Journal of Endocrinological Investigation

, Volume 15, Issue 6, pp 443–452 | Cite as

The silent corticotropinoma: is clinical diagnosis possible?

  • B. Ambrosi
  • P. Colombo
  • D. Bochicchio
  • M. Bassetti
  • B. Masini
  • G. Faglia


Up to now, the diagnosis of silent corticotropin cell pituitary adenomas has been made only on histopathological basis. In this paper we describe 6 women affected with pituitary adenomas, without evident clinical features of hypercortisolism, in whom retrospective data suggested the possibility of clinically diagnosing silent corticotropinomas in vivo. In all patients basal ACTH and Cortisol levels were normal, and the low-dose dexamethasone test constantly suppressed serum Cortisol and urinary 17-hydroxycorti-costeroid levels. The CRH and/or lysine-vasopressin tests, performed in five patients, always induced exaggerated ACTH/cortisol rises. In three cases the response to the opiate agonist loperamide was assessed and no inhibition of ACTH/cortisol levels was found. All patients underwent pituitary surgery. In five cases evidence of corticotropinoma was obtained by immunohistochemistry or immunofluorescence studies; moreover, in one adenoma ACTH was secreted into the culture medium, and in another one CRH and arginine-vasopressin induced a marked intracellular [Ca++] rise. Electron microscopy study of the adenoma, removed from three patients, showed the presence of adenomatous corticotropin cells. Finally, in another woman no hormonal abnormalities were initially observed and she was operated for a “nonfunctioning” pituitary adenoma, but four years later an overt Cushing’s disease appeared, suggesting that a silent corticotropinoma subsequently became functional, although the formation of a different adenoma cannot be excluded. In conclusion, the occurrence of ACTH/cortisol hyperresponsiveness to CRH and/or lysine-vasopressin and the lack of suppression of ACTH/cortisol secretion to opioid agonists in patients with apparently “nonfunctioning” pituitary tumors might allow the in vivo recognition of silent corticotropinomas.


Pituitary adenoma Cushing’s disease ACTH immunohisto-chemistry loperamide opioids dexamethasone corticotropinoma 


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  1. 1.
    Mashiter K., Adams E., van Noorden S. Secretion of LH, FSH and PRL shown by cell culture and immunocytochemistry of human functionless pituitary adenomas. Clin. Endocrinol. (Oxf.) 15: 103, 1981.CrossRefGoogle Scholar
  2. 2.
    Landolt A.M., Heitz P.U. Alpha-subunit-producing pituitary adenomas: immunocytochemical and ultrastructural studies. Virchows Arch. (Pathol. Amat.) 409: 417, 1986.CrossRefGoogle Scholar
  3. 3.
    Asa S.L., Gerrie B.M., Singer W., Horvath E., Kovacs K., Smyth H.S. Gonadotropin secretion in vitro by human pituitary null cell adenomas and oncocytomas. J. Clin. Endocrinol. Metab. 62: 1011, 1986.PubMedCrossRefGoogle Scholar
  4. 4.
    Jameson J.L., Klibanski A., Black P.M., Zervas N.T., Lindell C.M., Hsu D.W., Ridgway E.C., Habener J.F. Glycoprotein hormone genes are expressed in clin ically non-functioning pituitary adenomas. J. Clin. Invest. 80: 1472, 1987.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Kwekkeboom D.J., Leunisse M., van der Zwan L., de Jong F.H., Lamberts S.W.J. Non-functioning pituitary adenomas in vivo and in vitro. In: Landolt A.M., Heitz P.U., Zapf J., Girard J., del Pozo E. (Eds.), Advances in pituitary adenoma research. Pergamon Press, Oxford, 1988, vol. 69, p. 417.Google Scholar
  6. 6.
    Kwekkeboom D.J., de Jong F.H., Lamberts S.W.J. Gonadotropin release by clinically nonfunctioning and gonadotroph pituitary adenomas in vivo and in vitro: relation to sex and effects of thyrotropin-releasing hormone, gonadotropin-releasing hormone and bromocriptine. J. Clin. Endocrinol. Metab. 68: 1128, 1989.PubMedCrossRefGoogle Scholar
  7. 7.
    Yamada S., Asa S.L., Kovacs K., Muller P., Smyth H.S. Analysis of hormone secretion by clinically nonfunctioning human pituitary adenomas using the reverse hemolytic plaque assay. J. Clin. Endocrinol. Metab. 68: 73, 1989.PubMedCrossRefGoogle Scholar
  8. 8.
    Oppenheim D.S., Kana A.R., Sangha J.S., Klibanski A. Prevalence of α-subunit hypersecretion in patients with pituitary tumors: clinically nonfunctioning and somatotroph adenomas. J. Clin. Endocrinol. Metab. 70: 859, 1990.PubMedCrossRefGoogle Scholar
  9. 9.
    White M.C., Daniels M., Newland P., Thompson C.J., Cook D., Dewar J., Perry R., Jewitt R., Mathias D., Murdoch A.P., Kendall-Taylor P. LH and FSH secretion and responses to GnRH and TRH in patients with clinically functionless pituitary adenomas. Clin. Endocrinol. (Oxf.) 32: 681, 1990.CrossRefGoogle Scholar
  10. 10.
    Daneshdoost L., Gennarelli T.A., Bashey H.M., Savino P.J., Sergott R.C., Bosley T.M., Snyder P.J. Recognition of gonadotroph adenomas in women. N. Engl. J. Med. 324: 589, 1991.PubMedCrossRefGoogle Scholar
  11. 11.
    Kovacs K., Horvath E., Bayley T.A., Hassaram S.T., Ezrin C. Silent corticotropin cell adenoma with lysosomal accumulation and crinophagy: a distinct clinicopathologic entity. Am. J. Med. 64: 492, 1978.PubMedCrossRefGoogle Scholar
  12. 12.
    Horvath E., Kovacs K., Killinger D.W., Smyth H.S., Platts M.E., Singer W. Silent corticotropic adenomas of the human pituitary gland; a histologic, immunocytologic and ultrastructural study. Am. J. Pathol. 98: 617, 1980.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Horvath E., Kovacs K., Smyth H.S., Killinger D.W., Scheithauer B.W., Randall R., Laws E.R. Jr., Singer W. A novel type of pituitary adenoma: morphological features and clinical correlations. J. Clin. Endocrinol. Metab. 66: 1111, 1988.PubMedCrossRefGoogle Scholar
  14. 14.
    Ambrosi B., Bochicchio D., Ferrario R., Colombo P., Faglia G. Effects of the opiate agonist loperamide on pituitary adrenal-function in patients with suspected hypercortisolism. J. Endocrinol. Invest. 12: 31, 1989.PubMedGoogle Scholar
  15. 15.
    Steinberger L.A., Hardy P.H. Jr., Cuculis J.J., Meyer H.J. The unlabelled antibody-enzyme method of immunohistochemistry. Preparation and properties of soluble antigen-antibody complex (horseradish peroxidase-antihorseradish peroxidase) and its use in the identification of spirochetes. J. Histochem. Cytochem. 18: 315, 1970.CrossRefGoogle Scholar
  16. 16.
    Bassetti M., Spada A., Arosio M., Vallar L., Brina M., Giannattasio G. Morphological studies on mixed growth hormone (GH)- and prolactin (PRL)-secreting human pituitary adenomas. Coexistence of GH and PRL in the same secretory granule. J. Clin. Endocrinol. Metab. 62: 1093, 1986.PubMedCrossRefGoogle Scholar
  17. 17.
    Spada A., Sartorio A., Bassetti M., Pezzo G., Giannattasio G. In vitro effect of dopamine on growth hormone (GH) release from human GH-secreting pituitary adenomas. J. Clin. Endocrinol. Metab. 55: 734, 1982.PubMedCrossRefGoogle Scholar
  18. 18.
    Grynkiewicz G., Poenie M., Tsien R.Y. A new generation of Ca++ indicators with greatly improved fluorescence properties. J. Biol. Chem. 260: 3440, 1985.PubMedGoogle Scholar
  19. 19.
    Ross E.J., Marshall-Jones P., Freedman M. Cushing’s syndrome: diagnostic criteria. Q.J. Med. 35: 149, 1966.PubMedGoogle Scholar
  20. 20.
    Trainer P.J., Grossman A. The diagnosis and differential diagnosis of Cushing’s syndrome. Clin. Endocrinol. (Oxf.) 34: 317, 1991.CrossRefGoogle Scholar
  21. 21.
    Tourniaire J., Chalendar D., Treluyer C., Trouillas J. Les adénomes hypophysaires dits silencieux. Rev. Fr. Endocrinol. Clin. 31: 301, 1990.Google Scholar
  22. 22.
    Désir D., L’Hermite M., Goldstein J., Franckson J.R.M., Copinschi G. Normal inhibition of Cortisol secretion by dexamethasone in the precocious stage of Cushing’s disease due to pituitary microadenoma. Horm. Res. 13: 338, 1980.Google Scholar
  23. 23.
    Aron D.C., Tyrrell J.B., Fitzgerald P.A., Findling J.W., Forsham P.H. Cushing’s syndrome: Problems in diagnosis. Medicine (Baltimore) 60: 25, 1981.CrossRefGoogle Scholar
  24. 24.
    Vagnucci A.H., Evans E. Cushing’s disease with intermittent hypercortisolism. Am. J. Med. 80: 83, 1986.PubMedCrossRefGoogle Scholar
  25. 25.
    Allolio B., Winkelmann W., Kaulen D., Reincke M., Jaursch-Hanke C., Schrell U., Fahlbusch R. A reversible defect in the opioidergic control of ACTH release in Cushing’s disease. In: Landolt A.M., Heitz P.U., Zapf J., Girard J., Del Pozo E. (Eds.), Advances in pituitary adenoma research. Pergamon Press, Oxford, 1988, vol. 69, p. 349.Google Scholar
  26. 26.
    Faglia G., Ambrosi B., Beck-Peccoz P., Travaglini P. Hypothalamic-pituitary-adrenal function in patients with pituitary tumors. Acta Endocrinol. (Copenh.) 73: 223, 1973.Google Scholar
  27. 27.
    Schulte H.M., Chrousos G.P., Avgerinos P., Oldfield E.H., Gold P.W., Cutler Jr G.B., Loriaux D.L. The corticotropin-releasing hormone stimulation test: a possible aid in the evaluation of patients with adrenal insufficiency. J. Clin. Endocrinol. Metab. 58: 1064, 1984.PubMedCrossRefGoogle Scholar
  28. 28.
    Colovsky R., Wajchenberg B.L., Noguiera O. Hyperresponsiveness to lysine-vasopressin in Cushing’s disease. Acta Endocrinol. (Copenh.) 75: 125, 1974.Google Scholar
  29. 29.
    Kaye T.B., Crapo L. The Cushing syndrome: an update on diagnostic tests. Ann. Intern. Med. 112: 434, 1990.PubMedCrossRefGoogle Scholar
  30. 30.
    Reincke M., Allolio B., Saeger W., Kaulen D., Winkelmann W. A pituitary adenoma secreting high molecular weight adrenocorticotropin without evidence of Cushing’s disease. J. Clin. Endocrinol. Metab. 65: 1296, 1987.PubMedCrossRefGoogle Scholar
  31. 31.
    Spada A., Reza-Elahi F., Lania A., Bassetti M., Atti E. Inhibition of basal and corticotropin-releasing hormone-stimulated adenylate cyclase activity and cytosolic Ca2+ levels by somatostatin in human corticotropin-secreting pituitary adenomas. J. Clin. Endocrinol. Metab. 70: 1262, 1990.PubMedCrossRefGoogle Scholar
  32. 32.
    Gogel E.L., Salber P.R., Tyrrell J.B., Rosenblum M.L., Findling J.W. Cushing’s disease in a patient with a “non-functioning” pituitary tumor. Spontaneous development and remission. Arch. Intern. Med. 143: 1040, 1983.PubMedCrossRefGoogle Scholar
  33. 33.
    Vaughan N.J.A., Laroche C.M., Goodman I., Davies M.J., Jenkins J.S. Pituitary Cushing’s disease arising from a previously non-functional corticotrophic chromophobe adenoma. Clin. Endocrinol. (Oxf.) 22: 147, 1985.CrossRefGoogle Scholar
  34. 34.
    Cooper M.E., Murray R.M.L., Kalnins R., Woodward J., Jerums G. The development of Cushing’s syndrome from a previously silent pituitary tumor. Aust. N.Z.J. Med. 17: 249, 1987.PubMedCrossRefGoogle Scholar
  35. 35.
    Fuller P.J., Lim A.T.W., Barlow J.W., White E.L., Khalid B.A.K., Copolov D.L., Lolait S., Funder J.W., Stockigt J.R. A pituitary tumor producing high molecular weight adrenocorticotropin-related peptides: Clinical and cell culture studies. J. Clin. Endocrinol. Metab. 58: 134, 1984.PubMedCrossRefGoogle Scholar
  36. 36.
    Chabre O., Martinie M., Vivier J., Eimin-Richard E., Bertagna X., Bachelot I. A clinically silent corticotrophic pituitary adenoma (CSCPA) secreting a biologically inactive but immunoreactive assayable ACTH. J. Endocrinol. Invest. (Suppl. 1) 14: 87, 1991.Google Scholar
  37. 37.
    Nagaya T., Seo H., Kuwayama A., Sakurai T., Tsukamoto N., Nakane T., Sugita K., Matsui N. Pro-opiomelanocortin gene expression in silent corticotroph-cell adenoma and Cushing’s disease. J. Neurosurg. 72: 262, 1990.PubMedCrossRefGoogle Scholar
  38. 38.
    Lloyd R.V., Fields K., Jin L., Horvath E., Kovacs K. Analysis of endocrine active and clinically silent corticotropic adenomas by in situ hybridization. Am. J. Pathol. 137: 479, 1990.PubMedCentralPubMedGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 1992

Authors and Affiliations

  • B. Ambrosi
    • 1
  • P. Colombo
    • 1
  • D. Bochicchio
    • 1
  • M. Bassetti
    • 2
  • B. Masini
    • 3
  • G. Faglia
    • 1
  1. 1.Istituto di Scienze EndocrineMilanoItaly
  2. 2.CNR, Centro di Citofarmacologia, Dipartimento di FarmacologiaUniversità di MilanoMilanoItaly
  3. 3.lstituto di Anatonomia PatologicaUniversità di MilanoMilanoItaly

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