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Optimal timing of dopamine agonist withdrawal in patients with hyperprolactinemia: a systematic review and meta-analysis

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Abstract

Purpose

Dopamine agonists (DAs) are recommended as first-line treatment for patients with hyperprolactinemia. Generally, it is accepted that patients with hyperprolactinemia do not need lifelong medication, but the optimal timing for DA withdrawal has not been determined. The aim of this systematic review and meta-analysis is to assess the impact of DA withdrawal on the clinical outcomes of patients with hyperprolactinemia, and to explore possible factors affecting successful DA withdrawal.

Methods

The databases of PubMed, Cochrane and EMBASE were searched up to May 2016.

Results

The proportion of patients with persisting normoprolactinemia after DA withdrawal reached 36.6% in a random effects model (95% CI, 29.4–44.2%; I-squared: 82.5%). Data of stratified analysis showed that the success rate of drug withdrawal was high in patients using cabergoline (CAB) as the only treatment (41.2%; 95% CI 32.3–50.4%) and those using CAB over 24 months (48.7%; 95% CI 38.9–58.5%), especially in patients with idiopathic hyperprolactinemia (73.2%; 95% CI 55.6–87.7%). In addition, patients who received a low maintenance dose of CAB, and had a significant reduction in tumor size (over 50%) before withdrawal, were more likely to achieve success (51.5 and 49.4%, respectively).

Conclusion

The success rate of DA withdrawal has increased in recent years. Further, the success rate of CAB withdrawal was higher than that of bromocriptine, especially in patients with a duration of treatment longer than 24 months. Conclusively, the probability of success was higher in patients who received low-dose CAB maintenance treatment and those who achieved a significant reduction in tumor size before withdrawal.

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References

  1. S. Melmed, F.F. Casanueva, A.R. Hoffman, D.L. Kleinberg, V.M. Montori, J.A. Schlechte, J.A. Wass, Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 96(2), 273–288 (2011). https://doi.org/10.1210/jc.2010-1692

    Article  CAS  PubMed  Google Scholar 

  2. A. Colao, A. Di Sarno, E. Guerra, M. De Leo, A. Mentone, G. Lombardi, Drug insight: cabergoline and bromocriptine in the treatment of hyperprolactinemia in men and women. Nat. Clin. Pract. Endocrinol. Metab. 2(4), 200–210 (2006). https://doi.org/10.1038/ncpendmet0160

    Article  CAS  PubMed  Google Scholar 

  3. Z.B. Wu, C.J. Yu, Z.P. Su, Q.C. Zhuge, J.S. Wu, W.M. Zheng, Bromocriptine treatment of invasive giant prolactinomas involving the cavernous sinus: results of a long-term follow up. J. Neurosurg. 104(1), 54–61 (2006). https://doi.org/10.3171/jns.2006.104.1.54

    Article  CAS  PubMed  Google Scholar 

  4. A. Colao, A. di Sarno, R. Pivonello, C. di Somma, G. Lombardi, Dopamine receptor agonists for treating prolactinomas. Expert Opin. Investig. Drugs 11(6), 787–800 (2002). https://doi.org/10.1517/13543784.11.6.787

    Article  CAS  PubMed  Google Scholar 

  5. M.P. Gillam, M.E. Molitch, G. Lombardi, A. Colao, Advances in the treatment of prolactinomas. Endocr. Rev. 27(5), 485–534 (2006). https://doi.org/10.1210/er.2005-9998

    Article  CAS  PubMed  Google Scholar 

  6. J.J. Orrego, W.F. Chandler, A.L. Barkan, Rapid re-expansion of a macroprolactinoma after early discontinuation of bromocriptine. Pituitary 3(3), 189–192 (2000)

    Article  CAS  PubMed  Google Scholar 

  7. M.E. Molitch, Medical treatment of prolactinomas. Endocrinol. Metab. Clin. N. Am. 28(1), 143–169 (1999)

    Article  CAS  Google Scholar 

  8. M.O. Thorner, R.L. Perryman, A.D. Rogol, B.P. Conway, R.M. Macleod, I.S. Login, J.L. Morris, Rapid changes of prolactinoma volume after withdrawal and reinstitution of bromocriptine. J. Clin. Endocrinol. Metab. 53(3), 480–483 (1981). https://doi.org/10.1210/jcem-53-3-480

    Article  CAS  PubMed  Google Scholar 

  9. F.F. Casanueva, M.E. Molitch, J.A. Schlechte, R. Abs, V. Bonert, M.D. Bronstein, T. Brue, P. Cappabianca, A. Colao, R. Fahlbusch, H. Fideleff, M. Hadani, P. Kelly, D. Kleinberg, E. Laws, J. Marek, M. Scanlon, L.G. Sobrinho, J.A. Wass, A. Giustina, Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clin. Endocrinol. 65(2), 265–273 (2006). https://doi.org/10.1111/j.1365-2265.2006.02562.x

    Article  Google Scholar 

  10. O.M. Dekkers, J. Lagro, P. Burman, J.O. Jorgensen, J.A. Romijn, A.M. Pereira, Recurrence of hyperprolactinemia after withdrawal of dopamine agonists: systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 95(1), 43–51 (2010). https://doi.org/10.1210/jc.2009-1238

    Article  CAS  PubMed  Google Scholar 

  11. P. Anagnostis, F. Adamidou, S.A. Polyzos, Z. Efstathiadou, E. Karathanassi, M. Kita, Long term follow-up of patients with prolactinomas and outcome of dopamine agonist withdrawal: a single center experience. Pituitary 15(1), 25–29 (2012). https://doi.org/10.1007/s11102-011-0303-6

    Article  PubMed  Google Scholar 

  12. J. Kharlip, R. Salvatori, G. Yenokyan, G.S. Wand, Recurrence of hyperprolactinemia after withdrawal of long-term cabergoline therapy. J. Clin. Endocrinol. Metab. 94(7), 2428–2436 (2009). https://doi.org/10.1210/jc.2008-2103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. A. Colao, A. Di Sarno, P. Cappabianca, C. Di Somma, R. Pivonello, G. Lombardi, Withdrawal of long-term cabergoline therapy for tumoral and nontumoral hyperprolactinemia. N. Engl. J. Med. 349(21), 2023–2033 (2003). https://doi.org/10.1056/NEJMoa022657

    Article  CAS  PubMed  Google Scholar 

  14. J.P. Higgins, S.G. Thompson, J.J. Deeks, D.G. Altman, Measuring inconsistency in meta-analyses. BMJ 327(7414), 557–560 (2003). https://doi.org/10.1136/bmj.327.7414.557

    Article  PubMed  PubMed Central  Google Scholar 

  15. R. Kwancharoen, R.S. Auriemma, G. Yenokyan, G.S. Wand, A. Colao, R. Salvatori, Second attempt to withdraw cabergoline in prolactinomas: a pilot study. Pituitary 17(5), 451–456 (2014). https://doi.org/10.1007/s11102-013-0525-x

    Article  CAS  PubMed  Google Scholar 

  16. L. Vilar, J.L. Albuquerque, P.S. Gadelha, F. Rangel Filho, A.M. Siqueira, M.M. da Fonseca, K.F. Viana, B.S. Gomes, R. Lyra, Second attempt of cabergoline withdrawal in patients with prolactinomas after a failed first attempt: is it worthwhile? Front. Endocrinol. 6, 11 (2015). https://doi.org/10.3389/fendo.2015.00011

    Article  Google Scholar 

  17. G. Faglia, A. Conti, M. Muratori, E. Togni, P. Travaglini, A. Zanotti, F. Mailland, Dihydroergocriptine in management of microprolactinomas. J. Clin. Endocrinol. Metab. 65(4), 779–784 (1987). https://doi.org/10.1210/jcem-65-4-779

    Article  CAS  PubMed  Google Scholar 

  18. A. Liuzzi, D. Dallabonzana, G. Oppizzi, G.G. Verde, R. Cozzi, P. Chiodini, G. Luccarelli, Low doses of dopamine agonists in the long-term treatment of macroprolactinomas. N. Engl. J. Med. 313(11), 656–659 (1985). https://doi.org/10.1056/nejm198509123131103

    Article  CAS  PubMed  Google Scholar 

  19. A. Di Sarno, M.L. Landi, P. Marzullo, C. Di Somma, R. Pivonello, G. Cerbone, G. Lombardi, A. Colao, The effect of quinagolide and cabergoline, two selective dopamine receptor type 2 agonists, in the treatment of prolactinomas. Clin. Endocrinol. 53(1), 53–60 (2000)

    Article  Google Scholar 

  20. W. Winkelmann, B. Allolio, U. Deuss, D. Heesen, D. Kaulen, in Persisting Normoprolactinemia After Withdrawal of Bromocriptine Long-term Therapy in Patients with Prolactinomas, (ed.), by R.M. Macleod, M.O. Thorner, U. Scapagnini. Basic and Clinical Correlates (Liviana Press, Padova, 1985), pp. 817–822

  21. M. Giusti, E. Porcella, A. Carraro, M. Cuttica, S. Valenti, G. Giordano, A cross-over study with the two novel dopaminergic drugs cabergoline and quinagolide in hyperprolactinemic patients. J. Endocrinol. Investig. 17(1), 51–57 (1994). https://doi.org/10.1007/bf03344963

    Article  CAS  Google Scholar 

  22. V.Q. Passos, J.J. Souza, N.R. Musolino, M.D. Bronstein, Long-term follow-up of prolactinomas: normoprolactinemia after bromocriptine withdrawal. J. Clin. Endocrinol. Metab. 87(8), 3578–3582 (2002). https://doi.org/10.1210/jcem.87.8.8722

    Article  CAS  PubMed  Google Scholar 

  23. A. Zarate, E.S. Canales, C. Cano, C.J. Pilonieta, Follow-up of patients with prolactinomas after discontinuation of long-term therapy with bromocriptine. Acta Endocrinol. 104(2), 139–142 (1983)

    CAS  PubMed  Google Scholar 

  24. S. Cannavo, L. Curto, S. Squadrito, B. Almoto, A. Vieni, F. Trimarchi, Cabergoline: a first-choice treatment in patients with previously untreated prolactin-secreting pituitary adenoma. J. Endocrinol. Investig. 22(5), 354–359 (1999). https://doi.org/10.1007/bf03343573

    Article  CAS  Google Scholar 

  25. M. Muratori, M. Arosio, G. Gambino, C. Romano, O. Biella, G. Faglia, Use of cabergoline in the long-term treatment of hyperprolactinemic and acromegalic patients. J. Endocrinol. Investig. 20(9), 537–546 (1997). https://doi.org/10.1007/bf03348016

    Article  CAS  Google Scholar 

  26. M.S. Huda, N.B. Athauda, M.M. Teh, P.V. Carroll, J.K. Powrie, Factors determining the remission of microprolactinomas after dopamine agonist withdrawal. Clin. Endocrinol. 72(4), 507–511 (2010). https://doi.org/10.1111/j.1365-2265.2009.03657.x

    Article  CAS  Google Scholar 

  27. T.M. Barber, J. Kenkre, C. Garnett, R.V. Scott, J.V. Byrne, J.A. Wass, Recurrence of hyperprolactinaemia following discontinuation of dopamine agonist therapy in patients with prolactinoma occurs commonly especially in macroprolactinoma. Clin. Endocrinol. 75(6), 819–824 (2011). https://doi.org/10.1111/j.1365-2265.2011.04136.x

    Article  CAS  Google Scholar 

  28. E.E. Buyukbayrak, A.Y. Karageyim Karsidag, B. Kars, O. Balcik, M. Pirimoglu, O. Unal, C. Turan, Effectiveness of short-term maintenance treatment with cabergoline in microadenoma-related and idiopathic hyperprolactinemia. Arch. Gynecol. Obstet. 282(5), 561–566 (2010). https://doi.org/10.1007/s00404-010-1562-6

    Article  CAS  PubMed  Google Scholar 

  29. P. Moriondo, P. Travaglini, M. Nissim, A. Conti, G. Faglia, Bromocriptine treatment of microprolactinomas: evidence of stable prolactin decrease after drug withdrawal. J. Clin. Endocrinol. Metab. 60(4), 764–772 (1985). https://doi.org/10.1210/jcem-60-4-764

    Article  CAS  PubMed  Google Scholar 

  30. M. Biswas, J. Smith, D. Jadon, P. McEwan, D.A. Rees, L.M. Evans, M.F. Scanlon, J.S. Davies, Long-term remission following withdrawal of dopamine agonist therapy in subjects with microprolactinomas. Clin. Endocrinol. 63(1), 26–31 (2005). https://doi.org/10.1111/j.1365-2265.2005.02293.x

    Article  CAS  Google Scholar 

  31. J.W. van‘t Verlaat, R.J. Croughs, Withdrawal of bromocriptine after long-term therapy for macroprolactinomas; effect on plasma prolactin and tumour size. Clin. Endocrinol. 34(3), 175–178 (1991)

    Article  Google Scholar 

  32. C. Ferrari, A. Paracchi, A.M. Mattei, S. de Vincentiis, A. D’Alberton, P. Crosignani, Cabergoline in the long-term therapy of hyperprolactinemic disorders. Acta. Endocrinol. 126(6), 489–494 (1992)

    CAS  PubMed  Google Scholar 

  33. K.Y. Ho, G.A. Smythe, P.J. Compton, L. Lazarus, Long-term bromocriptine therapy may restore the inhibitory control of prolactin release in some patients with pathological hyperprolactinemia. Aust. N. Z. J. Med. 15(2), 213–219 (1985)

    Article  CAS  PubMed  Google Scholar 

  34. A.M. Mattei, C. Ferrari, G. Ragni, R. Benco, M.C. Picciotti, P. Rampini, R. Caldara, P.G. Crosignani, Serum prolactin and ovarian function after discontinuation of drug treatment for hyperprolactinaemia: a study with bromocriptine and metergoline. Br. J. Obstet. Gynaecol. 91(3), 244–250 (1984)

    Article  CAS  PubMed  Google Scholar 

  35. M. Martin de Santa-Olalla y Llanes, V.M. Andia Melero, A. Jara Albarran, [Long-term evolution and outcomes of microprolactinoma with medical treatment]. Endocrinol. Nutr. 60(9), 489–494 (2013). https://doi.org/10.1016/j.endonu.2013.03.007

    Article  PubMed  Google Scholar 

  36. S.C. Dogansen, O.S. Selcukbiricik, S. Tanrikulu, S. Yarman, Withdrawal of dopamine agonist therapy in prolactinomas: In which patients and when? Pituitary 19(3), 303–310 (2016). https://doi.org/10.1007/s11102-016-0708-3

    Article  CAS  PubMed  Google Scholar 

  37. E. Sala, P. Bellaviti Buttoni, E. Malchiodi, E. Verrua, G. Carosi, E. Profka, G. Rodari, M. Filopanti, E. Ferrante, A. Spada, G. Mantovani, Recurrence of hyperprolactinemia following dopamine agonist withdrawal and possible predictive factors of recurrence in prolactinomas. J. Endocr. Investig. (2016). https://doi.org/10.1007/s40618-016-0483-z

  38. A. Colao, A. Di Sarno, E. Guerra, R. Pivonello, P. Cappabianca, F. Caranci, A. Elefante, L.M. Cavallo, F. Briganti, S. Cirillo, G. Lombardi, Predictors of remission of hyperprolactinaemia after long-term withdrawal of cabergoline therapy. Clin. Endocrinol. 67(3), 426–433 (2007). https://doi.org/10.1111/j.1365-2265.2007.02905.x

    Article  CAS  Google Scholar 

  39. M. Coculescu, N. Simionescu, M. Oprescu, D. Alessandrescu, Bromocriptine treatment of pituitary adenomas. Evaluation of withdrawal effect. Endocrinologie 21(3), 157–168 (1983)

    CAS  PubMed  Google Scholar 

  40. T. Eversmann, R. Fahlbusch, H.K. Rjosk, K. von Werder, Persisting suppression of prolactin secretion after long-term treatment with bromocriptine in patients with prolactinomas. Acta. Endocrinol. 92(3), 413–427 (1979)

    CAS  PubMed  Google Scholar 

  41. W.S. Maxson, M. Dudzinski, S.H. Handwerger, C.B. Hammond, Hyperprolactinemic response after bromocriptine withdrawal in women with prolactin-secreting pituitary tumors. Fertil. Steril. 41(2), 218–223 (1984)

    Article  CAS  PubMed  Google Scholar 

  42. L.G. Sobrinho, M.C. Nunes, C. Calhaz-Jorge, J.C. Mauricio, M.A. Santos, Effect of treatment with bromocriptine on the size and activity of prolactin producing pituitary tumours. Acta. Endocrinol. 96(1), 24–29 (1981)

    CAS  PubMed  Google Scholar 

  43. J. Hu, X. Zheng, W. Zhang, H. Yang, Current drug withdrawal strategy in prolactinoma patients treated with cabergoline: a systematic review and meta-analysis. Pituitary 18(5), 745–751 (2015). https://doi.org/10.1007/s11102-014-0617-2

    Article  CAS  PubMed  Google Scholar 

  44. M.E. Molitch, Pituitary gland: can prolactinomas be cured medically? Nat. Rev. Endocrinol. 6(4), 186–188 (2010). https://doi.org/10.1038/nrendo.2009.278

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Ms. Erin M. Botticelli of Massachusetts General Hospital for her careful reading and editing of the manuscript.

Funding

This work was supported by Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (Grant No. 20161407), and the National Natural Science Foundation of China (Grant No. 81471392, 81271523).

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    Authors and Affiliations

    1. Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China

      Miao Yun Xia, Shao Jian Lin & Zhe Bao Wu

    2. Department of Neurosurgery, Third Affiliated Hospital of Wenzhou Medical University, 325200, Wenzhou, China

      Xiao Hui Lou

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    Correspondence to Zhe Bao Wu.

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    Miao Yun Xia and Xiao Hui Lou contributed equally to this work.

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    Xia, M.Y., Lou, X.H., Lin, S.J. et al. Optimal timing of dopamine agonist withdrawal in patients with hyperprolactinemia: a systematic review and meta-analysis. Endocrine 59, 50–61 (2018). https://doi.org/10.1007/s12020-017-1444-9

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