Research Article| Volume 49, ISSUE 1, P58-66, September 24, 2004

Exogenous progestagens and the human breast


      The role of progestins (or progestagens) on the breast tissue remains controversial. However, according to the molecule and the duration of application, cell differentiation and apoptosis may predominate over proliferation. Progestins are also used as second-line agents for the treatment of metastatic breast cancer. In young women with benign breast disease, long-term treatment with 19-nortestosterone progestins had a trend to decrease breast cancer risk contrarily to what was observed in postmenopausal women receiving estrogens.
      Several compounds with progestational activity have been used for HRT. Small differences in the structure of the molecules may lead to pronounced differences in activities, some progestins exerting androgenic effects and some exerting estrogenic or glucocorticoid like activities. While most progestins do not bind to the estrogen receptors, it has been shown that some androgenic progestins stimulate MCF7 cells proliferation while progestins derived from progesterone did not induce cell multiplication in the same cell lines. Therefore, different progestins may induce different effects on the breast cells. Whether the progestins available to date are able to bind specifically to the progesterone receptors PR-A or PR-B and whether this is of clinical relevance to breast cell proliferation is still unclear.
      Although the relationship between progestin use and breast cancer risk is still the subject of debate and controversy, the data reported to date suggest that 5 years of treatment carry a low risk but further duration of use increases the risk. Further studies are still needed, randomised long-term prospective studies as well as from the laboratory, especially to determine whether a sequential or continuous regimen would be preferable as far as breast-cell response and apoptosis are concerned, and what are the effects of the various molecules used for HRT.


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        • Conneely O.M.
        • Lydon J.P.
        Progesterone receptors in reproduction: functional impact of the A and B isoforms.
        Steroids. 2000; 65: 571-577
        • Kenemans P.
        • Bosman A.
        Breast cancer and postmenopausal hormone therapy.
        Best Pract. Res. Clin. Endocrinol. Metab. 2003; 17: 123-137
        • Thijssen J.H.
        Oestrogens, progestins and breast proliferation.
        Zentralblatt fur Gynekologie. 1997; 119: 43-47
        • Gompel A.
        • Somai S.
        • Chaouat M.
        • et al.
        Hormonal regulation of apoptosis in breast cells and tissues.
        Steroids. 2000; 65: 593-598
        • Isaksson E.
        • Wang H.
        • Sahlin B.
        • von Schoultz B.
        • Cline J.M.
        • von Schoultz E.
        Effects of long-term HRT and tamoxifen on the expression of progesterone receptors A nd B in breast tissue from surgically postmenopausal cynomolgus macaques.
        Breast Cancer Res. Treat. 2003; 79: 233-239
        • Sitruk-Ware R.
        Progestogens in hormonal replacement therapy: new molecules, risks and benefits.
        Menopause. 2002; 9: 6-15
        • Schindler A.E.
        • Campagnoli C.
        • Druckmann R.
        • et al.
        Classification and pharmacology of progestins.
        Maturitas. 2003; 46: S7-S16
        • Kumar N.
        • Koide S.S.
        • Tsong Y.Y.
        • Sundaram K.
        Nestorone®: a progestin with a unique pharmacological profile.
        Steroids. 2000; 65: 629-636
        • Catherino W.H.
        • Jeng M.H.
        • Jordan V.C.
        Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism.
        Br. J. Cancer. 1993; 67: 945-952
        • Catherino W.H.
        • Jordan V.C.
        Nomegestrol acetate, a clinically useful 19-norprogesterone derivative which lacks estrogenic activity.
        J. Steroid Biochem. Mol. Biol. 1995; 55: 239-246
        • Pasqualini J.R.
        • Paris J.
        • Sitruk-Ware R.
        • et al.
        Progestins and breast cancer.
        J. Steroid Biochem. Mol. Biol. 1998; 65: 225-235
        • Druckmann R.
        Progestins and their effects on the breast.
        Maturitas. 2003; 46: S59-S69
        • Santen R.
        • Pinkeron J.
        • McCartney C.
        • Petroni G.R.
        Risk of breast cancer with progestins in combination with estrogen as hormone replacement therapy.
        JCEM. 2001; 86: 16-23
        • Yen S.S.C.
        • Martin P.L.
        • Burnier A.M.
        • et al.
        Circulating estradiol, estrone and gonadotropin levels following the administration of orally active 17β-estradiol in postmenopausal women.
        J. Clin. Endocrinol. Metab. 1975; 40: 518-521
        • Musgrove E.A.
        • Lee C.S.L.
        • Sutherland R.L.
        Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor, epidermal growth factor receptor, c-fos and c-myc genes.
        Mol. Cell Biol. 1991; 11: 5032-5043
        • Alkhalaf M.
        • El-Mowafy A.
        • Karam S.
        Growth inhibition of MCF-7 human breast cancer cells by progesterone is associated with cell differentiation and phosphorylation of Akt protein.
        Eur. J. Cancer Prev. 2002; 11: 481-488
        • Laidlaw I.J.
        • Clarke R.B.
        • Howell A.
        • Potten C.S.
        • Anderson E.
        The proliferation of normal human breast tissue implanted into athymic nude mice is stimulated by estrogen but not progesterone.
        Endocrinology. 1995; 136: 164-171
        • Clarke R.B.
        • Howell A.
        • Potten C.S.
        • Anderson E.
        Dissociation between steroid receptor expression ans cell proliferation in the human breast.
        Cancer Res. 1997; 57: 4987-4989
        • Seeger H.
        • Wallwiener D.
        • Mueck A.O.
        The effect of progesterone and synthetic progestins on serum- and estradiol-stimulated proliferation of human breast cancer cells.
        Horm. Metab. Res. 2003; 35: 76-80
        • Russo J.
        • Hu Y.F.
        • Silva I.D.
        • Russo I.H.
        Cancer risk related to mammary gland structure and development.
        Microsc. Res. Tech. 2001; 52: 204-223
        • Russo J.
        • Tay L.K.
        • Russo I.H.
        Differentiation of the mammary gland and susceptibility to carcinogenesis.
        Breast Cancer Res. Treat. 1982; 2: 5-73
        • McMahon B.
        • Cole P.
        • Lin T.M.
        • et al.
        Age at first birth and breast cancer risk.
        Bull. World Health Organ. 1970; 43: 209-221
        • McPherson K.
        • Steel C.M.
        • Dixon J.M.
        ABC of breast diseases. Breast cancer—epidemiology, risk factors, and genetics.
        Br. Med. J. 2000; 321: 624-628
        • Vogel P.M.
        • Georgiade N.G.
        • Fetter B.F.
        • Vogel F.S.
        • McCarty K.S.
        The correlation of histologic changes in the human breast with the menstrual cycle.
        Am. J. Pathol. 1981; 104: 23-34
        • Söderqvist G.
        • Isaksson E.
        • Von Schoulz B.
        • et al.
        Proliferation of breast epithelial cells in healthy women during the menstrual cycle.
        Am. J. Obstet. Gynecol. 1997; 176: 123-128
        • Dobson R.R.
        • Chan C.K.
        • Knox F.
        • Potten C.S.
        • Bundred N.J.
        The effects of prolonged HT treatment in normal post-menopausal breast epithelium.
        BCRT. 2000; 64 ([abstract]): 106
        • Miller N.A.
        • Thomas M.
        • Martin L.J.
        Feasibility of obtaining breast epithelial cells from healthy women for studies of cellular proliferation.
        Breast Cancer Res. Treat. 1997; 43: 201-210
        • Chang Lee T.T.
        • Linares-Cruz G.
        Influence of percutaneous administration of estradiol and progesterone on human breast epithelial cell in vivo.
        Fertil. Steril. 1995; 63: 785-791
        • Foidart J.M.
        • Colin C.
        • Denoo X.
        • et al.
        Estradiol and progesterone regulate the proliferaton of human breast epithelial cells.
        Fertil. Steril. 1998; 69: 963-969
        • Cline J.M.
        • Soderqvist G.
        • Von Shoultz B.
        Effects of hormone replacement therapy on the mammary gland of surgically postmenopausal cynolmogus macaques.
        Am. J. Obstet. Gynecol. 1996; 174: 93-100
        • Hofseth L.J.
        • Raafat A.M.
        • Osuch J.R.
        • et al.
        Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast.
        JCEM. 1999; 84: 4559-4565
        • 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
        • 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
        • Plu-Bureau G.
        • Lê M.
        • Sitruk-Ware R.
        • et al.
        Progestogen use and risk of breast cancer in a cohort study of premenopausal women with benign breast disease.
        Br. J. Cancer. 1994; 70: 270-277
      1. Writing group for the women’s health initiative investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the women’s health initiative randomized controlled trial. J Am Med Assoc 2002;288:321–33.

      2. Collaborative group on hormonal factors in breast cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047–59.

        • Schairer C.
        • Lubin J.
        • Troisi R.
        • et al.
        Menopausal estrogen and estrogen–progestin replacement therapy and breast cancer risk.
        J. Am. Med. Assoc. 2000; 283: 485-491
        • Magnusson C.
        • Baron J.A.
        • Correira N.
        Breast cancer risk following long term oestrogen and oestrogen–progestin replacement therapy.
        Int. J. Cancer. 1999; 31: 339-344
        • Ross R.K.
        • Paganni-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
        • Persson I.
        • Weiderpass E.
        • Bergkvist L.
        Risks of breast and endometrial cancer after estrogen and estrogen–progestin replacement.
        Cancer Causes Controls. 1999; 10: 253-260
        • De Lignières B.
        • de Vathaire F.
        • Fournier S.
        • Urbinello R.
        • Allaert F.
        • Lê M.B.
        Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women.
        Climacteric. 2002; 5: 332-340
      3. Million women study collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419–27.

        • Speroff L.
        The million women study and breast cancer.
        Maturitas. 2003; 46 ([editorial]): 1-6
        • Chlebowski R.T.
        • Hendrix S.I.
        • Langer R.D.
        • et al.
        Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women.
        J. Am. Med. Assoc. 2003; 289: 3243-3253
      4. Sitruk-Ware R (for the participants of the Round table). Progestins in hormonal therapy (HT): today, tomorrow and the next day: A round table discussion. Steroids 2003;68:973–9.

        • Anderson G.L.
        • Limacher M.
        • Assaf A.R.
        Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the women’s health initiative randomized controlled trial.
        J. Am. Med. Assoc. 2004; 291: 1701-1712
        • Luukkainen T.
        Issues to debate on the women’s health initiative: failure of estrogen plus progestin therapy for prevention of breast cancer risk.
        Hum. Reprod. 2003; 18: 1559-1561