Abstract
Resistance to dopamine agonists occurs in a subset of patients with prolactin-secreting pituitary tumors. The resistance is mediated by loss of pituitary D2 receptors and occurs in both microadenomas and macroadenomas. Cabergoline is the most effective dopamine agonist and tumors that do not respond to bromocriptine or quinagolide frequently respond to cabergoline. Treatment options include maximizing the dose of the dopamine agonist, changing agonists, trans-sphenoidal surgery and radiation therapy. The goal of therapy is to restore and maintain gonadal and neurologic function, and this might occur in the absence of a normal prolactin level or a significant change in tumor size. Trans-sphenoidal pituitary surgery should be reserved for patients who are intolerant of medical therapy, or in whom this has failed. Radiation therapy has a limited role in treatment of resistant prolactinomas and should be reserved for patients in whom medical and surgical therapy has failed.
Key Points
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10–20% of patients with microprolactinomas and 20–30% of patients with macroadenomas demonstrate resistance to a dopamine agonist
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Treatment might restore and maintain gonadal and neurologic function without normalization of prolactin levels or a change in tumor size
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Tumors resistant to bromocriptine or quinagolide frequently respond to cabergoline
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Trans-sphenoidal surgery should be reserved for treatment of patients who are intolerant of medical therapy, or in whom this has failed
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References
Jane JA and Laws ER (2001) The surgical management of pituitary adenomas in a series of 3093 patients. J Am Coll Surg 193: 651–659
Nomikos P et al. (2001) Current management of prolactinomas. J Neuroophthalmol 54: 139–150
Kovacs K et al. (1995) Prolactin-producing pituitary tumor: resistance to dopamine agonist therapy. J Neurosurg 82: 886–890
Delgrange E et al. (1996) Effects of the dopamine agonist cabergoline in patients with prolactinoma intolerant or resistant to bromocriptine. Eur J Endocrinol 134: 454–456
Pellegrini I et al. (1989) Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab 69: 500–509
Brue T et al. (1992) Effects of the dopamine agonist CV 205-502 in human prolactinomas resistant to bromocriptine. J Clin Endocrinol Metab 74: 577–584
Ho KY and Thorner MO (1988) Therapeutic applications of bromocriptine in endocrine and neurological diseases. Drugs 36: 67–82
Grossman A et al. (1980) Two new dopamine agonists that are long acting in vivo but short acting in vitro. Clin Endocrinol (Oxf) 13: 595–599
Rasmussen C et al. (1987) CV 205-602: A new long-acting drug for inhibition of prolactin hypersecretion. Clin Endocrinol (Oxf) 26: 321–326
Rains CP et al. (1995) Cabergoline. A review of its pharmacological properties and therapeutic potential in treatment of hyperprolactinaemia and inhibition of lactation. Drugs 49: 255–279
De Camilli P et al. (1979) Dopamine inhibits adenylate cyclase in human prolactin-secreting pituitary adenomas. Nature 278: 252–254
Liu YF et al. (1994) G protein specificity in receptor-effector coupling. Analysis of the roles of G0 and Gi2 in GH4C1 pituitary cells. J Biol Chem 269: 13880–13886
Maurer RA (1981) Transcriptional regulation of the prolactin gene by ergocryptine and cyclic AMP. Nature 294: 94–97
Kolesnick RN and Gershengorn MC (1986) Thyrotropin-releasing hormone stimulation of prolactin secretion is coordinately but not synergistically regulated by an elevation of cytoplasmic calcium and 1,2-diacylglycerol. Endocrinology 119: 2461–2466
Vallar L et al. (1988) Inhibition of inositol phosphate production is a late, Ca2+-dependent effect of D2 dopaminergic receptor activation in rat lactotroph cells. J Biol Chem 263: 10127–10134
Tindall GT et al. (1982) Human prolactin-producing adenomas and bromocriptine: a histological, immunocytochemical, ultrastructural, and morphometric study. J Clin Endocrinol Metab 55: 1178–1183
Duffy AE et al. (1988) Effect of bromocriptine on secretion and morphology of human prolactin cell adenomas in vitro. Horm Res 30: 32–38
Thorner MO et al. (1980) A broad spectrum of prolactin suppression by bromocriptine in hyperprolactinemic women: A study of serum prolactin and bromocriptine levels after acute and chronic administration of bromocriptine. J Endocrinol Metab 50: 1026–1033
Verhelst J et al. (1999) Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients. J Clin Endocrinol Metab 84: 2518–2522
Molitch ME et al. (1985) Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab 60: 698–705
Colao A et al. (2004) Outcome of cabergoline treatment in men with prolactinoma: effects of a 24-month treatment on prolactin levels, tumor mass, recovery of pituitary function, and semen analysis. J Clin Endocrinol Metab 89: 1704–1711
Ferrari CI et al. (1997) Treatment of macroprolactinoma with cabergoline: a study of 85 patients. Clin Endocrinol (Oxf) 46: 409–413
Di Sarno A et al. (2001) Resistance to cabergoline as compared with bromocriptine in hyperprolactinemia: prevalence, clinical definition, and therapeutic strategy. J Clin Endocrinol Metab 86: 5256–5261
Webster J et al. (1994) A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group. N Engl J Med 331: 904–909
McElvaney NG et al. (1988) Pleuropulmonary disease during bromocriptine treatment of Parkinson's disease. Arch Intern Med 148: 2231–2236
Turner TH et al. (1984) Psychotic reactions during treatment of pituitary tumours with dopamine agonists. Br Med J (Clin Res Ed) 289: 1101–1103
Sabuncu T et al. (2001) Comparison of the effects of cabergoline and bromocriptine on prolactin levels in hyperprolactinemic patients. Intern Med 40: 857–861
Badano AR et al. (1979) Bromocriptine in the treatment of hyperprolactinemic amenorrhea. Fertil Steril 31: 124–129
Moro M et al. (1991) Comparison between a slow-release oral preparation of bromocriptine and regular bromocriptine in patients with hyperprolactinemia: a double blind, double dummy study. Horm Res 35: 137–141
Crosignani PG et al. (1982) Treatment of hyperprolactinemic states with different drugs: a study with bromocriptine, metergoline, and lisuride. Fertil Steril 37: 61–67
Bergh T et al. (1978) Bromocriptine treatment of 42 hyperprolactinaemic women with secondary amenorrhoea. Acta Endocrinol (Copenh) 88: 435–451
Thorner MO and Besser GM (1978) Bromocriptine treatment of hyperprolactinaemic hypogonadism. Acta Endocrinol Suppl (Copenh) 216: 131–146
Wang C et al. (1987) Long-term treatment of hyperprolactinaemia with bromocriptine: effect of drug withdrawal. Clin Endocrinol (Oxf) 27: 363–371
Moriondo P et al. (1985) Bromocriptine treatment of microprolactinomas: evidence of stable prolactin decrease after drug withdrawal. J Clin Endocrinol Metab 60: 764–772
Cannavo S et al. (1999) Cabergoline: a first-choice treatment in patients with previously untreated prolactin-secreting pituitary adenoma. J Endocrinol Invest 22: 354–359
Colao A et al. (2003) Gender differences in the prevalence, clinical features and response to cabergoline in hyperprolactinemia. Eur J Endocrinol 148: 325–331
De Rosa M et al. (2004) Six months of treatment with cabergoline restores sexual potency in hyperprolactinemic males: an open longitudinal study monitoring nocturnal penile tumescence. J Clin Endocrinol Metab 89: 621–625
Ferrari C et al. (1989) Cabergoline: long-acting oral treatment of hyperprolactinemic disorders. J Clin Endocrinol Metab 68: 1201–1206
Wass JA et al. (1982) Bromocriptine in management of large pituitary tumours. Br Med J (Clin Res Ed) 284: 1908–1911
Liuzzi A et al. (1985) Low doses of dopamine agonists in the long-term treatment of macroprolactinomas. N Engl J Med 313: 656–659
Pinzone JJ et al. (2000) Primary medical therapy of micro- and macroprolactinomas in men. J Clin Endocrinol Metab 85: 3053–3057
Sieck JO et al. (1986) Extrasellar prolactinomas: successful management of 24 patients using bromocriptine. Horm Res 23: 67–76
van 't Verlaat JW et al. (1986) Bromocriptine treatment of prolactin secreting macroadenomas: a radiological, ophthalmological and endocrinological study. Acta Endocrinol (Copenh) 112: 487–493
Colao A et al. (2000) Macroprolactinoma shrinkage during cabergoline treatment is greater in naive patients than in patients pretreated with other dopamine agonists: a prospective study in 110 patients. J Clin Endocrinol Metab 85: 2247–2252
Pontikides N et al. (2000) Cabergoline as a first-line treatment in newly diagnosed macroprolactinomas. Pituitary 2: 277–281
Ferrari C et al. (1992) Cabergoline in the long-term therapy of hyperprolactinemic disorders. Acta Endocrinol (Copenh) 126: 489–494
Horowitz BL et al. (1983) Effect of bromocriptine and pergolide on pituitary tumor size and serum prolactin. Am J Neuroradiol 4: 415–417
Freda PU et al. (2000) Long-term treatment of prolactin-secreting macroadenomas with pergolide. J Clin Endocrinol Metab 85: 8–13
Orrego JJ et al. (2000) Pergolide as primary therapy for macroprolactinomas. Pituitary 3: 251–256
Kleinberg DL et al. (1983) Pergolide for the treatment of pituitary tumors secreting prolactin or growth hormone. N Engl J Med 309: 704–709
Hermite ML et al. (1983) Treatment of hyperprolactinemic patients with pergolide. Acta Endocrinol 103: 441–445
Di Sarno A et al. (2000) The effect of quinagolide and cabergoline, two selective dopamine receptor type 2 agonists, in the treatment of prolactinomas. Clin Endocrinol (Oxf) 53: 53–60
Caccavelli L et al. (1994) Decreased expression of the two D2 dopamine receptor isoforms in bromocriptine-resistant prolactinomas. Neuroendocrinology 60: 314–322
Delgrange E et al. (2005) Clinical and histological correlations in prolactinomas, with special reference to bromocriptine resistance. Acta Neurochir (Wien) 147: 751–758
Brue T et al. (1992) Prolactinomas and resistance to dopamine agonists. Horm Res 38: 84–89
Krupp P and Monka C (1987) Bromocriptine in pregnancy: safety aspects. Klin Wochenschr 65: 823–827
Musatti RE et al. (1996) Pregnancy outcome after treatment with the ergot derivative, cabergoline. Reprod Toxicol 10: 333–337
Ricci E et al. (2002) Pregnancy outcome after cabergoline treatment in early weeks of gestation. Reprod Toxicol 16: 791–793
Howell D et al. (2005) The use of high-dose cabergoline in an adolescent patient with macroprolactinoma. J Pediatr Hematol Oncol 27: 326–329
Gillam M et al. (2002) The novel use of very high doses of cabergoline and a combination of testosterone and an aromatase inhibitor in the treatment of a giant prolactinoma. J Clin Endocrinol Metab 87: 4447–4451
Morange I et al. (1996) Prolactinomas resistant to bromocriptine: long-term efficacy of quinagolide and outcome of pregnancy. Eur J Endocrinol 135: 413–420
Rohmer V et al. (2000) Efficacy of quinagolide in resistance to dopamine agonists: results of a multicenter study. Club de l'Hypophyse. Ann Endocrinol (Paris) 61: 411–417
Colao A et al. (1997) Prolactinomas resistant to standard dopamine agonists respond to chronic cabergoline treatment. J Clin Endocrinol Metab 82: 876–883
Hamilton DK et al. (2005) Surgical outcomes in hyporesponsive prolactinomas: Analysis of patients with resistance or intolerance to dopamine agonists. Pituitary 8: 53–60
Landolt AM et al. (1982) Bromocriptine: does it jeopardize the result of later surgery for prolactinomas? Lancet 2 (8299): 657–658
Faglia G et al. (1883) Influence of previous bromocriptine therapy on surgery for microprolactinomas. Lancet 1(8316): 133–134
Thomson JA et al. (1994) Ten year follow-up of microprolactinoma treated by trans-sphenoidal surgery. BMJ 309: 409–410
Becker G et al. (2002) Radiation therapy in the multimodal treatment approach of pituitary adenoma. Strahlenther Onkol 178: 173–186
Gittoes NJL (2005) Pituitary radiotherapy: current controversies. Trends Endocrinol Metab 16: 407–413
Laws ER et al. (2004) Stereotactic radiosurgery for pituitary adenomas: a review of the literature. J Neurooncol 69: 257–272
Pan L et al. (1998) Pituitary adenomas: the effect of gamma knife radiosurgery on tumor growth and endocrinopathies. Stereotact Funct Neurosurg 70 (Suppl 1): 119–126
Brada M et al. (2004) Radiosurgery for pituitary adenomas. Clin Endocrinol (Oxf) 61: 531–543
Sheehan JP et al. (2005) Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy and role in the neurosurgical treatment armamentarium. J Neurosurg 102: 678–691
Molitch ME (1985) Pregnancy and the hyperprolactinemic woman. N Engl J Med 312: 1365–1370
Brodsky JB et al. (1980) Surgery during pregnancy and fetal outcome. Am J Obstet Gynecol 138: 1165–1167
Testa G et al. (1998) Two-year treatment with oral contraceptives in hyperprolactinemic patients. Contraception 58: 69–73
Corenblum B and Donovan L (1993) The safety of physiological estrogen plus progestin replacement therapy and with oral contraceptive therapy in women with pathological hyperprolactinemia. Fertil Steril 59: 671–673
Schlechte J et al. (1987) Forearm and vertebral bone mineral in treated and untreated hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 64: 1021–1026
Klibanski A and Greenspan SL (1986) Increase in bone mass after treatment of hyperprolactinemic amenorrhea. N Engl J Med 315: 542–546
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Olafsdottir, A., Schlechte, J. Management of resistant prolactinomas. Nat Rev Endocrinol 2, 552–561 (2006). https://doi.org/10.1038/ncpendmet0290
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DOI: https://doi.org/10.1038/ncpendmet0290
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