Diagnosis and management of hyperprolactinemia

ReviewSynthèseDiagnosis and management of hyperprolactinemiaOmar Serri, Constance L. Chik, Ehud Ur, Shereen EzzatAbstractorrhea, 25% among women with galactorrhea and as high as70% among women with amenorrhea and galactorrhea.1PROLACTIN IS A PITUITARY HORMONE that plays a pivotal role in a vari-The prevalence is about 5% among men who present withety of reproductive functions. Hyperprolactinemia is a commonimpotence or infertility.1condition that can result from a number of causes, includingmedication use and hypothyroidism as well as pituitary disorders.Regulation of prolactin secretionDepending on the cause and consequences of the hyperpro-lactinemia, selected patients require treatment. The underlyingLike most anterior pituitary hormones, prolactin is undercause, sex, age and reproductive status must be considered. Wedual regulation by hypothalamic hormones delivereddescribe the diagnostic approach and management of hyperpro-through the hypothalamic–pituitary portal circulationlactinemia in various clinical settings, with emphasis on newer di-(Fig. 1). Under most conditions the predominant signal is in-agnostic strategies and the role of various therapeutic options, in-hibitory, preventing prolactin release, and is mediated by thecluding treatment with selective dopamine agonists.neurotransmitter dopamine. The stimulatory signal is medi-CMAJ 2003;169(6):575-81ated by the hypothalamic hormone thyrotropin-releasinghormone. The balance between the 2 signals determines theProlactin is a pituitary-derived hormone that plays a amount of prolactin released from the anterior pituitarypivotal role in a variety of reproductive functions. Itgland.2 Furthermore, the amount cleared by the kidneys in-is an essential factor for normal production of breastfluences the concentration of prolactin in the blood.2,3milk following childbirth. Furthermore, prolactin nega-tively modulates the secretion of pituitary hormones re-sponsible for gonadal function, including luteinizing hor-mone and follicle-stimulating hormone. An excess ofBox 1: Clinical presentations of hyperprolactinemiaprolactin, or hyperprolactinemia, is a commonly encoun-Premenopausal womentered clinical condition.1 Management of this condition de-pends heavily on the cause and on the effects it has on the• Marked prolactin excess (> 100 µg/L [normallypatient. In this review we summarize advances in our un-< 25 µg/L]) is commonly associated withderstanding of the clinical significance of hyperprolactine-hypogonadism,* galactorrhea and amenorrheamia and its pathogenetic mechanisms, including the influ-• Moderate prolactin excess (51–75 µg/L) is associatedence of concomitant medication use. Emphasis will bewith oligomenorrheaplaced on newer diagnostic strategies and the role of vari-• Mild prolactin excess (31–50 µg/L) is associated withous therapeutic options, including treatment with selectiveshort luteal phase, decreased libido and infertilitydopamine agonists, in various clinical settings.• Increased body weight may be associated withprolactin-secreting pituitary tumour5Epidemiologic features• Osteopenia is present mainly in people withassociated hypogonadismAn excess of prolactin above a reference laboratory’s up-• Degree of bone loss is related to duration and severityper limits, or “biochemical hyperprolactinemia,” can beof hypogonadism*6identified in up to 10% of the population.1 Women witholigomenorrhea, amenorrhea, galactorrhea or infertility,Menand men with hypogonadism, impotence or infertility must• Hyperprolactinemia presents with decreased libido,have serum prolactin levels measured.impotence, decreased sperm production, infertility,The occurrence of clinically apparent hyperprolactinemiagynecomastia and, rarely, galactorrheadepends on the study population. The prevalence has been• Impotence is unresponsive to testosterone treatmentreported to range from 0.4% in an unselected healthy adultand is associated with decreased muscle mass, bodypopulation in Japan to 5% among clients at a family plan-hair and osteoporosis7ning clinic.1 The rate is even higher among patients with*The degree of hypogonadism is generally proportionate to the degree ofspecific symptoms that may be attributable to hyperpro-prolactin elevationlactinemia: it is estimated at 9% among women with amen-CMAJ • SEPT. 16, 2003; 169 (6)575© 2003 Canadian Medical Association or its licensorsSerri et alMedicationsNeuroleptics: phenothiazines, haloperidolHypothalamic PRL stimulationAntihypertensives: calcium-channel blockers, methyldopaPrimary hypothyroidismPsychotropic agents: tricyclic antidepressantsAdrenal insufficiencyAnti-ulcer agents: H2 antagonistsOpiates+–Inhibit dopamine release, thus leading to reduced inhibition and increased prolactin productionTRHDopamine–+–NeurogenicVia autonomicChest-wall injurynervous systemBreast stimulationBreast-feedingOpticchiasmHypophyseal stalkPhysiologic causes+Estrogen+PregnancyPosteriorpituitary lobeAnterior pituitary lobeReduced PRL eliminationProlactin+Renal failureOther causes,+Hepatic insufficiencymechanism unclear++Abnormal moleculesIncreased PRL productionMacroprolactinemiaOvarian: polycystic ovarian syndromePituitary tumours: AdenomasHypothalamic stalk interruptionHypophysitis (inflammation)NormalMacroprolactinemiaPRL bindingNormalAdenoma"StalkHypophysitiseffect"–Inhibitory signal+Stimulatory signalMyra RudakewichFig. 1: Causes of hyperprolactinemia. Prolactin (PRL) is under dual control from the hypothalamus, where dopamine serves as an in-hibitory signal, preventing PRL secretion, and thyrotropin-releasing hormone (TRH), under some conditions, stimulates increased PRLproduction and release. Increased anterior pituitary hormone production can occur from a PRL-producing adenoma or from inflamma-tion (hypophysitis). However, conditions that result in impaired dopamine delivery or enhanced TRH signalling, or both, will also resultin increased PRL release. In general, medications result in increased PRL production through their anti-dopaminergic properties. Chest-wall injury and breast stimulation serve as peripheral triggers of autonomic control, which impinge on central neurogenic pathwaysthat attenuate dopamine release into the hypophyseal portal circulation. In some conditions, such as renal or hepatic insufficiency, PRLis cleared less rapidly from the systemic circulation, which results in increased blood levels of PRL.576JAMC • 16 SEPT. 2003; 169 (6)Management of hyperprolactinemiastimulation of prolactin secretion.2 Furthermore,Box 2: Objectives of treatment of hyperprolactinemiaprolactin elimination from the systemic circula-tion is reduced, which contributes to increased• Restoration and maintenance of normal gonadal functionprolactin concentrations.2 Primary hypothyroidism• Restoration of normal fertilitycan be associated with diffuse pituitary enlarge-• Prevention of osteoporosisment, which will reverse with appropriate thyroidhormone replacement therapy.2If a pituitary tumour is present:• Correction of visual or neurological abnormalitiesPituitary tumours• Reduction or removal of tumour mass• Preservation of normal pituitary functionPituitary tumours are common neoplasms that• Prevention of progression of pituitary or hypothalamic diseaseexhibit a wide range of biological behaviour, as evi-denced by hormonal and proliferative activities.2Among pituitary adenomas, prolactin-producing pi-tuitary tumours are the most common type. AboutCauses of hyperprolactinemiaone-third of all pituitary tumours are not associated with hy-persecretory syndromes but, rather, present with symptomsThe differential diagnosis and causes of pathological hy-of an intracranial mass, such as headaches, nausea, vomitingperprolactinemia are summarized in Fig. 1. The presenceor visual field disturbances. Because of suprasellar extension,of a secondary cause and fluctuating degrees of hyperpro-pituitary tumours may interrupt dopamine delivery from thelactinemia should raise the suspicion of a nontumoroushypothalamus to the pituitary, resulting in loss of inhibitioncause. Consideration of such secondary contributions canof prolactin release, or the “stalk effect.” In contrast, tumoursobviate the need for unnecessary testing and inappropriatethat produce growth hormone (GH) may also secrete pro-treatment.lactin in nearly 25% of cases.2 This is a common source ofmisdiagnosis, as the features of prolactin excess may captureMacroprolactinemiaattention while the more subtle features of GH excess go un-noticed. In both cases the distinction is important. Surgery isAsymptomatic patients with intact gonadal and repro-indicated for a nonfunctional pituitary adenoma that is largeductive function and moderately elevated prolactin levelsenough to cause the stalk effect. For tumours that are secret-may have macroprolactinemia.3 This term should not being both GH and prolactin, therapy with GH-inhibitoryconfused with macroprolactinoma, which refers to a largeagents is the preferred treatment in most cases. Finally, anpituitary tumour greater than 10 mm in diameter. Macro-autoimmune condition of the pituitary with lymphocytic in-prolactinemia refers to a polymeric form of prolactin infiltration can lead to hyperprolactinemia.4 This form of lym-which several prolactin molecules form a polymer that isphocytic hypophysitis is typically noted in the postpartumrecognized by immunologically based serum assays. Inphase in women of childbearing age. Surgery is rarely indi-general, macroprolactin results from the binding of pro-cated, and spontaneous resolution is common.4lactin to IgG antibodies. The large pro-lactin polymer is unable to interact withthe prolactin receptor. Little, if any, bio-logical effect of prolactin excess is noted.Box 3: Medical therapeutic options for the managment ofIf macroprolactinemia is suspected, thehyperprolactinemialaboratory should be notified, and the• Dopamine agonists are currently the first therapeutic option (Table 1)specimen can be subjected to polyethyl-• Dopamine agonists have proven efficacy in reducing prolactin levels,ene glycol precipitation before assess-restoring ovulation in premenopausal women and restoring gonadalment.3 If macroprolactinemia accountsfunction in men7,9for most of the prolactin excess, no spe-• Prolactin levels may remain above normal in about 20% of cases ofcific treatment is needed.macroprolactinoma and about 10% of cases of microprolactinomadespite dopamine agonist therapy9Hypothyroidism• Bromocriptine has been used the longest.The hyperprolactinemia of hypothy-• Cabergoline has greater affinity and selectivity for pituitary dopamineroidism is related to several mechanisms.D receptors and longer duration of action.9–11 It is indicated in cases of2In response to the hypothyroid state, abromocriptine resistance or intolerancecompensatory increase in the discharge• Quinagolide is an alternative dopamine agonist10 but with limitedof central hypothalamic thyrotropin-accessreleasing hormone results in increasedCMAJ • SEPT. 16, 2003; 169 (6)577Serri et alClinical presentationsels between 20 and 200 µg/L can be found in patients withhyperprolactinemia due to any cause, prolactin levels aboveThe clinical manifestations of prolactin excess (Box 1)200 µg/L usually indicate the presence of a lactotroph ade-can be divided into 2 main categories: those that are medi-noma. In general, there is a relatively linear relation be-ated by prolactin excess directly and those representing thetween the degree of prolactin elevation and the size of aconsequences of the resulting hypogonadism.true prolactinoma. If a patient with only a mildly elevatedserum prolactin level has a pituitary macroadenoma, the di-Diagnosisagnosis is more likely to be a non-prolactin-producing pi-tuitary adenoma or other sellar mass causing the stalk ef-The evaluation is aimed at excluding physiologic, phar-fect. The approach to the diagnosis of hyperprolactinemiamacologic or other secondary causes of hyperprolactinemiais summarized in Fig. 2.(Fig. 1). In the absence of such causes, imaging (preferablyMRI) of the pituitary fossa is recommended to establishNatural historywhether a prolactin-secreting pituitary tumour or other le-sion is present. CT scanning may not be sensitive enoughSeveral series of patients with prolactin-secretingto identify small lesions or large lesions that are isodensemicroadenomas observed for long periods without treat-with surrounding structures. Whereas serum prolactin lev-ment have shown that the risk of progression to macro-Prolactin levelRule outMacroprolactinemiaRepeat measurementsecondary causesPathologicalCorrect underlying cause:hyperprolactinemiareplace thyroid hormone,remove/substitute potentiallyoffending medicationMRI of pituitaryNormal pituitary Micro lesion (<10 mm)Macro lesion (≥10 mm)AsymptomaticSymptomaticFollow-up prolactinTreatmentmeasurement(see Fig. 3)once yearlyFig. 2: Approach to diagnosis of hyperprolactinemia.578JAMC • 16 SEPT. 2003; 169 (6)Management of hyperprolactinemiaadenoma over 10 years is small (about 7%).8 In some cases,Medical therapyprolactin levels returned to normal in patients who did notreceive treatment or who received treatment intermittentlyMedical therapy has traditionally involved agonists of thewith dopamine agonists. Women with prolactin-secretingphysiologic inhibitor of prolactin, dopamine (Box 3, Tablemicroadenomas who became pregnant during this interval1). Although initially it was thought that patients would re-had a higher rate of remission than women who did not be-quire dopamine agonist therapy all their lives, the currentcome pregnant (35% v. 14%).use of these agents has evolved into a dynamic process de-pending on the patient’s needs and circumstances.ManagementSurgical therapyThe objective of hyperprolactinemia treatment is tocorrect the biochemical consequences of the hormonalSurgical removal of tumours associated with prolactinexcess (Box 2). When present, the compressive featuresexcess requires careful consideration of treatment objec-of a large (macro) tumour must also be alleviated and thetives (Box 4). It is indicated in patients with nonfunctionaltumour prevented from regrowing. The approach to thepituitary adenomas or other nonlactotroph adenomas asso-management of hyperprolactinemia is summarized inciated with hyperprolactinemia and in patients in whomFig. 3.medical therapy has been unsuccessful or poorly tolerated.MRI of pituitaryNormal andMicro andMacrosymptomaticsymptomaticDopamine agonistMeasure other pituitarytherapyhormones to exclude associateddeficiency or excessReduced Prolactin levelStalk effectNormalprolactin levelstill elevatedIsolated prolactin(prolactin level not highprolactin levelafter 6 mo therapyafter 6 mo therapyexcessenough for size of tumour)Dopamine agonistPituitary surgeryAsymptomaticSymptomatictherapyrecommendedMeasureNormalReduced No effect onprolactin levelConsider pituitaryprolactin levelprolactin levelprolactin levelevery 4–6 mosurgeryafter 6 mo therapyafter 6 mo therapySymptomaticAsymptomaticdespite prolactinreductionMeasure prolactinPituitarylevel every 4–6 mo;surgeryMRI every 1–2 yrFig. 3: Approach to management of hyperprolactinemia.CMAJ • SEPT. 16, 2003; 169 (6)579Serri et alThe best results with transsphenoidal resection ofMonitoring and follow-upthe prolactinoma are limited to centres that have thegreatest experience. In one study, the apparent surgicalBiochemical and clinical improvements in response tocure rate for prolactinomas, although good in the shortdopamine agonist therapy are readily apparent in most pa-term, decreased on re-evaluation during long-term fol-tients. In addition, tumour shrinkage can be expected inlow-up.12 Hyperprolactinemia recurred within 5 yearsabout 80% of macroadenomas.17 However, a major draw-after surgery in about 50% of patients with micropro-back of medical therapy is the potential need for lifelonglactinomas who were initiallytreatment. Discontinuation ofthought to be cured.12 In otherbromocriptine therapy hasseries, the rate of recurrence ofbeen shown to lead to recur-Box 4: Indications for pituitary surgeryhyperprolactinemia followingrence of hyperprolactinemia ininitial cure by surgery rangedin patients with hyperprolactinemiamost patients and to tumourfrom 20% to 40%.13 However,• Surgery is indicated in cases of resistance orregrowth if treatment durationrecurrence of hyperprolacti-intolerance to optimal medical therapyhas been less than 2 years.18nemia after surgery is not nec-Passos and associates18 reported• Surgery should be considered in patientsessarily a permanent featuremaintenance of normal pro-with intrasellar tumour for whom long-termand does not inevitably indi-drug treatment is not acceptablelactin levels and absence ofcate operative failure.13,14 Re-adenoma re-expansion after• Surgical decompression may be required forevaluation of long-term resultswithdrawal of dopamine ago-tumours pressing on the optic chiasmindicates a success rate of aboutnist therapy in 6.6% to 37.5%• Surgery should be avoided in cases of75% for surgical removal ofof patients. Recurrence usuallyextrasellar (without optic chiasmmicroprolactinoma. However,occurs within months aftercompression) expanding tumours because ofthe results of surgery fordrug withdrawal. These au-the low success ratemacroprolactinoma are poor,thors also reported reduced andwith a long-term success ratenormal prolactin levels afterof only 26%.13pregnancy in women who hadprolactinomas treated with dopamine agonists. MenopauseManagement of hyperprolactinemia in pregnancyhas also been suggested as a factor that increases the proba-bility of maintaining normoprolactinemia after dopamineThe collaboration of various specialists, including an ob-agonist therapy is stopped.18 Unless there is evidence ofstetrician, is required for the careful planning of pregnancygrowth of a prolactinoma or related symptoms, such asin women with hyperprolactinemia (Box 5). Ideally, thisheadache, there is no indication to continue dopamine ago-should occur before conception, to permit a full assessmentnist therapy after menopause.18 There are no significant dif-of the risks and benefits of dopamine agonist therapy dur-ferences in age, sex, initial dopamine agonist dose or lengthing pregnancy.of treatment between those with continued normopro-Table 1: Advantages, disadvantages and cost of various dopamine agonist agentsavailable in CanadaAgentMain advantagesDisadvantagesTypical doseMonthly cost, $BromocriptineLongest track recordHigh frequency2.5 mg/d112.97of gastrointestinalupset and sedationCabergolineHigh efficacy; lowExperience during0.5 mg/wk139.50frequency ofpregnancyadverse events;relatively limitedindicated in casesof bromocriptineresistance orintoleranceQuinagolidePituitary selectivity;Daily use; limited0.075 mg/d129.90indicated in casesaccessof bromocriptineresistance orintolerancePergolideOccasionallyHigh frequency0.25 mg/d127.19beneficial inof adverse eventsresistant cases580JAMC • 16 SEPT. 2003; 169 (6)Management of hyperprolactinemiaContributors: All of the authors contributed to the conception and design of thepaper, review of the data and drafting of the manuscript. Drs. Ezzat and Serri wereBox 5: Management of hyperprolactinemia inresponsible for editing the manuscript.pregnancyReferences• There is no evidence of increased teratogenicityassociated with bromocriptine or cabergoline use1. Josimovich JB, Lavenhar MA, Devanesan MM, Sesta HJ, Wilchins SA, Smithduring pregnancy15,16AC. Heterogeneous distribution of serum prolactin values in apparentlyhealthy young women, and the effects of oral contraceptive medication. Fertil• Similarly, there is no evidence of increased risk ofSteril 1987;47:785-91.2. Asa SL, Ezzat S. The pathogenesis of pituitary tumours. Nat Rev Cancer 2002;abortion or multiple pregnancies with dopamine2:836-49.agonist use3. Vallette-Kasic S, Morange-Ramos I, Selim A, Gunz G, Morange S, EnjalbertA, et al. Macroprolactinemia revisited: a study on 106 patients. J Clin Endocrinol• If the tumour size before pregnancy is < 10 mm,Metab 2002;87:581-8.dopamine agonist therapy is stopped during pregnancy4. Thodou E, Asa SL, Kontogeorgos G, Kovacs K, Horvath E, Ezzat S. Clinicalbecause the risk of tumour expansion is low15case seminar: lymphocytic hypophysitis: clinicopathological findings. J ClinEndocrinol Metab 1995;80:2302-11.• If the tumour size before pregnancy is ≥ 10 mm before5. Yermus R, Ezzat S. Does normalization of prolactin levels result in weight losspregnancy, bromocriptine use is advised duringin patients with prolactin secreting pituitary adenomas? [letter] Clin Endocrinol(Oxf) 2002;56:562.pregnancy to avoid significant tumour expansion156. Biller BMK, Baum HB, Rosenthal DI, Saxe VC, Charpie PM, Klibanski A.Progressive trabecular osteopenia in women with hyperprolactinemic amen-• All patients should be evaluated every 2 monthsorrhea. J Clin Endocrinol Metab 1992;75:692-7.during pregnancy7. Di Somma C, Colao A, Di Sarno A, Klain M, Landi ML, Facciolli G, et al.Bone marker and bone density responses to dopamine agonist therapy in hy-• Formal visual field testing is indicated in patients withperprolactinemic males. J Clin Endocrinol Metab 1998;83:807-13.symptoms or a history of macroadenoma8. Schlechte J, Dolan K, Sherman B, Chapler F, Luciano A. The natural historyof untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol• If visual field defects develop despite dopamineMetab 1989;68:412-8.agonist treatment, early delivery or pituitary surgery9. Di Sarno A, Landi ML, Cappabianca P, Di Salle F, Rossi FW, Pivonello R, etshould be considered15al. Resistance to cabergoline as compared with bromocriptine in hyperpro-lactinemia: prevalence, clinical definition and therapeutic strategy. J Clin En-docrinol Metab 2001;86:5256-61.10. De Luis DA, Becerra A, Lahera M, Botella JI, Valero, Varela C. A random-ized cross-over study comparing cabergoline and quinagolide in the treatmentlactinemia and those with recurrence of hyperprolacti-of hyperprolactinemic patients. J Endocrinol Invest 2000;23:428-34.11. Jeffcoate WJ, Pound N, Sturrock NDC, Lambourne J. Long-term follow-upnemia.18 We suggest that the dopamine agonist dose be de-of patients with hyperprolactinaemia. Clin Endocrinol (Oxf) 1996;45:299-303.creased after 2 or 3 years of normal prolactin levels and12. Serri O, Rasio E, Beauregard H, Hardy J, Somma M. Recurrence of hyper-prolactinemia after selective transsphenoidal adenomectomy in women withthat therapy be stopped if the prolactin levels remain un-prolactinoma. N Engl J Med 1983;309:280-3.changed after 1 year at the reduced dose. The dose can be13. Serri O, Hardy J, Massoud F. Relapse of hyperprolactinemia revisited. N EnglJ Med 1993;329:1357. reduced by half over the course of 3 months while pro-14. Thompson JA, Gray CE, Teasdale GM. Relapse of hyperprolactinemia afterlactin levels are measured monthly. After complete discon-transsphenoidal surgery for microprolactinoma: lessons from long-term fol-low-up. Neurosurgery 2002;50:36-9.tinuation of treatment, regular monitoring of clinical15. Molitch ME. Management of prolactinomas during pregnancy. J Reprod Medsymptoms and prolactin levels is recommended. Given the1999;44:1121-6.propensity for early recurrence, prolactin levels should be16. Ricci E, Parazzini F, Motta T, Ferrari CI, Colao A, Clavenna A, et al. Preg-nancy outcome after cabergoline treatment in early weeks of gestation. Reprodmeasured monthly for the first 3 months and every 6Toxicol 2002;16:791-3.months thereafter.17. Webster J, Piscitelli G, Polli A, Ferrari CI, Ismail I, Scanlon MF, for theCabergoline Comparative Study Group. A comparison of cabergoline andbromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl JMed 1994;331:904-9.This article has been peer reviewed.18. Passos VQ, Souza JJ, Musolino NR, Bronstein MD. Long-term follow-up ofprolactinomas: normoprolactinemia after bromocriptine withdrawal. J ClinFrom the Divisions of Endocrinology and Metabolism at the University of Mon-Endocrinol Metab 2002;87:3578-82.tréal, Montréal, Que. (Serri), the University of Alberta, Edmonton, Alta. (Chik),Dalhousie University, Halifax, NS (Ur), and the University of Toronto, Toronto,Ont. (Ezzat)Correspondence to: Dr. Shereen Ezzat, Mount Sinai Hospital,Competing interests: The authors received an unrestricted educational grant fromSte. 437, 600 University Ave., Toronto ON M5G 1X5; Paladin Labs Inc.fax 416 586-8834; sezzat@mtsinai.on.caCMAJ • SEPT. 16, 2003; 169 (6)581