Abstract
Obesity is associated with a decreased risk of breast cancer in premenopausal women but an increased risk in postmenopausal women, an effect that increases with time since menopause. Analysis of these effects of obesity shows that there is a ceiling to the carcinogenic effect of estrogen on the breast; increases in nonsex hormone-binding globulin-bound estradiol (non-SHBG bound E2) exceeding approximately 10.2 pg/ml have no further effect on breast cancer risk; this ceiling is lower than the lowest level seen during the menstrual cycle. This suggests that the effects of menopausal estrogen therapy (ET) and menopausal estrogen–progestin therapy (EPT) on a woman's breast cancer risk will greatly depend on her body mass index (BMI; weight in kilograms/height in meters squared, kg/m2) with the largest effects being in slender women. Epidemiological studies confirm this prediction. Our best estimates, per 5 years of use, of the effects of ET on breast cancer risk is a 30% increase in a woman with a BMI of 20 kg/m2 decreasing to an 8% increase in a woman with a BMI of 30 kg/m2; the equivalent figures for EPT are 50% and 26%. The analysis of the effects of estrogen also shows that even reducing the dose of estrogen in ET and EPT by as much as a half will have little or no effect on these risks. Reducing the progestin dose is likely to significantly reduce the risk of EPT: this is possible with an endometrial route of administration.
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References
Anderson TJ, Ferguson DJ, Raab GM (1982) Cell turnover in the “resting” human breast: influence of parity, contraceptive pill, age and literality. Br J Cancer 46:376–382
Beral V, Reeves G, Banks E (2005) Current evidence about the effect of hormone replacement therapy on the incidence of major conditions in postmenopausal women. Br J Obstet Gynaecol 112:692–695
Cairns J (2002) Somatic stem cells and the kinetics of mutagenesis and carcinogenesis. Proc Natl Acad Sci USA 99:10567–10570
Chlebowski RT, Hendrix SL, Langer RD et al. (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289:3243–3253
Colditz GA, Rosner B (2000) Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses' Health Study. Am J Epidemiol 152:950–964
Collaborative Group on Hormonal Factors in Breast Cancer (1997) 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
Cook PJ, Doll R, Fellingham SA (1969) A mathematical model for the age distribution of cancer in man. Cancer 4:93–112
Cutler SY, Young JL (1975) Third national cancer survey: incidence data. National Cancer Institute monograph No. 41. National Cancer Institute, Washington DC
Dunn JF, Nisula BC, Rodbard D (1981) Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 53:58–68
Endogenous Hormones and Breast Cancer Collaborative Group (2003a) Free estradiol and breast cancer risk in postmenopausal women: comparison of measured and calculated values. Cancer Epidemiol Biomarkers Prev 12:1457–1461
Endogenous Hormones and Breast Cancer Collaborative Group (2003b) Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95:1218–1226
Fournier A, Berrino F, Riboli E et al. (2005) Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer 114:448–454
Goebelsmann U, Mishell DR (1979) The menstrual cycle. In: Mishell DR, Davajan V (eds) Reproductive endocrinology, infertility and contraception. FA Davis, Philadelphia, pp 67–89
Greendale GA, Reboussin BA, Slone S et al. (2003) Postmenopausal hormone therapy and change in mammographic density. J Natl Cancer Inst 95:30–37
Hartz AJ, Barboriak TN, Wong A et al. (1979) The association of obesity with infertility and related menstrual abnormalities in women. Int J Obes 3:57–73
Henderson BE, Ross RK, Judd HL et al. (1985) Do regular ovulatory cycles increase breast cancer risk? Cancer 56:1206–1208
Kelsey JL, Bernstein L (1996) Epidemiology and prevention of breast cancer. Annu Rev Public Health 17:47–67
Lee SA, Ross RK, Pike MC (2005) An overview of menopausal oestrogen-progestin hormone therapy and breast cancer risk. Br J Cancer 92:2049–2058
MacMahon B, Cole P, Brown J (1973) Etiology of human breast cancer: a review. J Natl Cancer Inst 50:21–42
Meyer JS, Connor RE (1982) Cell proliferation in fibrocystic disease and postmenopause breast ducts measured by thymidine labeling. Cancer 50:746–750
Million Women Study Collaborators (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362:419–427
Nachtigall LE, Raju U, Banerjee S et al. (2000) Serum estradiol profiles in postmenopausal women undergoing three common estrogen replacement therapies: associations with sex hormone-binding globulin, estradiol, and estrone levels. Menopause 7:243–250
Pike MC, Krailo MD, Henderson BE et al. (1983) “Hormonal” risk factors, “breast tissue age” and the age-incidence of breast cancer. Nature 303:767–770
Pike MC, Spicer DV, Dahmoush L, Press MF (1993) Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev 15:17–35
Powers MS, Schennkel L, Darley PE et al. (1985) Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17-β estradiol: comparison with conventional oral estrogens used for hormone replacement. Am J Obstet Gynecol 152:1099–1106
Ropponen A, Aittomaki K, Vihma V et al. (2005) Effects of oral estradiol administration on levels of sex hormone-binding globulin in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy. J Clin Endocrinol Metab 90:3431–3434
Rosner B, Colditz GA, Willett WC (1994) Reproductive risk factors in a prospective study of breast cancer: The Nurses' Health Study. Am J Epidemiol 139:819–835
Schairer C, Lubin J, Troisi R et al. (2000) Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 283:485–491
Schiff I, Sela HK, Cramer D et al. (1982) Endometrial hyperplasia in women on cyclic or continuous estrogen regimens. Fertil Steril 37:79–82
Selby PL, Peacock M (1986) Dose dependent response of symptoms, pituitary, and bone to transdermal estrogen in postmenopausal women. BMJ 293:1337–1339
Shoupe D, Meme D, Mezrow G, Lobo RA (1991) Prevention of endometrial hyperplasia in postmenopausal women with intrauterine progesterone. N Engl J Med 325:1811–1812
Södergard R, Backstrom T, Shanbhag V, Carstensen H (1982) Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. J Steroid Biochem 16:801–810
Stanczyk FZ (2002) Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception. Rev Endocr Metab Disord 3:211–224
Trichopoulos D, MacMahon B, Cole P (1972) Menopause and breast cancer risk. J Natl Cancer Inst 48:605–613
Trichopoulos D, Hsieh CC, MacMahon B et al. (1983) Age at any birth and breast cancer risk. Int J Cancer 31:701–704
van den Brandt P, Spiegelman D, Yaun SS et al. (2000) Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol 152:514–527
Varila E, Wahlstrom T, Rauramo I (2001) A 5-year follow-up study on the use of a levonorgestrel intrauterine system in women receiving hormone replacement therapy. Fertil Steril 76:969–973
Wohlfahrt J, Melbye M (2001) Age at any birth is associated with breast cancer risk. Epidemiology 12:68–73
Women's Health Initiative (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 291:1701–1712
Wood CE, Register TC, Lees CJ et al. (2007) Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat 101:125–134
Acknowledgements
This work was supported by a Department of Defense Congressionally Directed Breast Cancer Program Grant BC 044808; by the USC/Norris Comprehensive Cancer Center Core Grant P30 CA14089; and by generously donated funds from the endowment established by Flora L. Thornton for the Chair of Preventive Medicine at the USC/Norris Comprehensive Cancer Center. The funding sources had no role in this report.
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Pike, M.C., Wu, A.H., Spicer, D.V., Lee, S., Pearce, C.L. (2008). Estrogens, Progestins, and Risk of Breast Cancer. In: Conneely, O., Otto, C. (eds) Progestins and the Mammary Gland. Ernst Schering Foundation Symposium Proceedings, vol 2007/1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/2789_2007_059
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DOI: https://doi.org/10.1007/2789_2007_059
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