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Molecular basis of pharmacological therapy in Cushing’s disease

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Abstract

Cushing’s disease (CD) is a severe endocrine condition caused by an adrenocorticotropin (ACTH)-producing pituitary adenoma that chronically stimulates adrenocortical cortisol production and with potentially serious complications if not or inadequately treated. Active CD may produce a fourfold increase in mortality and is associated with significant morbidities. Moreover, excess mortality risk may persist even after CD treatment. Although predictors of risk in treated CD are not fully understood, the importance of early recognition and adequate treatment is well established. Surgery with resection of a pituitary adenoma is still the first line therapy, being successful in about 60–70 % of patients; however, recurrence within 2–4 years may often occur. When surgery fails, medical treatment can reduce cortisol production and ameliorate clinical manifestations while more definitive therapy becomes effective. Compounds that target hypothalamic–pituitary axis, glucocorticoid synthesis or adrenocortical function are currently used to control the deleterious effects of chronic glucocorticoid excess. In this review we describe and analyze the molecular basis of the drugs targeting the disease at central level, suppressing ACTH secretion, as well as at peripheral level, acting as adrenal inhibitors, or glucocorticoid receptor antagonists. Understanding of the underlying molecular mechanisms in CD and of glucocorticoid biology should promote the development of new targeted and more successful therapies in the future. Indeed, most of the drugs discussed have been tested in limited clinical trials, but there is potential therapeutic benefit in compounds with better specificity for the class of receptors expressed by ACTH-secreting tumors. However, long-term follow-up with management of persistent comorbidities is needed even after successful treatment of CD.

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Acknowledgments

This study was supported by grants from the Italian Ministry of Education, Research and University (FIRB RBAP11884M; RBAP1153LS; PRIN 2008LFK7J5_004), Fondazione Cassa di Risparmio di Ferrara, and Associazione Italiana per la Ricerca sul Cancro (AIRC) in collaboration with Laboratorio in rete del Tecnopolo “Tecnologie delle terapie avanzate” (LTTA) of the University of Ferrara; CARIGE Foundation, Genova.

Disclosure

D. Ferone, A. Colao, R. Pivonello report serving as an ad hoc consultant to Novartis, and receiving research grant support. The remaining authors do not have any relationships to disclose.

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Authors and Affiliations

  1. Endocrinology, Department of Internal Medicine and Medical Specialties & Center of Excellence for Biomedical Research, IRCCS AOU San Martino-IST, University of Genova, Viale Benedetto XV, 6, 16132, Genoa, Italy

    Diego Ferone

  2. Endocrinology, Department of Clinical Medicine and Surgery, Federico II, University of Naples, Naples, Italy

    Claudia Pivonello, Annamaria Colao & Rosario Pivonello

  3. Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy

    Giovanni Vitale

  4. Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy

    Giovanni Vitale

  5. Section of Endocrinology, Department of Medical Sciences and LTTA, University of Ferrara, Ferrara, Italy

    Maria Chiara Zatelli

Authors
  1. Diego Ferone
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  2. Claudia Pivonello
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  3. Giovanni Vitale
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  4. Maria Chiara Zatelli
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  5. Annamaria Colao
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  6. Rosario Pivonello
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Corresponding author

Correspondence to Diego Ferone.

Additional information

This study was conducted on behalf of ABC (Altogether to Beat Cushing’s syndrome) Group.

The members of the ABC Group are listed in Appendix.

D. Ferone, C. Pivonello, G. Vitale and M. C. Zatelli have contributed equally to this work.

Appendix

Appendix

ABC (Altogether to Beat Cushing’s syndrome) 2012 Group: N. Albiger, A. Ambrogio, G. Arnaldi, E. Arvat, R. Baldelli, R. Berardelli, M. Boscaro, S. Cannavò, F. Cavagnini, A. Colao, S.M. Corsello, A. Cozzolino, A. De Bartolomeis, M. De Leo, G. Di Minno, C. Di Somma, K. Esposito, G. Fabbrocini, D. Ferone, C. Foresta, M. Galderisi, C. Giordano, D. Giugliano, A. Giustina, F. Grimaldi, A.M. Isidori, E. Jannini, F. Lombardo, L. Manetti, M. Mannelli, F. Mantero, G. Marone, G. Mazziotti, S. Moretti, E. Nazzari, R.M. Paragliola, R. Pasquali, S. Pecorelli, F. Pecori Giraldi, C. Pivonello, R. Pivonello, G. Reimondo, C. Scaroni, A. Scillitani, C. Simeoli, A. Stigliano, V. Toscano, L. Trementino, G. Vitale, M.C. Zatelli.

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Ferone, D., Pivonello, C., Vitale, G. et al. Molecular basis of pharmacological therapy in Cushing’s disease. Endocrine 46, 181–198 (2014). https://doi.org/10.1007/s12020-013-0098-5

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