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Medication-Induced Hyperprolactinemia

  • Author Footnotes
    1 Dr Molitch is currently receiving research support from Pfizer, Inc, Novartis Pharmaceuticals Corp, Sanofi-Aventis Pharmaceuticals, and Amgen Inc and is serving as a consultant to Abbott Laboratories.,
    Mark E. Molitch
    Correspondence
    Address reprint requests and correspondence to Mark E. Molitch, MD, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave (Tarry 15-731), Chicago, IL 60611
    Footnotes
    1 Dr Molitch is currently receiving research support from Pfizer, Inc, Novartis Pharmaceuticals Corp, Sanofi-Aventis Pharmaceuticals, and Amgen Inc and is serving as a consultant to Abbott Laboratories.,
    Affiliations
    Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
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  • Author Footnotes
    1 Dr Molitch is currently receiving research support from Pfizer, Inc, Novartis Pharmaceuticals Corp, Sanofi-Aventis Pharmaceuticals, and Amgen Inc and is serving as a consultant to Abbott Laboratories.,
      Medication use is a common cause of hyperprolactinemia, and it is important to differentiate this cause from pathologic causes, such as prolactinomas. To ascertain the frequency of this clinical problem and to develop treatment guidelines, the medical literature was searched by using PubMed and the reference lists of other articles dealing with hyperprolactinemia due to specific types of medications. The medications that most commonly cause hyperprolactinemia are antipsychotic agents; however, some newer atypical antipsychotics do not cause this condition. Other classes of medications that cause hyperprolactinemia include antidepressants, antihypertensive agents, and drugs that increase bowel motility. Hyperprolactinemia caused by medications is commonly symptomatic, causing galactorrhea, menstrual disturbance, and impotence. It is important to ensure that hyperprolactinemia in an individual patient is due to medication and not to a structural lesion in the hypothalamic/pituitary area; this can be accomplished by (1) stopping the medication temporarily to determine whether prolactin levels return to normal, (2) switching to a medication that does not cause hyperprolactinemia (in consultation with the patient's psychiatrist for psychoactive medications), or (3) performing magnetic resonance imaging or computed tomography of the hypothalamic/pituitary area. If the patient's hyperprolactinemia is symptomatic, treatment strategies include switching to an alternative medication that does not cause hyperprolactinemia, using estrogen or testosterone replacement, or, rarely, cautiously adding a dopamine agonist.
      D2 (dopamine D2), HIV (human immunodeficiency virus), MRI (magnetic resonance imaging), PRL (prolactin), TRH (thyrotropin-releasing hormone)
      Critical to an understanding of the ways in which medications affect prolactin (PRL) secretion is an explanation of the neuroendocrine regulation of PRL secretion. The hypothalamus predominantly influences PRL secretion through 1 or more PRL inhibitory factors that reach the pituitary via the hypothalamic/pituitary portal vessels. Disruption of the pituitary stalk leads to moderately increased PRL secretion and to decreased secretion of the other pituitary hormones. Dopamine is the predominant physiological inhibitory factor; blockade of endogenous dopamine receptors by various drugs, including antipsychotic agents, causes PRL secretion to increase. There are PRL-releasing factors as well. Although thyrotropin-releasing hormone (TRH) causes a rapid release of PRL, numerous different experimental approaches have failed to clarify the physiological role of TRH as a PRL-releasing factor. Vasoactive intestinal peptide has stimulatory effects that are selective for PRL; also, a part of the vasoactive intestinal peptide precursor, a similarly sized peptide known as peptide histidine methionine, exerts PRL-releasing properties in humans. The precise roles of these peptides and other PRL-releasing factors such as TRH are unclear.
      • Molitch ME
      Disorders of prolactin secretion.
      The clinical consequences of hyperprolactinemia include galactorrhea and hypogonadotropic hypogonadism, the latter manifesting as oligomenorrhea or amenorrhea in women, erectile dysfunction in men, and loss of libido and infertility in both sexes.
      • Molitch ME
      Disorders of prolactin secretion.
      The hypogonadism primarily is due to the hyperprolactinemia causing a decrease in the pulsatile secretion of gonadotropin-releasing hormone by the hypothalamus.
      • Molitch ME
      Disorders of prolactin secretion.
      The differential diagnosis of hyperprolactinemia includes medication-induced hyperprolactinemia. It is important to differentiate medication-induced hyperprolactinemia from pathological causes, such as PRL-producing tumors (prolactinomas), hypothalamic disease, hypothyroidism, and renal insufficiency.
      • Molitch ME
      Disorders of prolactin secretion.
      Many medications reportedly cause hyperprolactinemia (Table 1). The medical literature was searched by using PubMed and the reference lists of other articles dealing with hyperprolactinemia due to specific types of medications. In this review, I critically evaluate the literature regarding the frequencies at which such medications cause hyperprolactinemia and whether the degree of hyperprolactinemia is sufficient to cause symptoms. The assessment and treatment of patients with suspected medication-induced hyperprolactinemia are described as well.
      TABLE 1Medications That May Cause Hyperprolactinemia
      • Antipsychotics (neuroleptics)
        • Phenothiazines
        • Thioxanthenes
        • Butyrophenones
        • Atypical antipsychotics
      • Antidepressants
        • Tricyclic and tetracyclic antidepressants
        • Monoamine oxidase inhibitors
        • Selective serotonin reuptake inhibitors
        • Other
      • Opiates and cocaine
      • Antihypertensive medications
        • Verapamil
        • Methyldopa
        • Reserpine
      • Gastrointestinal medications
        • Metoclopramide
        • Domperidone
        • Histamine2 receptor blockers?
      • Protease inhibitors?
      • Estrogens

      Medications Causing Hyperprolactinemia

      Antipsychotic (Neuroleptic) Medications

      The medications that most commonly cause hyperprolactinemia are antipsychotic (neuroleptic) agents (Table 2). These drugs are dopamine receptor blockers. Their antipsychotic effects are mediated by dopamine D2 (D2) and dopamine D4 receptors in the mesolimbic area of the brain, and their extrapyramidal adverse effects are mediated through D2 receptors in the striatal area.
      • Green AI
      • Brown WA
      Prolactin and neuroleptic drugs.
      • Wieck A
      • Haddad P
      Hyperprolactinaemia caused by antipsychotic drugs [editorial].
      Their hyper-prolactinemic effects are mediated by D2 receptors in the hypothalamic tuberoinfundibular system and on the lactotrophs.
      • Green AI
      • Brown WA
      Prolactin and neuroleptic drugs.
      • Wieck A
      • Haddad P
      Hyperprolactinaemia caused by antipsychotic drugs [editorial].
      • Rubin RT
      • Hays SE
      The prolactin secretory response to neuroleptic drugs: mechanisms, applications and limitations.
      The antipsychotic potency of the older phenothiazines (chlorpromazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, perphenazine), thioxanthenes (thiothixene), butyrophenones (haloperidol), and dibenzoxazepine (loxapine) was found generally to parallel their potency in increasing PRL levels.
      • Green AI
      • Brown WA
      Prolactin and neuroleptic drugs.
      • Rubin RT
      • Hays SE
      The prolactin secretory response to neuroleptic drugs: mechanisms, applications and limitations.
      • Kleinberg DL
      • Frantz AG
      Human prolactin: measurement in plasma by in vitro bioassay.
      • Langer G
      • Sachar EJ
      Dopaminergic factors in human prolactin regulation: effects of neuroleptics and dopamine.
      TABLE 2Effects of Psychotropic Medications on Prolactin Levels
      CR = isolated case reports of hyperprolactinemia but generally no increase in prolactin levels.
      Increase in prolactin
      0 = no effect; ± = minimal increase but not to abnormal levels; + = increase to abnormal levels in small percentage of patients; ++ = increase to abnormal levels in 25% to 50% of patients; +++ = increase to abnormal levels in more than 50% of patients.
      Antipsychotics
       Typical
        Phenothiazines+++
        Butyrophenones+++
        Thioxanthenes+++
       Atypical
        Risperidone+++
        Molindone++
        Clozapine0
        Quetiapine+
        Ziprasidone0
        Aripiprazole0
        Olanzapine+
      Antidepressants
       Tricyclics
        Amitriptyline+
        Desipramine+
        Clomipramine+++
        Nortriptyline
        ImipramineCR
        MaprotilineCR
        AmoxapineCR
       Monoamine oxidase inhibitors
        Pargyline+++
        Clorgyline+++
        Tranylcypromine±
       Selective serotonin reuptake inhibitors
        FluoxetineCR
        Paroxetine±
        Citalopram±
        Fluvoxamine±
       Other
        Nefazodone0
        Bupropion0
        Venlafaxine0
        Trazodone0
      * CR = isolated case reports of hyperprolactinemia but generally no increase in prolactin levels.
      0 = no effect; ± = minimal increase but not to abnormal levels; + = increase to abnormal levels in small percentage of patients; ++ = increase to abnormal levels in 25% to 50% of patients; +++ = increase to abnormal levels in more than 50% of patients.
      Overall, there is a highly variable PRL-releasing response to these drugs among individuals in both the level of PRL and the duration of PRL elevation. Levels of PRL increase usually within minutes after intramuscular injection.
      • Langer G
      • Sachar EJ
      • Halpern FS
      • Gruen PH
      • Solomon M
      The prolactin response to neuroleptic drugs: a test of dopaminergic blockade: neuroendocrine studies in normal men.
      After oral administration, levels increase gradually for about a week and then remain constant.
      • Spitzer M
      • Siajjad R
      • Benjamin F
      Pattern of development of hyperprolactinemia after initiation of haloperidol therapy.
      The levels of PRL found with these drugs generally are less than 100 µg/L, but some patients have been reported with levels as high as 365 µg/L.
      • Meltzer HY
      • Fang VS
      Serum prolactin levels in schizophrenia—effect of antipsychotic drugs: a preliminary report.
      • Rivera JL
      • Lal S
      • Ettigi P
      • Hontela S
      • Muller HF
      • Friesen HG
      Effect of acute and chronic neuroleptic therapy on serum prolactin levels in men and women of different age groups.
      • Pollock A
      • McLaren EH
      Serum prolactin concentration in patients taking neuroleptic drugs.
      • Smith S
      • Wheeler MJ
      • Murray R
      • O'Keane V
      The effects of antipsychotic-induced hyperprolactinaemia on the hypothalamic-pituitary-gonadal axis.
      Between 40% and 90% of patients taking butyrophenones and phenothiazines for years have maintained elevated PRL levels, and galactorrhea, amenorrhea, and impotence are common manifestations in such patients.
      • Rivera JL
      • Lal S
      • Ettigi P
      • Hontela S
      • Muller HF
      • Friesen HG
      Effect of acute and chronic neuroleptic therapy on serum prolactin levels in men and women of different age groups.
      • Zelaschi NM
      • Delucchi GA
      • Rodriguez JL
      High plasma prolactin levels after long-term neuroleptic treatment.
      • Kleinberg DL
      • Davis JM
      • de Coster R
      • Van Baelen B
      • Brecher M
      Prolactin levels and adverse events in patients treated with risperidone.
      • Kinon BJ
      • Gilmore JA
      • Liu H
      • Halbreich UM
      Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone.
      The PRL levels usually decline to normal within 48 to 96 hours after discontinuation of neuroleptic drug therapy.
      • Meltzer HY
      • Fang VS
      Serum prolactin levels in schizophrenia—effect of antipsychotic drugs: a preliminary report.
      In recent years, numerous newer medications in this class have been developed, often referred to as atypical antipsychotic agents.
      • Hamner M
      The effects of atypical antipsychotics on serum prolactin levels.
      Risperidone is a combined serotonin/dopamine receptor antagonist that can cause elevations in PRL level even higher than those caused by the typical antipsychotics.
      • Kleinberg DL
      • Davis JM
      • de Coster R
      • Van Baelen B
      • Brecher M
      Prolactin levels and adverse events in patients treated with risperidone.
      • Kinon BJ
      • Gilmore JA
      • Liu H
      • Halbreich UM
      Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone.
      • Hamner M
      The effects of atypical antipsychotics on serum prolactin levels.
      • Kinon BJ
      • Gilmore JA
      • Liu H
      • Halbreich UM
      Hyperprolactinemia in response to antipsychotic drugs: characterization across comparative clinical trials.
      • Kearns AE
      • Goff DC
      • Hayden DL
      • Daniels GH
      Risperidone-associated hyperprolactinemia.
      • David SR
      • Taylor CC
      • Kinon BJ
      • Breier A
      The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia.
      • Becker D
      • Liver O
      • Mester R
      • Rapoport M
      • Weizman A
      • Weiss M
      Risperidone, but not olanzapine, decreases bone mineral density in female premenopausal schizophrenia patients.
      • Findling RL
      • Kusumakar V
      • Daneman D
      • Moshang T
      • DeSmedt G
      • Binder C
      Prolactin levels during long-term risperidone treatment in children and adolescents.
      • Volavka J
      • Czobor P
      • Cooper TB
      • et al.
      Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol.
      Although in 1 study of children and adolescents the substantial PRL elevation seen with risperidone decreased to levels within the normal range but was still significantly elevated compared with baseline,
      • Findling RL
      • Kusumakar V
      • Daneman D
      • Moshang T
      • DeSmedt G
      • Binder C
      Prolactin levels during long-term risperidone treatment in children and adolescents.
      other studies have shown persistent substantial elevations for years.
      • Becker D
      • Liver O
      • Mester R
      • Rapoport M
      • Weizman A
      • Weiss M
      Risperidone, but not olanzapine, decreases bone mineral density in female premenopausal schizophrenia patients.
      Molindone is another of these newer drugs than can also cause hyperprolactinemia.
      • Pandurangi AK
      • Narasimhachari N
      • Blackard WG
      • Landa BS
      Relation of serum molindone levels to serum prolactin levels and antipsychotic response.
      In contrast, clozapine,
      • Volavka J
      • Czobor P
      • Cooper TB
      • et al.
      Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol.
      • Breier AF
      • Malhotra AK
      • Su TP
      • et al.
      Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response.
      • Turrone P
      • Kapur S
      • Seeman MV
      • Flint AJ
      Elevation of prolactin levels by atypical antipsychotics.
      olanzapine,
      • Kinon BJ
      • Gilmore JA
      • Liu H
      • Halbreich UM
      Hyperprolactinemia in response to antipsychotic drugs: characterization across comparative clinical trials.
      • David SR
      • Taylor CC
      • Kinon BJ
      • Breier A
      The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia.
      • Becker D
      • Liver O
      • Mester R
      • Rapoport M
      • Weizman A
      • Weiss M
      Risperidone, but not olanzapine, decreases bone mineral density in female premenopausal schizophrenia patients.
      • Volavka J
      • Czobor P
      • Cooper TB
      • et al.
      Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol.
      • Crawford AM
      • Beasley Jr, CM
      • Tollefson GD
      The acute and long-term effect of olanzapine compared with placebo and haloperidol on serum prolactin concentrations.
      • Kim KS
      • Pae CU
      • Chae JH
      • et al.
      Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone.
      quetiapine,
      • Hamner MB
      • Arvanitis LA
      • Miller BG
      • Link CG
      • Hong WW
      Plasma prolactin in schizophrenia subjects treated with SeroquelT (ICI 204,636).
      ziprasidone,
      • Goff DC
      • Posever T
      • Herz L
      • et al.
      An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder.
      and aripiprazole
      • Casey DE
      • Carson WH
      • Saha AR
      • Aripiprazole Study Group
      • et al.
      Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study.
      much less commonly elevate PRL levels. It is believed that the lack of effect of these atypical agents is due to their being only transiently and weakly bound to the D2 receptor
      • Seeman P
      Atypical antipsychotics: mechanism of action.
      or to their having agonist activity as well as antagonist activity at the D2 receptor.
      • Gründer G
      • Carlsson A
      • Wong DF
      Mechanism of new antipsychotic medications: occupancy is not just antagonism.
      Frequent sampling for PRL levels in patients taking clozapine or olanzapine long-term shows that PRL levels increase quickly 1.5-fold to 2.5-fold within 2 to 4 hours after the drugs are taken, only to decrease to baseline within 8 hours, thus supporting the hypothesis that these agents only transiently bind to the tuberoinfundibular D2 receptor. In contrast, risperidone causes a similar doubling of PRL levels, but the effects persist for 24 hours.
      • Turrone P
      • Kapur S
      • Seeman MV
      • Flint AJ
      Elevation of prolactin levels by atypical antipsychotics.
      Hyperprolactinemia caused by these drugs is accompanied usually by decreased libido, erectile dysfunction in men, and galactorrhea and amenorrhea in women.
      • Pollock A
      • McLaren EH
      Serum prolactin concentration in patients taking neuroleptic drugs.
      • Smith S
      • Wheeler MJ
      • Murray R
      • O'Keane V
      The effects of antipsychotic-induced hyperprolactinaemia on the hypothalamic-pituitary-gonadal axis.
      • Kinon BJ
      • Gilmore JA
      • Liu H
      • Halbreich UM
      Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone.
      • Cutler AJ
      Sexual dysfunction and antipsychotic treatment.
      • Knegtering H
      • van der Moolen AE
      • Castelein S
      • Kluiter H
      • van den Bosch RJ
      What are the effects of antipsychotics on sexual dysfunctions and endocrine functioning?.
      • Brunelleschi S
      • Zeppegno P
      • Risso F
      • Cattaneo CI
      • Torre E
      Risperidone-associated hyperprolactinemia: evaluation in twenty psychiatric outpatients.
      • Knegtering R
      • Castelein S
      • Bous H
      • et al.
      A randomized open-label study of the impact of quetiapine versus risperidone on sexual functioning.
      In 1 study, among all premenopausal women with antipsychotic-induced hyperprolactinemia, 31.6% had estradiol levels less than 73 pmol/L,
      • Kinon BJ
      • Gilmore JA
      • Liu H
      • Halbreich UM
      Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone.
      and preliminary data suggest that there may be an increased risk of osteopenia.
      • Becker D
      • Liver O
      • Mester R
      • Rapoport M
      • Weizman A
      • Weiss M
      Risperidone, but not olanzapine, decreases bone mineral density in female premenopausal schizophrenia patients.
      • Ataya K
      • Mercado A
      • Kartaginer J
      • Abbasi A
      • Moghissi KS
      Bone density and reproductive hormones in patients with neuroleptic-induced hyperprolactinemia.
      However, studies in children treated with risperidone have shown no delay in maturation.
      • Dunbar F
      • Kusumakar V
      • Daneman D
      • Schulz M
      Growth and sexual maturation during long-term treatment with risperidone.

      Antidepressant Medications

      Tricyclic antidepressants have caused mild hyperprolactinemia in some patients, but the data are scant (Table 2). In 1 series, amitriptyline reportedly caused a 100% increase in PRL levels in 2 (14%) of 14 patients.
      • Meltzer HY
      • Fang VS
      • Tricou BJ
      • Robertson A
      Effect of antidepressants on neuroendocrine axis in humans.
      Although desipramine caused a 100% increase in PRL levels in 2 (50%) of 4 patients in 1 study,
      • Meltzer HY
      • Fang VS
      • Tricou BJ
      • Robertson A
      Effect of antidepressants on neuroendocrine axis in humans.
      it caused no change in PRL levels in another study of 24 patients.
      • Price LH
      • Charney DS
      • Delgado PL
      • Anderson GM
      • Heninger GR
      Effects of desipramine and fluvoxamine treatment on the prolactin response to tryptophan: serotonergic function and the mechanism of antidepressant action.
      Meltzer et al
      • Meltzer HY
      • Fang VS
      • Tricou BJ
      • Robertson A
      Effect of antidepressants on neuroendocrine axis in humans.
      reported that neither nortriptyline nor mianserin caused increases in PRL levels, but no specific data were given in that report. Clomipramine has reportedly caused hyperprolactinemia in 60% of men and 87.5% of women.
      • Jones RB
      • Luscombe DK
      • Groom GV
      Plasma prolactin concentrations in normal subjects and depressive patients following oral clomipramine.
      With respect to other tricyclic and tetracyclic antidepressants, there are only individual case reports of symptomatic hyperprolactinemia with use of imipramine, maprotiline, and amoxapine.
      • Marken PA
      • Haykal RF
      • Fisher JN
      Management of psychotropic-induced hyperprolactinemia.
      With respect to monoamine oxidase inhibitors, PRL levels doubled in all 5 patients treated with pargyline and in all 5 treated with clorgyline.
      • Slater SL
      • Lipper S
      • Shiling DJ
      • Murphy DL
      Elevation of plasmaprolactin by monoamine-oxidase inhibitors.
      Currently, neither of these drugs is being used clinically. In contrast, in the only study of patients treated with a currently used monoamine oxidase inhibitor, tranylcypromine, PRL levels increased by only 3 µg/L in 9 patients treated for depression with doses of 10 to 40 mg/d for a mean of 16 days.
      • Price LH
      • Charney DS
      • Heninger GR
      Effects of tranylcypromine treatment on neuroendocrine, behavioral, and autonomic responses to tryptophan in depressed patients.
      The mechanisms by which these drugs increased PRL levels are uncertain, and this class of drugs likely facilitates several possible stimulatory pathways.
      Some reviews have stated that selective serotonin re-uptake inhibitors have become “the most commonly reported cause of drug-induced hyperprolactinaemia.”
      • Cohen MA
      • Davies PH
      Drug therapy and hyperprolactinaemia.
      However, the reference for this statement was a personal communication, and other evidence does not support this statement. In 1 study, fluoxetine was given at a dosage of 60 mg/d for 6 days to 7 healthy women, and their mean ± SD PRL levels increased from 9.6±1.6 µg/L to 11.1±1.7 µg/L (16%).
      • Urban RJ
      • Veldhuis JD
      A selective serotonin reuptake inhibitor, fluoxetine hydrochloride, modulates the pulsatile release of prolactin in postmenopausal women.
      In clinical trials of fluoxetine in 5920 patients, the PRL level was not measured, but galactorrhea was reported in only 0.07%, breast enlargement in 0.08%, and breast pain in 0.25% of subjects.
      • Marken PA
      • Haykal RF
      • Fisher JN
      Management of psychotropic-induced hyperprolactinemia.
      Paroxetine was given at a dosage of 20 mg/d for 3 weeks to 11 healthy subjects; during this study, the basal PRL level increased by only 35% to levels still within the normal range.
      • Cowen PJ
      • Sargent PA
      Changes in plasma prolactin during SSRI treatment: evidence for a delayed increase in 5-HT neurotransmission.
      In a second study of 8 patients treated with paroxetine, PRL levels increased similarly, from mean ± SD levels of 5.8+3.0 µg/L to 8.4+4.4 µg/L,
      • Amsterdam JD
      • Garcia-España F
      • Goodman D
      • Hooper M
      • Hornig-Rohan M
      Breast enlargement during chronic antidepressant therapy.
      and in a third study of 15 patients with depression, PRL levels increased similarly.
      • Mück-Seler D
      • Pivac N
      • Sagud M
      • Jakovljevic M
      • Mihaljevic-Peles A
      The effects of paroxetine and tianeptine on peripheral biochemical markers in major depression.
      In 12 healthy individuals in 1 study, a similar 40% increase in PRL levels was found with use of citalopram,
      • Laine K
      • Anttila M
      • Heinonen E
      • et al.
      Lack of adverse interactions between concomitantly administered selegiline and citalopram.
      but no change was found in 8 patients with panic disorder in another study.
      • Shlik J
      • Aluoja A
      • Vasar V
      • Vasar E
      • Podar T
      • Bradwejn J
      Effects of citalopram treatment on behavioural, cardiovascular and neuroendocrine response to cholecystokinin tetrapeptide challenge in patients with panic disorder.
      With respect to sertraline, no increase in PRL levels was found in 13 healthy individuals treated for up to 3 weeks
      • Gordon C
      • Whale R
      • Cowen PJ
      Sertraline treatment does not increase plasma prolactin levels in healthy subjects [letter].
      or in 15 subjects with depression treated for 24 weeks.
      • Šagud M
      • Pivac N
      • Mück-Šeler D
      • Jakovljević M
      • Mihaljević-Peleš A
      • Korsic M
      Effects of sertraline treatment on plasma cortisol, prolactin and thyroid hormones in female depressed patients.
      Fluvoxamine caused a significant increase in PRL to abnormal levels in 2 of 8 healthy subjects in 1 study
      • Spigset O
      • Mjörndal T
      The effect of fluvoxamine on serum prolactin and serum sodium concentrations: relation to platelet 5-HT2A receptor status.
      but only a minimal change (mean ± SD PRL level, 3.5±4.0 vs 5.3±5.0 µg/L) in 30 individuals with depression in another study.
      • Price LH
      • Charney DS
      • Delgado PL
      • Anderson GM
      • Heninger GR
      Effects of desipramine and fluvoxamine treatment on the prolactin response to tryptophan: serotonergic function and the mechanism of antidepressant action.
      The number of well-documented case reports of symptomatic hyperprolactinemia from selective serotonin reuptake inhibitors is extremely small.
      • Iancu I
      • Ratzoni G
      • Weitzman A
      • Apter A
      More fluoxetine experience [letter].
      • Peterson MC
      Reversible galactorrhea and prolactin elevation related to fluoxetine use.
      In one of the best-documented cases, a 71-year-old woman with galactorrhea and a PRL level of 37.4 µg/L during fluoxetine therapy stopped taking fluoxetine, after which her PRL level decreased to 6.1 µg/L and her galactorrhea resolved.
      • Peterson MC
      Reversible galactorrhea and prolactin elevation related to fluoxetine use.
      Regarding some of the other antidepressants, PRL level elevations have not been seen with long-term use of nefazodone,
      • Walsh AE
      • Cowen PJ
      Attenuation of the prolactin-stimulating and hyperthermic effects of nefazodone after subacute treatment.
      bupropion,
      • Whiteman PD
      • Peck AW
      • Fowle AS
      • Smith PR
      Failure of bupropion to affect prolactin or growth hormone in man.
      venlafaxine,
      • Amsterdam JD
      • Garcia-España F
      • Goodman D
      • Hooper M
      • Hornig-Rohan M
      Breast enlargement during chronic antidepressant therapy.
      or trazodone.
      • Price LH
      • Charney DS
      • Heninger GR
      Effects of trazodone treatment on serotonergic function in depressed patients.
      Interestingly, lithium carbonate appears to decrease PRL levels by about 40%.
      • Bastürk M
      • Karaaslan F
      • Esel E
      • Sofuoglu S
      • Tutus A
      • Yabanoglu I
      Effects of short and long-term lithium treatment on serum prolactin levels in patients with bipolar affective disorder.

      Opiates and Cocaine

      In humans, morphine and morphine analogues increase PRL release both short-term
      • Tolis G
      • Hickey J
      • Guyda H
      Effects of morphine on serum growth hormone, cortisol, prolactin and thyroid stimulating hormone in man.
      • Zis AP
      • Haskett RF
      • Albala AA
      • Carroll BJ
      Morphine inhibits cortisol and stimulates prolactin secretion in man.
      and long-term.
      • Chan V
      • Wang C
      • Yeung RT
      Effects of heroin addiction on thyrotrophin, thyroid hormones and prolactin secretion in men.
      • Afrasiabi MA
      • Flomm M
      • Friedlander H
      • Valenta LJ
      Endocrine studies in heroin addicts.
      Long-term methadone users have normal basal PRL levels that show a transient increase beginning 2 to 4 hours after each daily dose.
      • Bart G
      • Borg L
      • Schluger JH
      • Green M
      • Ho A
      • Kreek MJ
      Suppressed prolactin response to dynorphin A1-13 in methadone-maintained versus control subjects.
      Studies using specific agonists and antagonists operative on the µ, δ, and κ opioid receptors and antibodies directed against several opioid peptides have shown that the µ receptor is predominantly involved in PRL release, the κ receptor is involved to a lesser extent, and the δ receptor is not involved at all.
      • Panerai AE
      • Petraglia F
      • Sacerdote P
      • Genazzani AR
      Mainly μ-opiate receptors are involved in luteinizing hormone and prolactin secretion.
      • Pfeiffer A
      • Braun S
      • Mann K
      • Meyer HD
      • Brantl V
      Anterior pituitary hormone responses to a kappa-opioid agonist in man.
      • Leadem CA
      • Yagenova SV
      Effects of specific activation of mu-, delta- and kappa-opioid receptors on the secretion of luteinizing hormone and prolactin in the ovariectomized rat.
      Most evidence suggests that the opioid peptides do not directly affect the pituitary gland and stimulate PRL release by inhibiting hypothalamic dopamine secretion
      • Van Vugt DA
      • Bruni JF
      • Sylvester PW
      • Chen HT
      • Ieiri T
      • Meites J
      Interaction between opiates and hypothalamic dopamine on prolactin release.
      • van Loon GR
      • Ho D
      • Kim C
      β-Endorphin-induced decrease in hypothalamic dopamine turnover.
      • Gudelsky GA
      • Porter JC
      Morphine- and opioid peptide-induced inhibition of the release of dopamine from tuberoinfundibular neurons.
      Cocaine abuse also has been associated with chronic mild hyperprolactinemia.
      • Lee MA
      • Bowers MM
      • Nash JF
      • Meltzer HY
      Neuroendocrine measures of dopaminergic function in chronic cocaine users.
      • Mendelson JH
      • Mello NK
      • Teoh SK
      • Ellingboe J
      • Cochin J
      Cocaine effects on pulsatile secretion of anterior pituitary, gonadal, and adrenal hormones.

      Antihypertensive Medications

      Of the currently used antihypertensive medications, verapamil is the only one that causes hyperprolactinemia. Verapamil causes short-term and long-term increases in basal PRL secretion and in the PRL response to TRH.
      • Maestri E
      • Camellini L
      • Rossi G
      • Bordonali G
      • Bellodi G
      • Gnudi A
      Effects of five days verapamil administration on serum GH and PRL levels.
      • Kamal TJ
      • Molitch ME
      Effects of calcium channel blockade with verapamil on the prolactin responses to TRH, L-dopa, and bromocriptine.
      • Kelley SR
      • Kamal TJ
      • Molitch ME
      Mechanism of verapamil calcium channel blockade-induced hyperprolactinemia.
      Patients have been described with galactorrhea associated with sustained hyperprolactinemia due to verapamil.
      • Gluskin LE
      • Strasberg B
      • Shah JH
      Verapamil-induced hyperprolactinemia and galactorrhea.
      • Fearrington EL
      • Rand Jr, CH
      • Rose JD
      Hyperprolactinemia-galactorrhea induced by verapamil [letter].
      In a survey of patients taking verapamil in an outpatient clinic, PRL levels were elevated in 8.5% of patients,
      • Romeo JH
      • Dombrowski R
      • Kwak YS
      • Fuehrer S
      • Aron DC
      Hyperprolactinaemia and verapamil: prevalence and potential association with hypogonadism in men.
      and hyperprolactinemia was associated with lower testosterone levels. Verapamil is believed to cause hyperprolactinemia by blocking the hypothalamic generation of dopamine.
      • Kamal TJ
      • Molitch ME
      Effects of calcium channel blockade with verapamil on the prolactin responses to TRH, L-dopa, and bromocriptine.
      • Kelley SR
      • Kamal TJ
      • Molitch ME
      Mechanism of verapamil calcium channel blockade-induced hyperprolactinemia.
      Other calcium channel blockers such as the dihydropyridines and benzothiazepines have no action on PRL secretion.
      • Kelley SR
      • Kamal TJ
      • Molitch ME
      Mechanism of verapamil calcium channel blockade-induced hyperprolactinemia.
      α-Methyldopa causes moderate hyperprolactinemia, possibly by inhibiting the enzyme aromatic-L-amino-acid decarboxylase, which is responsible for converting L-dopa to dopamine, and by acting as a false neurotransmitter to decrease dopamine synthesis.
      • Steiner J
      • Cassar J
      • Mashiter K
      • Dawes I
      • Fraser TR
      • Breckenridge A
      Effect of methyldopa on prolactin and growth hormone.
      Reserpine, a little-used antihypertensive drug, causes hyperprolactinemia in about 50% of patients, likely by interfering with the storage of hypothalamic catecholamines in secretory granules.
      • Lee PA
      • Kelly MR
      • Wallin JD
      Increased prolactin levels during reserpine treatment of hypertensive patients.
      Enalapril, an angiotensin-converting enzyme inhibitor, inhibits PRL release in some individuals,
      • Winer LM
      • Molteni A
      • Molitch ME
      Effect of angiotensin-converting enzyme inhibition on pituitary hormone responses to insulin-induced hypoglycemia in humans.
      but sustained alterations of PRL levels have not been reported with use of this class of medications.

      Gastrointestinal Medications

      Two drugs commonly used to increase gastrointestinal motility and stomach emptying in patients with gastroparesis diabeticorum, metoclopramide and domperidone, are dopamine receptor blockers. These drugs cause hyperprolactinemia in more than 50% of patients and commonly cause symptoms of amenorrhea and galactorrhea in women and impotence in men.
      • Aono T
      • Shioji T
      • Kinugasa T
      • Onishi T
      • Kurachi K
      Clinical and endocrinological analyses of patients with galactorrhea and menstrual disorders due to sulpiride or metoclopramide.
      • Tamagna EI
      • Lane W
      • Hershman JM
      • et al.
      Effect of chronic metoclopramide therapy on serum pituitary hormone concentrations.
      • Fujino T
      • Kato H
      • Yamashita S
      • et al.
      Effects of domperidone on serum prolactin levels in human beings.
      Another drug used for this purpose, cisapride, does not block dopamine receptors and does not cause hyperprolactinemia. At present in the United States, only metoclopramide is available for this use, but the other drugs are available in many other countries. Chlorpromazine, a commonly used antinausea drug, is a phenothiazine and causes acute hyperprolactinemia
      • Langer G
      • Sachar EJ
      Dopaminergic factors in human prolactin regulation: effects of neuroleptics and dopamine.
      ; however, it is not commonly used long-term.
      Shortly after the approval of histamine2 receptor blockers such as cimetidine and ranitidine, several brief case reports were published about patients experiencing symptoms related to hyperprolactinemia.
      • Delle Fave GF
      • Tamburrano G
      • De Magistris L
      • et al.
      Gynaecomastia with cimetidine [letter].
      • Petrillo M
      • Prada A
      • Porro GB
      • Bevilacqua M
      • Raggi V
      • Norbiato G
      Plasma-prolactin and cimetidine [letter].
      However, in larger series, hyperprolactinemia has not been reported, and there have been no subsequent reports of hyperprolactinemia occurring with this class of drugs
      • Spiegel AM
      • Lopatin R
      • Peikin S
      • McCarthy D
      Serum-prolactin in patients receiving chronic oral cimetidine [letter].
      • Majumdar SK
      • Thomson AD
      • Shaw GK
      Cimetidine and serum prolactin.
      • Scarpignato C
      • Bertaccini G
      Cimetidine and endocrine secretions: a short review.
      • Lombardo L
      More about ranitidine and hyperprolactinaemia [letter].
      except for 1 case of a woman treated with a twice-maximum dose of famotidine.
      • Delpre G
      • Lapidot M
      • Lipchitz A
      • Livni E
      • Kadish U
      Hyperprolactinaemia during famotidine therapy [letter].

      Protease Inhibitors

      In 2000, Hutchinson et al
      • Hutchinson J
      • Murphy M
      • Harries R
      • Skinner CJ
      Galactorrhea and hyperprolactinemia associated with protease inhibitors [letter].
      described 4 patients who were hyperprolactinemic while receiving protease inhibitors as part of highly active antiretroviral therapy or prophylactic therapy. However, inspection of these case histories revealed that 1 patient also was receiving fluoxetine, 1 also was receiving metoclopramide, and 1 also was receiving domperidone.
      • Hutchinson J
      • Murphy M
      • Harries R
      • Skinner CJ
      Galactorrhea and hyperprolactinemia associated with protease inhibitors [letter].
      In a second series of 46 patients who were human immunodeficiency virus (HIV) positive, reported by Montero et al,
      • Montero A
      • Bottasso OA
      • Luraghi MR
      • Giovannoni AG
      • Sen L
      Galactorrhoea, hyperprolactinaemia, and protease inhibitors [letter].
      10 of 18 patients who were infected (opportunistic) were found to be hyperprolactinemic, whereas only 2 of 28 noninfected patients were hyperprolactinemic. Also, of 20 patients taking protease inhibitors, 4 (20%) were hyperprolactinemic; of 26 patients not taking protease inhibitors, 6 (23%) were hyperprolactinemic.
      • Montero A
      • Bottasso OA
      • Luraghi MR
      • Giovannoni AG
      • Sen L
      Galactorrhoea, hyperprolactinaemia, and protease inhibitors [letter].
      Thus, the hyperprolactinemia seen in HIV-positive patients is more likely caused by infections or by use of other medications than by protease inhibitors.

      Estrogens

      High levels of estrogens present during pregnancy are known to cause lactotroph hyperplasia and hyperprolactinemia.
      • Molitch ME
      Management of prolactinomas during pregnancy.
      Whether the estrogens in oral contraceptives or hormone replacement therapy are sufficient to cause hyperprolactinemia is controversial. Some studies have shown that estrogen-containing oral contraceptives indeed can cause hyperprolactinemia in percentages ranging from 12% to 30% of treated women, with the dose of estrogen having little influence,
      • Reyniak JV
      • Wenof M
      • Aubert JM
      • Stangel JJ
      Incidence of hyperprolactinemia during oral contraceptive therapy.
      • Luciano AA
      • Sherman BM
      • Chapler FK
      • Hauser KS
      • Wallace RB
      Hyperprolactinemia and contraception: a prospective study.
      but others have shown either a minimal or no increase in PRL levels.
      • Abu-Fadil S
      • DeVane G
      • Siler TM
      • Yen SS
      Effects of oral contraceptive steroids on pituitary prolactin secretion.
      • Davis JR
      • Selby C
      • Jeffcoate WJ
      Oral contraceptive agents do not affect serum prolactin in normal women.
      • Hwang PL
      • Ng CS
      • Cheong ST
      Effect of oral contraceptives on serum prolactin: a longitudinal study in 126 normal premenopausal women.
      • Josimovich JB
      • Lavenhar MA
      • Devanesan MM
      • Sesta HJ
      • Wilchins SA
      • Smith AC
      Heterogeneous distribution of serum prolactin values in apparently healthy young women, and the effects of oral contraceptive medication.
      • De Leo V
      • Lanzetta D
      • Vanni AL
      • D'Antona D
      • Severi FM
      Low estrogen oral contraceptives and the hypothalamo-pituitary axis.
      In contrast, most studies have shown either no
      • Grasso A
      • Baraghini F
      • Barbieri C
      • et al.
      Endocrinological features and endometrial morphology in climacteric women receiving hormone replacement therapy.
      • Perrone G
      • Falaschi P
      • Capri O
      • et al.
      Hormonal and metabolic effects of transdermal estradiol/progestagen administration in postmenopausal women.
      • Castel-Branco C
      • Martínez de Osaba MJ
      • Fortuny A
      • Iglesias X
      • González-Merlo J
      Circulating hormone levels in menopausal women receiving different hormone replacement therapy regimens: a comparison.
      • Foth D
      • Römer T
      Prolactin serum levels in postmenopausal women receiving long-term hormone replacement therapy.
      or minimal
      • Schlegel W
      • Petersdorf LI
      • Junker R
      • Schulte H
      • Ebert C
      • von Eckardstein A
      The effects of six months of treatment with a low-dose of conjugated oestrogens in menopausal women.
      effect on PRL levels of estrogen replacement therapy after oophorectomy or at menopause with varying dosages of up to 1.25 mg of conjugated estrogens or 50 µg of estradiol daily. Therefore, in a given patient who is found to be hyperprolactinemic while taking oral contraceptives, it is uncertain whether the estrogen plays a role.

      Other Medications

      An early study showed that use of 1,25-dihydroxyvitamin D3 for 7 days caused serum PRL levels to double in 5 healthy men,
      • Verbeelen D
      • Vanhaelst L
      • Fuss M
      • Van Steirteghem AC
      Effect of 1,25-dihydroxyvitamin D3 and nifedipine on prolactin release in normal man.
      but no subsequent studies have confirmed this finding.

      Assessment of A Patient with Suspected Medication-Induced Hyperprolactinemia

      In patients taking medications known to cause hyperprolactinemia, it is critical to establish that the medication is the cause (Table 3). Minor PRL elevations in the range seen with most of these medications also may be seen in patients with PRL-secreting microadenomas and, more importantly, in those with large mass lesions that can cause PRL elevation due to hypothalamic/stalk dysfunction, resulting in a decrease in dopamine reaching the lactotrophs, ie, a disinhibition of PRL secretion.
      • Molitch ME
      • Reichlin S
      Hypothalamic hyperprolactinemia: neuroendocrine regulation of prolactin secretion in patients with lesions of the hypothalamus and pituitary stalk.
      • Bevan JS
      • Burke CW
      • Esiri MM
      • Adams CB
      Misinterpretation of prolactin levels leading to management errors in patients with sellar enlargement.
      • Arafah BM
      • Nekl KE
      • Gold RS
      • Selman WR
      Dynamics of prolactin secretion in patients with hypopituitarism and pituitary macroadenomas.
      TABLE 3Treatment Strategies for the Patient With Symptomatic Medication-Induced Hyperprolactinemia
      • Diagnosis
        • Confirm that the medication is the cause of hyperprolactinemia
          • Discontinue medication for 3 or 4 days
            With psychoactive medications, this must be done cautiously in consultation with the patient's psychiatrist.
          • Image hypothalamic/pituitary area with use of magnetic resonance imaging or computed tomography
      • Treatment
        • Switch to an alternative medication that does not cause hyperprolactinemia
          With psychoactive medications, this must be done cautiously in consultation with the patient's psychiatrist.
          or
        • Treat the problem caused by the hyperprolactinemia
          • Estrogen or progesterone
          • Testosterone
          • Bisphosphonate or
        • Add dopamine agonist cautiously (rarely necessary)
      * With psychoactive medications, this must be done cautiously in consultation with the patient's psychiatrist.
      A careful patient history may elicit symptoms or documentation of hyperprolactinemia coinciding in time with initiation of medication. However, usually such a history is not forthcoming, and in these circumstances, the simplest approach is to have the patient discontinue the medication because PRL levels generally return to normal within 3 to 4 days, at least with phenothiazines.
      • Meltzer HY
      • Fang VS
      Serum prolactin levels in schizophrenia—effect of antipsychotic drugs: a preliminary report.
      Some antidepressants may have more prolonged action, but there are no data showing when their PRL-increasing effects wear off. In all patients taking psychoactive agents, discontinuation of the medication must be done in careful consultation with the psychiatrist or other prescribing physician to avoid sudden exacerbation of any underlying psychiatric disorder.
      If a patient cannot stop taking a given medication for even a short time, an alternative drug that does not cause hyperprolactinemia can be substituted for several days to determine whether PRL levels decrease (discussed subsequently). Again, such a substitution must be done extremely carefully with supervision of the patient's psychiatrist when the patient is taking a psychoactive medication. If such a substitution is not feasible, then the patient should undergo magnetic resonance imaging (MRI) of the hypothalamic/pituitary area or, if MRI is unavailable, computed tomography.
      • Naidich MJ
      • Russell EJ
      Current approaches to imaging of the sellar region and pituitary.
      It is much more important to exclude large mass lesions in such a patient rather than to establish the presence of a microadenoma.

      Patient Treatment for Medication-Induced Hyperprolactinemia

      The first step in treatment is to determine whether the patient has symptoms related to the hyperprolactinemia. In a woman with normal, regular menses, if nonbothersome galactorrhea is the only reason to perform the PRL measurement, simple reassurance may be all that is needed. In contrast, if a patient has highly symptomatic hyperprolactinemia that, along with amenorrhea, causes decreased libido, bothersome galactorrhea, impotence, or osteoporosis, then a more active treatment strategy is necessary.
      Assuming that the patient needs to continue taking medication for an underlying disorder, switching to another drug in the same class that does not cause hyperprolactinemia is the easiest way to correct the problem. Thus, for a patient with antipsychotic-induced hyperprolactinemia, switching to drugs such as olanzapine, clozapine, or quetiapine may eliminate hyperprolactinemia.
      • Kinon BJ
      • Gilmore JA
      • Liu H
      • Halbreich UM
      Hyperprolactinemia in response to antipsychotic drugs: characterization across comparative clinical trials.
      • Kim KS
      • Pae CU
      • Chae JH
      • et al.
      Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone.
      • Takahashi H
      • Higuchi H
      • Kamata M
      • et al.
      Effectiveness of switching to quetiapine for neuroleptic-induced amenorrhea.
      Similarly, for a patient with antidepressant-induced hyperprolactinemia, switching to an alternative antidepressant may be successful. Again, all such medication changes must be done under the supervision of the patient's psychiatrist, and consideration must be given to other potential adverse effects of these alternative medications. There are many antihypertensive agents; therefore, switching a patient from verapamil to an alternative generally should not be a problem. However, for a patient with gastroparesis, no good alternatives to metoclopramide exist currently in the United States, although erythromycin has been used in some studies. Because of its association with cardiac dysrhythmias, cisapride is no longer available in the United States.
      If a patient has symptomatic hyperprolactinemia and cannot be switched from his or her medication, other treatments could be considered. If the major concern is decreased estrogen or testosterone levels, then simple substitution with estrogen or testosterone can be done. If the concern is osteoporosis, a bisphosphonate could be used.
      The most difficult treatment modality is to treat a patient with a dopamine agonist while continuing current medication. This modality has been used primarily in small numbers of patients with antipsychotic-induced hyperprolactinemia; there is a small risk of the dopamine agonist exacerbating the underlying psychosis, and the dopamine agonist is not always successful in normalizing PRL levels. In 1 series of 7 patients with hyperprolactinemia and galactorrhea from various antipsychotic medications who were treated with bromocriptine, 2 achieved normal PRL levels, 4 experienced considerable decreases in PRL levels, and galactorrhea improved in all.
      • Beumont P
      • Bruwer J
      • Pimstone B
      • Vinik A
      • Utian W
      Brom-ergocryptine in the treatment of phenothiazine-induced galactorrhea.
      In another series of 9 patients with hyperprolactinemia from thioridazine, 4 achieved normal PRL levels with bromocriptine with no worsening of psychiatric status.
      • Cohen JB
      • Brust J
      • DiSerio F
      • Singer J
      Effect of bromocriptine mesylate on induced hyperprolactinemia in stabilized psychiatric outpatients undergoing neuroleptic treatment.
      In a third series of 6 women with hyperprolactinemia and amenorrhea or oligomenorrhea from various antipsychotics, 4 achieved normal PRL levels and experienced menstrual irregularity with bromocriptine, but in 1 of these 4, mental status worsened.
      • Smith S
      Neuroleptic-associated hyperprolactinemia: can it be treated with bromocriptine?.
      In a more recent series of 4 patients with risperidone-induced hyperprolactinemia, bromocriptine or cabergoline reduced PRL levels and alleviated hypogonadism in 3, with no worsening of the underlying psychosis.
      • Tollin SR
      Use of the dopamine agonists bromocriptine and cabergoline in the management of risperidone-induced hyperprolactinemia in patients with psychotic disorders.
      In another recent series, 11 of 19 patients with symptomatic, risperidoneinduced hyperprolactinemia experienced remission of clinical signs and normalization of PRL levels without exacerbation of the underlying psychopathology when treated with cabergoline.
      • Cavallaro R
      • Cocchi F
      • Angelone SM
      • Lattuada E
      • Smeraldi E
      Cabergoline treatment of risperidone-induced hyperprolactinemia: a pilot study.
      However, other case reports document the worsening of mental status with bromo-criptine,
      • Frye PE
      • Pariser SF
      • Kim MH
      • O'Shaughnessy RW
      Bromocriptine associated with symptom exacerbation during neuroleptic treatment of schizoaffective schizophrenia.
      so this complication must always be looked for carefully when adding a dopamine agonist to antipsychotic therapy.

      Conclusions

      Hyperprolactinemia caused by medications is commonly symptomatic, causing galactorrhea, menstrual disturbance, and impotence. It is important to ensure that hyperprolactinemia in an individual patient is due to medication and not to a structural lesion in the hypothalamic/pituitary area. A careful patient history may elicit symptoms or documentation of hyperprolactinemia coinciding in time with initiation of a medication; however, such a history usually is not forthcoming. In such circumstances, either the medication should be stopped temporarily to determine whether PRL levels return to normal or the drug should be switched to one that does not cause hyperprolactinemia. In cases of suspected psychoactive medication–induced hyperprolactinemia, changing or stopping medications must be done in consultation with the patient's psychiatrist. If this cannot be done, MRI or computed tomography will exclude a structural lesion. Treatment is needed only if the hyperprolactinemia is symptomatic. Treatment strategies include switching to an alternative medication that does not cause hyperprolactinemia, using estrogen or testosterone replacement, or cautiously adding a dopamine agonist.

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