The Journal of Minimally Invasive Gynecology
Volume 16, Issue 5 , Pages 533-539 , September 2009

Aromatase Inhibitors: Potential Reproductive Implications

  • Mohamed A. Bedaiwy, MD, PhD
  • ,
  • Noha A. Mousa, MD
  • ,
  • Robert F. Casper, MD

      Affiliations

    • Corresponding Author InformationCorresponding author: Robert F. Casper, MD, Division of Reproductive Sciences and Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave, Rm 876, Toronto, ON M5G 1X5, Canada.

Received 10 March 2009 ,Accepted 12 May 2009.

References 

  1. Cole PA, Robinson CH. Conversion of 19-oxo [2 beta-2H] androgens into oestrogens by human placental aromatase: an unexpected stereochemical outcome. Biochem J. 1990;268:553–561
  2. Simpson ER. Sources of estrogen and their importance. J Steroid Biochem Mol Biol. 2003;86:225–230
  3. Lonning P. Overview of aromatase inhibitors and inactivators in the treatment of advanced breast cancer. In:  Miller WR,  Ingle JN editor. Endocrine Therapy in Breast Cancer. New York, NY: Marcel Dekker, Inc; 2002;p. 33–46
  4. Casper RF. Aromatase inhibitors in ovarian stimulation. J Steroid Biochem Mol Biol. 2007;106:71–75
  5. Bonneterre J. Aromatase inhibitors as first line treatment: treatment cascade after failure of aromatase inhibitors. Breast Cancer Res Treat. 2003;81:57–61
  6. Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM. An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane. Cancer. 2002;95:2006–2016
  7. Mauras N, Lima J, Patel D, et al. Pharmacokinetics and dose finding of a potent aromatase inhibitor, aromasin (exemestane), in young males. J Clin Endocrinol Metab. 2003;88:5951–5956
  8. Felson DT, Cummings SR. Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation. Arthritis Rheum. 2005;52:2594–2598
  9. Liehr JG. Is estradiol a genotoxic mutagenic carcinogen?. Endocr Rev. 2000;21:40–54
  10. Harrell JC, Dye WW, Harvell DME, et al. Estrogen insensitivity in a model of estrogen receptor positive breast cancer lymph node metastasis. Cancer Res. 2007;67:10582–10591
  11. Miller WR, Larionov A, Renshaw L, et al. Aromatase inhibitors: gene discovery. J Steroid Biochem Mol Biol. 2007;106:130–142
  12. Miller WR, O'Neill J. The importance of local synthesis of estrogen within the breast. Steroids. 1987;50:537–548
  13. Labrie F. Intracrinology. Mol Cell Endocrinol. 1991;78:C113–C118
  14. Sasano H, Suzuki T, Harada N. From endocrinology to intracrinology. Endocr Pathol. 1998;9:9–20
  15. Simpson ER, Misso M, Hewitt KN, et al. Estrogen: the good, the bad, and the unexpected. Endocr Rev. 2005;26:322–330
  16. Misso ML, Jang C, Adams J, et al. Adipose aromatase gene expression is greater in older women and is unaffected by postmenopausal estrogen therapy. Menopause. 2005;12:210–215
  17. Cleland WH, Mendelson CR, Simpson ER. Effects of aging and obesity on aromatase activity of human adipose cells. J Clin Endocrinol Metab. 1985;60:174–177
  18. Tekmal RR, Ramachandra N, Gubba S, et al. Overexpression of int-5/aromatase in mammary glands of transgenic mice results in the induction of hyperplasia and nuclear abnormalities. Cancer Res. 1996;56:3180–3185
  19. Pasqualini JR, Chetrite G, Blacker C, et al. Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients. J Clin Endocrinol Metab. 1996;81:1460–1464
  20. Honma N, Takubo K, Sawabe M, et al. Estrogen-metabolizing enzymes in breast cancers from women over the age of 80 years. J Clin Endocrinol Metab. 2006;91:607–613
  21. Beslija S, Bonneterre J, Burstein H, et al. Second consensus on medical treatment of metastatic breast cancer. Ann Oncol. 2007;18:215–225
  22. Ellis MJ, Coop A, Singh B, et al. Letrozole Is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1– and/or ErbB-2–positive, estrogen receptor–positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol. 2001;19:3808–3816
  23. Ryan PD, Goss PE. Adjuvant hormonal therapy in peri- and postmenopausal breast cancer. Oncologist. 2006;11:718–731
  24. Altundag K, Bulut N, Sari E, Harputluoglu H. The role of aromatase inhibitors in the management of ductal carcinoma in situ with an estrogen receptor–positive/progesterone receptor–negative/Her-2/neu receptor–positive pattern. Am J Surg. 2007;194:272–273
  25. Anderson H, Bulun S, Smith I, Dowsett M. Predictors of response to aromatase inhibitors. J Steroid Biochem Mol Biol. 2007;106:49–54
  26. Richardson H, Johnston D, Pater J, Goss P. The National Cancer Institute of Canada Clinical Trials Group MAP3 trial: an international breast cancer prevention trial. Curr Oncol. 2007;14:89–96
  27. Kelloff GJ, Lubet RA, Lieberman R, et al. Aromatase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prev. 1988;7:65–78
  28. Miller W. Aromatase inhibitors and breast cancer. Minerva Endocrinol. 2006;31:27–46
  29. Kendall A, Dowsett M. Novel concepts for the chemoprevention of breast cancer through aromatase inhibition. Endocr Relat Cancer. 2006;13:827–837
  30. Cummings SR. Primary prevention of breast cancer: new approaches. Maturitas. 2007;57:39–41
  31. Howell A, Cuzick J. 2005 Vascular effects of aromatase inhibitors: data from clinical trials. J Steroid Biochem Mol Biol. 2005;95:143–149
  32. Gasco M, Argusti A, Bonanni B, Decensi A. SERMs in chemoprevention of breast cancer. Eur J Cancer. 2005;41:1980–1989
  33. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 1998;90:1371–1388
  34. Cuzick J. Aromatase inhibitors in prevention: data from the ATAC (arimidex, tamoxifen alone or in combination) trial and the design of IBIS-II (the second International Breast Cancer Intervention Study). Recent Results Cancer Res. 2003;163:96–103discussion 264–265
  35. Castagnetta LA, Granata OM, Traina A, et al. Tissue content of hydroxyestrogens in relation to survival of breast cancer patients. Clin Cancer Res. 2002;8:3146–3155
  36. Harper-Wynne C, Ross G, Sacks N, et al. Effects of the aromatase inhibitor letrozole on normal breast epithelial cell proliferation and metabolic indices in postmenopausal women: a pilot study for breast cancer prevention. Cancer Epidemiol Biomarkers Prev. 2002;11:614–621
  37. Lonning PE. Exemestane for breast cancer prevention: a feasible strategy?. Clin Cancer Res. 2005;11:918s–924s
  38. Macedo LF, Guo Z, Tilghman SL, Sabnis GJ, Qiu Y, Brodie A. Role of androgens on MCF-7 breast cancer cell growth and on the inhibitory effect of letrozole. Cancer Res. 2006;66:7775–7782
  39. Freedman OC, Verma S, Clemons MJ. Pre-menopausal breast cancer and aromatase inhibitors: treating a new generation of women. Breast Cancer Res Treat. 2006;99:241–247
  40. Kubatka P, Sadlonová V, Kajo K, Nosál'ová G, Ostatníková D, Adamicová K. Chemopreventive effects of anastrozole in a premenopausal breast cancer model. Anticancer Res. 2008;28:2819–2823
  41. Bulun SE, Zeitoun K, Takayama K, et al. Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis. Endocr Relat Cancer. 1999;6:293–301
  42. Shippen ER, West JWJ. Successful treatment of severe endometriosis in two premenopausal women with an aromatase inhibitor. Fertil Steril. 2004;81:1395–1398
  43. Soysal S, Soysal ME, Ozer S, Gul N, Gezgin T. The effects of post-surgical administration of goserelin plus anastrozole compared to goserelin alone in patients with severe endometriosis: a prospective randomized trial. Hum Reprod. 2004;19:160–167
  44. Nawathe A, Patwardhan S, Yates D, Harrison GR, Khan KS. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG. 2008;115:818–822
  45. Mousa NA, Bedaiwy MA, Casper RF. Aromatase inhibitors in the treatment of severe endometriosis. Obstet Gynecol. 2007;109:1421–1423
  46. Eastell R, Hannon R. Long-term effects of aromatase inhibitors on bone. J Steroid Biochem Mol Biol. 2005;95:151–154
  47. Amsterdam LL, Gentry W, Jobanputra S, Wolf M, Rubin SD, Bulun SE. Anastrazole and oral contraceptives: a novel treatment for endometriosis. Fertil Steril. 2005;84:300–304
  48. Ailawadi RK, Jobanputra S, Kataria M, Gurates B, Bulun SE. Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study. Fertil Steril. 2004;81:290–296
  49. Day Baird D, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003;188:100–107
  50. Balasch J, Manau D, Mimo J, Duran M, Puerto B, Vanrell JA. Trial of routine gonadotropin releasing hormone agonist treatment before abdominal hysterectomy for leiomyoma. Acta Obstet Gynecol Scand. 1995;74:562–565
  51. Higashijima T, Kataoka A, Nishida T, Yakushiji M. Gonadotropin-releasing hormone agonist therapy induces apoptosis in uterine leiomyoma. Eur J Obstet Gynecol Reprod Biol. 1996;68:169–173
  52. Gurates B, Parmaksiz C, Kilic G, Celik H, Kumru S, Simsek M. Treatment of symptomatic uterine leiomyoma with letrozole. Reprod Biomed Online. 2008;17:569–574
  53. Parsanezhad ME, Azmoon M, Alborzi S, et al. A randomized, controlled clinical trial comparing the effects of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status [published online ahead of print January 8, 2009]. Fertil Steril.
  54. Shozu M, Murakami K, Inoue M. Aromatase and leiomyoma of the uterus. Semin Reprod Med. 2004;22:51–60
  55. Ishikawa H, Reierstad S, Demura M, et al. High Aromatase Expression in Uterine Leiomyoma Tissues of African-American Women. J Clin Endocrinol Metab. 2009;94:1752–1756
  56. Attilakos G, Fox R. Regression of tamoxifen-stimulated massive uterine fibroid after conversion to anastrozole. J Obstet Gynaecol. 2005;25:609–610
  57. Varelas FK, Papanicolaou AN, Vavatsi-Christaki N, Makedos GA, Vlassis GD. The effect of anastrazole on symptomatic uterine leiomyomata. Obstet Gynecol. 2007;110:643–649
  58. Aleem FA, Predanic M. The hemodynamic effect of GnRH agonist therapy on uterine leiomyoma vascularity: a prospective study using transvaginal color Doppler sonography. Gynecol Endocrinol. 1995;9:253–258
  59. Bozzini N, Messina ML, Borsari R, Hilario SG, Pinotti JA. Comparative study of different dosages of goserelin in size reduction of myomatous uteri. J Am Assoc Gynecol Laparosc. 2004;11:462–463
  60. Casper RF. Clinical uses of gonadotropin-releasing hormone analogues. Can Med Assoc J. 1991;144:153–158
  61. Surrey ES, Silverberg KM, Surrey MW, Schoolcraft WB. Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis. Fertil Steril. 2002;78:699–704
  62. Hansen KA, Eyster KM. A review of current management of endometriosis in 2006: an evidence-based approach. S D Med. 2006;59:153–159
  63. Batzer FR. GnRH analogs: options for endometriosis-associated pain treatment. J Minim Invasive Gynecol. 2006;13:539–545
  64. Saito S, Murakami T, Suzuki K, Terada Y, Fukushima K, Moriya T. Intestinal endometriosis complicated by ileal perforation after initiation of gonadotropin-releasing hormone agonist therapy. Fertil Steril. 2007;88:969.e7–969.e9
  65. Hall LLH, Malone JM, Ginsburg KA. Flare-up of endometriosis induced by gonadotropin-releasing hormone agonist leading to bowel obstruction. Fertil Steril. 1995;64:1204–1206
  66. Bedaiwy MA, Mousa NA, Casper RF. Aromatase inhibitors prevent the estrogen rise associated with the flare effect of gonadotropins in patients treated with GnRH agonists. Fertil Steril. 2009;91:1574–1577
  67. Fontaine C, Meulemans A, Huizing M, et al. Tolerance of adjuvant letrozole outside of clinical trials. Breast. 2008;17:376–381
  68. Burstein HJ. Aromatase inhibitor-associated arthralgia syndrome. Breast. 2007;16:223–234
  69. Laroche M, Borg S, Lassoued S, De Lafontan B, Roche H. Joint pain with aromatase inhibitors: abnormal frequency of Sjogren's syndrome. J Rheumatol. 2007;34:2259–2263
  70. Folkestad L, Bjarnason NH, Bjerregaard JK, Brixen K. The effect of aromatase inhibitors on bone metabolism. Basic Clin Pharmacol Toxicol. 2009;104:3–10
  71. Lonning PE, Geisler J, Krag LE, et al. Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol. 2005;23:5126–5137
  72. Perez EA, Josse RG, Pritchard KI, et al. Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol. 2006;24:3629–3635
  73. Chlebowski RT. Bone health in women with early-stage breast cancer. Clin Breast Cancer. 2005;5(suppl.):S35–S40
  74. Kenemans P, Bundred NJ, Foidart JM, et al. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol. 2009;10:135–146
  75. Brufsky A. Management of cancer-treatment-induced bone loss in postmenopausal women undergoing adjuvant breast cancer therapy: a Z-FAST update. Semin Oncol. 2006;33:13–17
  76. Yonehara Y, Iwamoto I, Kosha S, Rai Y, Sagara Y, Douchi T. Aromatase inhibitor-induced bone mineral loss and its prevention by bisphosphonate administration in postmenopausal breast cancer patients. J Obstet Gynaecol Res. 2007;33:696–699
  77. Lewiecki EM, Miller PD, McClung MR. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res. 2007;22:1832–1841
  78. Fleurence RL, Iglesias CP, Johnson JM. The cost effectiveness of bisphosphonates for the prevention and treatment of osteoporosis: a structured review of the literature. Pharmacoeconomics. 2007;25:913–933
  79. Mousa NA, Crystal P, Wolfman WL, Bedaiwy MA, Mohamed A, Casper RF. Aromatase inhibitors and mammographic breast density in postmenopausal women receiving hormone replacement therapy. Menopause. 2008;15:875–884
  80. McCormack VA, dos Santos Silva I. Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2006;15:1159–1169
  81. Boyd NF, Guo H, Martin LJ, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007;356:227–236
  82. Fabian C, Kimler B, Zalles C, et al. Reduction in proliferation with six months of letrozole in women on hormone replacement therapy. Breast Cancer Res Treat. 2007;106:75–84
  83. Chen S, Masri S, Wang X, Phung S, Yuan YC, Wu X. What do we know about the mechanisms of aromatase inhibitor resistance?. J Steroid Biochem Mol Biol. 2006;102:232–240
  84. Johnston SR, Martin LA, Leary A, Head J, Dowsett M. Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer. J Steroid Biochem Mol Biol. 2007;106:180–186
  85. Moy B, Goss PE. Estrogen receptor pathway: resistance to endocrine therapy and new therapeutic approaches. Clin Cancer Res. 2006;12:4790–4793
  86. Swaby RF, Jordan VC. Low-dose estrogen therapy to reverse acquired antihormonal resistance in the treatment of breast cancer. Clin Breast Cancer. 2008;8:124–133
  87. Martin LA, Farmer I, Johnston SR, Ali S, Marshall C, Dowsett M. Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. J Biol Chem. 2003;278:30458–30468
  88. Li YF, Hu W, Fu SQ, Li JD, Liu JH, Kavanagh JJ. Aromatase inhibitors in ovarian cancer: is there a role?. Int J Gynecol Cancer. 2008;18:600–614
  89. Berstein L, Kovalevskij A, Zimarina T, et al. Aromatase and comparative response to its inhibitors in two types of endometrial cancer. J Steroid Biochem Mol Biol. 2005;95:71–74
  90. Li H, Chen X, Qiao J. Letrozole as primary therapy for endometrial hyperplasia in young women. Int J Gynecol Obstet. 2008;100:10–12
  91. Markovitch O, Tepper R, Fishman A, Aviram R, Cohen I. Aromatase inhibitors reverse tamoxifen induced endometrial ultrasonographic changes in postmenopausal breast cancer patients. Breast Cancer Res Treat. 2007;101:185–190
  92. Giles DL, Liu PT, Lidner TK, Magtibay PM. Treatment of aggressive angiomyxoma with aromatase inhibitor prior to surgical resection. Int J Gynecol Cancer. 2008;18:375–379

 The authors have no commercial, proprietary, or financial interest in the products or companies described in this article.

PII: S1553-4650(09)00250-7

doi: 10.1016/j.jmig.2009.05.009

The Journal of Minimally Invasive Gynecology
Volume 16, Issue 5 , Pages 533-539 , September 2009