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Contraceptive steroids and the mammary gland: Is there a hazard?

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Summary

The safety of synthetic steroid hormones to be used for contraception in the human female is tested in rats, beagle dogs, and (once marketing starts) in monkeys. Because early studies did not show a mammary tumor stimulating effect in the human, in contrast to findings in the dog, many objections have been raised to the use of the dog for these toxicity studies. It has been claimed that the dog is unique in its sensitivity to the mammary tumor promoting effect of progestins and that this tumorigenic effect results from progestin-induced growth hormone (GH) induction. A thorough review of the literature does not support these claims. Tumor stimulatory effects of progesterone or synthetic progestins can be observed under some conditions in rodents as well as in cats and monkeys. In addition, recent evidence suggests a role for progesterone in mammary tumorigenesis in the human, and contraceptive steroids may also not be completely without risk. While the suggested role for GH in dog mammary tumorigenesis is far from proven, such a role cannot be excluded in the other species. Whether tumor stimulatory effects of sex steroids are based upon induction of proliferation in target cells or upon genotoxic effects or both is not yet certain.

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References

  1. Casey HW, Giles RC, Kwapien RP: Mammary neoplasia in animals. Pathologic aspects and the effect of contraceptive steroids. Rec Res Cancer Res 66:129–160, 1979.

    Google Scholar 

  2. El Etreby MF, Gräf KJ: Effect of contraceptive steroids on mammary gland of female dog and its relevance to human carcinogenicity. Pharmac Ther 5:369–402, 1979.

    Google Scholar 

  3. Owen LN, Briggs MH: Contraceptive steroid toxicology in the beagle dog and its relevance to human carcinogenicity. Curr Med Res Opin 4: 309–329, 1976.

    PubMed  Google Scholar 

  4. McKenzie BE: Guidelines and requirements for the evaluation of contraceptive steroids. Toxicol Pathol 17:377–384, 1989.

    PubMed  Google Scholar 

  5. Nelson LW, Carlton WW, Weikel JHJ: Canine mammary neoplasms and progestogens. J Am Med Assoc 219:1601–1606, 1972.

    Google Scholar 

  6. Briggs M: The beagle dog and contraceptive steroids. Life Sci 21:275–284, 1983.

    Google Scholar 

  7. Johnson AN: Comparative aspects of contraceptive steroids — Effects observed in beagle dogs. Toxicol Pathol 17:389–395, 1989.

    PubMed  Google Scholar 

  8. Anonymous: Depot-medroxyprogesterone acetate (DMPA) and cancer: memorandum from a WHO meeting. Bull WHO 64:375–382, 1986.

  9. Huggins GR, Zucker PK: Oral contraceptives and neoplasia: 1987 update. Fert Steril 47:733–761, 1987.

    Google Scholar 

  10. Rosenfield A, Maine D, Rochat R, Shelton J, Hatcher RA: The Food and Drug Administration and medroxyprogesterone acetate. What are the issues? J Am Med Assoc 249:2922–2928, 1983.

    Google Scholar 

  11. Bergink EW, Attia M, De Jager E: Effects of estradiol-17β and progesterone on the mammary gland of the beagle dog: morphology and receptor levels in the cytosol fraction.In Wittliff JL, Dapunt O (eds) Steroid Receptors and Hormone-dependent Neoplasia. Masson USA, New York, 1980, pp 219–222.

    Google Scholar 

  12. Capel-Edwards K, Hall DE, Fellowes KP, Vallance DK: Long-term administration of progesterone to the female beagle dog. Toxicol Appl Pharmacol 24:474–488, 1973.

    PubMed  Google Scholar 

  13. Tucker MJ: Some effects of prolonged administration of a progestogen to dogs.In Baker SB (ed) The Correlation of Adverse Effects in Man with Observations in Animals. Excerpta Medica, Amsterdam, 1971, pp 228–238.

    Google Scholar 

  14. Giles RC, Kwapien RP, Geil RG, Casey HW: Mammary nodules in beagle dogs administered investigational oral contraceptive steroids. J Natl Cancer Inst 60:1351–1364, 1978.

    PubMed  Google Scholar 

  15. Jabara AG: Induction of canine ovarian tumors by diethylstilbestrol and progesterone. Aust J Exp Biol Med Sci 40:139–152, 1962.

    PubMed  Google Scholar 

  16. Jabara AG: Some tissue changes in the dog following stilbestrol administration. Aust J Exp Biol Med Sci 40:293–308, 1962.

    PubMed  Google Scholar 

  17. Frank DW, Kirton KT, Murchison TE, Quinlan WJ, Coleman ME, Gilbertson TJ, Feenstra ES, Kimball FA: Mammary tumors and serum hormones in the bitch treated with medroxyprogesterone acetate for four years. Fert Steril 31:340–346, 1979.

    Google Scholar 

  18. Concannon PW, Spraker TR, Casey HW, Hansel W: Gross and histopathologic effects of medroxyprogesterone acetate and progesterone on the mammary glands of adult female beagle bitches. Fert Steril 36:373–387, 1981.

    Google Scholar 

  19. Hill R, Dumas K: The use of dogs for studies of toxicity of contraceptive hormones. Acta Endocrinol (Kbh) 75 (Suppl 185):74–89, 1974.

    Google Scholar 

  20. Beier S, Haase F, Kosub B, Düsterberg B, Elger W: The progestational activity of different gestagens used for human contraception in the beagle bitch. Contraception 20:533–548, 1979.

    PubMed  Google Scholar 

  21. Neumann F, Gräf KJ: Some comparative endocrinopharmacological aspects and their relevance in the interpretation of adverse drug effects. Pharmac Ther 5:271–286, 1979.

    Google Scholar 

  22. Misdorp W: Progestagens and mammary tumours in dogs and cats. Acta Endocrinol (Kbh) 125(Suppl 1):27–31, 1991.

    PubMed  Google Scholar 

  23. Schneider R: Comparison of age, sex and incidence rates in human and canine breast cancer. Cancer 26:419–426, 1970.

    PubMed  Google Scholar 

  24. Kwapien RP, Giles RC, Geil RG, Casey HW: Malignant mammary tumors in beagle dogs dosed with investigational oral contraceptive steroids. J Natl Cancer Inst 65:137–144, 1980.

    PubMed  Google Scholar 

  25. Misdorp W: Canine mammary tumours: protective effect of late ovariectomy and stimulating effects of progestins. Vet Quart 10:26–33, 1988.

    Google Scholar 

  26. Bentvelzen P: Interaction between host and viral genomes in mouse mammary tumors. Ann Rev Genet 16:273–295, 1982.

    PubMed  Google Scholar 

  27. McConnell RF: Comparative aspects of contraceptive steroids: effects observed in rats. Toxicol Pathol 17:385–388, 1989.

    PubMed  Google Scholar 

  28. Meites J: Relation of the neuroendocrine system to the development and growth of experimental mammary tumors. J Neural Transmission 48:25–42, 1980.

    Google Scholar 

  29. Welsch CW: Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: a review and tribute to Charles Brenton Huggins. Cancer Res 45:3415–3443, 1985.

    Google Scholar 

  30. Grubbs CJ, Farnell DR, Hill DR, McDonough KC: Chemoprevention of N-nitroso-N-methylurea-induced rat mammary cancers by pretreatment with 17β-estradiol and progesterone. J Natl Cancer Inst 74:927–31, 1985

    PubMed  Google Scholar 

  31. Lanari C, Molinolo A, Pasqualina CD: Induction of mammary adenocarcinomas by medroxyprogesterone acetate in BALB/c female mice. Cancer Lett 33:215–223, 1986.

    PubMed  Google Scholar 

  32. Nagasawa H, Sakagami N, Ohbayashi R, Yamamoto K, Petrow V: Effect of megestrol acetate or melengestrol acetate on preneoplastic and neoplastic mammary growth in mice. Anticancer Res 8:1399–1404, 1988.

    PubMed  Google Scholar 

  33. Russo IH, Gimotty P, Dupuis M, Russo J: Effect of medroxyprogesterone acetate on the response of the rat mammary gland to carcinogenesis. Br J Cancer 59:210–216, 1989.

    PubMed  Google Scholar 

  34. Russo IH, Frederick J, Russo J: Hormone prevention of mammary carcinogenesis by norethynodrelmestranol. Breast Cancer Res Treat 14:43–56, 1989.

    PubMed  Google Scholar 

  35. Russo J, Gusterson BA, Rogers AE, Russo IH, Wellings SR, Van Zwieten MJ: Biology of disease: Comparative study of human and rat mammary tumorigenesis. Lab Invest 62:244–278, 1990.

    PubMed  Google Scholar 

  36. Russo IH, Russo J: Hormone prevention of mammary carcinogenesis: a new approach in anticancer research. Anticancer Res 8:1247–1264, 1988.

    Google Scholar 

  37. Russo IH, Russo J: Progestagens and mammary gland development: differentiation versus carcinogenesis. Acta Endocrinol (Kbh) 125 (Suppl 1):7–12, 1991.

    Google Scholar 

  38. Misdorp W, Romijn A, Hart AAM: Feline mammary tumours: a case-control study of hormonal factors. Anticancer Res 11:1793–1798, 1991.

    PubMed  Google Scholar 

  39. Tavassoli FA, Casey HW, Norris HJ: The morphologic effects of synthetic reproductive steroids on the mammary gland of rhesus monkeys. Am J Pathol 131:213–234, 1988.

    PubMed  Google Scholar 

  40. Sloan JM, Oliver IM: Progestogen-induced diabetes in the dog. Diabetes 24:337–344, 1975.

    PubMed  Google Scholar 

  41. Concannon PW, Altszuler N, Hampshire J, Butler WR, Hansel W: Growth hormone, prolactin and cortisol in dogs developing mammary nodules and an acromegaly-like appearance during treatment with medroxyprogesterone acetate. Endocrinology 106:1173–1177, 1980.

    PubMed  Google Scholar 

  42. Eigenmann JE, Rijnberk A: Influence of medroxy-progesterone acetate (Provera) on plasma growth hormone levels and on carbohydrate metabolism. I. Studies in the ovariohysterectomized bitch. Acta Endocrinol (Kbh) 98:599–602, 1981.

    PubMed  Google Scholar 

  43. El Etreby MF, Müller-Peddinghausen R, Bhargara AS, Fath El Bab MR, Gräf KJ, Trautwein G: The role of the pituitary gland in spontaneous canine mammary tumorigenesis. Vet Pathol 17: 2–16, 1980.

    PubMed  Google Scholar 

  44. Rutteman GR, Misdorp W, van den Brom WE, Rijnberk A: Anterior pituitary function in female dogs with mammary tumors: I. Growth hormone. Anticancer Res 9:235–240, 1989.

    PubMed  Google Scholar 

  45. Eigenmann JE, Eigenmann RY, Rijnberk A, van der Gaag I, Zapf J, Froesch ER: Progesterone-controlled growth hormone overproduction and naturally occurring canine diabetes and acromegaly. Acta Endocrinol (Kbh) 104:167–176, 1983.

    PubMed  Google Scholar 

  46. Rutteman GR, Stolp R, Rijnberk A, Loeffler S, Bakker JA, Bevers MM, Meulenberg PMM, Eigenmann JE: Medroxy-progesterone acetate administration to ovariohysterectomized, oestradiolprimed beagle bitches. Effect on secretion of growth hormone, prolactin and cortisol. Acta Endocrinol (Kbh) 114:275–282, 1987.

    PubMed  Google Scholar 

  47. Baker BL, Eskin TA, Clapp HW: The effect of medroxyprogesterone on cells of the pituitary pars distalis. Proc Soc Exp Biol Med 140:357–361, 1972.

    PubMed  Google Scholar 

  48. Winneker RC, Parsons JA: Glucocorticoid-like actions of medroxyprogesterone acetate upon MtTW15 rat mammosomatotropic pituitary tumors. Endocrinology 109:99–105, 1981.

    PubMed  Google Scholar 

  49. Selman PJ, Mol JA, Rutteman GR, Rijnberk A: Progestins and growth hormone excess in the dog. Acta Endocrinol (Kbh) 125 Suppl 1:42–47, 1991.

    PubMed  Google Scholar 

  50. Mishell DR Jr, Kletzky OA, Brenner PF, Roy S, Nicoloff J: The effect of contraceptive steroids on hypothalamic-pituitary function. Am J Obstet Gynecol 128:60–74, 1977.

    PubMed  Google Scholar 

  51. Eriksson L, Frankenne F, Edèn, Hennen G, Von Schoultz B: Growth hormone 24-h serum profiles during pregnancy — lack of pulsatility for the secretion of the placental variant. Br J Obstet Gynaecol 96:949–953, 1989.

    PubMed  Google Scholar 

  52. Rutteman GR, Misdorp W, Blankenstein MA, van den Brom WE: Oestrogen (ER) and progestin receptors (PR) in mammary tissue of the female dog: different receptor profile in nonmalignant and malignant states. Br J Cancer 58:594–599, 1988.

    PubMed  Google Scholar 

  53. De Souza I, Morgan L, Lewis UJ, Raggatt, PR, Salih H, Hobbs JR: Growth hormone dependence among human breast cancers. Lancet ii:182–184, 1974.

    Google Scholar 

  54. Emerman JT, Leahy M, Gout PW, Bruchovski N: Elevated growth hormone levels in sera from breast cancer patients. Horm Metab Res 17:421–424, 1985.

    PubMed  Google Scholar 

  55. Schlesselman JL: Oral contraceptives and neoplasia of the uterine corpus. Contraception 43:557–580, 1991.

    PubMed  Google Scholar 

  56. Stanford JL: Oral contraceptives and neoplasia of the ovary. Contraception 43:543–556, 1991.

    PubMed  Google Scholar 

  57. Vessey MP: Exogenous hormones.In Vessey MP, Gray M (eds) Cancer Risks and Prevention. Oxford Univ Press, Oxford, 1985, pp 166–194.

    Google Scholar 

  58. Brinton LA: Oral contraceptives and cervical neoplasia. Contraception 43:581–596, 1991.

    PubMed  Google Scholar 

  59. Key TJA, Pike MC: The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol 24:29–43, 1988.

    PubMed  Google Scholar 

  60. Olsson H: Oral contraceptives and breast cancer. A review. Acta Oncol 28:849–863, 1989.

    PubMed  Google Scholar 

  61. Romieu I, Berlin JA, Colditz G: Oral contraceptives and breast cancer. Review and meta-analysis. Cancer 66:2253–2263, 1990.

    PubMed  Google Scholar 

  62. Thomas DB: Oral contraceptives and breast cancer: review of the epidemiologic literature. Contraception 43:597–642, 1991.

    PubMed  Google Scholar 

  63. Van Leeuwen FE: Epidemiologic aspects of exogenous progestagens in relation to their role in the pathogenesis of human breast cancer. Acta Endocrinol (Kbh) 125(Suppl 1):13–26, 1991.

    PubMed  Google Scholar 

  64. McGonigle KF, Huggins GR: Oral contraceptives and breast disease. Fert Steril 56:799–819, 1991.

    Google Scholar 

  65. McPherson K, Coope PA, Vessey MP: Early oral contraceptive use and breast cancer: theoretical effects of latency. J Epidemiol Commun Health 40:289–294, 1986.

    Google Scholar 

  66. Swyer GIM: Determination of progestational potency: A review. J Royal Soc Med 77:406–409, 1984.

    Google Scholar 

  67. Schlesselman JJ, Stadel BV, Murray P, Lai S: Breast cancer in relation to early use of oral contraceptives. No evidence of a latent effect. J Am Med Assoc 259:1828–1833, 1988.

    Google Scholar 

  68. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Breast cancer and combined oral contraceptives: results from a multinational study. Br J Cancer 61:110–119, 1990.

    Google Scholar 

  69. Kay CR, Hannaford PC: Breast cancer and the pill — A further report from the Royal College of General Practitioners' oral contraception study. Br J Cancer 58:675–680, 1988.

    PubMed  Google Scholar 

  70. Paul C, Skegg DCG, Spears GFS: Depot medroxyprogesterone (Depo-provera) and risk of breast cancer. Br Med J 299:759–762, 1989.

    Google Scholar 

  71. Scott RE, Wille JJ Jr, Wier ML: Mechanism for the initiation and promotion of carcinogenesis: a review and a new concept. Mayo Clin Proc 59: 107–117, 1984.

    PubMed  Google Scholar 

  72. Cardiff RD, Wellings SR, Faulkin LJ: Biology of breast neoplasia. Cancer 39:2734–2746, 1977.

    PubMed  Google Scholar 

  73. Nielsen M, Thomson JL, Primdahl S, Dyreborg U, Andersen JA: Breast cancer and atypia among young and middle-aged women: A study of 110 medicolegal autopsies. Br J Cancer 56:814–819, 1987.

    PubMed  Google Scholar 

  74. Bergkvist L, Adami HO, Persson I, Hoover R, Schairer C: The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med 321:293–297, 1989.

    Google Scholar 

  75. Dupont WD, Page DL: Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 151:67–72, 1991.

    PubMed  Google Scholar 

  76. Clarke CL, Sutherland RL: Progestin regulation of cellular proliferation. Endocrine Rev 11:266–301, 1990.

    Google Scholar 

  77. King RJB: Biology of female sex hormone action in relation to contraceptive agents and neoplasia. Contraception 43:527–542, 1991.

    PubMed  Google Scholar 

  78. Henderson BE, Ross R, Bernstein L: Estrogens as a cause of human cancer: The Richard and Hinda Rosenthal Foundation award lecture. Cancer Res 48:246–253, 1988.

    PubMed  Google Scholar 

  79. Zumoff B: Hormonal profiles in women with breast cancer (Review). Anticancer Res 8:627–636, 1988.

    PubMed  Google Scholar 

  80. Liehr JG: Genotoxic effects of estrogens. Mutation Res 238:269–276, 1990.

    PubMed  Google Scholar 

  81. Liehr JG, Avitts TA, Randerath E, Randerath K: Estrogen-induced endogenous DNA adduction: Possible mechanism of hormonal cancer. Proc Natl Acad Sci USA 83:5301–5305, 1986.

    PubMed  Google Scholar 

  82. Bradlow HL, Hershcopf RE, Fishman JF: Oestradiol 16α-hydroxylase: a risk marker for breast cancer. Cancer Surv 5:573–583, 1986.

    PubMed  Google Scholar 

  83. Li JJ, Li SA: Estrogen carcinogenesis in hamster tissues: a critical review. Endocrine Rev 11:524–531, 1990.

    Google Scholar 

  84. Tsutsui T, Maizumi H, McLachlan JA, Barrett JC: Aneuploidy induction and cell transformation by diethylstilbestrol: a possible chromosomal mechanism in carcinogenesis. Cancer Res 43:3814–3821, 1983.

    PubMed  Google Scholar 

  85. Epe B, Harttig U, Stopper H, Metzler M: Covalent binding of reactive estrogen metabolites to microtubular protein as a possible mechanism of aneuploidy induction and neoplastic cell transformation. Environ Health Perspect 88:123–127, 1990.

    PubMed  Google Scholar 

  86. Moolgavkar SH: Hormones and multistage carcinogenesis. Cancer Surv 5:635–648, 1986.

    PubMed  Google Scholar 

  87. Rutteman GR: Hormones and mammary tumour disease in the female dog: an update. In Vivo 4:33–40, 1990.

    PubMed  Google Scholar 

  88. Secreto G, Toniolo P, Pisani P, Recchione C, Cavalleri A, Fariselli G, Totis A, Di Pietro S, Berrino F: Androgens and breast cancer in premenopausal women. Cancer Res 49:471–476, 1989.

    PubMed  Google Scholar 

  89. Angeli A, Dogliotti L, Faggiuolo R, Orlandi F, Bussolati G: Fibrocystic disease of the breast. A revisit and new perspectives. Excerpta Medica, Amsterdam, 1984, pp 20–31.

    Google Scholar 

  90. Going JJ, Anderson TJ, Battersby S, MacIntyre CCA: Proliferative and secretory activity in human breast during natural and artificial menstrual cycles. Am J Pathol 130:193–204.

  91. Masters JRW, Drife JO, Scarisbrick JJ: Cyclic variation of DNA synthesis in human breast epithelium. J Natl Cancer Inst 58:1263–1265, 1977.

    PubMed  Google Scholar 

  92. Potten CS, Watson RJ, Williams GT, Tickle S, Roberts SA, Harris M, Howell A: The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer 58:163–170, 1988.

    PubMed  Google Scholar 

  93. Williams G, Anderson E, Howell A, Watson R, Coyne J, Roberts SA, Potten CS: Oral contraceptive (OCP) use increases proliferation and decreases oestrogen receptor content of epithelial cells in the normal human breast. Int J Cancer 48:206–210, 1991.

    PubMed  Google Scholar 

  94. Mauvais-Jarvis P, Kuttenn F, Gompel A: Antiestrogen action of progesterone in breast tissue. Breast Cancer Res Treat 8:179–188, 1986.

    PubMed  Google Scholar 

  95. Anderson TJ, Battersby S, King RJB, McPherson K, Going JJ: Oral contraceptive use influences resting breast proliferation. Hum Pathol 20: 1139–1144, 1989.

    PubMed  Google Scholar 

  96. Imagawa W, Bandyopadhyay, Nandi S: Regulation of mammary epithelial cell growth in mice and rats. Endocrine Rev 11:494–523, 1990.

    Google Scholar 

  97. Wang S, Counterman LJ, Haslam SZ: Progesterone action in normal mouse mammary gland. Endocrinology 127:2183–2189, 1990.

    PubMed  Google Scholar 

  98. King RJB: Role of oestrogen and progestin in human mammary carcinogenesis.In Goldhirsch A (ed) Endocrine Therapy of Breast Cancer IV. European School of Oncology Monograph, Springer Verlag, Berlin, 1990, pp 3–8.

    Google Scholar 

  99. Longman SM, Buehring GC: In vitro effect of contraceptive steroids on human mammary cell growth. Cancer 59:281–287, 1987.

    PubMed  Google Scholar 

  100. Jeng MH, Jordan VC: Growth stimulation and differential regulation of transforming growth factor-β1 (TGFβ1), TGFβ2, and TGFβ3 messenger RNA levels by norethindrone in MCF-7 human breast cancer cells. Mol Endocrinol 5:1120–1128, 1991.

    PubMed  Google Scholar 

  101. Cohen SM, Ellwein LB: Cell proliferation in carcinogenesis. Science 249:1007–1011, 1990.

    PubMed  Google Scholar 

  102. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Breast cancer and depot-medroxy-progesterone acetate: a multinational study. Lancet 338:833–838, 1991.

    Google Scholar 

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Rutteman, G. Contraceptive steroids and the mammary gland: Is there a hazard?. Breast Cancer Res Tr 23, 29–41 (1992). https://doi.org/10.1007/BF01831473

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