Hormone Replacement Therapy and the Risk of Breast Cancer

According to several studies, women who develop cystic breasts when they are taking hormone replacement therapy (HRT) have a slightly increased risk of developing breast cancer when taking high doses of unopposed estrogen.  The addition of progesterone to that therapy acts in 2 ways to reduce cell division and proliferation.  Women not at risk for breast cancer may benefit from HRT.

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Perhaps no disease has had more frightening publicity than breast cancer.  The specter of disfigurement and potential metastasis is terrifying to most women.  Because of the relationship between hormones, benign breast disease, and breast cancer, the subject of hormonal replacement therapy (HRT) and breast cancer should include a consideration of its relationship to benign breast disease.

Fibrocystic breast disease occurs in about 1 in 3 women.  Breast cancer is much less common, and statistics show variable incidence rates.  Although the idea that 10% of women will experience breast cancer is common, the actual data appear to be different.  By the time women are 75 years old, 6% to 10% of them have clinical breast cancer.  Studies of women who have died show that about 6% had breast cancer but never knew it.[1]

Other studies continue to demonstrate lower incidence rates than the common perception.  For example, one report described 10 years’ evaluation (32,351 office examinations) of nearly 9000 patients.  In the 10-year study period, manual palpation, mammograms, and fine-needle aspiration biopsy when a tumor was suspected found only 25 cancers among all 9000 patients.[2]

Statistics of female death rates confirm this less-frightening pattern.  The annual incidence of death from all cardiovascular disease in women in the U.S. is 485,000.  The annual incidence of death from breast cancer in the U.S. is less than 10% of this figure, 38,400.[3]  The risk of an average 40-year-old woman for breast cancer sometime in the next year is 1.1 per 1000 women.[4]

Fibrocystic breast disease often appears to develop as a result of hormonal imbalance.[5,6]  Women whose breasts become cystic while taking HRT may be at a slightly increased risk of developing breast cancer.  But, according to several studies, this risk is found only in users of higher doses of unopposed estrogen (more than 0.625mg of conjugated estrogen).[7,8]

For the last 10 years, researchers in France and the U.S. have been investigating the progesterone levels of women with benign breast disease.  They report that the levels are almost invariably abnormally low.[5,6,9]  They suggest that theses women suffer from a “luteal phase deficiency.”  Hormonal therapies with progesterone to overcome this luteal phase deficiency are effective in reducing benign breast disease.[6,10]

These researchers conclude that benign breast disease is only part of the pathway to breast cancer, and that this pathway to disease can be overcome with progesterone.[5]  Laboratory studies with women show that progesterone lowers the estrogen receptor levels and inhibits the conversion of androstenedione into estrogen.  These 2 actions reduce mitosis, cell division, and cell proliferation.[11]

Fibrocystic breast disease tends to increase with age until menopause, when it shows a sharp decline.[11,12]  Breast cancer increases throughout the menopausal years.[10,13]  The developmental process of breast cancer may require 9 years of silent growth before the cancer becomes apparent as a tiny lump.[14]

Who Is at Risk?
Benign breast disease.  Women at highest risk appear to be those approaching menopause and experiencing luteal phase defects.  Because luteal phase deficiencies are the normal condition of women in their late 30s and early 40s, a large proportion of women not using hormones are at risk for benign breast disease.  Appropriately dosed hormonal therapy that includes progesterone appears to be effective in reducing the incidence and experience of benign breast disease.[5,6]

Some investigators favor use of stronger nortestosterone progestins for benign breast disease hormonal regimens.[6]  If that approach is followed, it is very important to monitor patients’ blood lipids because the stronger progestins, when given in higher doses, can increase plasma lipids.  Proper dosing involves a delicate balance between providing enough hormone to reduce the tumor without circulating so much that cholesterol levels rise.  Individuation of dosage is necessary.

Breast cancer.  Family history of breast cancer is known to increase the risk that a woman will develop it.  Proliferative disease, a benign breast disease, also increases the risk.  In one large study of more than 10,000 women with benign breast disease, the proliferative disease subtype of benign breast disease was present in 30%.[15]  It increased the risk of breast cancer about 4-fold in those women.  Smoking also increases the risk of breast cancer.[16]

Does HRT Cause Breast Cancer?

Studies with both oral contraceptives and with HRT have shown benefits of appropriate dosing in reducing the incidence of cancer of the breast for women who were not at high risk for breast cancer.[11,13]  Table I summarizes some of the oral contraceptive and breast cancer publications through 1986.[10]

Two reports differ from the large number of studies supporting hormonal therapy.  One in 1986 evaluated the use of conjugated equine estrogen in fibrocystic breast disease.[17]  In that study, a higher rate of fibrocystic breast disease was found in users of estrogen replacement therapy than in nonusers.  The researcher concluded that it could not be determined from these data whether the higher rate of disease was the result of higher hormone use or of the higher detection rate of breast disease in women who were taking hormone therapy and having their breasts examined regularly.[17]

More recently, a large epidemiologic study of women in Upsala, Sweden, evaluated the incidence of breast cancer in 2 populations, 23,000 women who had prescriptions filled for hormonal replacement therapy and the rest of the women in the city.[18]  The investigators suggested that their data showed an increased incidence of breast cancer among women who were having hormonal replacement therapy prescriptions filled.  The overall increased risk was 1.1.

A closer look at the study, however, leads to serious questions about whether the data indeed show an increased risk of breast cancer after hormonal therapy.

In the nearly 6 years of the study, breast cancer incidence among the 23,000 women using hormone therapy was 1.1% (253 cancer cases divided by 23,000 HRT registry women).  This 1.1% was higher than the percentage of non-hormone users who experienced breast cancer in the same period.

A detection bias may be present in this study.  The report did not provide any evidence that women who were not receiving hormonal therapy were having their breasts examined.  In contrast, before a woman could get a prescription for HRT, she had to see her doctor.  Presumably, HRT prescriptions were given after breast examinations.

Recent screening of over 16,000 women in the Women’s Cancer Program revealed that close to 90% of prevalent breast cancer cases detected on mammography emerged in the first baseline reading.[16]  Because almost 90% of prevalent breast cancers are discovered at first mammogram, a more thorough search and consequent greater detection of existing disease may occur in women who go to their doctors for medical care.  Early detection may well be what emerged, rather than the actual incidence of cancer.  It is not really known from the way this study was done what was actually discovered.

When these investigators looked more closely at their own data, they concluded that there was no increased risk for those who used conjugated equine estrogens or the estriol form of estrogen.  The increased incidence of breast cancer emerged in the users of “estradiol.”  According to a letter from L. Bergkvist and associates in September 1989, estradiol valerate tends to be the form of estradiol prescribed in Sweden.  This synthetic oral estrogen is not available in North America.  These results may provide another argument for avoiding the synthetic estrogens.

These researchers also evaluated progestin given in opposition to estrogen and concluded that although the numbers of cancer cases were too few to evaluate, specific progestins in general progestin use emerged as a risk factor after 6 years of combined hormone use.  Because women with benign breast disease are often treated with progestin rather than estrogen; and because benign proliferative breast disease occurs in 30% of women with benign breast disease, increases the risk of breast cancer, and often leads to progestin treatment, these results cannot logically lead to a conclusion that HRT increases the risk of breast cancer.  This study did not present any data on the incidence of benign breast disease in the hormone users.

There is no way to evaluate the risk factors for cancer claimed as a result of this epidemiologic study, both because the control group did not have to undergo medical evaluation and because benign breast disease was not evaluated among the HRT users.  The details are worthy of close attention because the study has drawn so much publicity and because the publicity has not helped the public discern the facts.  The study is an epidemiologic report, not a prospective study with an appropriate control group.  Under ordinary circumstances, a good epidemiologic report points the way to planning for prospective double-blind studies.  But other prospective studies have already shown a decreased incidence of breast cancer in the populations of not-at-risk women using estrogen with progestin.[13]

In the study by Gambrell and associates [13] (Table II), women using combined estrogen and progestagen showed the lowest rate of breast cancer.  This study also must be evaluated with reservation, because women at increased risk for breast cancer were not included in hormone therapy groups.

Summary

For women who are not at increased risk for breast cancer, the weight of evidence seems to argue for the benefit of HRT (specifically a combination of estrogen and progestin) in lowering the risk.  For women at risk for breast cancer, no proper prospective data have yet been collected.  Each woman should make the decision to take HRT on the basis of her interaction with her physician.

In considering whether HRT should be prescribed, particularly in light of concerns about breast cancer, it is important to be aware of the benefits of HRT on the cardiovascular and bone systems and on the sexual and emotional well-being of the patient.

It is the author’s conclusion that there are no substantive data to show that hormones cause cancer when the hormones are prescribed in the estrogen-progestin combination referred to throughout the author’s most recent textbook.[3] 

References

1.  Skrabanek P:  False premises and false promises of breast cancer screening. Lancet, 10 Aug 1985, pp 316-320.           
2.  Nyirjesy I, Billingsley FS:  Detection of breast carcinoma in a gynecologic practice.  Obstet Gynecol 64:  747-751, 1984.
3.  Cutler, W:  Hysterectomy Before and After.  New York, Harper & Row, 1988.
4.  Eddy DM, Hasselblad V, McGivney W, et al:  The value of mammography screening in women under age 50 years.  JAMA 259:  1512-1519, 1988.
5.  Mauvais-Jarvis P, Sitruk-Ware R, Kuttenn F:  Luteal phase defect and benign breast disease:  Relationship to breast cancer genesis.  Breast Diseases-Semologia 1(2):  58-66, 1985.
6.  Sitruk-Ware R, deLingnieres B, Mauvais-Jarvis P:  Progestogen treatment in post-menopausal woman.  Maturitas 8:  95-100, 1986.
7.  Hoover R, Gray LA, Cole P, et al:  Menopausal estrogens and breast cancer. N Engl J Med 295:  401-405. 1976.
8.  Ross RK, Paganini-Hill A, Gerkins VR, et al:  A case control study of menopausal estrogen therapy and breast cancer.  JAMA 243:  1635, 1980.
9.  Sitruk-Ware LR, Sterkers N, Mowxzowicz I, et al:  Inadequate corpus luteal function in women with benign breast diseases.  J Clin Endocrinol Metab 44:  771-774, 1977.
10.  Vorherr H:  Fibrocystic breast disease:  Pathophysiology, pathomorphology, clinical picture, and management.  Am J Obstet Gynecol 154:  161-179, 1986.
11.  Vorherr H:  Endocrinology of breast cancer.  Maturitas 9:  113-122, 1987.
12.  Greenblatt RB, Mahesh VB, Sullivan D:  Gross cystic disease of the breast.  Maturitas 9:  171-181, 1987.
13.  Gambrell RD, Maler RC, Sanders BI:  Decreased incidence of breast cancer in postmenopausal estrogen-progestogen users.  Obstet Gynecol 62:  435-443, 1983.
14.  Huggins GR, Zucker PK:  Oral contraceptives and neoplasia:  1987 update.  Fertil Steril 47:  733-761, 1987.
15.  Dupont WD, Page DL:  Risk factors for breast cancer in women with proliferative breast disease.  N Engl J Med 312:  146-151, 1985.
16.  Brownson RC, Blackwell CW, Pearson DK, et al:  Risk of breast cancer in relation to cigarette smoking.  Arch Intern Med 148:  140-144, 1988.
17.  Jick SS, walker AM, Jick H:  Conjugated estrogens and fibrocystic breast disease.  Am J Epidemiol 124:  746-751, 1986.
18.  Bergkvist L, Adami HO, Persson I, et al:  The risk of breast cancer after estrogen and estrogen-progestin replacement.  N Engl J Med 321:  293-297, 1989.