Optimizing Medical Therapy of Acromegaly: Beneficial Effects of Cabergoline in Patients Uncontrolled with Long-Acting Release Octreotide

Background: Previous data indicate a beneficial effect of cabergoline (CAB) association to somatostatin analogs (SA) in acromegalics resistant to SA monotherapy. Objective: To assess the efficacy of CAB association on acromegalics with high IGF-I on stable long-acting release octreotide (OCT-LAR) (30 mg/28 days). Design, Subjects and Methods: 34 patients (17 male, 25–85 years, 33 macroadenomas) were enrolled in this prospective study. OCT-LAR was administered as primary (n = 4) and as secondary (n = 30) treatment: after surgery (n = 16), after surgery + radiotherapy (RT) (n = 11), and after RT only (n = 3). Duration of OCT-LAR therapy prior to CAB was 24 ± 12 months. The immunohistochemical features of the tumors disclosed GH/PRL co-secretion in 11/21 patients. 13 patients had high PRL levels prior to CAB. The initial CAB dose was 1.5 mg/week. No IGF-I normalization led to a dose increase to 3.5 mg/week. The OCT-LAR dose was kept stable during treatment. IGF-I, GH and PRL levels were compared before and after CAB association. OCT-LAR was withdrawn in patients who achieved IGF-I normalization, in order to assess the influence of CAB. Results: Comparing OCT-LAR to OCT-LAR/CAB treatment, there was a significant decrease in mean GH, IGF-I, %ULNR-IGF-I and PRL levels. During OCT-LAR/CAB treatment, IGF-I normalized in 19 patients (56%). IGF-I normalization was correlated to lowest IGF-I levels on OCT-LAR monotherapy, but not to baseline PRL levels or GH/PRL co-expression. OCT-LAR withdrawn in all who had achieved IGF-I normalization on combined therapy resulted in IGF-I elevation to abnormal levels in all patients. Gastrointestinal symptoms were reported by 12 patients. Conclusion: OCT-LAR and CAB association has been shown to be an effective alternative therapy for those acromegalics who still have active acromegaly despite monotherapy with SA, mainly for those with lower pretreatment IGF-I concentrations. According to previous studies, the beneficial effects of CAB occur even when pretreatment PRL is normal and/or there is no tumor GH/PRL co-expression.

[1]  Jeroen J. Bax,et al.  Cabergoline and cardiac valve disease in prolactinoma patients: additional studies during long-term treatment are required. , 2008, European journal of endocrinology.

[2]  S. Melmed,et al.  Regulation of growth hormone and prolactin gene expression and secretion by chimeric somatostatin-dopamine molecules. , 2007, Endocrinology.

[3]  A. Antonini,et al.  Valvular heart disease and the use of dopamine agonists for Parkinson's disease. , 2007, The New England journal of medicine.

[4]  W. Haverkamp,et al.  Dopamine agonists and the risk of cardiac-valve regurgitation. , 2007, The New England journal of medicine.

[5]  Doan Huu Hau,et al.  Re‐evaluation of the efficacy of the association of cabergoline to somatostatin analogues in acromegalic patients , 2005, Clinical endocrinology.

[6]  A. Bottoni,et al.  Dopamine receptor subtype 2 and somatostatin receptor subtype 5 expression influences somatostatin analogs effects on human somatotroph pituitary adenomas in vitro. , 2005, Journal of molecular endocrinology.

[7]  D. Rabinowitz,et al.  Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. , 2005, The Journal of clinical endocrinology and metabolism.

[8]  J. Taylor,et al.  Efficacy of chimeric molecules directed towards multiple somatostatin and dopamine receptors on inhibition of GH and prolactin secretion from GH-secreting pituitary adenomas classified as partially responsive to somatostatin analog therapy. , 2005, European journal of endocrinology.

[9]  D. Selvarajah,et al.  Effectiveness of adding dopamine agonist therapy to long-acting somatostatin analogues in the management of acromegaly. , 2005, European journal of endocrinology.

[10]  G. Lasio,et al.  Cabergoline addition to depot somatostatin analogues in resistant acromegalic patients: efficacy and lack of predictive value of prolactin status , 2004, Clinical endocrinology.

[11]  S. Melmed,et al.  Suppression of rat and human growth hormone and prolactin secretion by a novel somatostatin/dopaminergic chimeric ligand. , 2003, The Journal of clinical endocrinology and metabolism.

[12]  D. Bonaduce,et al.  High prevalence of cardiac valve disease in acromegaly: an observational, analytical, case-control study. , 2003, The Journal of clinical endocrinology and metabolism.

[13]  J. Taylor,et al.  Demonstration of enhanced potency of a chimeric somatostatin-dopamine molecule, BIM-23A387, in suppressing growth hormone and prolactin secretion from human pituitary somatotroph adenoma cells. , 2002, The Journal of clinical endocrinology and metabolism.

[14]  A. Barkan,et al.  Acromegaly with apparently normal GH secretion: implications for diagnosis and follow-up. , 2002, The Journal of clinical endocrinology and metabolism.

[15]  U. Kumar,et al.  Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. , 2000, Science.

[16]  M. Veysey,et al.  Prolonged large bowel transit increases serum deoxycholic acid: a risk factor for octreotide induced gallstones , 1999, Gut.

[17]  S. Wardlaw,et al.  Evaluation of disease status with sensitive measures of growth hormone secretion in 60 postoperative patients with acromegaly. , 1998, The Journal of clinical endocrinology and metabolism.

[18]  A. Beckers,et al.  Cabergoline in the treatment of acromegaly: a study in 64 patients. , 1998, The Journal of clinical endocrinology and metabolism.

[19]  A. Gulino,et al.  Acute effects of octreotide, cabergoline and a combination of both drugs on GH secretion in acromegalic patients. , 1997, La Clinica terapeutica.

[20]  M. Arosio,et al.  Use of cabergoline in the long-term treatment of hyperprolactinemic and acromegalic patients , 1997, Journal of endocrinological investigation.

[21]  T. Howlett,et al.  Cabergoline treatment of acromegaly: a preliminary dose finding study , 1997, Clinical endocrinology.

[22]  P. Marzullo,et al.  Effect of different dopaminergic agents in the treatment of acromegaly. , 1997, The Journal of clinical endocrinology and metabolism.

[23]  M. Veysey,et al.  Roles of gall bladder emptying and intestinal transit in the pathogenesis of octreotide induced gall bladder stones. , 1996, Gut.

[24]  F Pedersen,et al.  Volume of Pituitary Macroadenomas: Assessment by MRI , 1992, Journal of computer assisted tomography.

[25]  A. Dubini,et al.  LONG‐LASTING LOWERING OF SERUM GROWTH HORMONE AND PROLACTIN LEVELS BY SINGLE AND REPETITIVE CABERGOLINE ADMINISTRATION IN DOPAMINE‐RESPONSIVE ACROMEGALIC PATIENTS , 1988, Clinical endocrinology.

[26]  J. Klijn,et al.  THE SENSITIVITY OF GROWTH HORMONE AND PROLACTIN SECRETION TO THE SOMATOSTATIN ANALOGUE SMS 201–995 IN PATIENTS WITH PROLACTINOMAS AND ACROMEGALY , 1986, Clinical endocrinology.

[27]  J. Taylor,et al.  BIM-23A760, a chimeric molecule directed towards somatostatin and dopamine receptors, vs universal somatostatin receptors ligands in GH-secreting pituitary adenomas partial responders to octreotide. , 2005, Journal of endocrinological investigation.

[28]  K. Kovacs,et al.  Growth hormone (GH) and prolactin (PRL) gene expression and immunoreactivity in GH- and PRL-producing human pituitary adenomas , 2005, Virchows Archiv A.

[29]  P. Marzullo,et al.  Efficacy of Combined Treatment with Lanreotide and Cabergoline in Selected Therapy-Resistant Acromegalic Patients , 2004, Pituitary.