Early postoperative prediction of both disease remission and long-term disease control in acromegaly using the oral glucose tolerance test

Abstract

Purpose

Transsphenoidal surgery (TSS) is the cornerstone of acromegaly treatment. Two biochemical parameters, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels, sometimes diverge postoperatively; however, it is important to maintain disease control without further treatment, regardless of whether these parameters converge. This study investigated whether remission and long-term disease control could be predicted using early postoperative GH and IGF-1 levels.

Methods

We reviewed 36 consecutive surgically treated patients with acromegaly. IGF-1 levels and minimum GH levels during an oral glucose tolerance test (OGTT) were evaluated at 2 weeks, as well as at 3 months postoperatively. After comparison between the remission and nonremission groups, we analyzed whether early postoperative parameters could predict remission and long-term disease control.

Results

Twenty-five patients (69.4%, Group A) achieved remission within 1 year postoperatively. Of the remaining patients (median follow-up period, 53 months), seven (19.5%, Group B) maintained normal IGF-1 levels without treatment, whereas four (11.1%, Group C) required additional treatment. GH levels <1.5 ng/mL measured on the morning after surgery and nadir GH levels <0.7 ng/mL during the OGTT conducted at 2 weeks postoperatively were predictive of remission, with the latter demonstrating 95.2% sensitivity and 100% specificity. All group C patients had nadir GH levels ≥0.7 ng/mL during the OGTT and IGF-1 levels ≥SD +3 at 2 weeks postoperatively.

Conclusion

Early postoperative nadir GH levels during the OGTT and IGF-1 levels at 2 weeks postoperatively demonstrated excellent predictive value for both endocrinological remission and the necessity for additional treatment.

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Data availability

The datasets and analyzed data in this current study are available from the corresponding author upon reasonable request.

References

  1. 1.

    Alexopoulou O, Bex M, Abs R, T’Sjoen G, Velkeniers B, Maiter D (2008) Divergence between growth hormone and insulin-like growth factor-1 concentrations in the follow-up acromegaly. J Clin Endocrinol Metab 93:1324–1330. https://doi.org/10.1210/jc.2007-2104

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Anik I, Cabuk B, Gokbel A, Selek A, Cetinarslan B, Anik Y, Ceylan S (2017) Endoscopic transsphenoidal approach for acromegaly with remission rates in 401 patients: 2010 consensus criteria. World Neurosurg 108:278–290. https://doi.org/10.1016/j.wneu.2017.08.182

    Article  PubMed  Google Scholar 

  3. 3.

    Antunes X, Ventura N, Camilo GB, Wildemberg LE, Guasti A, Pereira PJM, Camacho AHS, Chimelli L, Niemeyer P, Gadelha MR, Kasuki L (2018) Predictors of surgical outcome and early criteria remission in acromegaly. Endocrine 60:415–422. https://doi.org/10.1007/s12020-018-1590-8

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Asha MJ, Takami H, Velasquez C, Oswari S, Almeida JP, Zadeh G, Gentili F (2019) Long-term outcomes of transsphenoidal surgery for management of growth hormone-secreting adenomas: single-center results. J. Neurosurg Oct 11:1–11. https://doi.org/10.3171/2019.6.JNS191187 [Epub ahead of print]

    Article  Google Scholar 

  5. 5.

    Babu H, Ortega A, Nuno M, Dehghan A, Schweitzer A, Bonert HV, Carmichael JD, Cooper O, Melmed S, Mamelak A (2017) Long-term endocrine outcomes following endoscopic endonasal transsphenoidal surgery for acromegaly and associated prognostic factors. Neurosurgery 81:357–366. https://doi.org/10.1093/neuros/nyx020

    Article  PubMed  Google Scholar 

  6. 6.

    Burton T, Nestour EL, Neary M, Ludlam WH (2016) Incidence and prevalence of acromegaly in large US health plan database. Pituitary 19:262–267. https://doi.org/10.1007/s11102-015-071-2

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Colao A, Auriemma RS, Pivonello R (2016) The effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly. Pituitary 19:210–221. https://doi.org/10.1007/s11102-015-0677-y

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Colao A, Pivonello R, Cavallo LM, Gaccione M, Auriemma RS, Esposito F, Cappabianca P, Lombardi G (2006) Age changes the diagnostic accuracy of mean profile and nadir growth hormone levels after oral glucose in postoperative patients with acromegaly. Clin Endocrinol (Oxf) 65:250–256. https://doi.org/10.1111/j.1365-2265.2006.02584.x

    CAS  Article  Google Scholar 

  9. 9.

    Dekkers OM, Biermasz NR, Pereira AM, Romijn JA, Vandenbroucke JP (2008) Mortality in acromegaly: a metaanalysis. J Clin Endocrinol Metab 93:61–67. https://doi.org/10.1210/jc.2007-1191

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Ding D, Mehta GU, Patibandla MR, Lee CC, Liscak R, Kano H, Pai FY, Kosak M, Sisterson ND, Martinez-Alvarez R, Martinez-Moreno N, Mathieu D, Grills IS, Blas K, Lee K, Cifarelli CP, Katsevman GA, Lee JYK, McShane B, Kondziolka D, Lunsford LD, Vance ML, Sheehan JP (2019) Stereotactic radiosurgery for acromegaly: an international multicenter retrospective cohort study. Neurosurgery 84:717–725. https://doi.org/10.1093/neuros/nyy178

    Article  PubMed  Google Scholar 

  11. 11.

    Dutta P, Korbonits M, Sachdeva N, Gupta P, Srinivasan A, Devgun JS, Bajaj A, Mukherjee KK (2016) Can immediate postoperative random growth hormone levels predict long-term cure in patients with acromegaly? Neurol India 64:252–258. https://doi.org/10.4103/0028-3886.177622

    Article  PubMed  Google Scholar 

  12. 12.

    Faje AT, Barken AL (2010) Basal, but not pulsatile, growth hormone secretion determines the ambient circulating levels of insulin-like growth factor-I. J Clin Endocrinol Metab 95:2486–2491. https://doi.org/10.1210/jc.2009-2634

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Feelders RA, Bidlingmaier M, Strasburger CJ, Janssen JA, Uitterlinden P, Hofland LJ, Lamberts SW, van der Lely AJ, de Herder WW (2005) Postoperative evaluation of patients with acromegaly: clinical significance and timing of oral glucose tolerance testing and measurement of (free) insulin-like growth factor-I, acid-labile subunit, and growth hormone-binding protein levels. J Clin Endocrinol Metab 90:6480–6489

    CAS  Article  Google Scholar 

  14. 14.

    Freda PU, Nuruzzaman AT, Reyrs CM, Sundeen RE, Post KD (2004) Significance of “abnormal” nadir growth hormone levels after oral glucose in postoperative patients with acromegaly in remission with normal insulin-like growth factor-I levels. J Clin Endocrinol Metab 89:495–500

    CAS  Article  Google Scholar 

  15. 15.

    Freda PU (2009) Monitoring of acromegaly: What should be performed when GH and IGF-1 levels are discrepant? Clin Endocrinol (Oxf) 71:166–170. https://doi.org/10.1111/j.1365-2265.2009.03556.x

    CAS  Article  Google Scholar 

  16. 16.

    Gheorghiu ML (2017) Updates in outcomes of stereotactic radiation therapy in acromegaly. Pituitary 20:154–168. https://doi.org/10.1007/s11102-016-0783-5

    Article  PubMed  Google Scholar 

  17. 17.

    Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, Veldhuis J, Wass J, Von Werder K, Melmed S (2000) Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 85:526–529. https://doi.org/10.1210/jc.85.2.526

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Giustina A, Chanson P, Bronstein MD, Klibanski A, Lamberts S, Casanueva FF, Trainer P, Ghigo E, Ho K, Melmed S (2010) Acromegaly Consensus Group. J Clin Endocrinol Metab 95:3141–3148. https://doi.org/10.1210/jc.2009-2670

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Hage M, Kamenický P, Chanson P (2019) Growth hormone response to oral glucose load: from normal to pathological conditions. Neuroendocrinology 108:244–255. https://doi.org/10.11159/000497214

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Haliloglu O, Kuruoglu E, Ozkaya HM, Keskin FE, Gunaldi O, Gazioglu N, Kadioglu P, Tanriover N (2016) Multidisciplinary approach for acromegaly: a single tertiary center’s experience. World Neurosurg 88:270–276. https://doi.org/10.1016/j.wneu.2015.12.092

    Article  PubMed  Google Scholar 

  21. 21.

    Hazer DB, Işik S, Berker D, Güler S, Gürlek A, Yücel T, Berker M (2013) Treatment of acromegaly by endoscopic transsphenoidal surgery: surgical experience in 214 cases and cure rates according to current consensus criteria. J Neurosurg 119:1467–1477. https://doi.org/10.3171/2013.8.JNS13224

    Article  PubMed  Google Scholar 

  22. 22.

    Katznelson L, Laws ER, Melmed S, Molitch ME, Utz A, Wass JA (2014) Endocrine Society. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocriol Metab 99:3933–3951. https://doi.org/10.1210/jc.2014-2700

    CAS  Article  Google Scholar 

  23. 23.

    Kim EH, Oh MC, Lee EJ, Kim SH (2012) Predicting long-term remission by measuring immediate postoperative growth hormone levels and oral glucose tolerance test in acromegaly. Neurosurgery 70:1106–1113. https://doi.org/10.1227/NEU.0b013e31823f5c16

    Article  PubMed  Google Scholar 

  24. 24.

    Kinoshita Y, Tominaga A, Usui S, Arita K, Sakaguchi T, Sugiyama K, Kuris K (2016) Clinical features and natural course of acromegaly in patients with discordance in the nadir GH level on the oral glucose test and IGF-1 value at 3 months after adenomectomy. Neurosurg Rev 39:313–319. https://doi.org/10.1007/s10143-015-0692-5

    Article  PubMed  Google Scholar 

  25. 25.

    Knosp E, Steiner E, Kitz K, Matula C (1993) Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33:610–617; discussion 617–618. https://doi.org/10.1227/00006123-199310000-00008

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Leonart LP, Borba HHL, Ferreira VL, Riveros BS, Pontarolo R (2018) Cost-effectiveness of acromegaly treatments: a systematic review. Pituitary 21:642–652. https://doi.org/10.1007/s11102-018-0908-0

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Markkanen H, Pekkarinen T, Välimäki MJ, Alfthan H, Kauppinen-Mäkelin R, Sane T, Stenman UH (2006) Effect of sex and assay method on serum concentrations of growth hormone in patients with acromegaly and in healthy controls. Clin Chem 52:468–473. https://doi.org/10.1373/clinchem.2005.060236

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Melmed S, Casanueva FF, Klibanski A, Bronstein MD, Chanson P, Lamberts SW, Strasburger CJ, Wass JA, Giustina A (2013) A consensus on the diagnosis and treatment of acromegaly complications. Pituitary 16:294–302. https://doi.org/10.1007/s11102-012-0420-x

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Nagata Y, Inoshita N, Fukuhara N, Yamaguchi-Okada M, Nishioka H, Iwata T, Yoshimoto K, Yamada S (2018) Growth hormone-producing pituitary adenomas in childhood and young adulthood: clinical features and outcomes. Pituitary 21:1–9. https://doi.org/10.1007/s11102-017-0836-4

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Nishioka H, Fukuhara N, Yamaguchi-Okada M, Takeshita A, Takeuchi Y, Yamada S (2017) Pitfalls in early biochemical evaluation after transsphenoidal surgery in patients with acromegaly. Endocrine J 64:1073–1078. https://doi.org/10.1507/endocrj.EJ17-0261

    CAS  Article  Google Scholar 

  31. 31.

    Otani R, Fukuhara N, Ochi T, Oyama K, Yamada S (2012) Rapid growth hormone measurement during transsphenoidal surgery: analysis of 252 acromegalic patients. Neurol Med Chir (Tokyo) 52:558–562. https://doi.org/10.2176/nmc.52.558

    Article  Google Scholar 

  32. 32.

    Pivonello R, Auriemma RS, Grasso LF, Pivonello C, Simeoli C, Patalano R, Galdiero M, Colao A (2017) Complications of acromegaly: cardiovascular, respiratory8, and metabolic comorbidities. Pituitary 20:46–62. https://doi.org/10.1007/s11102-017-0797-7

    Article  PubMed  Google Scholar 

  33. 33.

    Rostomyan L, Daly AF, Petrossians P, Nachev E, Lila AR, Lecoq AL et al (2015) Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr Relat Cancer 22:745–757. https://doi.org/10.1530/ERC-15-0320

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Rotermund R, Burkhardt T, Rohani Z, Jung R, Aberle J, Flitsch J (2018) Value of early postoperative random growth hormone levels and nadir growth hormone levels after oral glucose tolerance testing in acromegaly. Growth Horm IGF Res 41:64–70. https://doi.org/10.1016/j.ghir.2018.03.002v

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Sarkar S, Jacob KS, Pratheesh R, Chacko AG (2014) Transsphenoidal surgery for acromegaly: predicting remission with early postoperative growth hormone assays. Acta Neurochir (Wien) 156:1379–1387. https://doi.org/10.1007/s00701-014-2098-5

    Article  Google Scholar 

  36. 36.

    Schilbach K, Gar C, Lechner A, Nicolay SS, Schwerdt L, Haenelt M, Dal J, Jørgensen JOL, Störmann S, Schopohl J, Bidlingmaier M (2019) Determinants of the growth hormone nadir during oral glucose tolerance test in adults. Eur J Endocrinol 181:55–67. https://doi.org/10.1530/EJE-19-0139

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Shen M, Tang Y, Shou X, Wang M, Zhang Q, Qiao N, Ma Z, Ye Z, He W, Zhang Y, Chen Z, Zhang Z, Ye H, Li Y, Li S, Zhao Y, Zhou Z, Wang Y (2019) Surgical results and predictors and delayed remission for growth hormone-secreting pituitary adenoma using the 2010 consensus criteria in 162 patients from a single center. World Neurosurg 124:e39–e50. https://doi.org/10.1016/j.wneu.2018.11.179

    Article  Google Scholar 

  38. 38.

    Shin MS, Yu JH, Choi JH, Jung CH, Hwang JY, Cho YH, Kim CJ, Kim MS (2013) Long-term changes in serum IGF-1 levels after successful surgical treatment of growth hormone-secreting pituitary adenoma. Neurosurgery 73:473–479. https://doi.org/10.1227/01.neu.0000431480.87160.84

    Article  PubMed  Google Scholar 

  39. 39.

    Starke RM, Raper DM, Payne SC, Vance ML, Oldfield EH, Jane JA (2013) Endoscopic vs microsurgical transsphenoidal surgery for acromegaly: outcomes in a concurrent series of patients using modern criteria for remission. J Clin Endocrinol Metab 98:3190–3198. https://doi.org/10.1210/jc.2013-1036

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Taghvaei M, Sadrehosseini SM, Ardakani JB, Nakhjavani M, Zeinalizadeh M (2018) Endoscopic endonasal approach to the growth hormone-secreting pituitary adenomas: endocrinologic outcome in 68 patients. World Neurosurg 117:e259–e268. https://doi.org/10.1016/j.wneu.2018.06.009

    Article  PubMed  Google Scholar 

  41. 41.

    Theodosopoulos PV, Leach J, Kerr RG, Zimmer LA, Denny AM, Guthikonda B, Froelich S, Tew JM (2010) Maximizing the extent of tumor resection during transsphenoidal surgery for pituitary macroadenomas: can endoscopy replace intraoperative magnetic resonance imaging? J Neurosurg 112:736–743. https://doi.org/10.3171/2009.6.JNS08916

    Article  PubMed  Google Scholar 

  42. 42.

    Vierhapper H, Heinze G, Gessl A, Exner M, Bieglmayr C (2003) Use of the oral glucose tolerance test to define remission in acromegaly. Metabolism 52:181–185. https://doi.org/10.1053/meta.2003.50036

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Vilar L, Vilar CF, Lyra R, Lyra R, Naves LA (2017) Acromegaly: clinical features at diagnosis. Pituitary 20:22–32. https://doi.org/10.1007/s11102-016-0772-8

    Article  PubMed  Google Scholar 

  44. 44.

    Wang Z, Guo X, Gao L, Feng C, Lian W, Deng K, Bao X, Feng M, Wang R, Xing B (2019) Delayed remission of growth hormone-secreting pituitary adenoma after transsphenoidal adenectomy. World Neurosurg 122:e1137–e1145. https://doi.org/10.1016/j.wneu.2018.11.004

    Article  PubMed  Google Scholar 

  45. 45.

    Xie T, Liu T, Zhang X, Chen L, Luo R, Sun W, Hu F, Yu Y, Gu Y (2016) Time to revive the value of the pseudocapsule in endoscopic endonasal transsphenoidal surgery for growth hormone adenomas. World Neurosurg 89:65–71. https://doi.org/10.1016/j.wneu.2016.01.036

    Article  PubMed  Google Scholar 

  46. 46.

    Yano S, Shinojima N, Kawashima J, Kondo T, Hide T (2017) Intraoperative scoring system to predict postoperative remission in endoscopic endonasal transsphenoidal surgery for growth hormone-secreting pituitary adenomas. World Neurosurg 105:375–385. https://doi.org/10.1016/j.wneu.2017.05.162

    Article  PubMed  Google Scholar 

  47. 47.

    Yu M, Bruns DE, Jane JA, Nass RM, Oldfield EH, Vance ML, Thorner MO (2017) Decrease of serum IGF-1 following transsphenoidal pituitary surgery for acromegaly. Clin Chem 63:486–494. https://doi.org/10.1373/clinchem.2016.262592

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Zahr R, Fleseriu M (2018) Updates in diagnosis and treatment of acromegaly. Eur Endocrinol 14:57–61. https://doi.org/10.17925/EE.2018.14.2.57

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank our helpful and efficient nursing, ENT, and anesthesiology teams for perioperative management of the endoscopic endonasal pituitary surgery.

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Authors

Contributions

Conceptualization: Kiyohiko Sakata and Nobuyuki Takeshige.

Methodology: Kiyohiko Sakata, Yui Nagata, Nobuyuki Takeshige, and Kenji Ashida.

Formal analysis and investigation: Kiyohiko Sakata, Yui Nagata, and Masato Shikata.

Writing—original draft preparation: Kiyohiko Sakata.

Writing—review and editing: Motohiro Morioka

Funding acquisition: Kiyohiko Sakata and Motohiro Morioka.

Resources: Jin Kikuchi and Masato Shikata.

Supervision: Kenji Ashida and Masahito Nomura.

Corresponding author

Correspondence to Kiyohiko Sakata.

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Ethical approval

This study was approved by the ethics committee of the Kurume University School of Medicine (approval number: 18019).

Consent to participate

All patients concurred with the proposed treatment plan after all options for the management of acromegaly were clearly explained. Informed consent was obtained from all individual participants included in this study.

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All authors have read and approved the final manuscript.

Conflict of interest

The authors declare no competing interests.

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Sakata, K., Nagata, Y., Takeshige, N. et al. Early postoperative prediction of both disease remission and long-term disease control in acromegaly using the oral glucose tolerance test. Hormones (2021). https://doi.org/10.1007/s42000-021-00281-7

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Keywords

  • Acromegaly
  • Growth hormone
  • Endoscopic transsphenoidal surgery
  • Remission
  • Oral glucose tolerance test
  • Insulin-like growth factor-1