Dopamine agonist–resistant prolactinomas

A review

Restricted access

The authors' object in this paper was to review the definition, epidemiology, biology, resistance mechanisms, and treatment options for dopamine agonist–resistant prolactinomas (DARPs).

Prolactinomas are relatively unique among primary brain tumors in that medical treatment alone using dopamine agonists carries a high probability of disease control or even radiographic and endocrine remission, and thus has replaced surgery as the first line of therapy. Unfortunately, slightly less than 10% of patients with prolactinomas do not experience normalization of their prolactin levels in response to dopamine agonists, and harbor tumors that are resistant to dopamine agonist therapy. A literature review underscores that in male patients these DARPs are more likely to be invasive macroadenomas than dopamine agonist–responsive prolactinomas and that they are also more angiogenic, more proliferative, and more likely to exhibit cellular atypia. Estrogen receptor antagonists and temozolomide are the most commonly applied medical therapies in cases in which resection and radiosurgery have not induced remission of the hyperprolactinemia.

Dopamine agonist–resistant prolactinomas exhibit aggressive behavior and tend to be large, invasive, hyperangiogenic tumors with high mitotic indices, which makes their management via surgery, radiosurgery, or alternative medical therapies challenging, thus underscoring the need for novel medical therapies or treatment regimens that target these lesions.

Abbreviations used in this paper: cAMP = cyclic adenosine monophosphate; DARP = dopamine agonist–resistant prolactinoma; NGF = nerve growth factor; NGFR = NGF receptor; SSTR = somatostatin receptor.
Article Information

Contributor Notes

Address correspondence to: Manish K. Aghi, M.D., Ph.D., The California Center for Pituitary Disorders, University of California, San Francisco, 505 Parnassus Avenue, Room M779, San Francisco, California 94143-0112. email: AghiM@neurosurg.ucsf.edu.Please include this information when citing this paper: published online January 7, 2011; DOI: 10.3171/2010.11.JNS101369.

© AANS, except where prohibited by US copyright law.

Headings
References
  • 1

    Bassetti MSpada APezzo GGiannattasio G: Bromocriptine treatment reduces the cell size in human macroprolactinomas: a morphometric study. J Clin Endocrinol Metab 58:2682731984

    • Search Google Scholar
    • Export Citation
  • 2

    Behan LADraman MSMoran CKing TCrowley RKO'Sullivan EP: Secondary resistance to cabergoline therapy in a macroprolactinoma: a case report and literature review. Pituitary [epub ahead of print]2009

    • Search Google Scholar
    • Export Citation
  • 3

    Biller BMMolitch MEVance MLCannistraro KBDavis KRSimons JA: Treatment of prolactin-secreting macroadenomas with the once-weekly dopamine agonist cabergoline. J Clin Endocrinol Metab 81:233823431996

    • Search Google Scholar
    • Export Citation
  • 4

    Bression DBrandi AMMartres MPNousbaum ACesselin FRacadot J: Dopaminergic receptors in human prolactin-secreting adenomas: a quantitative study. J Clin Endocrinol Metab 51:103710441980

    • Search Google Scholar
    • Export Citation
  • 5

    Brue TPellegrini IGunz GMorange IDewailly DBrownell J: Effects of the dopamine agonist CV 205–502 in human prolactinomas resistant to bromocriptine. J Clin Endocrinol Metab 74:5775841992

    • Search Google Scholar
    • Export Citation
  • 6

    Brue TPellegrini IPriou AMorange IJaquet P: Prolactinomas and resistance to dopamine agonists. Horm Res 38:84891992

  • 7

    Caccavelli LFeron FMorange IRouer EBenarous RDewailly D: Decreased expression of the two D2 dopamine receptor isoforms in bromocriptine-resistant prolactinomas. Neuroendocrinology 60:3143221994

    • Search Google Scholar
    • Export Citation
  • 8

    Caccavelli LMorange-Ramos IKordon CJaquet PEnjalbert A: Alteration of G alpha subunits mRNA levels in bromocriptine resistant prolactinomas. J Neuroendocrinol 8:7377461996

    • Search Google Scholar
    • Export Citation
  • 9

    Cannavò SBartolone LBlandino ASpinella SGalatioto STrimarchi F: Shrinkage of a PRL-secreting pituitary macroadenoma resistant to cabergoline. J Endocrinol Invest 22:3063091999

    • Search Google Scholar
    • Export Citation
  • 10

    Casanueva FFMolitch MESchlechte JAAbs RBonert VBronstein MD: Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas. Clin Endocrinol (Oxf) 65:2652732006

    • Search Google Scholar
    • Export Citation
  • 11

    Colao A: Pituitary tumours: the prolactinoma. Best Pract Res Clin Endocrinol Metab 23:5755962009

  • 12

    Colao ADi Sarno ALandi MLCirillo SSarnacchiaro FFacciolli G: Long-term and low-dose treatment with cabergoline induces macroprolactinoma shrinkage. J Clin Endocrinol Metab 82:357435791997

    • Search Google Scholar
    • Export Citation
  • 13

    Colao Adi Sarno APivonello Rdi Somma CLombardi G: Dopamine receptor agonists for treating prolactinomas. Expert Opin Investig Drugs 11:7878002002

    • Search Google Scholar
    • Export Citation
  • 14

    Colao ADi Sarno ASarnacchiaro FFerone DDi Renzo GMerola B: Prolactinomas resistant to standard dopamine agonists respond to chronic cabergoline treatment. J Clin Endocrinol Metab 82:8768831997

    • Search Google Scholar
    • Export Citation
  • 15

    Colao ALombardi G: Growth-hormone and prolactin excess. Lancet 352:145514611998

  • 16

    Colao APivonello RDi Somma CSavastano SGrasso LFLombardi G: Medical therapy of pituitary adenomas: effects on tumor shrinkage. Rev Endocr Metab Disord 10:1111232009

    • Search Google Scholar
    • Export Citation
  • 17

    Cronin MJCheung CYWilson CBJaffe RBWeiner RI: [3H]Spiperone binding to human anterior pituitaries and pituitary adenomas secreting prolactin, growth hormone, and adrenocorticotropic hormone. J Clin Endocrinol Metab 50:3873911980

    • Search Google Scholar
    • Export Citation
  • 18

    Daly AFRixhon MAdam CDempegioti ATichomirowa MABeckers A: High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium. J Clin Endocrinol Metab 91:476947752006

    • Search Google Scholar
    • Export Citation
  • 19

    De Camilli PMacconi DSpada A: Dopamine inhibits adenylate cyclase in human prolactin-secreting pituitary adenomas. Nature 278:2522541979

    • Search Google Scholar
    • Export Citation
  • 20

    Delgrange ECrabbé JDonckier J: Late development of resistance to bromocriptine in a patient with macroprolactinoma. Horm Res 49:2502531998

    • Search Google Scholar
    • Export Citation
  • 21

    Delgrange EDaems TVerhelst JAbs RMaiter D: Characterization of resistance to the prolactin-lowering effects of cabergoline in macroprolactinomas: a study in 122 patients. Eur J Endocrinol 160:7477522009

    • Search Google Scholar
    • Export Citation
  • 22

    Delgrange ESassolas GPerrin GJan MTrouillas J: Clinical and histological correlations in prolactinomas, with special reference to bromocriptine resistance. Acta Neurochir (Wien) 147:7517582005

    • Search Google Scholar
    • Export Citation
  • 23

    Delgrange ETrouillas JMaiter DDonckier JTourniaire J: Sex-related difference in the growth of prolactinomas: a clinical and proliferation marker study. J Clin Endocrinol Metab 82:210221071997

    • Search Google Scholar
    • Export Citation
  • 24

    Di Sarno ALandi MLCappabianca PDi Salle FRossi FWPivonello R: Resistance to cabergoline as compared with bromocriptine in hyperprolactinemia: prevalence, clinical definition, and therapeutic strategy. J Clin Endocrinol Metab 86:525652612001

    • Search Google Scholar
    • Export Citation
  • 25

    Duranteau LChanson PLavoinne AHorlait SLubetzki JKuhn JM: Effect of the new dopaminergic agonist CV 205–502 on plasma prolactin levels and tumour size in bromocriptine-resistant prolactinomas. Clin Endocrinol (Oxf) 34:25291991

    • Search Google Scholar
    • Export Citation
  • 26

    Faria MA JrTindall GT: Transsphenoidal microsurgery for prolactin-secreting pituitary adenomas. J Neurosurg 56:33431982

  • 27

    Ferrante EFerraroni MCastrignanò TMenicatti LAnagni MReimondo G: Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumors. Eur J Endocrinol 155:8238292006

    • Search Google Scholar
    • Export Citation
  • 28

    Ferrari CIAbs RBevan JSBrabant GCiccarelli EMotta T: Treatment of macroprolactinoma with cabergoline: a study of 85 patients. Clin Endocrinol (Oxf) 46:4094131997

    • Search Google Scholar
    • Export Citation
  • 29

    Filopanti MBarbieri AMAngioni ARColao AGasco VGrottoli S: Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas. Pharmacogenomics J 8:3573632008

    • Search Google Scholar
    • Export Citation
  • 30

    Fiorentini CGuerra NFacchetti MFinardi ATiberio LSchiaffonati L: Nerve growth factor regulates dopamine D(2) receptor expression in prolactinoma cell lines via p75(NGFR)-mediated activation of nuclear factor-kappaB. Mol Endocrinol 16:3533662002

    • Search Google Scholar
    • Export Citation
  • 31

    Fusco AGunz GJaquet PDufour HGermanetti ALCuller MD: Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas. Eur J Endocrinol 158:5956032008

    • Search Google Scholar
    • Export Citation
  • 32

    Gillam MPMolitch MELombardi GColao A: Advances in the treatment of prolactinomas. Endocr Rev 27:4855342006

  • 33

    Gürlek AKaravitaki NAnsorge OWass JA: What are the markers of aggressiveness in prolactinomas? Changes in cell biology, extracellular matrix components, angiogenesis and genetics. Eur J Endocrinol 156:1431532007

    • Search Google Scholar
    • Export Citation
  • 34

    Hagen CSchroeder HDHansen SHagen CAndersen M: Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy. Eur J Endocrinol 161:6316372009

    • Search Google Scholar
    • Export Citation
  • 35

    Hamilton DKVance MLBoulos PTLaws ER: Surgical outcomes in hyporesponsive prolactinomas: analysis of patients with resistance or intolerance to dopamine agonists. Pituitary 8:53602005

    • Search Google Scholar
    • Export Citation
  • 36

    Hardy JBeauregard HRobert F: Prolactin-secreting pituitary adenomas: transsphenoidal microsurgical treatment. Clin Neurosurg 27:38471980

    • Search Google Scholar
    • Export Citation
  • 37

    Heiman MLBen-Jonathan N: Rat anterior pituitary dopaminergic receptors are regulated by estradiol and during lactation. Endocrinology 111:105710601982

    • Search Google Scholar
    • Export Citation
  • 38

    Jaquet POuafik LSaveanu AGunz GFina FDufour H: Quantitative and functional expression of somatostatin receptor subtypes in human prolactinomas. J Clin Endocrinol Metab 84:326832761999

    • Search Google Scholar
    • Export Citation
  • 39

    Kansra SChen SBangaru MLSneade LDunckley JABen-Jonathan N: Selective estrogen receptor down-regulator and selective estrogen receptor modulators differentially regulate lactotroph proliferation. PLoS ONE 5:e100602010

    • Search Google Scholar
    • Export Citation
  • 40

    Kaptain GJSimmons NEAlden TDLopes MBVance MLLaws ER: Estrogen receptors in prolactinomas: a clinicopathological study. Pituitary 1:91981999

    • Search Google Scholar
    • Export Citation
  • 41

    Kitano MTaneda MShimono TNakao Y: Extended transsphenoidal approach for surgical management of pituitary adenomas invading the cavernous sinus. J Neurosurg 108:26362008

    • Search Google Scholar
    • Export Citation
  • 42

    Kovacs KHorvath ESyro LVUribe HPenagos LCOrtiz LD: Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: morphological findings. Hum Pathol 38:1851892007

    • Search Google Scholar
    • Export Citation
  • 43

    Lamberts SWde Quijada MKlijn JG: The effect of tamoxifen on GH and PRL secretion by human pituitary tumors. J Endocrinol Invest 3:3433471980

    • Search Google Scholar
    • Export Citation
  • 44

    Lamberts SWVerleun TOosterom R: Effect of tamoxifen administration on prolactin release by invasive prolactin-secreting pituitary adenomas. Neuroendocrinology 34:3393421982

    • Search Google Scholar
    • Export Citation
  • 45

    Losa MMortini PBarzaghi RGioia LGiovanelli M: Surgical treatment of prolactin-secreting pituitary adenomas: early results and long-term outcome. J Clin Endocrinol Metab 87:318031862002

    • Search Google Scholar
    • Export Citation
  • 46

    Louis DNOhgaki HWiestler ODCavenee WKBurger PCJouvet A: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:971092007

    • Search Google Scholar
    • Export Citation
  • 47

    Mallea-Gil MSCristina CPerez-Millan MIVillafañe AMBallarino CStalldecker G: Invasive giant prolactinoma with loss of therapeutic response to cabergoline: expression of angiogenic markers. Endocr Pathol 20:35402009

    • Search Google Scholar
    • Export Citation
  • 48

    Maurer RA: Estradiol regulates the transcription of the prolactin gene. J Biol Chem 257:213321361982

  • 49

    Merola BSarnacchiaro FColao ADi Somma CDi Sarno AFerone D: Positive response to compound CV 205–502 in hyperprolactinemic patients resistant to or intolerant of bromocriptine. Gynecol Endocrinol 8:1751811994

    • Search Google Scholar
    • Export Citation
  • 50

    Molitch ME: The cabergoline-resistant prolactinoma patient: new challenges. J Clin Endocrinol Metab 93:464346452008

  • 51

    Molitch ME: Dopamine resistance of prolactinomas. Pituitary 6:19272003

  • 52

    Molitch ME: Medical management of prolactin-secreting pituitary adenomas. Pituitary 5:55652002

  • 53

    Molitch ME: Pharmacologic resistance in prolactinoma patients. Pituitary 8:43522005

  • 54

    Molitch MEElton RLBlackwell RECaldwell BChang RJJaffe R: Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab 60:6987051985

    • Search Google Scholar
    • Export Citation
  • 55

    Monson JP: The epidemiology of endocrine tumours. Endocr Relat Cancer 7:29362000

  • 56

    Morange IBarlier APellegrini IBrue TEnjalbert AJaquet P: Prolactinomas resistant to bromocriptine: long-term efficacy of quinagolide and outcome of pregnancy. Eur J Endocrinol 135:4134201996

    • Search Google Scholar
    • Export Citation
  • 57

    Muratori MArosio MGambino GRomano CBiella OFaglia G: Use of cabergoline in the long-term treatment of hyperprolactinemic and acromegalic patients. J Endocrinol Invest 20:5375461997

    • Search Google Scholar
    • Export Citation
  • 58

    Neff LMWeil MCole AHedges TRShucart WLawrence D: Temozolomide in the treatment of an invasive prolactinoma resistant to dopamine agonists. Pituitary 10:81862007

    • Search Google Scholar
    • Export Citation
  • 59

    Ono MMiki NKawamata TMakino RAmano KSeki T: Prospective study of high-dose cabergoline treatment of prolactinomas in 150 patients. J Clin Endocrinol Metab 93:472147272008

    • Search Google Scholar
    • Export Citation
  • 60

    Páez-Ribes MAllen EHudock JTakeda TOkuyama HViñals F: Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:2202312009

    • Search Google Scholar
    • Export Citation
  • 61

    Pascal-Vigneron VWeryha GBosc MLeclere J: [Hyperprolactinemic amenorrhea: treatment with cabergoline versus bromocriptine. Results of a national multicenter randomized double-blind study.]. Presse Med 24:7537571995. (Fr)

    • Search Google Scholar
    • Export Citation
  • 62

    Pasqualini CBojda FKerdelhué B: Direct effect of estradiol on the number of dopamine receptors in the anterior pituitary of ovariectomized rats. Endocrinology 119:248424891986

    • Search Google Scholar
    • Export Citation
  • 63

    Passos VQFortes MAGiannella-Neto DBronstein MD: Genes differentially expressed in prolactinomas responsive and resistant to dopamine agonists. Neuroendocrinology 89:1631702009

    • Search Google Scholar
    • Export Citation
  • 64

    Pellegrini IRasolonjanahary RGunz GBertrand PDelivet SJedynak CP: Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab 69:5005091989

    • Search Google Scholar
    • Export Citation
  • 65

    Pinero AMarcos-Alberca PFortes J: Cabergoline-related severe restrictive mitral regurgitation. N Engl J Med 353:197619772005

  • 66

    Pollock BEBrown PDNippoldt TBYoung WF Jr: Pituitary tumor type affects the chance of biochemical remission after radiosurgery of hormone-secreting pituitary adenomas. Neurosurgery 62:127112782008

    • Search Google Scholar
    • Export Citation
  • 67

    Rohmer VFreneau EMorange ISimonetta C: Efficacy of quinagolide in resistance to dopamine agonists: results of a multicenter study. Club de l'Hypophyse. Ann Endocrinol (Paris) 61:4114172000

    • Search Google Scholar
    • Export Citation
  • 68

    Sheehan JRainey JNguyen JGrimsdale RHan S: Temozolomide-induced inhibition of pituitary adenoma cells. Laboratory investigation. J Neurosurg [epub ahead of print May 14 2010. DOI: 10.3171/2010.4.JNS1024]

    • Search Google Scholar
    • Export Citation
  • 69

    Simonis GFuhrmann JTStrasser RH: Meta-analysis of heart valve abnormalities in Parkinson's disease patients treated with dopamine agonists. Mov Disord 22:193619422007

    • Search Google Scholar
    • Export Citation
  • 70

    Spinks JJRyan FJ: Cabergoline resistance in pediatric prolactinomas. J Pediatr Hematol Oncol 31:3773792009

  • 71

    Sughrue MEChang EFTyrell JBKunwar SWilson CBBlevins LS Jr: Pre-operative dopamine agonist therapy improves post-operative tumor control following prolactinoma resection. Pituitary 12:1581642009

    • Search Google Scholar
    • Export Citation
  • 72

    Thomson JADavies DLMcLaren EHTeasdale GM: Ten year follow up of microprolactinoma treated by transsphenoidal surgery. BMJ 309:140914101994

    • Search Google Scholar
    • Export Citation
  • 73

    Tindall GTKovacs KHorvath EThorner MO: Human prolactin-producing adenomas and bromocriptine: a histological, immunocytochemical, ultrastructural, and morphometric study. J Clin Endocrinol Metab 55:117811831982

    • Search Google Scholar
    • Export Citation
  • 74

    Turner HENagy ZGatter KCEsiri MMHarris ALWass JA: Angiogenesis in pituitary adenomas and the normal pituitary gland. J Clin Endocrinol Metab 85:115911622000

    • Search Google Scholar
    • Export Citation
  • 75

    Turner HENagy ZGatter KCEsiri MMHarris ALWass JA: Angiogenesis in pituitary adenomas—relationship to endocrine function, treatment and outcome. J Endocrinol 165:4754812000

    • Search Google Scholar
    • Export Citation
  • 76

    Tyrrell JBLamborn KRHannegan LTApplebury CBWilson CB: Transsphenoidal microsurgical therapy of prolactinomas: initial outcomes and long-term results. Neurosurgery 44:2542631999

    • Search Google Scholar
    • Export Citation
  • 77

    Van Camp GFlamez ACosyns BWeytjens CMuyldermans LVan Zandijcke M: Treatment of Parkinson's disease with pergolide and relation to restrictive valvular heart disease. Lancet 363:117911832004

    • Search Google Scholar
    • Export Citation
  • 78

    Verhelst JAbs RMaiter Dvan den Bruel AVandeweghe MVelkeniers B: Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients. J Clin Endocrinol Metab 84:251825221999

    • Search Google Scholar
    • Export Citation
  • 79

    Völker WGehring WGBerning RSchmidt RCSchneider Jvon zur Mühlen A: Impaired pituitary response to bromocriptine suppression: reversal after bromocriptine plus tamoxifen. Acta Endocrinol (Copenh) 101:4915001982

    • Search Google Scholar
    • Export Citation
  • 80

    Webster JPiscitelli GPolli AD'Alberton AFalsetti LFerrari C: The efficacy and tolerability of long-term cabergoline therapy in hyperprolactinaemic disorders: an open, uncontrolled, multicentre study. Clin Endocrinol (Oxf) 39:3233291993

    • Search Google Scholar
    • Export Citation
  • 81

    Webster JPiscitelli GPolli AFerrari CIIsmail IScanlon MF: A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 331:9049091994

    • Search Google Scholar
    • Export Citation
  • 82

    Wood DFJohnston JMJohnston DG: Dopamine, the dopamine D2 receptor and pituitary tumours. Clin Endocrinol (Oxf) 35:4554661991

  • 83

    Zornitzki TKnobler HNass DHadani MShimon I: Increased MIB-1/Ki-67 labeling index as a predictor of an aggressive course in a case of prolactinoma. Horm Res 61:1111162004

    • Search Google Scholar
    • Export Citation
TrendMD
Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 620 616 104
Full Text Views 330 200 3
PDF Downloads 165 96 4
EPUB Downloads 0 0 0
PubMed
Google Scholar