Progestins and risk of breast cancer. Much ado about nothing?

In vivo and in vitro studies; epidemiological and statistical publications concerning a possible carcinogenic effect of progesterone--and progestins--raise a question mark. Too many contradictions exist in experimental and clinical studies. A very small increased risk of breast cancer with estrogen therapy has been shown; however bias are often present. It is not clearly demonstrated that the adjunction of progestin to estrogen significantly increases the risk, nor that it brings about a protective effect. Some recent works seem to indicate that continuous estroprogestin replacement therapy might be deleterious, while a sequential regimen would be not. This is to be confirmed. The results of the Women's Health Initiative Study have been analyzed. The data and conclusions of the medical literature should be interpreted very cautiously.

Progestins; Breast cancer

[1] Anderson T. J., Ferguson D. J.P., Raab G. M.: "Cell tum over in the'resting' human breast. Influence of parity, contraceptive pill, age". Brit. J. Cancer , 1982, 46, 376.

[2] Gorins A.: "La densite mammographique". In: Le Sein (ed.) Paris, ESKA, 2001, 647.

[3] Barrat J.,D e Lignieres B.,M arpeau L. et al.: "Effet in vivo de !'administration locale de progesterone sur l'activite mitotique des galactophores humains. Resultats d'une etude pilote". J. Gynecol. Obstet. Biol. Reproduc., 1990, 19, 269.

[4] Berkvist L., Adami H. O., Persson I. et al.: "The risk of breast cancer after estrogen and estrogen-progestin replacement". New Engl. J. Med., 1989, 321, 293.

[5] Botella J.: "Inhibition by Nomegestrol acetate and other synthetic progesterone on proliferation and progesterone receptor content of T47 D human breast cancer cells". J. Steroid. Biochem. Malec. Biol., 1994, 50, 41.

[6] Cline J.M., Soderquist G., Von Schoultz E. et al.: "Effects of hormone replacement therapy in the mammary gland of surgically post-menopausal cynomolgus macaques".Am. J. Obstet. Gynecol., 1996, 174, 93.

[7] Colditz G. A., Hankinson H. E., Hunter D. J. et al.: "The use of estrogens and progestins and the risk of breast cancer in postmenopausal women". New Engl. J. Med., 1995, 332, 1589.

[8] Colditz G. A., Rosner B.: "Use of estrogen plus progestin is associated with greater increase in breast cancer risk than estrogen alone 51 Dt annual meeting of the Society for epidemiologic research". Chicago June 24-26, 1998 (in Am. J. Epidermiol.)

[9] Coletta A., Wakefield L. M., Honell F. V. et al.:'The growth inhibition of human mature breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta". 1. Clin; Invest., 1991, 87, 277.

[10] Desreux J., Kebers F., Noel A. et al.: "Effets des progestatifs sur I'apoptose des cellules epitheliales mammaires in vivo et in vitro" Reproduct. Humaine et Hormones, 1998, 11, 273.

[11] Gambrell D.: "Hormone replacement therapy and breast cancer". Maturitas, 1987, 9, 123.

[12] Gompel A., Malet C., Spritzer P. et al.: "Progestin effect on cell proliferation and 178 hydroxysteroid; deshydrogenase activity in normal human breast cells in culture". J. Clin. Endocrin. Metabol., 1986, 63, 1174.

[13] Gorins A.: "May progestogens induce breast cancer? No?". Menopause European Consensus Development Conference. MontreuxSwiterzerland, Le Sein (ed.), Paris ESKA, 1996, 219.

[14] Gorins A.: "Estrogenes, alcool, cancer du sein: un trio infernal". Actualites Gynecolog. 30eme Serie. Paris, ESK A (ed.), 1999, 75.

[15] Hofseth L. J.,R aafat A. M.,O such J. R. et al.: "Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal post-menopausal breast". 1. Clin. Endocrinol. Metab., 1999, 84, 4559

[ 16] Howell A., Anderson E., Lailan I. et al.: "Cyclical activity and'aging' of the human breast dues to risk and strategies for prevention". (in press).

[ 17] Jordan V.O., Jeng M. H., Catherino W. et al.: "The estrogenic activity of synthetic progestins used in oral contraceptives". Cancer, 1993, 21, 1501.

[18] Le G. M., Flu-Bureau G.: "Contraception orale et risque de mastopathie benigne. Revue de la litterature. Reproduction". Humaine et Hormones, 1999, 12 (5), 457.

[19] Li C. I., Weiss N. S., Staford J. et al.: "Hormone replacement therapy in relation to risk of lobulai and ductal breast carcinoma in middle aged women". Cancer, 2000, 88, 2570.

[20] Longman S. M., Buehring G. C.: "Oral contraception and breast cancer. In vivo effects of contraceptive steroids on human mammary cell growth". Cancer, 1987, 59, 281.

[21] Magnusson C., Baron J. A., Correia N. et al.: "Breast cancer risk following long-term oestrogen-progestin replacement therapy" Int. J. Cancer, 1999, 81, 339.

[22] Musgrove E. A.: "Hormonal control of cell proliferation in the breast and breast cancer". Abstract A 19. Int. Congress Menopause, Sydney, Australia, 1996.

[23] Paul C., Skegg D. C. C., Spears G. F. S.: "Depo-medroxyprogesterone (depo provera). Risk of breast cancer". Br. Med. J., 1989, 759.

[24] Persson I.: "Possible adverse effects of progestins on breast cancer risk". Menopause European Consensus Development Conference. Montreux-Switzerland, Paris ESKA (ed.), 1996, 211.

[25] Pike M. C., Henderson B. E., Krailo M. D. et al.: "Breast cancer in young women and use of oral contraceptive; possible modifying effect of formulation and age at use". Lancet, 1983, ii, 926.

[26] Plu Bureau G., Le M. G., Sitruk-Ware R. et al.: "Progestogen use and decreased risk of breast cancer in a cohort study of premenopausal women with benign breast disease". Br. 1. Cancer, 1994, 70, 270.

[27] 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. 1. Cancer, 1988, 58, 163.

[28] Poulin R., Baker D., Poirier D. et al.: "Multiple actions of synthetic'progestins' on the growth of ZR 75.1 human breast cancer cells: an in vitro model for the simultaneCJuS assay of androgen, progestin, estrogen and glucocorticoid agonistic and antiagonistic activities of steroids". Breast Cancer Res. Treat., 1990, 17, 197.

[29] Ross R. K., Paganini-Hill A., Wan P. C. et al.: "Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin". J. Nat. Cancer, 2000, 92, 328.

[30] Santen R. J., Pinkerton J., McCartney C. et al.: "Risk of breast cancer with progestin in combination with estrogen as hormone replacement therapy. Clinical review". J. Clin. Endocrinol. Metab., 2001, 86, 1623.

[31] Schairer C., Lubin J., Troisi R. et al.: "Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk" JAMA, 2000, 283 (4), 485.

[32] Selman P. J., Mol J. A., Rutteman G. R. et al.: "Progestin treatment in the dog-I effects on growth hormone, insuline like". Eur. 1. Endocrinol., 1994, 131, 413.

[33] Skegg D. C. G., Paul C., Spears G. F. S. et al.: "Progestogen only oral contraceptives and risk of breast cancer in New Zealand". Cancer Causes Control., 1996, 7, 513.

[34] Soderquist G., Schoultz Bo Von, Tani E. et al.: "Estrogen and progesterone receptor content in breast epithelial cells from healthy women during the menstrual cycle". Am. J. Obstet. Gynecol., 1993, 168, 874.

[35] Vecchio T. J.: "These wretched beagles. Depo-provera research". Newsletter no. 7, Oct. 1973.

[36] Vignon F., Bardon S., Chalbos D. et al.: "Antiestrogenic effect of R5020, a synthetic progestin in human breast cancer cells in culture". J. Clin. Endocrinol. Metab., 1983, 56, 1124.

[37] Welsch C. W., McManus M. J., Haviland T. J. et al.: "Hormone regulation of DNA synthesis of normal and hyperplastic human breast tissues in vitro and in vivo". Angeli et al. (eds.), New York, Raven Press, 1983, 47.

[38] Wolfe J.: "Breast parenchymal patterns and their relationship to carcinoma". In: Strax P.: "Control of breast cancer through mass screening". Littleton, NJ, PSG Publ. Co., 1979, 115.

[39] The WHI study (Women's Health Initiative) is entitled: "Risks and benefits of estrogen plus progestin in healthy postmenopausal women". Principal results from the Women's Health Initiative - randomized controlled study. JAMA, 2002, 288, 321.