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Hormone Replacement Therapy: Making Informed Decisions

Hormone Replacement Therapy: Making Informed Decisions

The controversies regarding the association between hormonal replacement therapy (HRT) and cancers, the questions about HRT use in women with a high risk of breast cancer, and the increasing number of women with breast cancer and menopausal symptoms make HRT a significant cancer issue.

The scope is immense and growing as the baby boom generation approaches menopause. Currently, more than 30 million woman are postmenopausal, and the average life expectancy after menopause is 30 years.[1] Despite the well-recognized benefits of HRT with regards to heart disease and osteoporosis, concern about the risk of cancer seems to prevent some physicians from prescribing HRT and many patients from using HRT.

Since the 1930s, physicians have known that estrogen therapy reduces menopausal symptoms. The 1960s saw a dramatic increase in the number of women using estrogen. The number of prescriptions for estrogen decreased from 1975 to 1980 because of reports of an association of unopposed estrogen and endometrial cancer, and then increased through the mid-1980s.[2]

Despite findings in the late 1980s and 1990s that estrogen reduces the risk of osteoporosis, heart disease, and Alzhei-mer's dementia, many women still are reluctant to take estrogen because of fear of endometrial and breast cancer.[3-6]

As with any medication, the benefits of symptom relief and disease prevention must be weighed against the risks or side effects. If women are to make such decisions about HRT based on evidence rather than fear, they need a clear understanding of their individual risks and benefits.

Women opt to use HRT to alleviate menopausal symptoms, reduce their risk of heart disease and/or osteoporosis, or as part of a treatment plan for recently diagnosed heart disease. Alternatively, women may choose not to use HRT due to cost, physician advice, unwanted side effects, withdrawal bleeding, inconvenience, and fear of the risks, especially the risk of breast cancer.[6]

Surveys on women's attitudes and knowledge regarding HRT use suggest that they know more about potential risks, such as breast cancer, than about proven benefits, such as preventing osteo-porosis and heart disease.[6-8] Consequently, they may give more weight to potential cancer risks than to benefits.

Endometrial cancer is not very common. A metaanalysis of studies that examined the association between unopposed estrogen and endometrial cancer found a summary relative risk of 2.3 (CI 2.1 to 2.5), comparing the risk of endometrial cancer in women who took unopposed estrogen at any time with those who never took estrogen.[9]

Both increasing the dose and duration of unopposed estrogen therapy further increases the risk of endometrial cancer. Most women who develop endometrial cancer on HRT can be treated effectively with a hysterectomy. To avoid the increased risk of endo-metrial cancer, women with a uterus should be treated with either cyclic or continuous progestin.

There is significant controversy in the literature about HRT as a risk for breast cancer. The most recent studies do not suggest a significant increase in the risk of breast cancer with the current estrogen and progestin combination regimens.[10]

Studies consistently find no excess risk of breast cancer associated with relatively short-term (less than five years) HRT use.[11] Exceptions to this include long-term HRT users and individuals already at an increased risk because of a family history of breast cancer.

HRT may protect women from colon cancer. Several studies have shown that HRT use is associated with a lower risk of colon cancer.[12] Most recently, Newcomb et al found HRT use was associated with a significant reduction (about 30% for ever use and 46% for recent use) in colon cancer incidence.[13]

This inverse association with risk for colon cancer was observed among users of both estrogen only and estrogen and progestin combination therapy, and was maintained for at least 10 years after stopping HRT use.

HRT for Cancer Survivors

A contraindication to HRT is an estrogen-dependent neoplasia; however, stage I endometrial cancer is not a contra-indication.[14] Creasman et al found that patients with stage I endometrial cancer treated with estrogen survived longer than those patients who were not treated with estrogen.[14]

Lee et al treated patients with endometrial cancer (low-grade lesions, less than 50% local invasion, and without nodal metastasis) with estrogen. In five years of follow-up, no recurrence of endometrial cancer was identified in the treatment group, and a higher mortality was observed in the control group from cardiovascular disease.[15]

Guidelines for the use of estrogen therapy in endometrial cancer survivors have been proposed:

  1. Estrogen-receptor (ER) and progesterone-receptor (PR) status of the tumor should be determined at the time of surgical staging.
  2. Patients who are found to be at low risk for cancer recurrence may begin taking estrogen therapy.
  3. Patients who are found to be at high risk for cancer recurrence but who are ER negative may begin estrogen therapy.
  4. Patients who are found to be at high risk for recurrence and are ER positive are to be monitored for a three- to five-year disease-free interval prior to initiating estrogen therapy.[16]

Many women are surviving breast cancer, and a large proportion of women who are premenopausal when breast cancer is diagnosed develop chemotherapy-induced menopause.[17] Although having a history of breast cancer is a relative contraindication to HRT, some physicians prescribe HRT for survivors of breast cancer, especially those with severe menopausal symptoms.[18]

A few studies have looked at the impact of HRT in breast cancer survivors.[19-21] The most recent study from Australia found no deaths and significantly fewer recurrences in patients who were given continuous estrogen-proges-terone, compared with controls (despite the high doses of progestin, 10 to 20 times higher than used in the United States).[21]

While the definitive prospective studies to show that HRT is safe in survivors of breast cancer are still needed, the risks and benefits of HRT should be discussed.

Informed Decision Making

Counseling patients about the benefits and risks of HRT is a complex process made particularly difficult by the need for probabilistic thinking, with which many patients are neither familiar nor comfortable. Nevertheless, patients want to be and should be involved in the decision-making process.

Patient involvement is particularly important when the decision involves an intervention in asymptomatic patients, ie, when HRT is used for long-term benefits. Patients need to have the critical facts to make these decisions, but many physicians may not be aware of the risks and benefits of HRT.

Core Information Patients Need to Make Informed Decisions About Hormone Replacement Therapy
  • An understanding of menopause
  • The benefits of taking HRT considering the patient's individual risk profile
  • The risk of developing cancer as a result of HRT
  • The potential need for endometrial biopsy if irregular bleeding occurs
  • The different regimens that are available
  • The frequency of physician visits required
  • The duration of therapy necessary for maximum benefit of HRT

Women's Health Initiative

Although controversy exists with regards to the benefits and risks of HRT, the Women's Health Initiative sponsored by NIH, has been designed to test many of these effects. The primary outcomes to be studied are cardiovascular disease, breast cancer, colorectal cancer, and osteoporotic fractures.

The interventions include a trial of HRT, a trial of a low-fat diet to prevent breast and colon cancer, and a trial of calcium and vitamin D to prevent osteo-porotic fractures. The answers to the primary design questions will be available by the year 2007.[22]

Many questions about HRT in cancer patients remain unanswered, and more research is needed to address questions in the following areas:

  1. The effects of HRT from randomized trials that eliminate the problems of selection bias.
  2. The effects of HRT in specific subgroups, ie, women with known family history of breast cancer or the BRCA1 or BRCA2 cancer genes.
  3. The effects of HRT using continuous versus cyclic progestin therapy or other progesterone compounds.


1. Henderson BE, Bernstein L: Endogenous and Exogenous Hormonal Factors. Diseases of the Breast. Philadelphia, Lippincott-Raven Publishers, 1996.

2. Hemminki E, Kennedy DL, Baum C, et al: Prescribing of noncontraceptive estrogens and progestins in the United States, 1974-1986. Am J Public Health 78:1479-1481, 1988.

3. Ettinger B, Friedman GD, Bush T, et al: Reduced mortality associated with long-term post- menopausal estrogen therapy. Obstet Gynecol 87:6-12, 1996.

4. Grady D, Rubin S, Petitti D, et al: Hormone therapy to prevent disease and prolong life in post-menopausal women. Ann Intern Med 117:1016-1037, 1992.

5. Paganini-Hill A, Henderson VW: Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med 156:2213-2217, 1996.

6. Sinclair HK, Bond CM, Taylor RJ: Hormone replacement therapy: A study of women's knowledge and attitudes. Br J Gen Pract 43:365-370, 1993.

7. Pilote L, Hlatky MA: Attitudes of women toward hormone therapy and prevention of heart disease. Am Heart J 129:1237-1238, 1995.

8. Ferguson KJ, Hoegh C, Johnson S: Estrogen replacement therapy: A survey of women's knowledge and attitudes. Arch Intern Med 149:133-136, 1989.

9. Grady D, Gebretsadik T, Kerlikowske K, et al: Hormone replacement therapy and endometrial cancer risk: A meta-analysis. Obstet Gynecol 85:304-313, 1995.

10. Smith HO, Kammerer-Doak DN, Barbo DM, et al: Hormone replacement therapy in the menopause: A pro opinion. Cancer J Clin 46:343-363, 1996.

11. Adami H-O, Persson I: Hormone replacement therapy and breast cancer: A remaining controversy? JAMA 274:178-179, 1995.

12. Potter JD: Hormones and colon cancer. J Natl Cancer Inst 87:1039-1040, 1995.

13. Newcomb PA, Storer BE: Postmenopausal hormone use and risk of large-bowel cancer. J Natl Cancer Inst 87:1067-1071, 1995.

14. Creasman W, Henderson D, Hinshaw W, et al: Estrogen replacement therapy in the patient treated for endometrial cancer. Obstet Gynecol 67:326-330, 1986.

15. Lee RB, Burke TW, Park RC: Estrogen replacement therapy following treatment for stage 1 endometrial carcinoma. Gynecol Oncol 36:189-191, 1990.

16. Buller RE: Hormone replacement therapy following gynecologic cancer. Postgrad Obstet Gynecol 13:1-5, 1993.

17. Runowicz CD: Hormone replacement therapy in cancer survivors: A con opinion. Cancer J Clin 46:365-373, 1996.

18. Cobleigh MA, Berris RF, Bush T, et al: Estrogen replacement therapy in breast cancer survivors: A time for change. JAMA 272:540-545, 1994.

19. DiSala PJ, Creasman WT, Odicino F, et al: Hormone replacement therapy in breast cancer. Lancet 342:1232, 1993.

20. Wile AG, Opfell RW, Margileth DA: Hormone replacement therapy in previously treated breast cancer patients. Am J Surg 165:372-375, 1993.

21. Eden JA, Bush T, Nand S, et al: A case-control study of combined-continuous estrogen-progestin replacement therapy among women with a personal history of breast cancer. Menopause 2:67-72, 1995.

22. Rossouw JE, Finnegan LP, Harlan WR, et al: The evolution of the women's health initiative: Perspectives from the NIH. JAMA 50:50-55, 1995.

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