, Volume 3, Issue 5, pp 383–390 | Cite as

Decreased plasma gonadotropin and testosterone levels in arthritic rats: are corticosteroids involved?

  • Catherine Rivier


Infectious and inflammatory diseases are often accompanied by abnormal reproductive functions, and the present working hypothesis is that proteins (called cytokines or interleukins, ILs) released by activated immune cells are at least in part responsible for these neuroendocrine changes. In order to test this hypothesis, we need paradigms of immune pathologies in which concentrations of cytokines are increased, and those of hormones of the hypothalamic-pituitary-gonadal (HPG) axis are blunted. We chose a rodent model of arthritis, adjuvant-induced arthritis (AIA), in which rats show elevated plasma IL-6 and decreased testosterone (T) concentrations. We describe here the first phase of our studies, in which we determined whether gonadotropin release was also altered, whether this change was responsible for the low T levels, and whether elevated corticosterone participated in the decreased activity of the HPG axis.

AIA is induced by the intramuscular injection ofMycobacterium butyricum (MBB) into the tail base of the rat, with swelling of the limbs occurring 11–12 days later. We observed significant decreases in LH and FSH secretion of castrated AIA male rats, suggesting that altered gonadotropin output was independent of the gonads. The absence of significant alterations in GnRH gene expression in the hypothalamus of AIA rats, as well as only modest declines in pituitary responsiveness to GnRH, indicate that these mechanisms are not primarily responsible for the blunted gonadotropin concentrations. Intact AIA rats exhibited a dramatic decline in T levels, but no concimitant rise in LH concentrations. The observation that gonadotropin secretion does not increase despite significantly reduced T levels suggests the presence of an unidentified defect within the GnRH neuronal circuitry that prevents the gonadotrophs to respond to decreased steroid feedback. Testicular responsiveness to hCG was significantly blunted in AIA rats, and this decrease was not reversed by acute blockade of nitric oxide formation or of prostaglandin synthesis. Interestingly, the onset of these hormonal changes preceded the appearance of symptoms (limb swelling), as well as the decrease in body weight that accompanies visible joint enlargement. On the other hand, blunted T secretion coincided with rising levels of ACTH and corticosterone. This suggested that adrenal steroids might be responsible for the decrease in LH and T values, but this hypothesis did not prove valid. Indeed, we observed that adrenalectomized AIA animals implanted with corticosterone pellets retained their low T levels. Furthermore, clamping corticosterone levels was only moderately effective in reversing the inhibitory influence of the arthritic process on LH secretion.

In the absence of significant alterations in GnRH gene expression, it is possible that low Gn levels are secondary to an abnormal pattern in GnRH pulse amplitude and/or frequency. While the decrease in plasma LH concentrations may play a role in the dramatically lowered plasma T values, it is more likely that the inability of the testes to respond to gonadotropin is of significance. While we cannot rule out the participation of perceived stress at the onset of the changes in pituitary and testicular function of AIA rats, we hypothesize that cytokines released by the inflamed tissues, an event that may well precede the appearance of overt swelling, are responsible for the activation of the HPA axis and independently, for the decreased activity of the HPG axis. The AIA model may therefore provide an experimental paradigm in which to test hypotheses related to the cross-talk between the immune system and reproductive parameters.


arthritis corticosterone testosterone neuroimmunology 


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  1. Adams, M.L., Meyer, E.R., Sewing, B.N. & Cicero, T.J. (1994).J. Pharmacol. Exper. Therap.,269, 230–237.Google Scholar
  2. Bambino, T.H. & Hsueh, A.J.W. (1981).Endocrinology,108, 2142–2148.PubMedGoogle Scholar
  3. Ban, E., Haour, F. & Lenstra, R. (1992).Cytokine,4, 48–54.PubMedCrossRefGoogle Scholar
  4. Belhadj, H., De Besi, L., Bardin, C.W. & Thau, R.B. (1989).J. Endocrinol.,122, 451–456.PubMedCrossRefGoogle Scholar
  5. Bruot, B. & Clemens, J. (1989).J. Androl.,10, 419–424.PubMedGoogle Scholar
  6. Bruot, B.C. & Clemens, J.W. (1987).Life Sci.,41, 1559–1565.PubMedCrossRefGoogle Scholar
  7. Calkins, J.H., Guo, H., Sigel, M.M. & Lin, T. (1990).Biochem Biophys Res Commun.,167, 548–553.PubMedCrossRefGoogle Scholar
  8. Ceriani, G., Diaz, J., Murphree, S., Catania, A. & Lipton, J.M. (1994).Neuroimmunomodulation,1, 28–32.PubMedCrossRefGoogle Scholar
  9. Chowdrey, H.S., Larsen, P.J., Harbuz, M.S., Jessop, D.S., Aguilera, G. & Lightman, S.L. (1994). First World Congress on Stress (Washington, DC), p. 44.Google Scholar
  10. Durie, F.H., Fava, R.A. & Noelle, R.J. (1994).Clin. Immunol Immunopathol.,73, 11–18.PubMedCrossRefGoogle Scholar
  11. Fabbri, A., Tinajero, J.C. & DuFau, M.L. (1990).Endocrinology,127, 1541–1543.PubMedGoogle Scholar
  12. Gatti, S. & Bartfai, T. (1993).Brain Res.,624, 291–294.PubMedCrossRefGoogle Scholar
  13. Gordon, D., Eastall, G., Thomson, J. & Sturrock, R. (1988).Br. J. Rheumatol.,27, 440–444.PubMedCrossRefGoogle Scholar
  14. Harbuz, M.S., Rees, R.G., Eckland, D., Jessop, D.S., Brewerton, D. & Lightman, S.L. (1992).Endocrinology,130, 1394–1400.PubMedCrossRefGoogle Scholar
  15. Holt, I., Cooper, R., Denton, J., Meager, A. & Hopkins, S. (1992).Br. J. Rheumatol.,31, 725–733.PubMedCrossRefGoogle Scholar
  16. Jessop, D.S., Lightman, S.L. & Chowdrey, H.S. (1994).J. Neuroimmunol.,49, 197–203.PubMedCrossRefGoogle Scholar
  17. Kalra, S.P. & Kalra, P.S. (1983).Endocrine Reviews,4, 311–351.PubMedCrossRefGoogle Scholar
  18. Kamel, F. & Kubajak, C.L. (1987).Endocrinology,121, 561–568.PubMedGoogle Scholar
  19. Karalis, K., Sano, H., Redwine, J., Listwak, S., Wilder, R.L. & Chrousos, G.P. (1991).Science,254, 421–423.PubMedCrossRefGoogle Scholar
  20. Lin, T., Wang, D., Nagpal, M.L., Calkins, J.H., Chang, W. & Chi, R. (1991).Endocrinology,129, 1305–1311.PubMedGoogle Scholar
  21. Lopez-Calderon, A., Ariznavarreta, C., Gonzales-Quijano, M., Tresguerres, J. & Calderon, M. (1991).J. Ster. Molec. Biol.,40, 473–479.CrossRefGoogle Scholar
  22. Mann, D.R., Free, C., Nelson, C., Scott, C. & Collins, D.C. (1987).Endocrinology,120, 1542–1550.PubMedGoogle Scholar
  23. Martens, H.F., Sheets, P.K., Tenover, J.S., Dugowson, C.E., Bremner, W.J. & Starkebaum, G. (1994).J. Rheumatol.,21, 1427–1431.PubMedGoogle Scholar
  24. Matsukawa, A., Ohkawara, S., Maeda, T., Takagi, K. & Yoshinaga, M. (1993).Clin. Exp. Immunol.,93, 206–211.PubMedGoogle Scholar
  25. Mauduit, C., Hartmann, D.J., Chauvin, M.A., Revol, A., Morera, A.M. & Benahmed, M. (1991).Endocrinology,129, 2933–2940.PubMedGoogle Scholar
  26. Millan, M.J., Millan, M.H., Czionkowski, A., Hollt, V., Pilcher, C.W., Herz, A. & Colpaert, F.C. (1986).J. Neurosci.,6, 899–906.PubMedGoogle Scholar
  27. Neidhart, M. & Flückiger, E.W. (1992).Immunology,77, 449–455.PubMedGoogle Scholar
  28. North, J., Situnayake, R.D., Tikly, M., Cremona, A., Nicholl, J., Kumararatne, D.S. & Nuki, G. (1994).Ann. Rheum Dis.,53, 543–546.PubMedCrossRefGoogle Scholar
  29. Orr, T.E. & Mann, D.R. (1992).Horm & Behav.,26, 350–363.CrossRefGoogle Scholar
  30. Orr, T.E., Taylor, M.F., Bhattacharyya, A.K., Collins, D.C. & Mann, D.R. (1994).J. Androl.,15, 302–308.PubMedGoogle Scholar
  31. Quan, N., Sundar, S.K. & Weiss, J.M. (1994).Neuroimmunol.,49, 125–135.CrossRefGoogle Scholar
  32. Ringstrom, S.J. & Schwartz, N.B. (1984).Endocrinology,114, 880–887.PubMedGoogle Scholar
  33. Rivest, S., Lee, S., Attardi, B. & Rivier, C. (1993).Endocrinology,133, 2424–2430.PubMedCrossRefGoogle Scholar
  34. Rivest, S. & Rivier, C. (1993).Brain Res.,613, 132–142.PubMedCrossRefGoogle Scholar
  35. Rivier, C. (1993).Alcoholism: Clin Exp Res.,17, 854–859.CrossRefGoogle Scholar
  36. Rivier, C. & Rivest, S. (1991).Biol. Reprod.,45, 523–532.PubMedCrossRefGoogle Scholar
  37. Rivier, C. & Rivest, S. (1993).Proc. of Ciba Foundation Symposium No. 172. Chadwick, D.J., Marsh, J. & Ackrill, K. (eds.) John Wiley & Sons. pp. 204–225.Google Scholar
  38. Rivier, C. & Vale, W. (1989).Endocrinology,124, 2105–2109.PubMedGoogle Scholar
  39. Roth, J., Conn, C.A., Kluger, M.J. & Zeisberger, E. (1993).Am. J. Physiol.,265, R653-R658.PubMedGoogle Scholar
  40. Sarlis, N.J., Chowdrey, H.S., Stephanou, A.K. & Lightman, S.L. (1992).Endocrinology 130, 1775–1779.PubMedCrossRefGoogle Scholar
  41. Stefanovic-Racic, M., Stadler, J. & Evans, C.H. (1993).Arthrit. Rheum.,36, 1036–1044.CrossRefGoogle Scholar
  42. Sternberg, E.M. (1992).Ann. Int. Med.,117, 854–866.PubMedGoogle Scholar
  43. Sugita, T., Furukawa, O., Ueno, M., Murakami, T., Takata, I. & Tosa, T. (1993).Int. J. Immunopharmacol.,15, 469–476.PubMedCrossRefGoogle Scholar
  44. Suter, D.E., Schwartz, N.B. & Ringstrom, S.J. (1988).Am. J. Physiol.,254, E595-E600.PubMedGoogle Scholar
  45. Tortorella, C., Malendowicz, L.K., Andreis, P.G., Markowska, A., Neri, G., Mazzocchi, G. & Nussdorfer, G.G. (1993).Biomed. Res.,14, 209–215.Google Scholar
  46. Turnbull, A.V., Dow, R.C., Hopkins, S.J., White, A., Fink, G. & Rothwell, N.J. (1994).Psychoneuroendocrinology,19, 165–178.PubMedCrossRefGoogle Scholar
  47. Vale, W., Vaughan, J., Yamamoto, G., Bruhn, T., Douglas, C., Dalton, D., Rivier, C. & Rivier, J. (1983).Methods in Enzymology: Neuroendocrine Peptides. Conn, P.M. (ed.) Academic Press: New York. pp. 565–577.CrossRefGoogle Scholar
  48. VanDam, A.-M., Brouns, M., Louisse, S. & Berkenbosch, F. (1992).Brain Res.,588, 291–296.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 1995

Authors and Affiliations

  • Catherine Rivier
    • 1
  1. 1.The Clayton Foundation Laboratories for Peptide BiologyThe Salk InstituteLa JollaUSA

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