Abstract
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.
Similar content being viewed by others
References
Cosman, F. and Lindsay, R. (1999). Endocrine Rev. 20, 418–434.
Dardes, R. C. and Jordan, V. C. (2000). Br. Med. Bull. 56, 773–786.
Knobil, E. (1988). Hum. Reprod. 3, 469–472.
Overlie, I., Moen, M. H., Morkrid, L., Skjaeraasen, J. S., and Holte, A. (1999). Acta Obstet. Gynecol. Scand. 78, 642–647.
Urshiroyama, T. and Sugimoto, O. (1995). Horm. Res. 44, 64–68.
Longcope, C. (2001). J. Soc. Gynecol. Investig. 8, S67-S68.
Sluijmer, A. V., Heineman, M. J., De Jong, F. H., and Evers, J. L. (1995). J. Clin. Endocrinol. Metab. 80, 2163–2167.
Jordan, V. C., Fritz, N. F., and Tormey, D. C. (1987). Cancer Res. 47, 624–630.
Ravdin, P. M., Fritz, N. F., Tormey, D. C., and Jordan, V. C. (1988). Cancer Res. 48, 1026–1029.
Welt, C. K., Pagan, Y. L., Smith, P. C., Rado, K. B., and Hall, J. E. (2003). J. Clin. Endocrinol. Metab. 88, 1766–1771.
Boostanfar, R., Jain, J. K., Mishell, D. R. Jr. and Paulson, R. J. (2001). Fert. Steril. 75, 1024–1026.
Suginami, H., Kitagawa, H., Nakahashi, N., Yano, K., and Matsubara, K. (1993). Fertil. Steril. 59, 976–979.
Robertson, J. F. and Blamey, R. W. (2003). Eur. J. Cancer 39, 861–869.
Goss, P. E., Clark, R. M., Ambus, U., et al. (1995). Clin. Cancer Res. 1, 287–294.
Donath, J. and Nishino, Y. (1998). J. Steroid Biochem. Mol. Biol. 66, 247–254.
Sanchez-Criado, J. E., Guelmes, P., Bellido, C., et al. (2002). Neuroendocrinology 76, 203–213.
Gao, X., Petroff, B. K., Oluola, O., Georg, G., Terranova, P. F., and Rozman, K. K. (2002). Toxicol. Appl. Pharmacol. 183, 179–188.
Paterson, A. G., Turkes, A., Groom, G. V., and Webster, D. J. (1983). Eur. J. Cancer Clin. Oncol. 19, 919–922.
Luciani, L., Oriana, S., Spatti, G., et al. (1984). Tumori 70, 189–192.
Alexieva-Figusch, J., Blankenstein, M. A., de Jong, F. H., and Lamberts, S. W. (1984). Eur. J. Cancer Clin. Oncol. 20, 135–140.
Gasparini, G., Canobbio, L., Galligioni, E., et al. (1987). Eur. J. Cancer Clin. Oncol. 23, 1451–1459.
Miodrag, A., Ekelund, P., Burton, R., and Castleden, C. M. (1991). Age Ageing 20, 52–54.
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.
Kostoglou-Athanassiou, I., Ntalles, K., Gogas, J., et al. (1997). Horm. Res. 47, 116–120.
Kavak, Z. N., Binoz, S., Ceyhan, N., and Pekin, S. (2000). Acta Obstet. Gynecol. Scand. 79, 604–607.
Harper-Wynne, C. L., Sacks, N. P., Shenton, K., et al. (2002). J. Clin. Oncol. 20, 1026–1035.
De Marinis, L., Mancini, A., Izzi, D., et al. (2000). Clin. Endocrinol. 52, 681–685.
Patchev, V. K. and Almeida, O. F. (1996). J. Neurosci. 16, 7077–7084.
Dayas, C. V., Xu, Y., Buller, K. M., and Day, T. A. (2000). J. Neuroendocrinol. 12, 784–794.
Roy, B. N., Reid, R. L., and Van Vugt, D. A. (1999). Endocrinology 140, 2191–2198.
Vamvakopoulos, N. C. and Chrousos, G. P. (1993). J. Clin. Invest. 92, 1896–1902.
Kerdelhue, B., Jones, G. S., Gordon, K., et al. (1995). J. Neurosci. Res. 42, 228–235.
Carey, M. P., Deterd, C. H., de Koning, J., Helmerhorst, F., and de Kloet, E. R. (1995). J. Endocrinol. 144, 311–321.
Smith, C. J. and Norman, R. L. (1987). Endocrinology 121, 2192–2198.
Giussani, D. A., Farber, D. M., Jenkins, S. L., et al. (2000). Biol. Reprod. 62, 1445–1451.
Gudmundsson, A., Goodman, B., Lent, S., et al. (1999). Exp. Gerontol. 34, 809–818.
Fonseca, E., Basurto, L., Velazquez, S., and Zarate, A. (2001). Maturitas 39, 57–62.
De Leo, V., la Marca, A., Talluri, B., D’Antona, D., and Morgante, G. (1998). Eur. J. Endocrinol. 138, 430–435.
Grino, M., Hery, M., Paulmyer-Lacroix, O., and Anglade, G. (1995). Endocrine 3, 395–398.
Figueiredo, H. F., Dolgas, C. M., and Herman, J. P. (2002). Endocrinology 143, 2534–2540.
Young, E. A., Altemus, M., Parkison, V., and Shastry, S. (2001). Neuropsychopharmacology 25, 881–891.
de Vries, G. J. and Miller, M. A. (1998). Prog. Brain Res. 119, 3–20.
van Leeuwen, F. W., Caffe, A. R., and De Vries, G. J. (1985). Brain Res. 325, 391–394.
Wood, C. E., Saoud, C. J., Stoner, T. A., and Keller-Wood, M. (2001). Reg. Peptides 98, 63–68.
Kailajarvi, M., Ahokoski, O., Virtanen, A., Salminen, E., and Irjala, K. (2000). Anticancer Res. 20, 1323–1327.
van der Pompe, G., Antoni, M. H., and Heijnen, C. J. (1996). Psychoneuroendocrinology 21, 361–374.
Gilardi, K. V., Shideler, S. E., Valverde, C. R., Roberts, J. A., and Lasley, B. L. (1997). Biol. Reprod. 57, 335–340.
Holsboer, F., Grasser, A., Friess, E., and Wiedemann, K. (1994). Ann. NY Acad. Sci. 746, 345–359; discussion 359–361.
Newport, D. J., Heim, C., Owens, M. J., et al. (2003). Neuropsychopharmacology 28, 569–576.
Walker, M. L., Gordon, T. P., and Wilson, M. E. (1982). J. Med. Primatol. 11, 291–302.
Blank, M. S., Gordon, T. P., and Wilson, M. E. (1983). Acta Endocrinol. (Copenh.) 102, 190–195.
Wilson, M. E., Gordon, T. P., and Collins, D. C. (1986). Endocrinology 118, 293–301.
Tess, D. A., Cole, R. O., and Toler, S. M. (1995). J. Chromatogr. B Biomed. Appl. 674, 253–260.
Rossmanith, W. G., Scherbaum, W. A., and Lauritzen, C. (1991). Neuroendocrinology 54, 211–218.
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.
Hall, J. E., Lavoie, H. B., Marsh, E. E., and Martin, K. A. (2000). J. Clin. Endocrinol. Metab. 85, 1794–1800.
Lambalk, C. B., de Boer, L., Schoute, E., Popp-Snyders, C., and Schoemaker, J. (1997). Clin. Endocrinol. (Oxf.) 46, 439–443.
Gill, S., Sharpless, J. L., Rado, K., and Hall, J. E. (2002). J. Clin. Endocrinol. Metab. 87, 2290–2296.
Chongthammakun, S. and Terasawa, E. (1993). Endocrinology 132, 735–743.
Lagrange, A. H., Ronnekleiv, O. K., and Kelly, M. J. (1995). Endocrinology 136, 2341–2344.
Legan, S. J. and Callahan, W. H. (1999). Neuroendocrinology 70, 237–245.
Wagner, E. J., Ronnekleiv, O. K., Bosch, M. A., and Kelly, M. J. (2001). J. Neurosci. 21, 2085–2093.
Chappel, S. C., Resko, J. A., Norman, R. L., and Spies, H. G. (1981). J. Clin. Endocrinol. Metab. 52, 1–8.
Attardi, B., Hotchkiss, J., and Knobil, E. (1980). Nature 285, 252–254.
Plant, T. M., Nakai, Y., Belchetz, P., Keogh, E., and Knobil, E. (1978). Endocrinology 102, 1015–1018.
Couse, J. F. and Korach, K. S. (1999). Endocr. Rev. 20, 358–417.
Wersinger, S. R., Haisenleder, D. J., Lubahn, D. B., and Rissman, E. F. (1999). Endocrine 11, 137–143.
Lindzey, J., Wetsel, W. C., Couse, J. F., Stoker, T., Cooper, R., and Korach, K. S. (1998). Endocrinology 139, 4092–4101.
Shively, C. A., Williams, J. K., Laber-Laird, K., and Anton, R. F. (2002). Psychosom. Med. 64, 699–706.
Handa, R. J., Burgess, L. H., Kerr, J. E., and O’Keefe, J. A. (1994). Horm. Behav. 28, 464–476.
McCormick, C. M., Linkroum, W., Sallinen, B. J., and Miller, N. W. (2002). Stress 5, 235–247.
Koolhaas, J. M., Korte, S. M., De Boer, S. F., et al. (1999). Neurosci. Biobehav. Rev. 23, 925–935.
Palanza, P., Gioiosa, L., and Parmigiani, S. (2001). Physiol. Behav. 73, 411–420.
Heim, C., Owens, M. J., Plotsky, P. M., and Nemeroff, C. B. (1997). Psychopharmacol. Bull. 33, 185–192.
Scott, L. V. and Dinan, T. G. (2002). J. Affect. Disord. 72, 113–124.
Patchev, V. K. and Almeida, O. F. (1998). Mol. Neurobiol. 16, 63–77.
Shupnik, M. A. (2002). J. Neuroendocrinol. 14, 85–94.
Givalois, L., Li, S., and Pelletier, G. (1999). J. Endocrinol. 161, 307–316.
Aguilera, G., Rabadan-Diehl, C., and Nikodemova, M. (2001). Peptides 22, 769–774.
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.
Keck, M. E., Wigger, A., Welt, T., et al. (2002). Neuropsychopharmacology 26, 94–105.
Hrabovszky, E., Kallo, I., Hajszan, T., Shughrue, P. J., Merchenthaler, I., and Liposits, Z. (1998). Endocrinology 139, 2600–2604.
Alves, S. E., Lopez, V., McEwen, B. S., and Weiland, N. G. (1998). Proc. Natl. Acad. Sci. USA 95, 3281–3286.
Nomura, M., McKenna, E., Korach, K. S., Pfaff, D. W., and Ogawa, S. (2002). Brain Res. Mol. Brain Res 109, 84–94.
Thomas, A., Kim, N. B., and Amico, J. A. (1996). Brain Res. 738, 48–52.
Hashimoto, K., Ohno, N., Aoki, Y., Kageyama, J., Takahara, J., and Ofuji, T. (1981). Acta Med. Okayama 35, 37–43.
Shughrue, P. J., Komm, B., and Merchenthaler, I. (1996). Steroids 61, 678–681.
Shughrue, P. J., Scrimo, P. J., and Merchenthaler, I. (1998). Endocrinology 139, 5267–5270.
Scott, L. V. and Dinan, T. G. (1998). Life Sci. 62, 1985–1998.
Dobson, H., Ghuman, S., Prabhakar, S., and Smith, R. (2003). Reproduction 125, 151–163.
Pacak, K. and Palkovits, M. (2001). Endocr. Rev. 22, 502–548.
Herman, J. P., Tasker, J. G., Ziegler, D. R., and Cullinan, W. E. (2002). Pharmacol. Biochem. Behav. 71, 457–468.
Koob, G. F. (1999). Biol. Psychiatry 46, 1167–1180.
Patisaul, H. B., Aultman, E. A., Bielsky, I. R., Young, L. J., and Wilson, M. E. (2003). Brain Res. 987, 185–193.
Patisaul, H. B., Melby, M., Whitten, P. L., and Young, L. J. (2002). Endocrinology 143, 2189–2197.
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.
Paech, K., Webb, P., Kuiper, G. G., et al. (1997). Science 277, 1508–1510.
Shang, Y. and Brown, M. (2002). Science 295, 2465–2468.
Shapiro, R. A., Xu, C., and Dorsa, D. M. (2000). Endocrinology 141, 4056–4064.
Luecken, L. J. and Compas, B. E. (2002). Ann. Behav. Med. 24, 336–344.
Sephton, S. E., Sapolsky, R. M., Kraemer, H. C., and Spiegel, D. (2000). J. Natl. Cancer Inst. 92, 994–1000.
Gold, S. M., Zakowski, S. G., Valdimarsdottir, H. B., and Bovbjerg, D. H. (2003). Psychoneuroendocrinology 28, 584–593.
McEwen, B. S. (1998). Ann. NY Acad. Sci. 840, 33–44.
McEwen, B. S. (2000). Brain Res. 886, 172–189.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wilson, M.E., Mook, D., Graves, F. et al. Tamoxifen is an estrogen antagonist on gonadotropin secretion and responsiveness of the hypothalamic-pituitary-adrenal axis in female monkeys. Endocr 22, 305–315 (2003). https://doi.org/10.1385/ENDO:22:3:305
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/ENDO:22:3:305