Future possibilities in the prevention of breast cancer: Luteinizing hormone-releasing hormone agonists
© Current Science Ltd 2000
Received: 13 March 2000
Accepted: 7 April 2000
Published: 1 August 2000
The cyclic production of estrogen and progesterone by the premenopausal ovary accounts for the steep rise in breast cancer risk in premenopausal women. These hormones are breast cell mitogens. By reducing exposure to these ovarian hormones, agonists of luteinizing hormone-releasing hormone (LHRH) given to suppress ovarian function may prove useful in cancer prevention. To prevent deleterious effects of hypoestrogenemia, the addition of low-dose hormone replacement to the LHRH agonist appears necessary. Pilot data with such an approach indicates it is feasible and reduces mammographic densities.
More than a decade ago Pike et al  first suggested a potential role for agonists of LHRH to prevent breast cancer. The rationale for considering LHRH agonists is due to their ability to suppress ovarian function and sex steroid production; the reduction in sex steroids is predicted to lead to the prevention of breast cancer.
Ovarian hormones (estrogens and progestogens) are critical factors in the genesis of human breast cancer. During the premenopausal years breast cancer risk increases steeply, but after cessation of ovarian function (menopause) it increases at a much lower rate. Epidemiologic studies have clearly demonstrated that early menopause, whether natural or artificial (bilateral oophorectomy), substantially reduces breast cancer risk. Menopause before age 35 years is associated with a 60-75% reduction in breast cancer risk [2,3,4,5,6]. The calculated effect of an early oophorectomy on the age-incidence curve of breast cancer is given in Figure 1; age at menopause determines the transition point from the steeply rising premenopausal slope to the more gentle postmenopausal slope. The protective effect of oophorectomy on breast cancer risk has recently been shown in women carrying BRCA1 germline mutations. Bilateral prophylactic oophorectomy (done to prevent ovarian cancer) is associated with a reduction in breast cancer risk . The magnitude of the protection reported by Rebbeck et al  is substantial (hazard ratio of 0.53) and increased with increasing duration of follow up after the prophylactic surgery.
Luteinizing hormone-releasing hormone
Native LHRH produced by the hypothalamus controls the secretion of follicle-stimulating hormone and luteinizing hormone by the pituitary gland, and hence gonadal steroid hormone production. Administration of potent synthetic agonists of LHRH to premenopausal women results in a transient rise in follicle-stimulating hormone/luteinizing hormone release, followed by a sustained suppression. The reduction in serum estradiol and serum progesterone to oophorectomized levels by LHRH agonists has been demonstrated in numerous reports , and led to their use in the treatment of hormone-responsive metastatic breast cancer in premenopausal women. Although the role of ovarian ablation in the management of early breast cancer remains unsettled, evidence  indicates that LHRH agonists may also prevent breast cancer recurrence in the adjuvant setting. Of particular interest is the large multicenter trial that evaluated the LHRH agonist goserelin in the adjuvant setting recently reported by Baum . In that study a substantially reduced incidence of contralateral new primary breast tumors was reported.
Use of LHRH in premenopausal women is predictably associated with hypoestrogenic symptoms, including hot flushes, vaginal dryness, and sleep disturbances. A loss of bone mineral density (BMD) has been seen in the majority of studies that involved protracted (6 months) LHRH agonist treatment. Because oophorectomy at a young age is associated with an increased risk of cardiovascular disease, the long-term use of a LHRH agonist is of concern. Although the side effects and risks associated with hypoestrogenemia are acceptable in the setting of metastatic breast cancer and in the adjuvant treatment of early breast cancer, such effects may not be acceptable to women who are only at risk for the development of the disease. A LHRH agonist given at a dose sufficient to suppress ovarian function to postmenopausal levels should achieve a major reduction in a woman's lifetime breast cancer risk, but the benefit will only occur if the agent is continued for prolonged periods of time.
In an effort to minimize the deleterious effects of hypoestrogenemia the addition of other agents, including bisphosphonates, selective estrogen receptor modulators, and low-dose add-back sex steroids, is under consideration or study. The rationale for bisphosphonates and selective estrogen receptor modulators is related to their protective effect on BMD. The tolerance of women to hypoestrogenic symptoms remains to be evaluated, however.
Predicted reduction in lifetime risk of cancer with the prototype contraceptive
Duration of regimen (years)
Clinical effects of luteinizing hormone-releasing hormone agonists
In a pilot study designed to determine the effects of an LHRH agonist plus low-dose replacement therapy, bone metabolism, lipoprotein metabolism, the endometrium, and menopausal symptoms were evaluated in women predisposed to familial breast cancer [15,16]. The regimen tested included a depot LHRH agonist administered monthly, low-dose estrogen with conjugated estrogens 0.625-0.9mg for 6 days each week, and the progestogen medroxyprogesterone acetate 10mg for 14 days every 112 days (4 months). Subsequently, the effects of replacing ovarian androgen (which is also suppressed by LHRH agonists) with the add-back hormone regimen were evaluated. Subjects were premenopausal women, aged 25-40 years, with one of the following breast cancer risk factors: lobular carcinoma in situ, mother and sister with breast cancer (at least one premenopausal), or a mother or sister with bilateral premenopausal breast cancer. Twenty-one individuals were entered and were randomized on a 2:1 basis to a treatment group and a control group.
Overall the regimen was well tolerated . A questionnaire assessed frequency and intensity of possible symptoms of menopausal distress and premenstrual syndrome. Symptoms of menopausal distress were infrequent, and the treated individuals had a decrease in luteal phase or premenstrual syndrome symptoms of 'abdominal bloating or fullness'; 'abdominal cramps or pain'; 'breast swelling'; 'breast pain or tenderness'; 'anxious, tense, or nervous'; 'irritable, angry, impatient'; and 'mood swings' .
Annualized change In BMD
Treated with CE + MPA
Treated with CE + MT + MPA
The initial regimen was associated with favorable effects on the lipids during the months when medroxyprogesterone acetate was not administered. The addition of the methyltestosterone eliminated the beneficial effect of the regimen on lipoproteins. However, the changes in cholesterol (compared with baseline values) were not different from those in the control individuals. Oral methyltestosterone is not considered an optimal method for replacement of ovarian androgens.
Unscheduled bleeding and spotting
Number of days/ 28-day cycle (mean [standard error])
Percentage of days
The risk of breast cancer rises steeply during the premenopausal years. This is, in all likelihood, a result of stochaistic mutations associated with ovarian hormone-driven repetitive breast epithelial cell proliferation. A regimen to reduce premenopausal exposure to estrogen and progesterone based on suppression of ovarian function by an agonist of LHRH and replacement of low-dose hormones would be expected to reduce breast cancer risk. A pilot trial of such an approach demonstrated both its feasibility and a beneficial reduction in mammographic density. Studies are in progress to improve the acceptability of the regimen and to test its effects on the mammogram in high-risk women.
Darcy Spicer and Malcolm Pike have a substantial interest in Balance Pharmaceuticals, Inc.
- Pike MC, Ross RK, Lobo RA, Key TJA, Potts M, Henderson BE: LHRH agonists and the prevention of breast and ovarian cancer. Br J Cancer. 1989, 60: 142-148., Detailed explanation of the rationale for considering the use of LHRH agonists for breast cancer prevention.View ArticlePubMedPubMed CentralGoogle Scholar
- Lilienfeld A: The relationship of cancer of the female breast to artificial menopause and marital status. Cancer. 1956, 9: 927-934.View ArticlePubMedGoogle Scholar
- Hirayama T, Wynder EL: A study of the epidemiology of cancer of the breast II. The influence of hysterectomy. Cancer. 1962, 15: 28-38.View ArticleGoogle Scholar
- Feinleib M: Breast cancer and artificial menopause: a cohort study. J Natl Cancer Inst. 1968, 41: 315-329.PubMedGoogle Scholar
- Trichopoulos D, MacMahon B, Cole P: Menopause and breast cancer risk. J Natl Cancer Inst. 1972, 48: 605-613.PubMedGoogle Scholar
- Kelsey J: A review of the epidemiology of human breast cancer. Epidemiol Rev. 1979, 1: 74-109.PubMedGoogle Scholar
- Rebbeck R, Levin A, Eisen A, et al: Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst. 1999, 91: 1475-1479. 10.1093/jnci/91.17.1475.View ArticlePubMedGoogle Scholar
- Ames BN, Gold LS: Too many rodent carcinogens: mitogenesis increases mutagenesis. Science. 1990, 249: 970-971.View ArticlePubMedGoogle Scholar
- Pike MC, Spicer DV, Dahmoush L, Press MF: Estrogens, progestogens, normal breast cell proliferation and breast cancer risk. Epidemiol Rev. 1993, 15: 17-35., Review of the effects of ovarian hormones on normal breast epithelial cell proliferationPubMedGoogle Scholar
- Kaufman M, Jonat W, Kleeberg U, et al: Goserelin, a depot gonadotrophin-releasing hormone agonist in the treatment of premenopausal patients with metastatic breast cancer. J Clin Oncol . 1989, 7: 1113-1119.Google Scholar
- Baum M: Adjuvant treatment of premenopausal breast cancer with zoladex and tamoxifen [abstract]. Breast Cancer Res Treat. 1999, 57: 30-Google Scholar
- Pike MC: Age-related factors in cancer of the breast, ovary and endometrium. J Chron Dis. 1987, 40: 59-69.View ArticleGoogle Scholar
- Spicer D, Shoupe D, Pike M: Gonadotropin-releasing hormone agonist plus add-back sex steroids to reduce risk of breast cancer [letter; comment]. J Natl Cancer Inst. 1991, 83:Google Scholar
- Ross RK, Paganini-Hill A, Wan PC, Pike MC: Estrogen versus estrogen-progestin hormone replacement therapy: effect on breast cancer risk. J Natl Cancer Inst. 2000, 92: 328-332. 10.1093/jnci/92.4.328.View ArticlePubMedGoogle Scholar
- Spicer DV, Shoupe D, Pike M: GnRH agonists as contraceptive agents: predicted significantly reduced risk of breast cancer. Contraception. 1991, 44: 289-310. 10.1016/0010-7824(91)90019-C.View ArticlePubMedGoogle Scholar
- Spicer DV, Pike MC, Pike A, Rude R, Shoupe D, Richardson J: Pilot trial of a gonadotropin hormone agonist with replacement hormones as a prototype contraceptive to prevent breast cancer. Contraception. 1993, 47: 427-444. 10.1016/0010-7824(93)90095-O.View ArticlePubMedGoogle Scholar
- Spicer D, Ursin G, Parisky Y, et al: Changes in mammographic densities induced by a hormonal contraceptive designed to reduce breast cancer risk. J Natl Cancer Inst. 1994, 86: 431-436.View ArticlePubMedGoogle Scholar
- Saftlas AF, Szklo M: Mammographic parenchymal patterns and breast cancer risk. Epidemiol Rev. 1987, 9: 146-174.PubMedGoogle Scholar
- Brisson J, Morrison AS, Khalid N: Mammographic parenchymal features and breast cancer in the brest cancer detection demonstration project. J Natl Cancer Inst. 1988, 80: 1532-1540.View ArticleGoogle Scholar
- Warner E, Lockwood G, Tritchler D, Boyd NF: The risk of breast cancer associated with mammographic parenchymal patterns: a meta-analysis of the published literature to examine the effect of method of classification. Cancer Detect Prev. 1992, 16: 67-72.PubMedGoogle Scholar
- Oza AM, Boyd NF: Mammographic parenchymal patterns: a marker of breast cancer risk. Epidemiol Rev. 1993, 15: 196-208.PubMedGoogle Scholar