Menopausa

HRT (Hormone Replacement Therapy) e rischio cancro

Hits: 91

Per HRT si intende la somministrazione di ormoni (estrogeni e/o progestinici e talvolta androgeni) al fine di colmare il deficit degli stessi derivante dalla naturale sospensione dell’attività endocrina ovarica che coincide con l’entrata in menopausa. Si stima che almeno 20 milioni di donne dei paesi occidentali utilizzino  la terapia ormonale sostitutiva (HRT). Ripristinare l’equilibrio ormonale presente prima della menopausa può attenuare i sintomi della menopausa stessa (vampate di calore, sudorazione, secchezza vaginale, ansia, irritabilità), e -se protratto per un tempo sufficientemente lungo – proteggere la donna dall’aumentato rischio osteoporotico.

Numerosi studi epidemiologici hanno riportato una diretta correlazione tra HRT e rischio di cancro degli organi riproduttivi femminili: mammella, utero e ovaio. Le donne in postmenopausa e non isterectomizzate,  che utilizzano la terapia ormonale sostitutiva (HRT, Hormone Replacement Therapy) a base di soli estrogeni, sono ad aumentato rischio (+ 2-10 volte)  di iperplasia endometriale e cancro dell’endometrio. Per minimizzare questo rischio, molte donne che ricorrono a HRT e che non sono state sottoposte ad isterectomia impiegano preparazioni estro-progestiniche o il Tibolone (Livia).  Il progestinico contrasta gli effetti indesiderati degli estrogeni sull’endometrio però produce un aumento (+ 0.6-1.5% dopo 5 anni di terapia) del rischio di cancro mammario

Anche la terapia con soli estrogeni potrebbe favorire l’insorgenza del ca. mammario, ma solo dopo una terapia prolungata per almeno 10 anni (2).

Secondo altri numerosi studi si dovrebbe ritenere che gli estrogeni non avrebbe un diretto ruolo oncogeno, dal momento che non sono mai stati evidenziati danneggiamenti del DNA correllati alla terapia con estrogeni. Quest  ultimi avrebbero un ruolo favorente l’azione di altri oncogeni nell’insorgenza e soprattutto nella progressione e crescita del tumore (2).

Nelle donne isterectomizzate,  la terapia ormonale sostitutiva si effettua in genere con soli estrogeni; in questa specifica circostanza l’HRT sembra addirittura esplicare un effetto protettivo nei confronti del cancro mammario.

Nutraceutica: è un neologismo sincratico da “nutrizione” e “farmaceutica” coniato da Stephen de Felice nel 1989. I nutraceutici possono essere estratti, sintetizzati e utilizzati per gli integratori alimentari, oppure addizionati negli alimenti. Più raro è trovarli negli alimenti in maniera naturale e in quantità sufficienti ad ottenere dei benefici. I prodotti a base di soia o sostanze similari proposti in alternativa egli estrogeni sono assolutamente controindicati nelle paz. con patologie mammarie ed inoltre riducono gli effetti del tamoxifene. Il resveratrolo e il polline rosso, facilmente reperibili in farmacia ed erboristeria, sono totalmente privi di effetti “estrogeno simili” pur esercitando un’azione eutrofizzante sull’apparato osteo-articolare, sistema nervoso centrale e cardiocircolatorio.

 

PREVENZIONE:

  1. accurata anamnesi personale e familiare della paziente prima di iniziare la terapia
  2. visita ginecologica
  3. esame mammario ogni 6 mesi
  4. controlli medici annuali
  5. screening mammografico
  6. PAP test ad intervalli regolariIn conclusione
  • In conclusione, i rischi ed i benefici della terapia ormonale sostitutiva devono sempre essere attentamente valutati, considerando anche l’importanza di posologia e durata della HRT.  Gli ormoni devono essere prescritti alla dose minima efficace e per il minor tempo possibile.  Se condotta nel rispetto delle regole sopra-riportate, il rischio appare abbastanza contenuto. Il rischio per ca. mammario è simile o addirittura inferiore a quello correlato ad altri fattori, come la familiarità per la patologia, presenza di mutazione di BRCA1 e BRCA2, la menopausa tardiva ed il menarca precoce, la nulliparità, la gravidanza tardiva (> 35 anni), l’obesità ed il sovrappeso.

 

Bibliografia:

  1. Doherty JA, Cushing-Haugen KL, Saltzman BS, Voigt LF, Hill DA, Beresford SA, Chen C, Weiss NS: ”Long-term use of postmenopausal estrogen and progestin hormone therapies and the risk of endometrial cancer”. Am J Obstet Gynecol. 2007 Aug;197(2):139.e1-7.
  2. M. Diete: Hormone replacement therapy (HRT), breast cancer and tumor pathology. Maturitas 2010;65,3:183-189

  3. 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 Assoc2002;288:321–333.
  4. Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the Million Women Study. Lancet2003;362:419–427
  5. Vickers, M.R., Martin, J., Meade, T.W. WISDOM study team. The Women’s international study of long-duration oestrogen after menopause (WISDOM): a randomised controlled trial. BMC Women’s Health2007;7:2.
  6. Turgeon, J.L., McDonnell, D.P., Martin, K.A., Wise, P.M. Hormone therapy: physiological complexity belies therapeutic simplicity. Science2004;304:1269–1273.
  7. American Institute for Cancer Research/World Cancer Research Fund. Food, nutrition and the prevention of cancer: a global perspective. BreastAmerican Institute of Cancer ResearchWashington, DC, USA2002 (p. 252–287, 20009, ISBN: 1 899533 05 2).
  8. Skouby, S.O., Jespersen, J. Progestins in HRT: sufferance or desire?. Maturitas2009;62:371–375
  9. Brekelmans, C.T. Risk factors and risk reduction of breast and ovarian cancer. Curr Opin Obstet Gynecol2003;15:63–68.
  10. Colditz, G.A., Hankinson, S.E., Hunter, D.J. et al, The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med1995;332:1589–1593
  11. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: further results. Contraception1996;54:1S–106S.
  12. Collaborative Group on Hormonal Factors in Breast Cancer. 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. Lancet1997;350:1047–1059
  13. Endogenous Hormones, Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst2002;94:606–616.
  14. Hankinson, S., Hunter, D. Breast cancer. in: H.O. Adami, D. Hunter, D. Trichopoulos (Eds.) Textbook of cancer epidemiologyOxford University PressNew York2002:301–339.
  15. La Vecchia, C., Franceschi, S. Hormone replacement therapy and cancer: an update. Eur J Cancer Prev2003;12:3–4.
  16. Magnusson, C., Baron, J.A., Correia, N., Bergström, R., Adami, H.O., Persson, I. Breast-cancer risk following long-term oestrogen- and oestrogen–progestin-replacement therapy. Int J Cancer1999;81:339–344.
  17. Olsson, H.L., Ingvar, C., Bladström, A. Hormone replacement therapy containing progestins and given continuously increase breast carcinoma risk in Sweden. Cancer2003;97:1387–1392.
  18. Schairer, C., Lubin, J., Troisi, R., Sturgeon, S., Brinton, L., Hoover, R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA2000;283:485–491.
  19. Porch, J.V., Lee, I.-M., Cook, N.R., Rexrode, K.M., Buring, J.E. Estrogen–progestin replacement therapy and breast cancer risk: the Women’s Health Study (United States). Cancer Causes Control2002;13:847–854.
  20. Ewertz, M., Mellemkjaer, L., Poulsen, A.H. et al, Hormone use for menopausal symptoms and risk of breast cancer. A Danish cohort study. Br J Cancer2005;92:1293–1297.
  21. 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. JAMA2003;289:3243–3253.
  22. Speroff, L. Postmenopausal hormone therapy and the risk of breast cancer: a contrary thought.Menopause2008;15:393–400 ([Review]).
  23. Dietel, M., Sers, C. Personalized medicine and development of targeted therapies: the upcoming challenge for diagnostic molecular pathology. A review. Virchows Arch2006;448:744–755 ([Review]).
  24. Dietel, M. Predictive medicine: incipient reality or fata morgana?. J Pathol2007;12:353–355.
  25. Adami, H.-O., Signorello, L.B., Trichopoulos, D. Towards an understanding of breast cancer etiology. in: Progress and enigmas in cancer epidemiology. vol. 8. Seminars in Cancer Biology, ; 1998:255–262.
  26. Hofseth, L.J., Raafat, A.M., Osuch, J.R., Pathak, D.R., Slomski, C.A., Haslam, S.Z. Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab1999;84:4559
  27. Li, C.I., Weiss, N.S., Stanford, J.L., Daling JR. Hormone replacement therapy in relation to risk of lobular and ductal breast carcinoma in middle-aged women. Cancer2000;88:2570–2577.
  28. Li, C.I., Malone, K.E., Porter, P.L. et al, Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA2003;289:3304–3306.
  29. Wiseman, R.A. Breast cancer hypothesis: a single cause for the majority of cases. J Epidemiol Community Health2000;54:851–858.
  30. Dietel, M., Lewis, M.A., Shapiro, S. Hormone replacement therapy: pathobiological aspects of hormone-sensitive cancers in women relevant to epidemiological studies on HRT: a mini-review.Hum Reprod2005;20:2052–2060.
  31. Kulendran, M., Salhab, M., Mokbel, K. Oestrogen-synthesising enzymes and breast cancer.Anticancer Res2009;29:1095–1109 ([Review]).
  32. Slanger, T.E., Chang-Claude, J.C., Obi, N. et al, Menopausal hormone therapy and risk of clinical breast cancer subtypes. Cancer Epidemiol Biomarkers Prev2009;18:1188–1196.
  33. Kumar, A.S., Cureton, E., Shim, V. et al, Type and duration of exogenous hormone use affects breast cancer histology. Ann Surg Oncol2007;14:695–703.
  34. Tjønneland, A., Christensen, J., Thomsen, B.L. et al, Hormone replacement therapy in relation to breast carcinoma incidence rate ratios: a prospective Danish cohort study. Cancer2004;100:2328–2337.
  35. Ravdin, P.M., Cronin, K.A., Howlader, N. et al, The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med2007;356:1670–1674.
  36. Friberg, S., Mattson, S. On the growth rates of human malignant tumors: implications for medical decision making. J Surg Oncol1997;65:284–297.
  37. Spratt, J.S., Meyer, J.S., Spratt, J.A. Rates of growth of human solid neoplasms. Part I. J Surg Oncol1995;60:137–146.
  38. Shackney, S.E., McCormack, G.W., Cuchural, G.J. Jr. Related articles, growth rate patterns of solid tumors and their relation to responsiveness to therapy: an analytical review. Ann Intern Med1978;89:107–121.
  39. Spratt, J.S., Kaltenbach, M.L., Spratt, J.A. Cytokinetic definition of acute and chronic breast cancer.Cancer Res1977;37:226–230.
  40. Spratt, J.S., Spratt, J.A. What is breast cancer doing before we can detect it?. J Surg Oncol1985;30:156–160.Gershon-Cohen, J., Berger, S.M., Klickstein, H.S. Roentgenography of breast cancer. Moderating concept of biologic predeterminism. Cancer1963;16:961–964.
  41. Gompertz, B. On the nature of the function expressive of the law of human mortality and on a new mode of determining the value of life contingencies. Philos Trans Roy Soc Lond (Biol)1825;115:513–583.
  42. Sausville, E.A., Longo, D.L. Principle of cancer treatment: surgery, chemotherapy and biological therapy. in: Harrisson (Ed.) Principle of internal medicine16th ed. McGraw-HillNY2005 (p. 464).
  43. Haskell, C.M. Thorax and unknown primary—breast cancer in cancer treatment. 2nd ed. WB Saunders Company, ; 1985 (p. 138).
  44. Kusama, S., Spratt, J.S. Jr., Donegan, W.L., Watson, F.R., Cunningham, C. The cross rates of growth of human mammary carcinoma. Cancer1972;30:594–599.
  45. Peer, P.G., Holland, R., Hendriks, J.H., Mravunac, M., Verbeek, A.L. Age-specific effectiveness of the Nijmegen population-based breast cancer-screening program: assessment of early indicators of screening effectiveness. J Natl Cancer Inst1994;86:436–441.
  46. Kuroishi, T., Tominaga, S., Morimoto, T. et al, Tumor growth rate and prognosis of breast cancer mainly detected by mass screening. Jpn J Cancer Res1990;81:454–462 ([Review]).
  47. Fournier, D.v., Weber, E., Hoeffken, W., Bauer, M., Kubli, F., Barth, V. Growth rate of 147 mammary carcinomas. Cancer1980;45:2198–2207.
  48. Arnerlöv, C., Emdin, S.O., Lundgren, B. et al, Breast carcinoma growth rate described by mammographic doubling time and S-phase fraction. Correlations to clinical and histopathologic factors in a screened population. Cancer1992;70:1928–1934.
  49. Hankinson, S.E., Willet, W.C., Colditz, G.A. et al, Endogeneous and exogeneous hormone factors.in: J.R. Harris, M.E. Lippman, M. Morrow, S. Hellman (Eds.) Disease of the breastLippincott-Raven PublishersPhiladelphia, PA1996:185–200.
  50. Sellers, T.A., Mink, P.J., Cerhan, J.R. et al, The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med1997;127:973–980.
  51. Fletcher, A.S., Erbas, B., Kavanagh, A.M., Hart, S., Rodger, A., Gertig, D.M. Use of hormone replacement therapy (HRT) and survival following breast cancer diagnosis. Breast2005;14:192–200.
  52. Gapstur, S.M., Morrow, M., Sellers, T.A. Hormone replacement therapy and risk of breast cancer with a favorable histology. JAMA1999;281:2091–2097.
  53. Hall, P., Ploner, A., Bjöhle, J. et al, Hormone-replacement therapy influences gene expression profiles and is associated with breast-cancer prognosis: a cohort study. BMC Med2006;4:16.
  54. Pappo, I., Meirshon, I., Karni, T. et al, The characteristics of malignant breast tumors in hormone replacement therapy users versus nonusers. Ann Surg Oncol2004;11:52–58.
  55. Sacchini, V., Zurrida, S., Andreoni, G. et al, Pathologic and biological prognostic factors of breast cancers in short- and long-term hormone replacement therapy users. Ann Surg Oncol2002;9:266–271.
  56. Erbas, B., Amos, A., Fletcher, A., Kavanagh, A.M., Gertig, D.M. Incidence of invasive breast cancer and ductal carcinoma in situ in a screening program by age: should older women continue screening?. Cancer Epidemiol Biomarkers Prev2004;13:1569–1573.
  57. Pirke, K.M., Doerr, P. Age-related changes in free plasma testosterone, dihydrotestosterone, and oestradiol. Acta Endocrinol1975;80:171–178.
  58. Neuhouser, M.L., Kristal, A.R., Penson, D.F. Steroid hormones and hormone-related genetic and lifestyle characteristics as risk factors for benign prostatic hyperplasia: review of epidemiologic literature. Urology2004;64:201–211.
  59. WHO Classification of tumors—Pathology and genetics of tumours of the urinary system and male genital organs. Eds. Eble JE, Sauter G, Epstein JI, Sesterhenn IA, IARC Press, Lyon 2004, p. 164..
  60. McNeal, J.E., Redwine, E.A., Freiha, F.S., Stamey, T.A. Zonal distribution of prostatic adenocarcinoma. Correlation with histologic pattern and direction of spread. Am J Surg Pathol1988;12:897–906.
  61. Erbersdobler, A.H., Augustin, T., Schlomm, R.-P. Henke prostate cancers in the transition zone. Part 1. Pathological aspects. BJU Int2004;94:1221–1225.
  62. Low, T.H., Clark, J., Gao, K., Eris, J., Shannon, K., O’Brien, C. Outcome of parathyroidectomy for patients with renal disease and hyperparathyroidism: predictors for recurrent hyperparathyroidism. ANZ J Surg2009;79:378–382.
  63. Anderson, G.L., Limacher, M., Assaf, A.R. et al, Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA2004;291:1701–1712.
  64. Seeger, H., Mueck, A.O. Are the progestins responsible for breast cancer risk during hormone therapy in the postmenopause? Experimental vs. clinical data. J Steroid Biochem Mol Biol2008;109:11–15.
  65. Pike, M.C., Wu, A.H., Spicer, D.V., Lee, S., Pearce, C.L. Estrogens, progestins, and risk of breast cancer. Ernst Schering Found Symp Proc2007;1:127–150 ([Review]).
  66. Ferguson, D.J., Anderson, T.J. Morphological evaluation of cell turnover in relation to the menstrual cycle in the “resting” human breast. Br J Cancer1981;44:177–181.
  67. Lee, S.A., Ross, R.K., Pike, M.C. An overview of menopausal oestrogen–progestin hormone therapy and breast cancer risk. Br J Cancer2005;92:2049–2058.
  68. Fournier, A., Berrino, F., Clavel-Chapelon, F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat2008;107:103–111.
  69. Lyytinen, H., Pukkala, E., Ylikorkala, O. Breast cancer risk in postmenopausal women using estradiol–progestogen therapy. Obstet Gynecol2009;113:65–73.
  70. Birrell, S.N., Butler, L.M., Harris, J.M., Buchanan, G., Tilley, W.D. Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer. FASEB J2007;21:2285–2293.
  71. Eigeliene, N., Härkönen, P., Erkkola, R. Effects of estradiol and medroxyprogesterone acetate on expression of the cell cycle proteins cyclin D1, p21 and p27 in cultured human breast tissues. Cell Cycle2008;7:71–80.
  72. Eigeliene, N., Härkönen, P., Erkkola, R. Effects of estradiol and medroxyprogesterone acetate on morphology, proliferation and apoptosis of human breast tissue in organ cultures. BMC Cancer2006;6:246.
  73. Hackenberg, R., Turgetto, I., Filmer, A., Schulz, K.D. Estrogen and androgen receptor mediated stimulation and inhibition of proliferation by androst-5-ene-3 beta,17 beta-diol in human mammary cancer cells. J Steroid Biochem Mol Biol1993;46:597–603.
  74. Birrell, S.N., Hall, R.E., Tilley, W.D. Role of the androgen receptor in human breast cancer. J Mammary Gland Biol Neoplasia1998;3:95–103 ([Review]).
  75. Hall, R.E., Birrell, S.N., Tilley, W.D., Sutherland, R.L. MDA-MB-453, an androgen-responsive human breast carcinoma cell line with a high level of androgen receptor expression. Eur J Cancer1994;30A:484–490.
  76. Recchione, C., Venturelli, E., Manzari, A., Cavalteri, A., Martinetti, A., Secreto, G. Testosterone, dihydrotestosterone and estradiol levels in postmenopausal breast cancer tissues. J Steroid Biochem Mol Biol1995;52:541–546.
  77. Lea, O.A., Varhaug, J.E., Skarstein, A., Kvinnsland, S. Androgen receptors in operable breast cancer: relation to other steroid hormone receptors, correlations to prognostic factors and predictive value for effect of adjuvant tamoxifen treatment. Eur J Surg Oncol1992;18:112–118.
  78. chippinger, W., Regitnig, P., Dandachi, N. et al, Evaluation of the prognostic significance of androgen receptor expression in metastatic breast cancer. Virchows Arch2006;449:24–30.
  79. Buchanan, G., Birrell, S.N., Peters, A.A. et al, Decreased androgen receptor levels and receptor function in breast cancer contribute to the failure of response to medroxyprogesterone acetate.Cancer Res2005;65:8487–8496.
  80. Parazzini, F., Colli, E., Scatigna, M., Tozzi, L. Treatment with tamoxifen and progestins for metastatic breast cancer in postmenopausal women: a quantitative review of published randomized clinical trials. Oncology1993;50:483–489.
  81. Taoufik, R., Ouatas, T., Halverson, D., Steeg, P.S. Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor gene expression in metastatic human breast carcinoma cells: new uses for old compounds. Clin Cancer Res2003;9:3763–3772.
  82. Holmes, M.D., Chen, W.Y., Feskanich, D., Kroenke, C.H., Colditz, G.A. Physical activity and survival after breast cancer diagnosis. JAMA2005;293:2479–2486.
  83. Armstrong, K., Eisen, A., Weber, B. Assessing the risk of breast cancer. N Engl J Med2000;342:564–571.
  84. Harris, J.R., Lippman, M.E., Veronesi, U., Willett, W. Breast cancer. N Engl J Med1992;327:319–328.
  85. Boyd, N.F., Rommens, J.M., Vogt, K. et al, Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol2005;6:798–808.


Lascia un commento

Il tuo indirizzo email non sarà pubblicato. I campi obbligatori sono contrassegnati *

Captcha loading...