Research Article| Volume 49, ISSUE 1, P79-89, September 24, 2004

Lessons to be learned from animal studies on hormones and the breast


      The relation of hormone use by postmenopausal women to breast cancer risk has been controversial and unclear. A recent large randomized trial, the Women’s Health Initiative (WHI) and a large observational study (Million Women Study) provided somewhat conflicting answers. The WHI found an increased incidence of breast cancer among women given hormone therapy (conjugated equine estrogen plus medroxyprogesterone acetate) but no increase in those given estrogen only therapy (conjugated equine estrogen alone). Whereas, the Million Women Study found an increased breast cancer risk among the estrogen plus progestin and the estrogen only users. This review brings comparative perspective to the issue of the effects of estrogen plus progestin versus estrogen only effects on breast cancer and is focused particularly on nonhuman primates. Although data from rodents is mixed, studies of monkeys suggest that estrogen only treatment has little or no effect on breast cell proliferation, and by inference, on breast cancer risk. On the other hand, data from both mouse and monkey studies strongly support the conclusion that the co-administration of a progestogen with an estrogen markedly increases breast cell proliferation and the potential for breast cancer promotion.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Maturitas
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Rossouw J.E.
        • Anderson G.L.
        • Prentice R.L.
        • et al.
        Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.
        JAMA. 2002; 288: 321-333
        • Weiss L.K.
        • Burkman R.T.
        • Cushing-Haugen K.L.
        • et al.
        Hormone replacement therapy regimens and breast cancer risk(1).
        Obstet. Gynecol. 2002; 100: 1148-1158
        • Chlebowski R.T.
        • Hendrix S.L.
        • Langer R.D.
        • et al.
        Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial.
        JAMA. 2003; 289: 3243-3253
        • Schairer C.
        • Lubin J.
        • Troisi R.
        • et al.
        Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk.
        JAMA. 2000; 283: 485-491
        • Ross R.K.
        • Paganini-Hill A.
        • Wan P.C.
        • Pike M.C.
        Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin.
        J. Natl. Cancer Inst. 2000; 92: 328-332
        • Kuller L.H.
        Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin.
        J. Natl. Cancer Inst. 2000; 92: 1100-1101
        • Moyer D.L.
        • Felix J.C.
        The effects of progesterone and progestins on endometrial proliferation.
        Contraception. 1998; 57: 399-403
        • Felix J.C.
        • Farahmand S.
        Endometrial glandular proliferation and estrogen receptor content during the normal menstrual cycle.
        Contraception. 1997; 55: 19-22
        • Soderqvist G.
        • Isaksson E.
        • von Schoultz B.
        • et al.
        Proliferation of breast epithelial cells in healthy women during the menstrual cycle.
        Am. J. Obstet. Gynecol. 1997; 176: 123-128
        • Longacre T.A.
        • Bartow S.A.
        A correlative morphologic study of human breast and endometrium in the menstrual cycle.
        Am. J. Surg. Pathol. 1986; 10: 382-393
        • Masters J.R.
        • Drife J.O.
        • Scarisbrick J.J.
        Cyclic variation of DNA synthesis in human breast epithelium.
        J. Natl. Cancer Inst. 1977; 58: 1263-1265
        • Meyer J.S.
        Cell proliferation in normal human breast ducts, fibroadenomas, age, and oral contraceptive hormones.
        Hum. Pathol. 1977; 8: 67-81
        • Anderson T.J.
        • Ferguson D.J.
        • Raab G.M.
        Cell turnover in the resting human breast: influence of parity, contraceptive pill, age and laterality.
        Br. J. Cancer. 1982; 46: 376-382
        • Potten C.S.
        • Watson R.J.
        • Williams G.T.
        • et al.
        The effect of age and menstrual cycle upon proliferative activity of the normal human breast.
        Br. J. Cancer. 1988; 58: 163-170
        • Fata J.E.
        • Chaudhary V.
        • Khokha R.
        Cellular turnover in the mammary gland is correlated with systemic levels of progesterone and not 17beta-estradiol during the estrous cycle.
        Biol. Reprod. 2001; 65: 680-688
        • Raafat A.M.
        • Hofseth L.J.
        • Haslam S.Z.
        Proliferative effects of combination estrogen and progesterone replacement therapy on the normal postmenopausal mammary gland in a murine model.
        Am. J. Obstet. Gynecol. 2001; 184: 340-349
        • Wang S.
        • Counterman L.J.
        • Haslam S.Z.
        Progesterone action in normal mouse mammary gland.
        Endocrinology. 1990; 127: 2183-2189
        • Said T.K.
        • Conneely O.M.
        • Medina D.
        • O’Malley B.W.
        • Lydon J.P.
        Progesterone, in addition to estrogen, induces cyclin D1 expression in the murine mammary epithelial cell, in vivo.
        Endocrinology. 1997; 138: 3933-3939
        • Haslam S.Z.
        Progesterone effects on deoxyribonucleic acid synthesis in normal mouse mammary glands.
        Endocrinology. 1988; 122: 464-470
        • Lydon J.P.
        • DeMayo F.J.
        • Funk C.R.
        • et al.
        Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.
        Genes Dev. 1995; 9: 2266-2278
        • Lydon J.P.
        • Ge G.
        • Kittrell F.S.
        • Medina D.
        • O’Malley B.W.
        Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function.
        Cancer Res. 1999; 59: 4276-4284
        • Sakamoto S.
        • Mori T.
        • Shinoda H.
        • Sassa S.
        • Koyama T.
        Effects of conjugated estrogens with or without medroxyprogesterone acetate on mammary carcinogenesis, uterine adenomyosis and femur in mice.
        Acta Anat. (Basel). 1997; 159: 204-208
        • Laidlaw I.J.
        • Clarke R.B.
        • Howell A.
        • et al.
        The proliferation of normal human breast tissue implanted into athymic nude mice is stimulated by estrogen but not progesterone.
        Endocrinology. 1995; 136: 164-171
        • McManus M.J.
        • Welsch C.W.
        The effect of estrogen, progesterone, thyroxine, and human placental lactogen on DNA synthesis of human breast ductal epithelium maintained in athymic nude mice.
        Cancer. 1984; 54: 1920-1927
        • Sakamoto S.
        • Kudo H.
        • Suzuki S.
        • et al.
        Additional effects of medroxyprogesterone acetate on mammary tumors in oophorectomized, estrogenized, DMBA-treated rats.
        Anticancer Res. 1997; 17: 4583-4587
        • Ohi Y.
        • Yoshida H.
        Influence of estrogen and progesterone on the induction of mammary carcinomas by 7,12-dimethylbenz(a)anthracene in ovariectomized rats.
        Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 1992; 62: 365-370
        • Huggins C.G.L.B.F.
        Mammary cancer induced by a single feeding of polynuclear hydrocarbons, and its suppression.
        Nature. 1961; 189: 204-207
        • Huggins C.Y.N.
        Induction and extinction of mammary cancer. A striking effect of hydrocarbons permits analysis of mechanisms of causes and cure of breast cancer.
        Science. 1962; 137: 257-262
        • Hennighausen L.
        • Robinson G.W.
        Think globally, act locally: the making of a mouse mammary gland.
        Genes Dev. 1998; 12: 449-455
        • Nandi S.
        • Guzman R.C.
        • Yang J.
        Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis.
        Proc. Natl. Acad. Sci. U.S.A. 1995; 92: 3650-3657
        • Yue W.
        • Wang J.P.
        • Hamilton C.J.
        • Demers L.M.
        • Santen R.J.
        In situ aromatization enhances breast tumor estradiol levels and cellular proliferation.
        Cancer Res. 1998; 58: 927-932
        • Labrie F.
        • Belanger A.
        • Simard J.
        • Van L.
        • Labrie C.
        DHEA and peripheral androgen and estrogen formation: intracinology.
        Ann. N. Y. Acad. Sci. 1995; 774: 16-28
        • Speert H.
        The normal and experimental development of the mammary gland of the rhesus monkey with some pathologic correlations. Contributions to embryology.
        Carnegie Inst. Washington. 1948; 32: 9-65
        • Mahoney C.J.
        A study of the menstrual cycle in Macaca irus with special reference to the detection of ovulation.
        J. Reprod. Fertil. 1970; 21: 153-163
        • Tsubura A.
        • Hatano T.
        • Hayama S.
        • Morii S.
        Immunophenotypic difference of keratin expression in normal mammary glandular cells from five different species.
        Acta Anat. (Basel). 1991; 140: 287-293
        • Cline J.M.
        • Soderqvist G.
        • von Schoultz E.
        • Skoog L.
        • von Schoultz B.
        Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynomolgus macaques.
        Am. J. Obstet. Gynecol. 1996; 174: 93-100
        • Cline J.M.
        • Soderqvist G.
        • von Schoultz E.
        • Skoog L.
        • von Schoultz B.
        Effects of conjugated estrogens, medroxyprogesterone acetate, and tamoxifen on the mammary glands of macaques.
        Breast Cancer Res. Treat. 1998; 48: 221-229
        • Macpherson E.E.
        • Montagna W.
        Proceedings: the mammary glands of rhesus monkeys.
        J. Invest. Dermatol. 1974; 63: 17-18
        • Uno H.
        Age-related pathology and biosenescent markers in captive rhesus macaques.
        Age. 1997; 20: 1-13
        • Cline J.M.
        • Register T.C.
        • Clarkson T.B.
        Effects of tibolone and hormone replacement therapy on the breast of cynomolgus monkeys.
        Menopause. 2002; 9: 422-429
        • Chetrite G.
        • Kloosterboer H.J.
        • Pasqualini J.R.
        Effect of tibolone (Org OD14) and its metabolites on estrone sulphatase activity in MCF-7 and T-47D mammary cancer cells.
        Anticancer Res. 1997; 17: 135-140
        • Chetrite G.S.
        • Kloosterboer H.J.
        • Philippe J.C.
        • Pasqualini J.R.
        Effect of Org OD14 (LIVIAL) and its metabolites on human estrogen sulphotransferase activity in the hormone-dependent MCF-7 and T-47D, and the hormone-independent MDA-MB-231, breast cancer cell lines.
        Anticancer Res. 1999; 19: 269-275
        • Chetrite G.S.
        • Kloosterboer H.J.
        • Philippe J.C.
        • Pasqualini J.R.
        Effects of Org OD14 (Livial) and its metabolites on 17 beta-hydroxysteroid dehydrogenase activity in hormone-dependent MCF-7 and T-47D breast cancer cells.
        Anticancer Res. 1999; 19: 261-267
        • Purohit A.
        • Malini B.
        • Hooymans C.
        • Newman S.P.
        Inhibition of oestrone sulphatase activity by tibolone and its metabolites.
        Horm. Metab. Res. 2002; 34: 1-6
        • van de Ven J.
        • Donker G.H.
        • Sprong M.
        • Blankenstein M.A.
        • Thijssen J.H.
        Effect of tibolone (Org OD14) and its metabolites on aromatase and estrone sulfatase activity in human breast adipose stromal cells and in MCF-7 and T47D breast cancer cells.
        J. Steroid Biochem. Mol. Biol. 2002; 81: 237-247
        • Dimitrakakis C.
        • Zhou J.
        • Wang J.
        • et al.
        A physiologic role for testosterone in limiting estrogenic stimulation of the breast.
        Menopause. 2003; 10: 292-298
        • Foth D.
        • Cline J.M.
        Effects of mammalian and plant estrogens on mammary glands and uteri of macaques.
        Am. J. Clin. Nutr. 1998; 68: 1413S-1417S
        • Mills L.H.
        • Lee A.J.
        • Parlow A.F.
        • Zhu B.T.
        Preferential growth stimulation of mammary glands over uterine endometrium in female rats by a naturally occurring estradiol-17beta-fatty acid ester.
        Cancer Res. 2001; 61: 5764-5770
        • Vihma V.
        • Tiitinen A.
        • Ylikorkala O.
        • Tikkanen M.J.
        Quantitative determination of estradiol fatty acid esters in lipoprotein fractions in human blood.
        J. Clin. Endocrinol. Metab. 2003; 88: 2552-2555
        • Larner J.M.
        • Shackleton C.H.
        • Roitman E.
        • Schwartz P.E.
        • Hochberg R.B.
        Measurement of estradiol-17-fatty acid esters in human tissues.
        J. Clin. Endocrinol. Metab. 1992; 75: 195-200
        • Leszczynski D.E.
        • Schafer R.M.
        Metabolic conversion of six steroid hormones by human plasma high-density lipoprotein.
        Biochim. Biophys. Acta. 1991; 1083: 18-28
        • Suparto I.H.
        • Williams J.K.
        • Cline J.M.
        • Anthony M.S.
        • Fox J.L.
        Contrasting effects of two hormone replacement therapies on the cardiovascular and mammary gland outcomes in surgically postmenopausal monkeys.
        Am. J. Obstet. Gynecol. 2003; 188: 1132-1140