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Combined treatment with octreotide LAR and pegvisomant in patients with pituitary gigantism: clinical evaluation and genetic screening

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Abstract

Introduction

Pituitary gigantism is a rare condition caused by growth hormone secreting hypersecretion, usually by a pituitary tumor. Acromegaly and gigantism cases that have a genetic cause are challenging to treat, due to large tumor size and poor responses to some medical therapies (e.g. AIP mutation affected cases and those with X-linked acrogigantism syndrome).

Materials and methods

We performed a retrospective study to identify gigantism cases among 160 somatotropinoma patients treated between 1985 and 2015 at the University Hospital of Caracas, Venezuela. We studied clinical details at diagnosis, hormonal responses to therapy and undertook targeted genetic testing. Among the 160 cases, eight patients (six males; 75 %) were diagnosed with pituitary gigantism and underwent genetic analysis that included array comparative genome hybridization for Xq26.3 duplications.

Results

All patients had GH secreting pituitary macroadenomas that were difficult to control with conventional treatment options, such as surgery or primary somatostatin receptor ligand (SRL) therapy. Combined therapy (long-acting SRL and pegvisomant) as primary treatment or after pituitary surgery and radiotherapy permitted the normalization of IGF-1 levels and clinical improvement. Novel AIP mutations were the found in three patients. None of the patients had Xq26.3 microduplications.

Conclusions

Treatment of pituitary gigantism is frequently challenging; delayed control increases the harmful effects of GH excess, such as, excessive stature and symptom burden, so early diagnosis and effective treatment are particularly important in these cases.

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References

  1. Stratakis CA, Tichomirowa MA, Boikos S, Azevedo MF, Lodish M, Martari M, Verma S, Daly AF, Raygada M, Keil MF, Papademetriou J, Drori-Herishanu L, Horvath A, Tsang KM, Nesterova M, Franklin S, Vanbellinghen JF, Bours V, Salvatori R, Beckers A (2010) The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes. Clin Genet 78(5):457–463. doi:10.1111/j.1399-0004.2010.01406.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF, Caberg JH, Castermans E, Villa C, Dimopoulos A, Chittiboina P, Xekouki P, Shah N, Metzger D, Lysy PA, Ferrante E, Strebkova N, Mazerkina N, Zatelli MC, Lodish M, Horvath A, de Alexandre RB, Manning AD, Levy I, Keil MF, Sierra Mde L, Palmeira L, Coppieters W, Georges M, Naves LA, Jamar M, Bours V, Wu TJ, Choong CS, Bertherat J, Chanson P, Kamenicky P, Farrell WE, Barlier A, Quezado M, Bjelobaba I, Stojilkovic SS, Wess J, Costanzi S, Liu P, Lupski JR, Beckers A, Stratakis CA (2014) Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. New Engl J Med 371(25):2363–2374. doi:10.1056/NEJMoa1408028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Daly AF, Tichomirowa MA, Petrossians P, Heliovaara E, Jaffrain-Rea ML, Barlier A, Naves LA, Ebeling T, Karhu A, Raappana A, Cazabat L, De Menis E, Montanana CF, Raverot G, Weil RJ, Sane T, Maiter D, Neggers S, Yaneva M, Tabarin A, Verrua E, Eloranta E, Murat A, Vierimaa O, Salmela PI, Emy P, Toledo RA, Sabate MI, Villa C, Popelier M, Salvatori R, Jennings J, Longas AF, Labartaaizpun JI, Georgitsi M, Paschke R, Ronchi C, Valimaki M, Saloranta C, De Herder W, Cozzi R, Guitelman M, Magri F, Lagonigro MS, Halaby G, Corman V, Hagelstein MT, Vanbellinghen JF, Barra GB, Gimenez-Roqueplo AP, Cameron FJ, Borson-Chazot F, Holdaway I, Toledo SP, Stalla GK, Spada A, Zacharieva S, Bertherat J, Brue T, Bours V, Chanson P, Aaltonen LA, Beckers A (2010) Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metab 95(11):E373–E383. doi:10.1210/jc.2009-2556

    Article  PubMed  Google Scholar 

  4. Beckers A, Lodish MB, Trivellin G, Rostomyan L, Lee M, Faucz FR, Yuan B, Choong CS, Caberg JH, Verrua E, Naves LA, Cheetham TD, Young J, Lysy PA, Petrossians P, Cotterill A, Shah NS, Metzger D, Castermans E, Ambrosio MR, Villa C, Strebkova N, Mazerkina N, Gaillard S, Barra GB, Casulari LA, Neggers SJ, Salvatori R, Jaffrain-Rea ML, Zacharin M, Santamaria BL, Zacharieva S, Lim EM, Mantovani G, Zatelli MC, Collins MT, Bonneville JF, Quezado M, Chittiboina P, Oldfield EH, Bours V, Liu P, Wdh W, Pellegata N, Lupski JR, Daly AF, Stratakis CA (2015) X-linked acrogigantism syndrome: clinical profile and therapeutic responses. Endocr Relat Cancer 22(3):353–367. doi:10.1530/ERC-15-0038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nozieres C, Berlier P, Dupuis C, Raynaud-Ravni C, Morel Y, Chazot FB, Nicolino M (2011) Sporadic and genetic forms of paediatric somatotropinoma: a retrospective analysis of seven cases and a review of the literature. Orphanet J Rare Dis 6:67. doi:10.1186/1750-1172-6-67

    Article  PubMed  PubMed Central  Google Scholar 

  6. Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, Tuppurainen K, Ebeling TM, Salmela PI, Paschke R, Gundogdu S, De Menis E, Makinen MJ, Launonen V, Karhu A, Aaltonen LA (2006) Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science 312(5777):1228–1230. doi:10.1126/science.1126100

    Article  CAS  PubMed  Google Scholar 

  7. Barlier A, Vanbellinghen JF, Daly AF, Silvy M, Jaffrain-Rea ML, Trouillas J, Tamagno G, Cazabat L, Bours V, Brue T, Enjalbert A, Beckers A (2007) Mutations in the aryl hydrocarbon receptor interacting protein gene are not highly prevalent among subjects with sporadic pituitary adenomas. J Clin Endocrinol Metab 92(5):1952–1955. doi:10.1210/jc.2006-2702

    Article  CAS  PubMed  Google Scholar 

  8. Choi Y, Chan AP (2015) PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31(16):2745–2747. doi:10.1093/bioinformatics/btv195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249. doi:10.1038/nmeth0410-248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Daly AF, Yuan B, Fina F, Caberg JH, Trivellin G, Rostomyan L, de Herder WW, Naves LA, Metzger D, Cuny T, Rabl W, Shah N, Jaffrain-Rea ML, Zatelli MC, Faucz FR, Castermans E, Nanni-Metellus I, Lodish M, Muhammad A, Palmeira L, Potorac I, Mantovani G, Neggers S, Klein M, Barlier A, Liu P, Ouafik L, Bours V, Lupski JR, Stratakis CA, Beckers A (2016) Somatic mosaicism underlies X-linked acrogigantism (XLAG) syndrome in sporadic male subjects. Endocr Relat Cancer. doi:10.1530/ERC-16-0082

    Google Scholar 

  11. Rostomyan L, Daly AF, Petrossians P, Nachev E, Lila AR, Lecoq AL, Lecumberri B, Trivellin G, Salvatori R, Moraitis AG, Holdaway I, Kranenburg-van Klaveren DJ, Chiara Zatelli M, Palacios N, Nozieres C, Zacharin M, Ebeling T, Ojaniemi M, Rozhinskaya L, Verrua E, Jaffrain-Rea ML, Filipponi S, Gusakova D, Pronin V, Bertherat J, Belaya Z, Ilovayskaya I, Sahnoun-Fathallah M, Sievers C, Stalla GK, Castermans E, Caberg JH, Sorkina E, Auriemma RS, Mittal S, Kareva M, Lysy PA, Emy P, De Menis E, Choong CS, Mantovani G, Bours V, De Herder W, Brue T, Barlier A, Neggers SJ, Zacharieva S, Chanson P, Shah NS, Stratakis CA, Naves LA, Beckers A (2015) Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr Relat Cancer 22(5):745–757. doi:10.1530/ERC-15-0320

    Article  CAS  PubMed  Google Scholar 

  12. Abe T, Tara LA, Ludecke DK (1999) Growth hormone-secreting pituitary adenomas in childhood and adolescence: features and results of transnasal surgery. Neurosurgery 45(1):1–10

    Article  CAS  PubMed  Google Scholar 

  13. Whitehead EM, Shalet SM, Davies D, Enoch BA, Price DA, Beardwell CG (1982) Pituitary gigantism: a disabling condition. Clin Endocrinol 17(3):271–277

    Article  CAS  Google Scholar 

  14. Holdaway IM, Bolland MJ, Gamble GD (2008) A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur J Endocrinol 159(2):89–95. doi:10.1530/EJE-08-0267

    Article  CAS  PubMed  Google Scholar 

  15. Holdaway IM, Rajasoorya RC, Gamble GD (2004) Factors influencing mortality in acromegaly. J Clin Endocrinol Metab 89(2):667–674. doi:10.1210/jc.2003-031199

    Article  CAS  PubMed  Google Scholar 

  16. Hernandez-Ramirez LC, Gabrovska P, Denes J, Stals K, Trivellin G, Tilley D, Ferrau F, Evanson J, Ellard S, Grossman AB, Roncaroli F, Gadelha MR, Korbonits M, International FIPA Consortium (2015) Landscape of familial isolated and young-onset pituitary adenomas: prospective diagnosis in AIP mutation carriers. J Clin Endocrinol Metab. doi:10.1210/jc.2015-1869

    PubMed  PubMed Central  Google Scholar 

  17. Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, Wass JA, Endocrine S (2014) Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99(11):3933–3951. doi:10.1210/jc.2014-2700

    Article  CAS  PubMed  Google Scholar 

  18. Orvidas LJ, Kasperbauer JL, Meyer FB, Zimmerman D (2000) Pediatric transseptal transsphenoidal pituitary surgery. Am J Rhinol 14(4):265–271

    Article  CAS  PubMed  Google Scholar 

  19. Bronstein MD, Bruno OD, Abreu A, Mangupli R, Mercado M (2014) A practical approach to acromegaly management in Latin America. Pituitary 17(Suppl 1):S30–S35. doi:10.1007/s11102-013-0531-z

    Article  PubMed  Google Scholar 

  20. Mangupli R, Camperos P, Webb SM (2014) Biochemical and quality of life responses to octreotide-LAR in acromegaly. Pituitary 17(6):495–499. doi:10.1007/s11102-013-0533-x

    Article  CAS  PubMed  Google Scholar 

  21. Mangupli R, Lisette A, Ivett C, Paul C, de los Rios Victoria C, Luis CJ (2003) Improvement of acromegaly after octreotide LAR treatment. Pituitary 6(1):29–34

    Article  CAS  PubMed  Google Scholar 

  22. Maheshwari HG, Prezant TR, Herman-Bonert V, Shahinian H, Kovacs K, Melmed S (2000) Long-acting peptidomimergic control of gigantism caused by pituitary acidophilic stem cell adenoma. J Clin Endocrinol Metab 85(9):3409–3416. doi:10.1210/jcem.85.9.6824

    CAS  PubMed  Google Scholar 

  23. Schoof E, Dorr HG, Kiess W, Ludecke DK, Freitag E, Zindel V, Rascher W, Dotsch J (2004) Five-year follow-up of a 13-year-old boy with a pituitary adenoma causing gigantism–effect of octreotide therapy. Horm Res 61(4):184–189. doi:10.1159/000076386

    Article  CAS  PubMed  Google Scholar 

  24. Alikasifoglu A, Kandemir N, Akalan N, Yordam N (2001) Pituitary adenoma associated with gigantism and hyperprolactinemia. Pediatr Neurosurg 35(6):325–328

    Article  CAS  PubMed  Google Scholar 

  25. Rix M, Laurberg P, Hoejberg AS, Brock-Jacobsen B (2005) Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl. Eur J Endocrinol 153(2):195–201. doi:10.1530/eje.1.01956

    Article  CAS  PubMed  Google Scholar 

  26. Goldenberg N, Racine MS, Thomas P, Degnan B, Chandler W, Barkan A (2008) Treatment of pituitary gigantism with the growth hormone receptor antagonist pegvisomant. J Clin Endocrinol Metab 93(8):2953–2956. doi:10.1210/jc.2007-2283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mussig K, Gallwitz B, Honegger J, Strasburger CJ, Bidlingmaier M, Machicao F, Bornemann A, Ranke MB, Haring HU, Petersenn S (2007) Pegvisomant treatment in gigantism caused by a growth hormone-secreting giant pituitary adenoma. Exp Clin Endocrinol Diabetes Off J Ger Soc Endocrinol Ger Diabetes Assoc 115(3):198–202. doi:10.1055/s-2007-956172

    Article  CAS  Google Scholar 

  28. Bergamaschi S, Ronchi CL, Giavoli C, Ferrante E, Verrua E, Ferrari DI, Lania A, Rusconi R, Spada A, Beck-Peccoz P (2010) Eight-year follow-up of a child with a GH/prolactin-secreting adenoma: efficacy of pegvisomant therapy. Horm Res Paediatr 73(1):74–79. doi:10.1159/000271919

    Article  CAS  PubMed  Google Scholar 

  29. Naves LA, Daly AF, Dias LA, Yuan B, Zakir JC, Barra GB, Palmeira L, Villa C, Trivellin G, Junior AJ, Neto FF, Liu P, Pellegata NS, Stratakis CA, Lupski JR, Beckers A (2016) Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome. Endocrine 51(2):236–244. doi:10.1007/s12020-015-0804-6

    Article  CAS  PubMed  Google Scholar 

  30. Neggers SJ, de Herder WW, Feelders RA, van der Lely AJ (2011) Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs, in controlled acromegaly patients. Pituitary 14(3):253–258. doi:10.1007/s11102-010-0289-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Neggers SJ, de Herder WW, Janssen JA, Feelders RA, van der Lely AJ (2009) Combined treatment for acromegaly with long-acting somatostatin analogs and pegvisomant: long-term safety for up to 4.5 years (median 2.2 years) of follow-up in 86 patients. Eur J Endocrinol 160(4):529–533. doi:10.1530/EJE-08-0843

    Article  CAS  PubMed  Google Scholar 

  32. Neggers SJ, Franck SE, de Rooij FW, Dallenga AH, Poublon RM, Feelders RA, Janssen JA, Buchfelder M, Hofland LJ, Jorgensen JO, van der Lely AJ (2014) Long-term efficacy and safety of pegvisomant in combination with long-acting somatostatin analogs in acromegaly. J Clin Endocrinol Metab 99(10):3644–3652. doi:10.1210/jc.2014-2032

    Article  CAS  PubMed  Google Scholar 

  33. Neggers SJ, van Aken MO, de Herder WW, Feelders RA, Janssen JA, Badia X, Webb SM, van der Lely AJ (2008) Quality of life in acromegalic patients during long-term somatostatin analog treatment with and without pegvisomant. J Clin Endocrinol Metab 93(10):3853–3859. doi:10.1210/jc.2008-0669

    Article  CAS  PubMed  Google Scholar 

  34. Neggers SJ, van Aken MO, Janssen JA, Feelders RA, de Herder WW, van der Lely AJ (2007) Long-term efficacy and safety of combined treatment of somatostatin analogs and pegvisomant in acromegaly. J Clin Endocrinol Metab 92(12):4598–4601. doi:10.1210/jc.2007-1234

    Article  CAS  PubMed  Google Scholar 

  35. Petrossians P, Borges-Martins L, Espinoza C, Daly A, Betea D, Valdes-Socin H, Stevenaert A, Chanson P, Beckers A (2005) Gross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs. Eur J Endocrinol 152(1):61–66

    Article  CAS  PubMed  Google Scholar 

  36. Jallad RS, Musolino NR, Kodaira S, Cescato VA, Bronstein MD (2007) Does partial surgical tumour removal influence the response to octreotide-LAR in acromegalic patients previously resistant to the somatostatin analogue? Clin Endocrinol 67(2):310–315. doi:10.1111/j.1365-2265.2007.02885.x

    Article  CAS  Google Scholar 

  37. Karavitaki N, Turner HE, Adams CB, Cudlip S, Byrne JV, Fazal-Sanderson V, Rowlers S, Trainer PJ, Wass JA (2008) Surgical debulking of pituitary macroadenomas causing acromegaly improves control by lanreotide. Clin Endocrinol 68(6):970–975. doi:10.1111/j.1365-2265.2007.03139.x

    Article  CAS  Google Scholar 

  38. Barkan A, Bronstein MD, Bruno OD, Cob A, Espinosa-de-los-Monteros AL, Gadelha MR, Garavito G, Guitelman M, Mangupli R, Mercado M, Portocarrero L, Sheppard M (2010) Management of acromegaly in Latin America: expert panel recommendations. Pituitary 13(2):168–175. doi:10.1007/s11102-009-0206-y

    Article  PubMed  Google Scholar 

  39. Jaffrain-Rea ML, Angelini M, Gargano D, Tichomirowa MA, Daly AF, Vanbellinghen JF, D’Innocenzo E, Barlier A, Giangaspero F, Esposito V, Ventura L, Arcella A, Theodoropoulou M, Naves LA, Fajardo C, Zacharieva S, Rohmer V, Brue T, Gulino A, Cantore G, Alesse E, Beckers A (2009) Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications. Endocr Relat Cancer 16(3):1029–1043. doi:10.1677/ERC-09-0094

    Article  CAS  PubMed  Google Scholar 

  40. Kasuki L, Colli LM, Elias PC, Castro M, Gadelha MR (2012) Resistance to octreotide LAR in acromegalic patients with high SSTR2 expression: analysis of AIP expression. Arq Bras Endocrinol Metab 56(8):501–506

    Article  Google Scholar 

  41. Daly AF, Beckers A (2015) Familial isolated pituitary adenomas (FIPA) and mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocrinol Metab Clin North Am 44(1):19–25. doi:10.1016/j.ecl.2014.10.002

    Article  PubMed  Google Scholar 

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Funding

The research was supported in part by the Fonds d’Investissement pour la Recherche Scientifique (FIRS) of the Centre Hospitalier Universitaire de Liège, Liège, Belgium.

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    Authors and Affiliations

    1. Section of Neuroendocrinology, Department of Neurosurgery, Hospital Universitario de Caracas, Caracas, Venezuela

      Ruth Mangupli, Paul Camperos, Jaime Krivoy & Elvia Cuauro

    2. Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000, Liège, Belgium

      Liliya Rostomyan, Adrian F. Daly & Albert Beckers

    3. Department of Human Genetics, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, 4000, Liège, Belgium

      Emilie Castermans, Jean-Hubert Caberg & Vincent Bours

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    1. Ruth Mangupli
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    Ruth Mangupli and Liliya Rostomyan have contributed equally to the conduct of the study.

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    Mangupli, R., Rostomyan, L., Castermans, E. et al. Combined treatment with octreotide LAR and pegvisomant in patients with pituitary gigantism: clinical evaluation and genetic screening. Pituitary 19, 507–514 (2016). https://doi.org/10.1007/s11102-016-0732-3

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