope without solid basis at this point in time.
Long-Term Risks of HRT
The long-term risks of hormone therapy have been widely discussed. Unopposed estrogen substantially increases the risk of endometrial cancer, and concomitant progestin use largely abrogates this effect. There is some question as to whether the abolition is totally or only partially complete.
With regard to breast cancer, ever- use or short-term use of estrogen has not been associated with an increased risk. In a number of studies, long-term use appears to be associated with an increased risk on the order of 30%. Questions about surveillance bias and patient selection bias (ie, the withholding of estrogens from individuals at increased risk) remain as confounding factors. Also, the effect of added progestins is unclear.
Since current data indicate that breast cancer is more common than heart disease in women between 50 and 65 years old, perhaps we need to be particularly careful about recommending HRT in that age group. Most women, however, are likely to derive an overall benefit from estrogen because of the reduction in heart disease, with only a small increase in the risk of developing breast cancer.
“Established” contraindications to hormone therapy include a history of breast and endometrial cancer, liver disease, and venous thromboembolism. In some of the older publications, established heart disease was also thought to be a contraindication, and this has been reconfirmed by the HERS study results. Undiagnosed vaginal bleeding, pregnancy, and certain pregnancy-associated disorders are universally regarded as contraindications.
There remains great controversy over the use of hormone therapy in women with a history of breast cancer. A 1997 review by Vassilopoulou-Sellin et al suggested that hormone therapy does not appear to have a pronounced adverse effect on cancer outcome, although the number of patients studied and the resulting amount of data are small. It will be important to discuss in this conference whether women with a history of breast cancer should be denied hormone therapy when there are other conditions present for which HRT is indicated.
With regard to liver disease, a recent review suggested that hormone therapy should be considered in all menopausal women with chronic liver disease, regardless of whether menopause was spontaneous or surgically induced, and regardless of the presence of primary or secondary amenorrhea. Women with primary biliary cirrhosis or sclerosing cholangitis from alcohol or tobacco use or those who are receiving long-term steroids for autoimmune hepatitis are at particular risk for osteoporosis and ought to be treated with estrogens.
With regard to venous thromboembolism, three observational studies published in late 1996 found an association between hormone therapy and venous thromboembolism, although that would only confer an extra risk of about 1 case per 5,000 women per year. Five other studies found no association. In a very good review published in 1997, Douketis et al argued that all of these studies have methodologic problems that preclude one from making definitive conclusions about the association, and that the biological plausibility of the association is not convincing.
As summarized in Table 1, estrogens are generally indicated for women with symptoms of estrogen deficiency, such as hot flashes and urogenital atrophy, depending on their severity. For women without significant risk factors for heart disease, osteoporosis, and Alzheimer’s disease, the indications for hormone therapy are equivocal. For those with significant risks of heart disease or osteoporosis, the benefits strongly outweigh the risks.
Current contraindications to HRT should be viewed with skepticism, as most may not be valid. Finally, ongoing clinical trials hopefully will provide helpful guidelines for the use of hormone replacement. Other options must always be considered for management, including advice on lifestyle modifications, avoidance of smoking, dietary measures, exercise, lipid-lowering agents, and bisphosphonates.
1. Australian Study: Unpublished data on record at National Heart Foundation of Australia.
2. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280(7):605-613, 1998.
3. Tang MX, Jacobs D, Stern Y, et al: Effect of oestrogen during menopause on risk and age at outset of Alzheimer’s disease. Lancet 348:429-432, 1996.
4. Kuller LH: Hormone replacement therapy and its potential relationship to dementia. J Am Geriatr Soc 44: 878-880, 1996.
5. Vassilopoulou-Sellin R, Theriault R, Klein MJ: Estrogen replacement therapy in women with prior diagnosis and treatment of breast cancer. Gynecol Oncol 65:89-93, 1997.
6. O’Donohue J, Williams R: Hormone replacement therapy in women with liver disease. Br J Obstet Gynaecol 104:1-3, 1977.
7. Douketis JD, Ginsberg JS, Holbrook A, et al: A reevaluation of the risk for venous thromboembolism with the use of oral contraceptives and hormone replacement therapy. Arch Intern Med 157:1522-1530, 1997.
8. Steinberg KK, Smith SJ, Thacker SB, et al: Breast cancer risk and duration of estrogen use: The role of study design in meta-analysis. Epidemiology 5:415-421, 1994.
9. Steinberg KK, Thacker SB, Smith SJ, et al: A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 265:1985-1990, 1991.
10. Pike MC, Bernstein L, Spicer DV: Exogenous hormones and breast cancer risk. Niederhuber JE (ed): Current Therapy in Oncology. St. Louis, BC Decker Mosby Year Book, 1993.
11. Persson I: Cancer risk in women receiving estrogen-progestin replacement therapy.Maturitas 23(suppl):S37-45, 1996.
12. Cancer Collaborationist’s Group: Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350:1047-1059, 1997.
13. Goodwin PJ, Esplen MJ, Winocur J, et al: Development of a weight management program in women with newly diagnosed locoregional breast cancer, in Bitzer J, Stauber M (eds): Psychosomatic Obstetrics/Gynecology, pp 491-496. Bologna, Italy, Monduzzi Editore, International Proceedings Division, 1995.
14. Colditz G, Hankinson S, Hunter D, et al: The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 332:1589-1593, 1995.
15. Feinleib M: Breast cancer and artificial menopause: A cohort study. J Natl Cancer Inst 41:315-329, 1968.
16. Trichopoulos D, MacMahon B, Cole P: Menopause and breast cancer rIsk. J Natl Cancer Inst 48:605-613, 1972.
17. Toniolo PG, Levitz M, Zeleniuch-Jacquotte A, et al: A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst 87:190-197, 1995.
18. Berrino F, Muti P, Micheli A, et al: Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst 88:291-296, 1996.
19. Wysowski DK, Comstock GW, Helsing KJ, et al: Sex hormone levels in serum in relation to the development of breast cancer. Am J Epidemiol 125:791-799, 1987.
20. Dorland JF, Longcope C, Stephenson HE Jr, et al: Serum sex hormone levels are related to breast cancer risk in postmenopausal women. Environ Health Perspect 105(suppl 3):583-585, 1997.
21. Garland CF, Friedlander NJ, Barrett-Connor E, et al: Sex hormones and postmenopausal breast cancer: A prospective study in an adult community. Am J Epidemiol 135:1220-1230, 1992.
22. Helzlsouer KJ, Alberg AJ, Bush TL, et al: A prospective study of endogenous hormones and breast cancer. Cancer Detect Prev 18:79-85, 1994.
23. Ekbom A, Hsieh CC, Lipworth L, et al: Intrauterine environment and breast cancer risk: A population-based study. J Natl Cancer Inst 89(1):71-76, Jan 1 1997.
24. Lavigne JA, Helzlsouer KJ, Huang HY, et al: An association between the allele coding for a low activity variant of catechol-O-methyltransferase and the risk for breast cancer. Cancer Res 57(24):5493-5497, 1997.
25. Tekmal RR, Ramachandra N, Gubba S, et al: Overexpression of int-5/aromatase in mammary glands of transgenic mice results in the induction of hyperplasia and nuclear abnormalities. Cancer Res 56:3180-3185, 1996.
26. Chang K, Lee T, Linares-Cruz G, et al: Influence of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril 63:785-791, 1995.
27. Soderqvist G, Isaksson E, von Schoultz BO, et al: Proliferation of breast epithelial cells in healthy women during the menstrual cycle. Am J Obstet Gynecol 176:123-128, 1997.
28. Sutherland R, Watts C, Musgrove E: Cell cycle control by steroid hormones in breast cancer: Implications for endocrine resistance. Endocr Related Cancer 2:87-96, 1995.
29. Plu-Bureau G, Le MG, Sitruk-Ware R, et al: Progestogen use and decreased risk of breast cancer in a cohort study of premenopausal women with benign breast disease. Br J Cancer 70(2):270-277, 1994.
30. Singletary SE, Taylor SH, Guinee VF, et al: Occurrence and prognosis of contralateral carcinoma of the breast. J Am Coll Surg 178(4):390-396, 1994.
31. Broet P, de al Rochefordiere A, Scholl SM, et al: Contralateral breast cancer: Annual incidence and risk parameters. J Clin Oncol 13(7):1578-1583, 1995.
32. Yeatman TJ, Lyman GH, Smith SK, et al: Bilaterality and recurrence rates for lobular breast cancer: Considerations for treatment. Ann Surg Oncol 4(3):198-202, 1997.
33. Laya MB, Larson EB, Taplin SH, et al: Effect of estrogen replacement therapy on the specificity of screening mammography. J Natl Cancer Inst 88:643-649, 1996.