, Volume 22, Issue 3, pp 305–315 | Cite as

Tamoxifen is an estrogen antagonist on gonadotropin secretion and responsiveness of the hypothalamic-pituitary-adrenal axis in female monkeys

  • M. E. Wilson
  • D. Mook
  • F. Graves
  • J. Felger
  • I. F. Bielsky
  • K. Wallen


The selective estrogen receptor modulator, tamoxifen, effectively slows the progression of estrogen-positive breast cancer and reduces the possibility of this cancer developing in women at high risk. Despite the widespread acceptance of tamoxifen as a therapeutic agent for this disease, its effects on other estrogen-dependent pathways, particularly on neural circuits regulating brain function and peripheral hormone secretion, are poorly understood. The present study, using previously ovariectomized rhesus monkeys, examined the effects of tamoxifen, in both the presence and absence of estradiol replacement, on the reproductive and hypo-thalamic-pituitary-adrenal (HPA) axes. In Experiment 1, monkeys randomly assigned to three groups (n=8 each) were treated with placebo and either two doses of estradiol, two doses of tamoxifen alone, or two doses of tamoxifen plus high-dose estradiol to assess the effects on negative feedback suppression of luteinizing hormone (LH). Both doses of tamoxifen effectively antag-onized the negative feedback efficacy of estradiol on LH secretion. In contrast, neither the low- or high-dose tamoxifen alone had any effect on LH secretion, as con-centrations during tamoxifen treatments were indistinguishable from those during placebo. In Experiment 2, females were randomly assigned to one of four treatment groups (placebo, n=6; estradiol, n=5; tamoxifen only, n=5; or tamoxifen plus estradiol, n=6) to assess the effects on glucocorticoid negative feedback and pituitary and adrenal responsiveness to exogenous corticotropin-releasing hormone (CRH). Tamoxifen also antagonized the facilitating effects of estradiol on basal and CRH-induced ACTH and cortisol secretion. However, this antagonism produced basal and CRH-stimulated cortisol and ACTH concentrations that were lower than placebo-treated females. Interestingly, tamoxifen in the absence of estradiol produced a similar diminution in ACTH and cortisol response. These data suggest that, in the presence of estradiol, tamoxifen not only antagonized estrogenic facilitation of HPA responsivity but also actually attenuated the response compared with the placebo-treatment condition. Taken together, these data indicate that tamoxifen acts as an estrogen antagonist on the neural circuits controlling the neuroendocrine regulation of the hypothalamic-pituitary-ovarian and adrenal axes in ovariectomized macaque females.

Key Words

Estradiol tamoxifen SERM LH cortisol ACTH dexamethasone corticotropin-releasing hormone 


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  1. 1.
    Cosman, F. and Lindsay, R. (1999). Endocrine Rev. 20, 418–434.CrossRefGoogle Scholar
  2. 2.
    Dardes, R. C. and Jordan, V. C. (2000). Br. Med. Bull. 56, 773–786.PubMedCrossRefGoogle Scholar
  3. 3.
    Knobil, E. (1988). Hum. Reprod. 3, 469–472.PubMedGoogle Scholar
  4. 4.
    Overlie, I., Moen, M. H., Morkrid, L., Skjaeraasen, J. S., and Holte, A. (1999). Acta Obstet. Gynecol. Scand. 78, 642–647.PubMedCrossRefGoogle Scholar
  5. 5.
    Urshiroyama, T. and Sugimoto, O. (1995). Horm. Res. 44, 64–68.Google Scholar
  6. 6.
    Longcope, C. (2001). J. Soc. Gynecol. Investig. 8, S67-S68.PubMedCrossRefGoogle Scholar
  7. 7.
    Sluijmer, A. V., Heineman, M. J., De Jong, F. H., and Evers, J. L. (1995). J. Clin. Endocrinol. Metab. 80, 2163–2167.PubMedCrossRefGoogle Scholar
  8. 8.
    Jordan, V. C., Fritz, N. F., and Tormey, D. C. (1987). Cancer Res. 47, 624–630.PubMedGoogle Scholar
  9. 9.
    Ravdin, P. M., Fritz, N. F., Tormey, D. C., and Jordan, V. C. (1988). Cancer Res. 48, 1026–1029.PubMedGoogle Scholar
  10. 10.
    Welt, C. K., Pagan, Y. L., Smith, P. C., Rado, K. B., and Hall, J. E. (2003). J. Clin. Endocrinol. Metab. 88, 1766–1771.PubMedCrossRefGoogle Scholar
  11. 11.
    Boostanfar, R., Jain, J. K., Mishell, D. R. Jr. and Paulson, R. J. (2001). Fert. Steril. 75, 1024–1026.CrossRefGoogle Scholar
  12. 12.
    Suginami, H., Kitagawa, H., Nakahashi, N., Yano, K., and Matsubara, K. (1993). Fertil. Steril. 59, 976–979.PubMedGoogle Scholar
  13. 13.
    Robertson, J. F. and Blamey, R. W. (2003). Eur. J. Cancer 39, 861–869.PubMedCrossRefGoogle Scholar
  14. 14.
    Goss, P. E., Clark, R. M., Ambus, U., et al. (1995). Clin. Cancer Res. 1, 287–294.PubMedGoogle Scholar
  15. 15.
    Donath, J. and Nishino, Y. (1998). J. Steroid Biochem. Mol. Biol. 66, 247–254.PubMedCrossRefGoogle Scholar
  16. 16.
    Sanchez-Criado, J. E., Guelmes, P., Bellido, C., et al. (2002). Neuroendocrinology 76, 203–213.PubMedCrossRefGoogle Scholar
  17. 17.
    Gao, X., Petroff, B. K., Oluola, O., Georg, G., Terranova, P. F., and Rozman, K. K. (2002). Toxicol. Appl. Pharmacol. 183, 179–188.PubMedCrossRefGoogle Scholar
  18. 18.
    Paterson, A. G., Turkes, A., Groom, G. V., and Webster, D. J. (1983). Eur. J. Cancer Clin. Oncol. 19, 919–922.PubMedCrossRefGoogle Scholar
  19. 19.
    Luciani, L., Oriana, S., Spatti, G., et al. (1984). Tumori 70, 189–192.PubMedGoogle Scholar
  20. 20.
    Alexieva-Figusch, J., Blankenstein, M. A., de Jong, F. H., and Lamberts, S. W. (1984). Eur. J. Cancer Clin. Oncol. 20, 135–140.PubMedGoogle Scholar
  21. 21.
    Gasparini, G., Canobbio, L., Galligioni, E., et al. (1987). Eur. J. Cancer Clin. Oncol. 23, 1451–1459.PubMedCrossRefGoogle Scholar
  22. 22.
    Miodrag, A., Ekelund, P., Burton, R., and Castleden, C. M. (1991). Age Ageing 20, 52–54.PubMedCrossRefGoogle Scholar
  23. 23.
    Lonning, P. E., Johannessen, D. C., Lien, E. A., Ekse, D., Fotsis, T., and Adlercreutz, H. (1995). J. Steroid Biochem. Mol. Biol. 52, 491–496.PubMedCrossRefGoogle Scholar
  24. 24.
    Kostoglou-Athanassiou, I., Ntalles, K., Gogas, J., et al. (1997). Horm. Res. 47, 116–120.PubMedGoogle Scholar
  25. 25.
    Kavak, Z. N., Binoz, S., Ceyhan, N., and Pekin, S. (2000). Acta Obstet. Gynecol. Scand. 79, 604–607.PubMedCrossRefGoogle Scholar
  26. 26.
    Harper-Wynne, C. L., Sacks, N. P., Shenton, K., et al. (2002). J. Clin. Oncol. 20, 1026–1035.PubMedCrossRefGoogle Scholar
  27. 27.
    De Marinis, L., Mancini, A., Izzi, D., et al. (2000). Clin. Endocrinol. 52, 681–685.CrossRefGoogle Scholar
  28. 28.
    Patchev, V. K. and Almeida, O. F. (1996). J. Neurosci. 16, 7077–7084.PubMedGoogle Scholar
  29. 29.
    Dayas, C. V., Xu, Y., Buller, K. M., and Day, T. A. (2000). J. Neuroendocrinol. 12, 784–794.PubMedCrossRefGoogle Scholar
  30. 30.
    Roy, B. N., Reid, R. L., and Van Vugt, D. A. (1999). Endocrinology 140, 2191–2198.PubMedCrossRefGoogle Scholar
  31. 31.
    Vamvakopoulos, N. C. and Chrousos, G. P. (1993). J. Clin. Invest. 92, 1896–1902.PubMedGoogle Scholar
  32. 32.
    Kerdelhue, B., Jones, G. S., Gordon, K., et al. (1995). J. Neurosci. Res. 42, 228–235.PubMedCrossRefGoogle Scholar
  33. 33.
    Carey, M. P., Deterd, C. H., de Koning, J., Helmerhorst, F., and de Kloet, E. R. (1995). J. Endocrinol. 144, 311–321.PubMedCrossRefGoogle Scholar
  34. 34.
    Smith, C. J. and Norman, R. L. (1987). Endocrinology 121, 2192–2198.PubMedGoogle Scholar
  35. 35.
    Giussani, D. A., Farber, D. M., Jenkins, S. L., et al. (2000). Biol. Reprod. 62, 1445–1451.PubMedCrossRefGoogle Scholar
  36. 36.
    Gudmundsson, A., Goodman, B., Lent, S., et al. (1999). Exp. Gerontol. 34, 809–818.PubMedCrossRefGoogle Scholar
  37. 37.
    Fonseca, E., Basurto, L., Velazquez, S., and Zarate, A. (2001). Maturitas 39, 57–62.PubMedCrossRefGoogle Scholar
  38. 38.
    De Leo, V., la Marca, A., Talluri, B., D’Antona, D., and Morgante, G. (1998). Eur. J. Endocrinol. 138, 430–435.PubMedCrossRefGoogle Scholar
  39. 39.
    Grino, M., Hery, M., Paulmyer-Lacroix, O., and Anglade, G. (1995). Endocrine 3, 395–398.CrossRefGoogle Scholar
  40. 40.
    Figueiredo, H. F., Dolgas, C. M., and Herman, J. P. (2002). Endocrinology 143, 2534–2540.PubMedCrossRefGoogle Scholar
  41. 41.
    Young, E. A., Altemus, M., Parkison, V., and Shastry, S. (2001). Neuropsychopharmacology 25, 881–891.PubMedCrossRefGoogle Scholar
  42. 42.
    de Vries, G. J. and Miller, M. A. (1998). Prog. Brain Res. 119, 3–20.PubMedGoogle Scholar
  43. 43.
    van Leeuwen, F. W., Caffe, A. R., and De Vries, G. J. (1985). Brain Res. 325, 391–394.PubMedCrossRefGoogle Scholar
  44. 44.
    Wood, C. E., Saoud, C. J., Stoner, T. A., and Keller-Wood, M. (2001). Reg. Peptides 98, 63–68.CrossRefGoogle Scholar
  45. 45.
    Kailajarvi, M., Ahokoski, O., Virtanen, A., Salminen, E., and Irjala, K. (2000). Anticancer Res. 20, 1323–1327.PubMedGoogle Scholar
  46. 46.
    van der Pompe, G., Antoni, M. H., and Heijnen, C. J. (1996). Psychoneuroendocrinology 21, 361–374.PubMedCrossRefGoogle Scholar
  47. 47.
    Gilardi, K. V., Shideler, S. E., Valverde, C. R., Roberts, J. A., and Lasley, B. L. (1997). Biol. Reprod. 57, 335–340.PubMedCrossRefGoogle Scholar
  48. 48.
    Holsboer, F., Grasser, A., Friess, E., and Wiedemann, K. (1994). Ann. NY Acad. Sci. 746, 345–359; discussion 359–361.PubMedCrossRefGoogle Scholar
  49. 49.
    Newport, D. J., Heim, C., Owens, M. J., et al. (2003). Neuropsychopharmacology 28, 569–576.PubMedCrossRefGoogle Scholar
  50. 50.
    Walker, M. L., Gordon, T. P., and Wilson, M. E. (1982). J. Med. Primatol. 11, 291–302.PubMedGoogle Scholar
  51. 51.
    Blank, M. S., Gordon, T. P., and Wilson, M. E. (1983). Acta Endocrinol. (Copenh.) 102, 190–195.Google Scholar
  52. 52.
    Wilson, M. E., Gordon, T. P., and Collins, D. C. (1986). Endocrinology 118, 293–301.PubMedGoogle Scholar
  53. 53.
    Tess, D. A., Cole, R. O., and Toler, S. M. (1995). J. Chromatogr. B Biomed. Appl. 674, 253–260.PubMedCrossRefGoogle Scholar
  54. 54.
    Rossmanith, W. G., Scherbaum, W. A., and Lauritzen, C. (1991). Neuroendocrinology 54, 211–218.PubMedGoogle Scholar
  55. 55.
    Kwekkeboom, D. J., de Jong, F. H., van Hemert, A. M., Vandenbroucke, J. P., Valkenburg, H. A., and Lamberts, S. W. (1990). J. Clin. Endocrinol. Metab. 70, 944–950.PubMedGoogle Scholar
  56. 56.
    Hall, J. E., Lavoie, H. B., Marsh, E. E., and Martin, K. A. (2000). J. Clin. Endocrinol. Metab. 85, 1794–1800.PubMedCrossRefGoogle Scholar
  57. 57.
    Lambalk, C. B., de Boer, L., Schoute, E., Popp-Snyders, C., and Schoemaker, J. (1997). Clin. Endocrinol. (Oxf.) 46, 439–443.Google Scholar
  58. 58.
    Gill, S., Sharpless, J. L., Rado, K., and Hall, J. E. (2002). J. Clin. Endocrinol. Metab. 87, 2290–2296.PubMedCrossRefGoogle Scholar
  59. 59.
    Chongthammakun, S. and Terasawa, E. (1993). Endocrinology 132, 735–743.PubMedCrossRefGoogle Scholar
  60. 60.
    Lagrange, A. H., Ronnekleiv, O. K., and Kelly, M. J. (1995). Endocrinology 136, 2341–2344.PubMedCrossRefGoogle Scholar
  61. 61.
    Legan, S. J. and Callahan, W. H. (1999). Neuroendocrinology 70, 237–245.PubMedCrossRefGoogle Scholar
  62. 62.
    Wagner, E. J., Ronnekleiv, O. K., Bosch, M. A., and Kelly, M. J. (2001). J. Neurosci. 21, 2085–2093.PubMedGoogle Scholar
  63. 63.
    Chappel, S. C., Resko, J. A., Norman, R. L., and Spies, H. G. (1981). J. Clin. Endocrinol. Metab. 52, 1–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Attardi, B., Hotchkiss, J., and Knobil, E. (1980). Nature 285, 252–254.PubMedCrossRefGoogle Scholar
  65. 65.
    Plant, T. M., Nakai, Y., Belchetz, P., Keogh, E., and Knobil, E. (1978). Endocrinology 102, 1015–1018.PubMedCrossRefGoogle Scholar
  66. 66.
    Couse, J. F. and Korach, K. S. (1999). Endocr. Rev. 20, 358–417.PubMedCrossRefGoogle Scholar
  67. 67.
    Wersinger, S. R., Haisenleder, D. J., Lubahn, D. B., and Rissman, E. F. (1999). Endocrine 11, 137–143.PubMedCrossRefGoogle Scholar
  68. 68.
    Lindzey, J., Wetsel, W. C., Couse, J. F., Stoker, T., Cooper, R., and Korach, K. S. (1998). Endocrinology 139, 4092–4101.PubMedCrossRefGoogle Scholar
  69. 69.
    Shively, C. A., Williams, J. K., Laber-Laird, K., and Anton, R. F. (2002). Psychosom. Med. 64, 699–706.PubMedCrossRefGoogle Scholar
  70. 70.
    Handa, R. J., Burgess, L. H., Kerr, J. E., and O’Keefe, J. A. (1994). Horm. Behav. 28, 464–476.PubMedCrossRefGoogle Scholar
  71. 71.
    McCormick, C. M., Linkroum, W., Sallinen, B. J., and Miller, N. W. (2002). Stress 5, 235–247.PubMedCrossRefGoogle Scholar
  72. 72.
    Koolhaas, J. M., Korte, S. M., De Boer, S. F., et al. (1999). Neurosci. Biobehav. Rev. 23, 925–935.PubMedCrossRefGoogle Scholar
  73. 73.
    Palanza, P., Gioiosa, L., and Parmigiani, S. (2001). Physiol. Behav. 73, 411–420.PubMedCrossRefGoogle Scholar
  74. 74.
    Heim, C., Owens, M. J., Plotsky, P. M., and Nemeroff, C. B. (1997). Psychopharmacol. Bull. 33, 185–192.PubMedGoogle Scholar
  75. 75.
    Scott, L. V. and Dinan, T. G. (2002). J. Affect. Disord. 72, 113–124.PubMedCrossRefGoogle Scholar
  76. 76.
    Patchev, V. K. and Almeida, O. F. (1998). Mol. Neurobiol. 16, 63–77.PubMedGoogle Scholar
  77. 77.
    Shupnik, M. A. (2002). J. Neuroendocrinol. 14, 85–94.PubMedCrossRefGoogle Scholar
  78. 78.
    Givalois, L., Li, S., and Pelletier, G. (1999). J. Endocrinol. 161, 307–316.PubMedCrossRefGoogle Scholar
  79. 79.
    Aguilera, G., Rabadan-Diehl, C., and Nikodemova, M. (2001). Peptides 22, 769–774.PubMedCrossRefGoogle Scholar
  80. 80.
    Torpy, D. J., Grice, J. E., Hockings, G. I., Walters, M. M., Crosbie, G. V., and Jackson, R. V. (1994). J. Clin. Endocrinol. Metab. 79, 140–144.PubMedCrossRefGoogle Scholar
  81. 81.
    Keck, M. E., Wigger, A., Welt, T., et al. (2002). Neuropsychopharmacology 26, 94–105.PubMedCrossRefGoogle Scholar
  82. 82.
    Hrabovszky, E., Kallo, I., Hajszan, T., Shughrue, P. J., Merchenthaler, I., and Liposits, Z. (1998). Endocrinology 139, 2600–2604.PubMedCrossRefGoogle Scholar
  83. 83.
    Alves, S. E., Lopez, V., McEwen, B. S., and Weiland, N. G. (1998). Proc. Natl. Acad. Sci. USA 95, 3281–3286.PubMedCrossRefGoogle Scholar
  84. 84.
    Nomura, M., McKenna, E., Korach, K. S., Pfaff, D. W., and Ogawa, S. (2002). Brain Res. Mol. Brain Res 109, 84–94.PubMedCrossRefGoogle Scholar
  85. 85.
    Thomas, A., Kim, N. B., and Amico, J. A. (1996). Brain Res. 738, 48–52.PubMedCrossRefGoogle Scholar
  86. 86.
    Hashimoto, K., Ohno, N., Aoki, Y., Kageyama, J., Takahara, J., and Ofuji, T. (1981). Acta Med. Okayama 35, 37–43.PubMedGoogle Scholar
  87. 87.
    Shughrue, P. J., Komm, B., and Merchenthaler, I. (1996). Steroids 61, 678–681.PubMedCrossRefGoogle Scholar
  88. 88.
    Shughrue, P. J., Scrimo, P. J., and Merchenthaler, I. (1998). Endocrinology 139, 5267–5270.PubMedCrossRefGoogle Scholar
  89. 89.
    Scott, L. V. and Dinan, T. G. (1998). Life Sci. 62, 1985–1998.PubMedCrossRefGoogle Scholar
  90. 90.
    Dobson, H., Ghuman, S., Prabhakar, S., and Smith, R. (2003). Reproduction 125, 151–163.PubMedCrossRefGoogle Scholar
  91. 91.
    Pacak, K. and Palkovits, M. (2001). Endocr. Rev. 22, 502–548.PubMedCrossRefGoogle Scholar
  92. 92.
    Herman, J. P., Tasker, J. G., Ziegler, D. R., and Cullinan, W. E. (2002). Pharmacol. Biochem. Behav. 71, 457–468.PubMedCrossRefGoogle Scholar
  93. 93.
    Koob, G. F. (1999). Biol. Psychiatry 46, 1167–1180.PubMedCrossRefGoogle Scholar
  94. 94.
    Patisaul, H. B., Aultman, E. A., Bielsky, I. R., Young, L. J., and Wilson, M. E. (2003). Brain Res. 987, 185–193.CrossRefGoogle Scholar
  95. 95.
    Patisaul, H. B., Melby, M., Whitten, P. L., and Young, L. J. (2002). Endocrinology 143, 2189–2197.PubMedCrossRefGoogle Scholar
  96. 96.
    Ni, X., Nicholson, R. C., King, B. R., Chan, E. C., Read, M. A., and Smith, R. (2002). J. Clin. Endocrinol. Metab. 87, 3774–3778.PubMedCrossRefGoogle Scholar
  97. 97.
    Paech, K., Webb, P., Kuiper, G. G., et al. (1997). Science 277, 1508–1510.PubMedCrossRefGoogle Scholar
  98. 98.
    Shang, Y. and Brown, M. (2002). Science 295, 2465–2468.PubMedCrossRefGoogle Scholar
  99. 99.
    Shapiro, R. A., Xu, C., and Dorsa, D. M. (2000). Endocrinology 141, 4056–4064.PubMedCrossRefGoogle Scholar
  100. 100.
    Luecken, L. J. and Compas, B. E. (2002). Ann. Behav. Med. 24, 336–344.PubMedCrossRefGoogle Scholar
  101. 101.
    Sephton, S. E., Sapolsky, R. M., Kraemer, H. C., and Spiegel, D. (2000). J. Natl. Cancer Inst. 92, 994–1000.PubMedCrossRefGoogle Scholar
  102. 102.
    Gold, S. M., Zakowski, S. G., Valdimarsdottir, H. B., and Bovbjerg, D. H. (2003). Psychoneuroendocrinology 28, 584–593.PubMedCrossRefGoogle Scholar
  103. 103.
    McEwen, B. S. (1998). Ann. NY Acad. Sci. 840, 33–44.PubMedCrossRefGoogle Scholar
  104. 104.
    McEwen, B. S. (2000). Brain Res. 886, 172–189.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • M. E. Wilson
    • 1
  • D. Mook
    • 2
    • 3
  • F. Graves
    • 1
    • 4
  • J. Felger
    • 5
  • I. F. Bielsky
    • 5
  • K. Wallen
    • 1
    • 4
  1. 1.Division of Psychobiology, Yerkes National Primate Research CenterEmory UniversityAtlanta
  2. 2.Division of Animal ResourcesEmory UniversityAtlanta
  3. 3.Department of Pathology and Laboratory MedicineEmory UniversityAtlanta
  4. 4.Department of PsychologyEmory UniversityAtlanta
  5. 5.Center for Behavioral NeurosciencesEmory UniversityAtlanta

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