Abstract
Resistance to dopamine agonists can be defined with respect to failure to normalize PRL levels and failure to decrease tumor size by ≥50%. Using these definitions, failure to normalize PRL levels is seen in 24% of those treated with bromocriptine, 13% of those treated with pergolide and 11% of those treated with cabergoline. Failure to achieve at least a 50% reduction in tumor size occurs in about one-third of those treated with bromocriptine and 10–15% of those treated with pergolide or cabergoline. Studies of in vitro cell preparations show that the D2 receptors of resistant tumors are decreased in number but have normal affinity.
Treatment approaches for resistant patients include switching to another dopamine agonist and raising the dose of the drug as long as there is continued response to the dose increases and no adverse effects. Transsphenoidal surgery can also be done. If fertility is desired, clomiphene, gonadotropins, and GnRH are also options. If fertility is not desired, estrogen replacement may be used unless there is a macroadenoma, in which case control of tumor growth is also an issue and dopamine agonists are generally necessary. However, in many cases modest or even no reduction may be acceptable long-term as long as there is not tumor growth. Hormone replacement (estrogen or testosterone) may cause a decrease in efficacy of the dopamine agonist so that it must be carried out cautiously. Reduction of endogenous estrogen, use of selective estrogen receptor modulators, and aromatase inhibitors are potential experimental approaches.
Similar content being viewed by others
References
Molitch ME. Disorders of prolactin secretion. Endocrinol Metab Clin N Amer 2001;30:585–610.
Soule SG, Powell M, Jacobs HS. Prolactinomas resistant to dopamine agonists: Insights into pathogenesis and therapy. Curr Opin Obstet Gynecol 1994;6:393–397.
Monsma FJ Jr, McVittie LD, Gerfen CR, Mahan LC, Sibley DR. Multiple D2 dopamine receptors produced by alternative RNA splicing. Nature 1989;342:926–929.
DeCamilli P, Macconi D, Spada A. Dopamine inhibits adenylate cyclase in human prolactin-secreting pituitary adenomas. Nature 1979;278:252–254.
Senogles SE. The D2 dopamine receptor isoforms signal through distinct Gia proteins to inhibit adenylyl cyclase. J Biol Chem 1994;269:23120–23127.
Rasolonjanahary R, Gerard C, Dufour MN, Homburger V, Enjalbert A, Guillon G. Evidence for a direct negative coupling between dopamine-D2 receptors and PLC by heterotrimeric Gi1/2 proteins in rat anterior pituitary cell membranes. Endocrinology 2002:143:747–754.
Vallar L, Vicentini LM, Meldolesi J. Inhibition of inositol phosphate production is a late, Ca2+-dependent effect of D2 dopaminergic receptor activation in rat lactotroph cells. J Biol Chem 1988;263:10127–10134.
Liu JC, Baker RE, Sun C, Sundmark VC, Elsholtz HP. Activation of Go-coupled dopamine D2 receptors inhibits ERK1/ERK2 in pituitary cells. A key step in the transcriptional suppression of the prolactin gene. J Biol Chem 2002;277:35819–35825.
Iaccarino C, Samad TA, Mathis C, Kercret H, Picetti R, Borrelli E. Control of lactotroph proliferation by dopamine: Essential role of signaling through D2 receptors and ERKS. PNAS 2002;99:14530–14535.
Tindall GT, Kovacs Tindall GT, Kovacs K, Horvath E, Thorner MO. Human prolactin-producing adenomas and bromocriptine: A histological, immunocytochemical, ultrastructural, and morphometric study. J Clin Endocrinol Metab 1982;55:1178–1183.
Bassetti M, Spada A, Pezzo G, Giannattasio G. Bromocriptine treatment reduces the cell size in human macroprolactinomas: A morphometric study. J Clin Endocrinol Metab 1984;58:268–273.
Stefaneanu L, Kovacs K, Scheithauer BW, Konogeorgos G, Riehle DL, Sebo TJ, Murray D, Vidal S, Tran A, Buchfelder M, Fahlbusch R. Effect of dopamine agonists on lactotroph adenomas of the human pituitary. Endocrine Pathol 2000;11:341–352.
Aoki MDP, Aoki A, Maldonado CA. Sexual dimorphism of apoptosis in lactotrophs induced by bromocryptine. Histochem Cell Biol 2001;116:215–222.
Pellegrini I, Rasolonjanahary R, Gunz G, Bertrand P, Delivet S, Jedynak CP, Kordon C, Peillon F, Jaquet P, Enjalbert A. Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab 1989;69:500–509.
Brue T, Pellegrini I, Gunz G, Morange I, DeWailly D, Brownell J, Enjalbert A, Jaquet P. Effects of the dopamine agonist CV 205-502 in human prolactinomas resistant to bromocriptine. J Clin Endocrinol Metab 1992;74:577–584.
Delgrange E, Maiter D, Donckier J. Effects of the dopamine agonist cabergoline in patients with prolactinomas intolerant or resistant to bromocriptine. Eur J Endocrinol 1996;134:454–456.
DiSarno A, Landi ML, Cappabianca P, DiSalle F, Rossi FW, Pivonello R, DiSomma C, Faggiano A, Lombardi G, Colao A. Resistance to cabergoline as compared with bromocriptine in hyperprolactinemia: Prevalence, clinical definition, and therapeutic strategy. J Clin Endocrinol Metab 2001;86:5256–5261.
Cannavó S, Bartolone L, Blandino A, Spinella S, Galatioto S, Trimarchi F. Shrinkage of a PRL-secreting pituitary macroadenoma resistant to cabergoline. J Endocrinol Invest 1999;22:306–309.
Delgrange E, Crabbé J, Donckier J. Late development of resistance to bromocriptine in a patient with macroprolactinoma. Horm Res 1998;49:250–253.
Hurel SJ, Harris PE, McNicol AM, Foster S, Kelly WF, Baylis PH. Metastatic prolactinoma: Effect of octreotide, cabergoline, carboplatin and etoposide; immunocytochemical analysis of proto-oncogene expression. J Clin Endocrinol Metab 1997;2962–2965.
Fossati P, Strauch G, Tournaiaire J. Etude de l'activité de la bromocriptine dans les états d'hyperprolactinémie. Nouv Presse Med 1976;5:1687–1691.
Friesen HG, Tolis G. The use of bromocriptine in the galactorrhoea-amenorrhoea syndromes: The Canadian Cooperative Study. Clin Endocrinol 1977;6(Suppl):91s–99s.
Bergh T, Nillius SJ, Wide L. Bromocriptine treatment of 42 hyperprolactinaemic women with secondary amenorrhoea. Acta Endocrinol 1978;88:435–451.
Badano AR, Miechi HR, Mirkin A, Arcángeli OA, Aparicio NJ, Rodríguez A, Oliva A, Turner D, Casas PRF. Bromocriptine in the treatment of hyperprolactinemic amenorrhea. Fertil Steril 1979;31:124–128.
Crosignani PG, Ferrari C, Liuzzi A, Benco R, Mattei A, Rampini P, Dellabonanza D, Scarduelli C, Spelta B. Treatment of hyperprolactinemic states with different drugs: A study with bromocriptine, metergoline, and lisuride. Fertil Steril 1982;37:61–67.
Horowitz BL, Hamilton DJ, Sommers CJ, Bryan RN, Boyd AE III. Effect of bromocriptine and pergolide on pituitary tumor size and serum prolactin. AJNR 1983;4:415–417.
Molitch ME, Elton RL, Blackwell RE, Caldwell B, Chang RJ, Jaffe R, Joplin G, Robbins RJ, Tyson J, Thorner MO. Bromocriptine as primary therapy for prolactin-secreting macroadenomas: Results of a prospective multicenter study. J Clin Endocrinol Metab 1985;60:698–705.
Liuzzi A, Dallabonzana D, Giuseppe MD et al. Low doses of dopamine agonists in the long-term treatment of macroprolactinomas. N Engl J Med 1985;313:656–659.
Van der Heijden PFM, de Wit W, Brownell J, Schoemaker J, Rolland R. CV 205-502, a new dopamine agonist, versus bromocriptine in the treatment of hyperprolactinaemia. Eur J Obstet Gynecol Reprod Biol 1991;40:111–118.
Brue T, Pellegrini I, Priou A, Morange I, Jaquet P. Prolactinomas and resistance to dopamine agonists. Horm Res 1992;38:84–89.
Webster J, Piscitelli G, Polli A, Ferrari CI, Ismail I, Scanlon MF for the Cabergoline Comparative Study Group. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 1994;331:904–909.
Pascal-Vigneron V, Weryha G, Bose M, Leclere J. Hyperprolactinemic amenorrhea: Treatment with cabergoline versus bromocriptine. Results of a national multicenter randomized double-blind study. Presse Med 1995;24:754–757.
Pinzone JJ, Katznelson L, Danila DC, Pauler DK, Miller CS, Klibanski A. Primary medical therapy of micro-and macroprolactinomas in men. J Clin Endocrinol Metab 2000;85:3053–3057.
Sabancu T, Arikan E, Tasan E, Hatemi H. Comparison of the effects of cabergoline and bromocriptine on prolactin levels in hyperprolactinemic patients. Intern Med 2001;40:857–861.
Kleinberg DL, Boyd AE III, Wardlaw S, Frantz AG, George A, Bryan N, Hilal S, Greising J, Hamilton D, Seltzer T, Sommers CJ. Pergolide for the treatment of pituitary tumors secreting prolactin or growth hormone. N Engl J Med 1983;309:704–709.
L'Hermite M, Debusschere PM, Gillet C, Deschepper C. Treatment of hyperprolactinaemic patients with pergolide. Acta Endocrinol 1983;103:441–445.
Freda PU, Andreadis CI, Knandji AG, Khoury M, Bruce JN, Jacobs TP, Wardlaw SL. Long-term treatment of prolactinsecreting macroadenomas with pergolide. J Clin Endocrinol Metab 2000;85:8–13.
Ferrari C, Mattei A, Melis GB et al. Cabergoline: Long-acting oral treatment of hyperprolactinemic disorders. J Clin Endocrinol Metab 1989;68:1201–1206.
Ferrari C, Paracchi A, Mattei AM, de Vincentils S, D'Alberton A, Crosignani PG. Cabergoline in the long-term therapy of hyperprolactinemic disorders. Acta Endocrinol 1992;126:489–494.
Muratori M, Arosio M, gambino G, Romano C, Biella O, Faglia G. Use of cabergoline in the long-term treatment of 26 Molitch hyperprolactinemic and acromegalic patients. J Endocrinol Invest 1997;20:537–546.
Verhelst J, Abs R, Maiter D et al. Cabergoline in the treatment of hyperprolactinemia:Astudy in 455 patients. J Clin Endocrinol Metab 1999;84:2518–2522.
Colao A, DiSarno A, Landi ML, Scavuzzo F, Cappabianca P, Pivonello R, Volpe R, DiSalle F, Cirillo S, Annunziato L, Lombardi G. 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 2000;85:2246–2252.
Thorner MO, Schran HF, Evans WS, Rogol AD, Morris JL, MacLeod RM. 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 Clin Endocrinol Metab 1980;50:1026–1033.
Burris TP, Stringer LC, Freeman ME. Pharmacologic evidence that a D2 receptor subtype mediates dopaminergic stimulation of prolactin secretion from the anterior pituitary gland. Neuroendocrinology 1991;54:175–183.
Caccavelli L, Feron F, Morange I et al. Decreased expression of the two D2 dopamine receptor isoforms in bromocriptineresistant prolactinomas. Neuroendocrinol 1994;60:314–322.
Caccavelli L, Morange-Ramos I, Kordon C, Jaquet P, Enjalbert A. Alteration of Ga subunits mRNA levels in bromocriptine resistant adenomas. J Neuroendocrinol 1996;8:737–746.
Ahmed SR, Shalet SM. Discordant responses of prolactinomas to two different dopamine agonists. Clin Endocrinol 1986;24:421–426.
Berezin M, Avidan D, Baron E. Long-term pergolide treatment of hyperprolactinemic patients previously unsuccessfully treated with dopaminergic drugs. Isr J Med Sci 1991;27:375–379.
Duranteau L, Chanson P, Lavoinne A, Horlait S, Lubetzki J, Kuhn JM. Effect of the new dopaminergic agonist CV205-502 on plasma prolactin levels and tumour size in bromocriptineresistant prolactinomas. Clin Endocrinol 1991;34:25–29.
Razzaq R, O'Halloran DJ, Beardwell CG, Shalet SM. The effects of CV205-502 in patients with hyperprolactinaemia intolerant and/or resistant to bromocriptine. Horm Res 1993;39:218–222.
Merola B, Sarnacchiaro F, Colao A, DiSomma C, DiSarno A, Ferone D, Selleri A, Landi ML, Schettini G, Nappi C, Lombardi G. Positive response to compound CV205-502 in hyperprolactinemic patients resistant to or intolerant of bromocriptine. Gynecol Endocrinol 1994;8:175–181.
Morange I, Barlier A, Pellegrini I, Brue T, Enjalbert A, Jaquet P. Prolactinomas resistant to bromocriptine: Long-term efficacy of quinagolide and outcome of pregnancy. Eur J Endocrinol 1996;135:413–420.
Rohmer V, Freneau E, Morange I, Simonetta C, and Le Club de l'Hypophyse. Efficiency of quinagolide in resistance to ergotderived dopamine agonists: Results of a multicenter study.Ann Endocrinol 2000;61:411–417.
Colao A, DiSarno A, Sarnacchiaro F, Ferone D, DiRenzo G, Merola B, Annunziato L, Lombardi G. Prolactinomas resistant to standard dopamine agonists respond to chronic cabergoline treatment. J Clin Endocrinol Metab 1997;82:876–883.
Gillam MP, Middler S, Freed DJ, Molitch ME. 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 2002;87:4447–4451.
Ahlskog JE, Wright KF, Muenter MD, Adler CH. Adjunctive cabergoline therapy of Parkinson's disease: Comparison with placebo and assessment of dose responses and duration of effect. Clin Neuropharmacol 1996;19:202–212.
Inzelberg R, Nisipeanu P, Rabey JM, Orlov E, Catz T, Kippervasser S, Schechtman E, Korczyn AD. Doubleblind comparison of cabergoline and bromocriptine in Parkinson's disease patients with motor fluctuations. Neurology 1996;47:785–788.
Rinne UK, Bracco F, Chouza C, Dupont E, Gershanik O, Masso JFM, Montastruc JL, Marsden CD, Dubini A, Orlando N, Grimaldi R, and the PKDS009 Collaborative Study Group. Cabergoline in the treatment of early Parkinson's disease: Results of the first year of treatment in a double-blind comparison of cabergoline and levodopa. Neurology 1997;48:363–368.
Radwanska E, McGarrigle HH, Little V, Lawrence D, Saris S, Swyer GI. Induction of ovulation in women with hyperprolactinemic amenorrhea using clomiphene and human chorionic gonadotropin or bromocriptine. Fertil Steril 1979;32:187–192.
Crosignani PG, Ferrari C, Scarduelli C, Picciotti MC, Caldara R, Malinverni A. Spontaneous and induced pregnancies in hyperprolactinemic women. Obstet Gynecol 1981;58:708–713.
Leyendecker G, Sruve T, Plotz EJ. Induction of ovulation with chronic intermittent (pulsatile) administration of LH-RH in women with hypothalamic and hyperprolactinemic amenorrhea. Arch Gynecol 1980;229:177–190.
Maurer RA. Estradiol regulates the transcription of the prolactin gene. J Biol Chem 1982;257:2133–2136.
Shull JD, Gorski J. Estrogen regulates the transcription of the rat prolactin gene in vivo through at least two independent mechanisms. Endocrinology 1985;116:2456–2462.
Lloyd GM, Meares JD, Jacobi J. Effects of oestrogen and bromocriptine on in vivo secretion and mitosis in prolactin cells. Nature 1975;255:497–498.
Raymond V, Beaulieu M, Labrie F, Boissier J. Potent antidopaminergic activity of estradiol at the pituitary level on prolactin release. Science 1979;200:1173–1175.
West B, Dannies PS. Effects of estradiol on prolactin production and dihydroergocryptine-induced inhibition of prolactin production in primary cultures of rat pituitary cells. Endocrinology 1980;106:1108–1113.
Jaquet P, Gunz G, Grisoli F. Hormonal regulation of prolactin release by human prolactinoma cells cultured in serum-free conditions. Horm Res 1985;22:153–163.
Heiman ML, Ben-Jonathan N. Rat anterior pituitary dopaminergic receptors are regulated by estradiol during lactation. Endocrinology 1982;111:1057–1060.
Pasqualini C, Bojda F, Kerdelhué B. Direct effect of estradiol on the number of dopamine receptors in the anterior pituitary of ovariectomized rats. Endocrinology 1986;119:2484–2489.
Nansel DD, Gudelsky GA, Reymond MJ, Porter JC. Estrogen alters the responsiveness of the anterior pituitary gland to the actions of dopamine on lysosomal enzyme activity and prolactin release. Endocrinology 1981;108:903–907.
Lamberts SWJ, Verleun T, Hofland L, Oosterom R. Differences in the interaction between dopamine and estradiol on prolactin release by cultured normal and tumorous human pituitary cells. J Clin Endocrinol Metab 1986;63:1342–1347.
Lamberts SWJ. Interactions of steroids with prolactin secretion in vitro. Horm Res 1985;22:172–178.
Corenblum B, Donovan L. The safety of physiological estrogen plus progestin replacement therapy and with oral contraceptive therapy in women with pathological hyperprolactinemia. Fertil Steril 1993;59:671–673.
Testa G, Vegetti W, Motta T et al. Two-year treatment with oral contraceptives in hyperprolactinemic patients. Contraception 1998;58:69–73.
Fahy UM, Foster PA, Torode HW, Hartog M, Hull MGR. The effect of combined estrogen/progestogen treatment in women with hyperprolactinemic amenorrhea. Gynecol Endocrinol 1992;6:183–188.
Kovacs K, Stefaneanu L, Ezzat S, Smyth HS. Prolactinproducing pituitary adenoma in a male-to-female transsexual patient with protracted estrogen administration. Arch Pathol Lab Med 1994;118:562.
Garcia MM, Kapcala LP. Growth of a microprolactinoma to a macroprolactinoma during estrogen therapy. J Endocrinol Invest 1995;18:450–455.
Lamberts SWJ, Verleun T, Oosterom R. Effect of tamoxifen administration on prolactin release by invasive prolactinsecreting pituitary adenomas. Neuroendocrinology 1982;34: 339–342.
Prior JC, Cox TA, Fairholm D, Kostashuk E, Nugent R. Testosterone-related exacerbation of a prolactin-producing macroadenoma: Possible role for estrogen. J Clin Endocrinol Metab 1987;64:391–394.
Missale C, Boroni F, Losa M, Giovanelli M, Zanellato A, dal Toso R, Balsari A, Spano PF. Nerve growth factor suppresses the transforming phenotype of human prolactinomas. Proc Natl Acad Sci USA 1993;90:7961–7965.
Missale C, Losa M, Boroni F, Giovanelli M, Balsari A, Spano PF. Nerve growth factor and bromocriptine: A sequential therapy for human bromocriptine-resistant prolactinomas. Brit J Cancer 1995;72:1397–1399.
Fiorentini C, Guerra N, Facchetti M, Finardi A, Tiberio L, Schiaffonati L, Spano P, Missale C. Nerve growth factor regulates dopamine D2 receptor expression in prolactinoma cell lines via p75NGFR-mediated activation of nuclear factor-κB. Mol Endocrinol 2002;16:353–366.
Apfel SC, Schwartz S, Adornato BT, Freeman R, Biton V, Rendell M, Vinik A, Guiliani M, Stevens JC, Barbano R, Dyck PJ for the rhNGF Clinical Investigator Group. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy. A randomized controlled trial. JAMA 2000;284:2215–2221.
Schifitto G, Yiannoutsos C, Simpson DM, Adornato BT, Singer EJ, Hollander H, Marra CM, Rubin M, Cohen BA, Tucker T, Koralnik IJ, Katzenstein D, Haidich B, Smith ME, Shriver S, Millar L, Clifford DB, McArthur JC, and the AIDS Clinical Trials Group Team 291. Long-term treatment with recombinant nerve growth factor for HIV-associated sensory neuropathy. Neurology 2001;57:1313–1316.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Molitch, M.E. Dopamine Resistance of Prolactinomas. Pituitary 6, 19–27 (2003). https://doi.org/10.1023/A:1026225625897
Issue Date:
DOI: https://doi.org/10.1023/A:1026225625897