Skip to main content
SpringerLink
Log in

Failure of long-term therapy with sodium valproate in Cushing’s disease

  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

The aim of the current study was to evaluate the effectiveness of a long-term treatment with sodium valproate in 19 patients with Cushing’s disease. Before therapy beginning, the patients were subjected to acute test with 600 mg sodium valproate. Then, they were subjected to a 3-month therapy with sodium valproate at the dose of 600 mg/day before surgery (presurgical study). The 7 patients not surgically cured were subjected again to a 3-month therapy with sodium valproate at the dose of 600 mg/day after surgery (postsurgical study). Circulating ACTH and cortisol and urinary free cortisol levels were evaluated before and monthly after the beginning of the therapy. A decrease of plasma ACTH and serum cortisol levels greater than 50% of baseline was considered as positive response to acute test whereas the normalization of plasma ACTH, serum cortisol and urinary free cortisol levels and the clinical remission were considered as positive response to the long-term treatment. At acute test, 8 patients were considered responders and 11 patients non-responders. In no patient plasma ACTH, serum cortisol and urinary free cortisol were normalized during the long-term treatment. Urinary free cortisol levels significantly decreased (483.2±33.8 vs 699.4±67.0 ug/24 h), whereas plasma ACTH (302.8±17.7 vs 183.3±25.0 ng/l) and serum cortisol (466.5±23.2 vs 356.7±19.6 µg/l) significantly increased during sodium valproate administration in the 19 patients enrolled in the presurgical study. Plasma ACTH (247.7±22.3 vs 168.6±15.0 ng/l), serum cortisol (387.4±35.8 vs 282.0±16.0 µg/l) and urinary free cortisol (370.9±70.6 vs 261.3±37.8 µg/24 h) levels significantly increased in the 7 patients enrolled in the postsurgical study. No patient had clinical remission of Cushing’s disease. In conclusion, the current study showed that long-term therapy with sodium valproate is not useful in the therapeutic management of Cushing’s disease neither as alternative nor as adjunctive therapy to surgery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ambrosi B., Faglia G., and the Multicenter Pituitary Study Group, Lombardia Region. Epidemiology of pituitary tumors. In: Faglia G., Beck-Peccoz P., Ambrosi B., Travaglini P., Spada A. (Eds.), Pituitary Adenomas. New Trends in Basic and Clinical Research. Excerpa Medica, Amsterdam, 1991, p. 159.

    Google Scholar 

  2. Etxabe J., Vázquez J.A. Morbidity and mortality in Cushing’s disease: an epidemiological approach. Clin. Endocrinol. (Oxf.) 40: 479, 1994.

    Article  CAS  Google Scholar 

  3. Melby J.C. Therapy of Cushing’s disease: a consensus for pituitary microsurgery. Ann. Intern. Med. 109: 445, 1988.

    Article  PubMed  CAS  Google Scholar 

  4. Burch W. A survey of results with transsphenoidal surgery in Cushing’s disease. N. Engl. J. Med. 308: 103, 1983.

    Article  PubMed  CAS  Google Scholar 

  5. Tagliaferri M., Bersetti M.E., Loli P. Transsphenoidal microsurgery for Cushing’s disease. Acta Endocrinol. (Copenh.) 113: 5, 1986.

    CAS  Google Scholar 

  6. Mampalam T.J., Tyrell J.B., Wilson C.B. Transsphenoidal microsurgery for Cushing’s disease. Ann. Intern. Med. 109: 487, 1988.

    Article  PubMed  CAS  Google Scholar 

  7. Bochicchio D., Losa M., Buchfelder M., and the European Cushing’s Disease Survey Study Group. Factors influencing the immediate and late outcome of Cushing’s disease treated by transsphenoidal surgery: a retrospective study by the European Cushing’s Disease Study Group. J. Clin. Endocrinol. Metab. 80: 3114, 1995.

    PubMed  CAS  Google Scholar 

  8. Welbourne R.B. Survival and causes of death after adrenalectomy in Cushing’s disease. Surgery 97: 16, 1985.

    Google Scholar 

  9. Littley M.D., Shalet S.M., Beardwell C.G., Ahmed S.R., Sutton M.L. Long-term follow-up of low-dose external pituitary irradiation for Cushing’s disease. Clin. Endocrinol. (Oxf.) 33: 445, 1990.

    Article  CAS  Google Scholar 

  10. Degerblad M., Rahn T., Bergstrand G., Thoren M. Long-term results of stereotactic radiosurgery to the pituitary gland in Cushing’s disease. Acta Endocrinol. (Copenh.) 112: 310, 1986.

    CAS  Google Scholar 

  11. Miller J.W., Crapo L. The medical treatment of Cushing’s syndrome. Endocr. Rev. 14: 443, 1993.

    Article  PubMed  CAS  Google Scholar 

  12. Maraka G.B., Stark E. Effect of γ-aminobutiric acid (GABA) and GABA antagonist drugs on ACTH release. Neuroendocrinology 16: 178, 1974.

    Article  Google Scholar 

  13. Jones M.T., Hillhouse E.W. Neurotransmitter regulation of corticotropin releasing factor in vitro. Ann. N. Y. Acad. Sci. 297: 536, 1977.

    Article  PubMed  CAS  Google Scholar 

  14. Kritzler R.K., Vining E.P.G., Plotnick L.P. Sodium valproate and corticotropin suppression in the child treated for seizures. J. Pediatr. 102: 142, 1983.

    Article  PubMed  CAS  Google Scholar 

  15. Cavagnini F., Invitti C., Polli E.E. Sodium valproate in Cushing’s disease (letter). Lancet 2: 162, 1984.

    Article  PubMed  CAS  Google Scholar 

  16. Koppeschaar H.P.F., Croughs R.J.M., Van’t Verlaat J.W., Hendricks M.J., Arts C.J.M., Thijssen J.H.H., Schwarz F. Successful treatment with sodium valproate of a patient with Cushing’s disease and gross enlargement of the pituitary. Acta Endocrinol. (Copenh.) 107: 471, 1984.

    CAS  Google Scholar 

  17. Allolio B., Winkelmann W., Kaulen D., Hipp F.X., Mies R. Valproate in Cushing’s syndrome (letter). Lancet 1: 171, 1982.

    Article  PubMed  CAS  Google Scholar 

  18. Ambrosi B., Bochicchio D., Riva E., Faglia G. Effects of sodium valproate administration on plasma ACTH levels in patients with ACTH hypersecretion. J. Endocrinol. Invest. 6: 305, 1983.

    Article  PubMed  CAS  Google Scholar 

  19. Loli P., Berselli M.E., Frascalani F., Muratori F., Tagliaferri M. Lack of ACTH lowering effect of sodium valproate in patients with ACTH hypersecretion. J. Endocrinol. Invest. 7: 93, 1984.

    Article  PubMed  CAS  Google Scholar 

  20. Colao A., Merola B., Tripodi F.S., Di Samo A., Esposito V., Marzullo P., La Tessa G., Spaziante R., Lombardi G. Simultaneous and bilateral inferior petrosal sinus sampling for the diagnosis of Cushing’s disease: comparison of multihormonal assay, baseline multiple sampling and ACTH-releasing hormone test. Horm. Res. 40: 209, 1993.

    Article  PubMed  CAS  Google Scholar 

  21. Koppeschaar H.P.F., Crough R.J.M., Thijssen J.H.H., Schwarz F. Sodium valproate and heterogeneity of pituitary dependent Cushing’s syndrome (letter). Lancet 1: 1253, 1982.

    Article  PubMed  CAS  Google Scholar 

  22. Koppeschaar H.P.F., Croughs R.J.M., Thijssen J.H.H., Schwarz F. Sodium valproate and cyproheptadine may independently induce a remission in the same patients with Cushing’s disease. Acta Endocrinol. (Copenh.) 104: 160, 1983.

    CAS  Google Scholar 

  23. Glaser B., Kahana L., Elias V., Sheinfeld M. Sodium valproate and metyrapone for pituitary-dependent Cushing’s disease (letter). Lancet 2: 640, 1984.

    Article  PubMed  CAS  Google Scholar 

  24. Koppeschaar H.P.F., Croughs R.J.M., Thijssen J.H.H., Schwarz F. Response to neurotransmitters modulating drugs in patients with Cushing’s disease. Clin. Endocrinol. (Oxf.) 25: 661, 1986.

    Article  CAS  Google Scholar 

  25. Beckers A., Stevenert A., Pirens G., Flandroy P., Sulon J., Hennen G. Cyclical Cushing’s disease and its successful control under sodium valproate. J. Endocrinol. Invest. 13: 923, 1990.

    Article  PubMed  CAS  Google Scholar 

  26. Kennedy A.L., Montgomery D.A.D. Bromocriptine for Cushing’s disease, (letter) Lancet 1: 1253, 1977.

    Google Scholar 

  27. Boscaro M., Benato M., Mantero F. Effect of bromocriptine in pituitary dependent Cushing’ s syndrome. Clin. Endocrinol. (Oxf.) 19: 485, 1983.

    Article  CAS  Google Scholar 

  28. Merola B., Colao A., Rossi R., Spaziante R., Manco A., Lombardi G. Bilateral and simultaneous inferior petrosal sinus sampling in the early diagnosis of an ACTH-producing pituitary macroadenoma and its detection by magnetic resonance one year later. Horm. Res. 37: 64, 1992.

    Article  PubMed  CAS  Google Scholar 

  29. Angeli A., Fraira R. Ketoconazole therapy in Cushing’s disease (letter). Lancet 1: 821, 1985.

    Article  PubMed  CAS  Google Scholar 

  30. Sonino N., Boscaro M., Merola G., Mantero F. Prolonged treatment of Cushing’s disease by ketoconazole. J. Clin. Endocrinol. Metab. 61: 718, 1985.

    Article  PubMed  CAS  Google Scholar 

  31. Terzolo M., Panarelli M., Piovesan A., Torta M., Paccotti P., Angeli A. Ketoconazole treatment in Cushing’s disease. Effect on the circadian profile of plasma ACTH and cortisol. J. Endocrinol. Invest. 11: 717, 1988.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular and Clinical Endocrinology and Oncology, “Federico II” University, Via Sergio Pansini 5, 80131, Napoli, Italy

    Annamaria Colao M.D., Ph.D., R. Pivonello, F. S. Tripodi, F. Orio Jr., D. Ferone, G. Cerbone, C. Di Somma, B. Merola & G. Lombardi

Authors
  1. Annamaria Colao M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. Pivonello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. S. Tripodi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F. Orio Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Ferone
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. Cerbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. Di Somma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B. Merola
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G. Lombardi
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Colao, A., Pivonello, R., Tripodi, F.S. et al. Failure of long-term therapy with sodium valproate in Cushing’s disease. J Endocrinol Invest 20, 387–392 (1997). https://doi.org/10.1007/BF03347989

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03347989

Key-words

Search

Navigation