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Patients should address specific medical concerns with their physicians. Toggle navigation. Pharmacology Chapter. From Related Chapters. These medication classes increase prolactin by decreasing dopamine, which facilitates disinhibition of prolactin synthesis and release, or increasing prolactin stimulating hormones, such as serotonin or estrogen. Antipsychotics are the most common medication-related cause of hyperprolactinemia. Skip to main content. Savvy Psychopharmacology. Strategies for managing medication-induced hyperprolactinemia.
Current Psychiatry. Author and Disclosure Information Dr. These results were confirmed a few years later, with olanzapine found to be able to reverse hyperprolactinemia in conventional or risperidone-treated female schizophrenic patients, to decrease amenorrhea, to improve cycle regularity and to reduce sexual side effects, thus creating a safe and effective alternative method for patients with antipsychotic-induced hyperprolactinemia Kim et al ; Kinon et al Patients switching to olanzapine, as well as those remaining on their pre-study medication, maintained clinical stability, their symptoms continued to improve, although there were no significant between-treatment differences in improvement.
Treatment-emergent adverse events occurred in both treatment groups, with no significant differences between groups. A case report confirmed the successful strategy of switching to olanzapine while tapering risperidone: one month of titrated dose 15 mg olanzapine normalized serum prolactin, restored menstrual regularity, resolved galactorrhea and improved the psychiatric condition Canuso et al This patient recovered from galactorrhea and menstrual irregularities and her psychiatric condition remained stable Canuso et al Bunker et al reported a case of correction of serum prolactin levels after conversion to clozapine therapy in a year-old female patient who had developed hyperprolactinemia with galactorrhea and amenorrhea while receiving thioridazine mg daily and after a period of treatment with bromocriptine Bunker et al Successful management of antipsychotic-induced hyperprolactinemia with switching to quetiapine has also been reported Keller and Mongini ; Kunwar and Megna Aripiprazole provides to clinicians another treatment option, both as a first-line antipsychotic agent and a switching possibility from maintenance therapy, as confirmed by the report of an expert consensus meeting of October that aimed to agree on a set of guidelines for best-practice use of aripiprazole in the acute and long-term management of schizophrenia in Italy Cassano et al A recent pilot study reported the successful replacement of amisulpride and risperidone with aripiprazole, with normalization of prolactin concentration at the end of week 4 Lee et al Given that it may be advantageous to avoid the use of direct dopaminergic agents in psychotic patients, for the risk of worsening psychosis, it is still unclear whether this risk is lower when using a partial agonist agent as aripiprazole in combination with a full antagonist Cassano et al Indeed, because of the coexistence of high dopamine receptor affinity and partial agonist properties, aripiprazole may act as a dopamine agonist and may restore tonic inhibition to anterior pituitary lactotrophs and correct dopamine hypoactivity induced by risperidone Whal and Ostroff A single case of aripiprazole used in combination with another antipsychotic risperidone for the treatment of symptomatic hyperprolactinemia was reported by Wahl and Ostroff In a year-old adolescent diagnosed with schizophrenia, treated with risperidone long acting formulation 25 mg i.
However, the safety and efficacy of the combined use of aripiprazole with other antipsychotics, for the treatment of drug-induced hyperprolactinemia, need to be demonstrated in large, controlled trials Cassano et al In conclusion, a systematic evaluation of atypical neuroleptics as an alternative treatment for conventional drug-induced hypeprolactinemia is recommended.
Switching to olanzapine has been proven to be an advantageous treatment of hyperprolactinemia in women with schizophrenia Kinon et al , ; Kim et al Also clozapine Bunker et al , quetiapine Kunwar and Megna and aripiprazole Lee et al ; Cassano et al seem to be reasonable substitutive treatment options for patients suffering from old neuroleptic- and risperidone-induced hyperprolactinemia.
As for the use of aripiprazole in combination with other antipsychotics, large clinical trials are needed. Only a few data concerning the effect of antidepressant drugs on prolactin secretion are currently available.
Unlike neuroleptics, the action of antidepressant drugs on the neuroendocrine system is highly variable and not strictly related to their therapeutic efficacy Meltzer et al This heterogeneity reflects the complexity of the aminergic control on pituitary hormone secretion and the role of antidepressants on these pathways Goyot et al Antidepressant drugs with serotoninergic activity, including selective serotonin reuptake inhibitors SSRI , monoamine oxidase inhibitors MAO-I and some tricyclics, can cause modest and generally asymptomatic hyperprolactinemia Wieck and Haddad ; Molitch Table 2 and Figure 2.
Monotherapy-treated patients rarely reported symptoms due to increased prolactin secretion, while in patients on antipsychotic drugs that stimulate prolactin secretion, serotoninergic antidepressants may elevate prolactin levels above symptomatic levels or worsen pre-existing symptoms Haddad and Wieck Most serotonin reuptake inhibitors can slightly elevate prolactin, with the exception of sertraline Foley and Kast The atypical ie, alone in their class antidepressants mirtazapine and bupropion, are prolactin neutral Foley and Kast the latter being previously reported to even decrease serum prolactin, maybe through a dopamine re-uptake blockade Meltzer et al Heterocyclic antidepressants are reported to induce only mild hyperprolactinemia, but further studies are needed.
Some of them, such as the tertiary amines imipramine Nutt et al , amitriptyline Schlienger et al and clomipramine Anderson and Cowen and the secondary amine desipramine Price et al , are thought to share a serotoninergic mechanism with SSRI.
Prolactin levels, evaluated in depressive patients after acute and chronic administration of tricyclic antidepressants clomipramine and amitriptyline, were found to temporary rise during the first day of treatment in 6 patients out of 11, with a delay in relation to the drug plasma peak. After 28 days of therapy, a significant increase was observed in the clomipramine-treated group and a significant decrease in the amitriptyline group Goyot et al The abolishment of prolactin response to clomipramine after pre-treatment with serotonin receptor blockers clozapine and olanzapine Markianos et al and its enhancement after L-tryptophan Anderson and Cowen confirm the involvement of serotoninergic pathway in clomipramine-induced prolactin increase.
Therapeutic doses of clomipramine had been associated with non-puerperal lactation and elevated plasma prolactin, both disturbances recovering within weeks after drug discontinuation Fowlie and Burton Treatment with either clomipramine or maprotiline in 17 patients with major depressive disorder and in healthy subjects increased significantly basal prolactin levels, that were also significantly higher in responders than in non-responders.
However, Schlienger et al showed that basal plasma levels of prolactin and delta prolactin response to TRH were increased in women on clomipramine but remained normal under maprotiline, in agreement with the different pharmacologic effect of these two classes of drugs, tricyclics mainly inhibiting serotonin, while tetracyclics rather norepinephrine recaptation Schlienger et al No evidence for a hyperprolactinemic effect of mianserine is reported Meltzer et al Desipramine administration was found not to affect prolactin levels in 24 patients on short term treatment one week , but significantly enhanced prolactin levels after four weeks Price et al The effect of traditional tricyclic antidepressant imipramine on serum prolactin levels is controversial: oral administration of mg, but not of 40 mg, led to consistent rise in prolactin levels, as measured in nine healthy young men, the effect being the result of serotonin enhancement following reuptake inhibition Nutt et al A previous five-week double-blind study on depressed patients did not show any significant change in serum prolactin levels after imipramine therapy Cooper et al The lack of prolactin raising effect and of antipsychotic properties is possibly explained with imipramine and other traditional tricyclic antidepressants not affecting dopamine transmission Cooper et al Amoxapine is an antidepressant known to have neuroleptic properties.
Its in vitro profile receptor occupancy pattern and preclinical effects are very similar to atypical antipsychotics, and it has also shown antipsychotic efficacy in clinical trials Antor et al ; Apiquian et al In agreement with such properties, amoxapine was found to increase serum prolactin in 10 major depressed men significantly more than the secondary amine desipramine in the control group Antor et al This prolactin raising effect, that amoxapine shares with loxapine, a related compound widely used as neuroleptic Robertson et al , is reported in both female and male patients and may be explained with the blockade of dopamine receptors in central tuberoinfundibular pathways Cooper et al or in the anterior pituitary gland Robertson et al Figure 2.
The precise mechanism underlying monoamine-oxidase inhibitors MAO-I -induced hyperprolactinemia is still unknown. These drugs interact with several possible stimulatory pathways Meltzer et al ; Price et al Tranylcypromine was proved to enhance prolactin production after administration of the serotonin precursor tryptophan, thus confirming its role in serotonin function. Instead, hyperprolactinemia was certainly documented for old drugs currently not in use, such as pargyline and clorgyline, which acted through unknown mechanisms Slater et al , a hypothesis being the production of a prolactin releasing factor Meltzer et al These drugs have the ability to enhance serotonin activity, by inhibition of CNS neuron serotonin reuptake.
Although several SSRI interact with other neurotransmitters for example sertraline with dopamine and paroxetine with norepinephrine , prolactin stimulation probably involves only serotoninergic pathways, since hyperprolactinemia is a constant class-related effect, regardless of other pharmacological interactions rev.
SSRI were reported to be the most frequent cause of drug-induced hyperprolactinemia Cohen and Davies , but other data do not confirm this conclusion. SSRI actually cause little, if any, increase in prolactin secretion. Several uncontrolled studies assessed prolactin rise during SSRI treatment, though only paroxetine-treated patients exhibited statistically significant elevations, while all subjects on fluoxetine, sertraline or venlafaxine showed not significant elevations of basal prolactin Urban and Veldhuis ; Spigset and Mjorndal ; Cowen and Sargent In all the reports, hyperprolactinemia promptly subsided after discontinuation of the drug Emiliano and Fudge Sertraline, used for depressive illness, is the strongest dopamine reuptake blocker among SSRIs.
Although one study of 15 female patients on Fluoxetine is indicated in major depression and panic disorders with agoraphobia, ossessive-compulsive disorders, binge eating, bulimia, premenstrual syndrome. Fluoxetine clinical efficacy is due to enhanced serotonin pathway mainly via postsynaptic mechanisms, with minimal effect on dopamine reuptake.
Fluoxetine induces a 5HT receptor—mediated stimulation of prolactin secretion and is reported to increase prolactin levels more than tricyclics Meltzer et al Since fluoxetine half-life varies upon duration of the treatment 1—3 days after short term intake, 4—6 days after chronic treatment and its metabolite norfluoxetine washout is complete only after 4—16 days, the resolution of symptoms after discontinuation may be slow.
Paroxetine is used for depression, panic disorder with agoraphobia, obsessive-compulsive disorder, binge eating. These data have been confirmed by another study that reported significant hyperprolactinemia in female patients treated with paroxetine for at least 2 months Amsterdam et al These clinical results support experimental data suggesting that SSRI produce a delayed increase in brain serotoninergic neurotransmission Cowen and Sargent ; Porter et al In the same study by Amsterdam et al, venlafaxine-treated patients showed no increase in prolactin concentration after two months Amsterdam et al Unlike other antidepressants, mirtazapine does not inhibit the reuptake of serotonin or norepinephrine but acts as an antagonist at presynaptic and, presumably, postsynaptic alpha 2-receptors as well as an antagonist of postsynaptic 5-HT2 and 5-HT3-receptors.
Prolactin levels, measured before and after administration of mirtazapine i. Schule found significant lowering in plasma prolactin following acute oral administration of 15 mg mirtazapine in 12 healthy male subjects, as compared to placebo Schule et al These recent results are at variance with those of older studies that documented a decrease in prolactin concentration in ten healthy patients treated with trazodone Rolandi et al In summary, controversial data are available on antidepressant-induced hyperprolactinemia.
Sustained and symptomatic hyperprolactinemia has been demonstrated with the heterocyclic antidepressants amitriptyline, desipramine, clomipramine and amoxapine. However, SSRI have been reported to be the most frequent cause of drug-induced hyperprolactinemia. Among those, sertraline appears to be the most frequent cause of sustained hyperprolactinemia, but also fluoxetine and paroxetine may induce pathologic and symptomatic increases in prolactin levels. Most of the other anti-depressants do not induce hyperprolactinemia or induce only transient or within normal range variations with no or little clinical relevance.
Other psychotropic drugs such as lithium, valproic acid, buspirone, carbamazepine, and benzodiazepines rarely produce clinically relevant increases in prolactin concentrations Marken et al Buspirone is an anxiolytic drug with mixed dopamine agonist-antagonist and 5-HT1A agonist properties. Hyperprolactinemia after acute buspirone administration is reported in both depressive and healthy subjects, responses being significantly higher in women than in men Meltzer and Maes However, it has not been entirely clarified whether the serotoninergic or the dopaminergic system is especially accountable for the buspirone-induced prolactin secretive response Maskall et al Figure 2.
No published reports have so far documented hyperprolactinemia as a side effect of carbamazepine treatment. In a study by Bonuccelli et al , on normal and epileptic subjects, no appreciable change in prolactin spontaneous secretion or in prolactin secretory circadian rhythm was observed, though a small increase in early sleep values was reported.
These results were interpreted to indicate that prolactin changes induced by carbamazepine are mediated by serotoninergic activity. Clonazepam a central type benzodiazepine agonist and diazepam a mixed agonist are reported to decrease prolactin levels, possibly through a direct action on the anterior pituitary gland Jarvinen et al Figure 2.
Prolactin levels are differentially influenced by GABA-ergic drugs, depending on their potency ie, receptor affinity and dose. Short-term GABA-mimetic valproate treatment in eight healthy male volunteers was found not to alter hypothalamic or pituitary 5-HT1A or dopamine receptor function Delva et al In , during studies on tuberoinfundibular-GABA TI-GABA system, mg oral valproate was found to decrease prolactin concentrations in 20 healthy women, the lack of effect in schizophrenic patients supporting the hypothesis of a defect of the TI-GABA system in chronic schizophrenia Monteleone et al The effects of lithium on prolactin secretion are controversial.
It had initially been proposed that lithium would increase prolactin, possibly through a decrease in dopamine receptor sensitivity Meltzer et al Studies that reported that lithium enhances significantly the hyperprolactinemic response after clomipramine but not after metoclopramide or haloperidol administration indicate that the lithium-mediated prolactin release may selectively involve serotoninergic pathways Mc Cance et al However, lithium-prolactin interactions are probably even more complex and involve both dopamine and serotonin pathways Basturk et al Two prokinetic drugs, that are commonly used in gastrointestinal disorders, induce hyperprolactinemia via a dopamine-antagonistic mechanism Figure 2 : metoclopramide, that blocks dopamine and, at higher doses, also serotonin receptors in chemoreceptor trigger zone of CNS, and domperidone, that does not cross the blood brain barrier and is therefore a selective peripheral extra cerebral dopamine antagonist.
These drugs have been reported to cause symptomatic hyperprolactinemia Tamagna et al ; Fujino et al Metoclopramide, a prokinetic drug used in nausea, vomiting, diabetic gastric stasis and gastroesophageal reflux, is a potent stimulator of prolactin release. Endocrine and metabolic side effects, such as amenorrhea, galactorrhea, gynecomastia and impotence are reported with undefined frequency. Serum prolactin concentration measured soon after metoclopramide administration was found acutely increased in five patients Tamagna et al It has been reported that prolactin concentration may acutely increase up to six-fold over baseline after a single oral administration of 10 mg metoclopramide Mc Callum et al and return to normal range after 12 hours.
In these and other studies Mc Callum et al ; Tamagna et al ; Browers et al mean serum prolactin concentration was confirmed to persist significantly high during oral chronic treatment, up to fold above baseline.
Domperidone 10 mg i. In contrast to metoclopramide, however, under chronic administration of domperidone, prolactin tends to decrease significantly, even if still above the normal range Browers et al This observation is consistent with the pharmacodynamic differences showed by these two drugs, as mentioned above.
The effect on prolactin levels of the classical antypsichotic chlorpromazine, used in clinical practice for its anti-nausea properties, has been discussed above. Alpha-methyldopa is an alpha-adrenergic inhibitor, which is likely to decrease dopamine synthesis acting as a false neurotransmitter and inhibits the enzymatic conversion of L-dopa to dopamine catalyzed by aromatic-L-aminoacid decarboxylase Steiner A single dose of — mg of alpha-methyldopa is reported to significantly increase prolactin, with a peak concentration occurring 4—6 hours after administration; long term treatment has been associated with three- to four-fold increases in basal prolactin levels compared to normal subjects Steiner et al The central monoamine reserpine, used in hypertension but also in psychosis, schizophrenia and tardive dyskinesia, acts by depletion of sympathetic biogenic amines among which dopamine inhibiting their hypothalamic storage in secretory granules Lee et al Figure 2.
The occurrence of gynecomastia is reported in patients treated with reserpine, with undefined frequency. Serum prolactin levels are significantly higher among hypertensive patients receiving reserpine, compared to those found six weeks after discontinuation of the treatment; prolactin elevation is proportional to the duration of the use.
Increased incidence of breast cancer has also been reported among patients on antihypertensive therapy reserpine Lee et al In this case, the mechanism sustaining hyperprolactinemia is not clear, a hypothesis being a reduction in hypothalamic dopamine generation, possibly through N-type calcium channels Kelley et al However, no other calcium-antagonist, such as diltiazem Veldhuis et al or dihydropiridine Kelley et al has ever been associated with prolactin increase.
A study published in on men receiving verapamil showed significantly higher prevalence of hyperprolactinemia in the treated group than in the control group 8. The antihypertensive beta-blocker labetalol has been described to increase prolactin levels when administered intravenously in hypertensive patients, but not when administered orally or mg. This effect seems to be related to a central action, because pre-treatment with L-DOPA and carbiDOPA, reported to blunt the prolactin responses to central stimuli, avoids prolactin response Barbieri et al Consistently with the large body of evidence that endogenous opioid peptides participate in the regulation of pituitary secretion, though with unfocused physiological roles, morphine and related drugs have been found to exert endocrine effects through interactions with dopaminergic and serotoninergic hypothalamic pathways and consequent modulation of pituitary hormone secretion Van Vugt and Meites Studies on both animals and humans demonstrated that endogenous opioids administered either intravenously or intraventricularly led to a rapid and dose-dependent plasma prolactin increase Van Vugt and Meites ; Risch et al In conclusion, morphine stimulatory effect on prolactin release may act through a mechanism which is not depending on dopaminergic receptors Shin et al , though morphine, cocaine and beta-endorphine have been long reported to increase prolactin through dopaminergic interactions Gold et al Long term methadone users have normal basal prolactin levels, even though a transient increase, beginning two-four hours after each daily dose, has been shown Bart et al Although histamine H2-receptor competitive antagonists cimetidine and ranitidine, used in active ulcers, ulcer prophylaxis and gastric hypersecretory conditions, have stimulatory effect on prolactin secretion Perret et al ; Knigge , hyperprolactinemia has never been systematically reported, except for isolated case reports published shortly after the approval of the drugs Petrillo et al The neurobehavioral syndrome, that appears with the withdrawal of H2 receptors blockers and subsides with the restoration of the treatment or with the administration of a potent prolactin inducing drug as domperidone, should be related to a prompt reduction of prolactin levels Rampello et al In accordance with a histamine-dependent prolactin regulatory pattern, the histamine H2-receptor competitive antagonist cimetidine can have an inhibitory following central administration or stimulatory following systemic administration effect on prolactin secretion Knigge , the latter being the result of a decreased dopamine release from hypothalamus to pituitary gland Morosini et al However, high doses of cimetidine possess an additional prolactin stimulatory action, not exerted by the other H2-receptor antagonist ranitidine, that does not seem to be related to blockade of H2-receptors Knigge nor to interaction with the dopaminergic system Knigge et al The observation that systemic administration of specific histamine-H2 agonist impromidine is not able to avoid the cimetidine-induced prolactin release, while pre-treatment with benzodiazepines or GABA respectively suppressed or reduced prolactin response, suggested that cimetidine does not induce prolactin hypersecretion through an action on histamine H2 receptors, but through the interaction with other neurotransmitters, such as the pituitaric GABA-ergic system Sibilia et al Figure 1.
Estrogen-induced hyperprolactinemia is directly dependent on the degree of estrogenization. Physiologic amounts of estrogen in women cause a minimal increase in basal serum prolactin Frantz , but may explain the greater prolactin response of women to physiologic and pharmacologic stimuli. Greater amounts of estrogens, as in pregnancy, increase basal prolactin concentration.
It is uncertain whether the amount of estrogens in hormonal contraceptives is able to induce hyperprolactinemia:heterogeneous data concerning oral estroprogestinic anti-contraceptive therapy are reported. Studies on women taking low-dose-estrogen compounds less than 50 micrograms of estradiol did not show a significant elevation response as compared to pretreatment levels De Leo et al or control patients with intrauterine devices Hwang et al In some of these studies, no correlation was found between the dosage of estrogenic component of the combined oral contraceptives, or duration of their use, and prolactin levels Reyniak et al ; Davis et al Little is known, however, about dose-dependency of estrogen effects on plasma hormone levels.
Hormone replacement therapy is usually prescribed as medium- to high-dose formulations. In surgically or naturally menopausal women receiving different kinds of hormone replacement therapies, over 2 years and 6 months, no significant differences in serum prolactin levels were found during subsequent treatment cycles, serum prolactin showing varying levels always within normal range Foth and Romer No increase in basal prolactin levels is reported during therapy with estrogen plus antiandrogen cyproterone acetate alone Acien et al or with additional spironolactone Kelestimur and Sahin , nor during hirsutism treatment with flutamide Muderris and Bayram ; Taner et al A significant decrease in prolactin levels has been reported in patients treated with flutamide alone Akaza et al or with flutamide and an oral contraceptive formulation with ethinyl estradiol and cyproterone acetate Taner et al However, in 60 postmenopausal women receiving replacement therapy with estrogen plus anti-androgen cyproterone acetate, a significant increase in hyperprolactinemic response to dopaminergic drug sulpiride was observed Paoletti et al , though normal basal prolactin levels were confirmed.
Fenfluramine is a sympathomimetic amine used as an appetite suppressant. It causes hyperprolactinemia by promoting the release of serotonin and blocking its neuronal uptake, that leads to an increased serotoninergic activity and postsynaptyc stimulation of 5HT2A Figure 2. In healthy subjects, prolactin release by fenfluramine is dose-dependent, negatively correlated with age and increased in young females, as compared to males Newman One case report documented hyperprolactinemia during chronic anticolvulsivant therapy with fenitoin and phenobarbital after the addition of oral fluoresone mg daily.
The pathogenetic mechanism is unclear Rossi et al Hyperprolactinemia in four patients on protease inhibitors presenting with galactorrhea likely resulted from the enhancement of dopamine antagonistic effects of other simultaneously administered drugs prokinetics and fluoxetine through inhibitory action on cytochrome P system Hutchinson et al Cholinomimetic drugs with central effect, such as physostigmine, have been differently reported either to have no effect, to increase, or to inhibit prolactin release, though physostigmine may produce significant increases in plasma prolactin concentrations in humans after intravenous infusion.
In three separate studies, reported by Risch et al , conducted collaboratively by the National Institute of Mental Health and the University of California at San Diego, prolactin rise following physostigmine and arecoline administration correlated with plasma concentrations of beta-endorphin immunoreactivity, cholinergic stimulation of hypothalamic beta-endorphin possibly representing an interesting example of peptidergic modulation of hypothalamic-pituitary hormonal regulation Risch et al Controversial data are available on the effect of chemotherapy and immunosuppression on prolactin levels.
In a study of 20 women with breast cancer who underwent high-dose chemotherapy and autologous blood stem-cell transplantation, plasma prolactin levels increased significantly during conditioning and within 30 days after transplant, remaining however within the normal age- and sex-adjusted range in all cases Hinterberger-Fischer M et al In the same study Hinterberger-Fischer MM et al , the use of antiemetic drugs induced further increase in prolactin levels.
However, this increase did not affect disease-free survival after transplant. These results are in line with those of previous studies that analyzed the long-term effect of allogeneic bone marrow transplantation on pituitary, gonad, thyroid and adrenal function in adult patients Kauppila M et al Thus, it is very well known that chemotherapy induces frequently hypogonadism in both men and women by a direct toxic action on the gonad Fairley KF et al ; Shamberger RC et al , but significant prolactin increases are not frequent and are normally mild Kauppila M et al b.
Hyperprolactinemia has been documented in the majority of patients treated with irradiation because of CNS malignancies Constine LS et al In patients with CNS tumor, the risk to develop iatrogenic hyperprolactinemia is mostly dependent on the radiation dose, with the majority of subjects who receive more than 55 Gy experiencing this endocrine disturbance Constine LS et al , but is also dependent on the concomitant use of chemotherapy which increases the probability to develop both prolactin and thyroid abnormalities Constine LS et al National Center for Biotechnology Information , U.
Ther Clin Risk Manag. Daria La Torre and Alberto Falorni. Author information Copyright and License information Disclaimer. All rights reserved. This article has been cited by other articles in PMC. Abstract Hyperprolactinemia is a common endocrinological disorder that may be caused by several physiological and pathological conditions. Keywords: anti-depressants, anti-psychotics, estrogens, opioids, prokinetics, prolactin.
Regulation of prolactin secretion Prolactin PRL is a 23 kDa polypeptide hormone secreted by the lactotroph cells of the anterior pituitary gland. Open in a separate window. Figure 1. Table 1 Major physiologic and pathologic causes of hyperprolactinemia. Drug-induced hyperprolactinemia Pharmacologic hyperprolactinemia is a problem of underestimated prevalence. Figure 2. Schematic representation of mechanisms of drug-induced hyperprolactinemia.
Table 2 Drugs inducing sustained hyperprolactinemia. Psychotropic drugs Antipsychotics Antipsychotics are the most common cause of pharmacologic hyperprolactinemia, and the majority of antipsychotic agents cause hyperprolactinemia Molitch Classical antipsychotics Classical antipsychotics are the most common cause of drug-induced hyperprolactinemia Molitch Butyrrophenones Haloperidol is a butyrrophenone used for the treatment of schizophrenia, tics, stutter or delirium.
Phenothiazines Acute increases, of two- to tenfold, have also been observed after single parenteral or oral doses of phenothiazines. Thioxanthenes In a study that compared the effects of thiothixhene and thioridazine Crowley and Hydinger-Macdonald , prolactin levels increased equally with the two drugs, but another study documented exaggerated hyperprolactinemic response to thiothixene in one subject Ash and Bouma Others The effect on prolactin levels of pimozide administration seems to be the result of an impaired dopamine secretion to portal vessels, rather than the consequence of a reduction of hypothalamic dopamine production Aguilar et al Atypical antipsychotics Atypical antipsychotics are characterized by increased antipsychotic efficacy and fewer neurological and endocrine-related side effects as compared to classical antipsychotic drugs.
Risperidone Risperidone is one of the atypical antipsychotics most likely to induce hyperprolactinemia. Amisulpride Amisulpride is a substituted benzamide derivative, characterized by little extrapyramidal symptoms EPS but great prolactin elevation, similar to that of conventional antipsychotics andoften clinically relevant Fric and Laux Clozapine Clozapine, the prototypic atypical antipsychotic drug, antagonizes serotonin and dopamine receptors.
Other atypical drugs Quetiapine, aripiprazole and ziprasidone are reported either to cause no prolactin increase at all or to increase it transiently and mildly: serial blood samples showed a rapid raise in prolactin levels up to 1.
Management of antipsychotic-induced hyperprolactinemia The importance of monitoring for health problems, among which amenorrhea, in patients on psychotropic treatment, has been stressed during an expert consensus on the pharmacologic treatment of psychotic disorders Kane et al Antidepressant drugs Only a few data concerning the effect of antidepressant drugs on prolactin secretion are currently available.
Heterocyclic antidepressants Heterocyclic antidepressants are reported to induce only mild hyperprolactinemia, but further studies are needed. Amoxapine Amoxapine is an antidepressant known to have neuroleptic properties.
Monoamine-oxidase inhibitors The precise mechanism underlying monoamine-oxidase inhibitors MAO-I -induced hyperprolactinemia is still unknown. Other psychotropic drugs Other psychotropic drugs such as lithium, valproic acid, buspirone, carbamazepine, and benzodiazepines rarely produce clinically relevant increases in prolactin concentrations Marken et al Prokinetics Two prokinetic drugs, that are commonly used in gastrointestinal disorders, induce hyperprolactinemia via a dopamine-antagonistic mechanism Figure 2 : metoclopramide, that blocks dopamine and, at higher doses, also serotonin receptors in chemoreceptor trigger zone of CNS, and domperidone, that does not cross the blood brain barrier and is therefore a selective peripheral extra cerebral dopamine antagonist.
Anti-hypertensive drugs Alpha-methyldopa is an alpha-adrenergic inhibitor, which is likely to decrease dopamine synthesis acting as a false neurotransmitter and inhibits the enzymatic conversion of L-dopa to dopamine catalyzed by aromatic-L-aminoacid decarboxylase Steiner Opiates Consistently with the large body of evidence that endogenous opioid peptides participate in the regulation of pituitary secretion, though with unfocused physiological roles, morphine and related drugs have been found to exert endocrine effects through interactions with dopaminergic and serotoninergic hypothalamic pathways and consequent modulation of pituitary hormone secretion Van Vugt and Meites H2-receptor antagonists Although histamine H2-receptor competitive antagonists cimetidine and ranitidine, used in active ulcers, ulcer prophylaxis and gastric hypersecretory conditions, have stimulatory effect on prolactin secretion Perret et al ; Knigge , hyperprolactinemia has never been systematically reported, except for isolated case reports published shortly after the approval of the drugs Petrillo et al Estrogens and anti-androgens Estrogen-induced hyperprolactinemia is directly dependent on the degree of estrogenization.
Other drugs Fenfluramine is a sympathomimetic amine used as an appetite suppressant. Clinical and hormonal effects of the combination gonadotrophin-releasing hormone agonist plus oral contraceptive pills containing ethinyl-oestradiol EE and cyproterone acetate CPA versus the EE-CPA pill alone on polycystic ovarian disease-related hyperandrogenism. Hum Rep. Breast enlargement during chronic antidepressant therapy. J Affect Disord. Effects of pimozide and domperidone administration on prolactin levels in neonatally estrogenized female rats.
Rev Esp Fisiol. Clomipramine enhances prolactin and growth hormone responses to L-tryptophan. Amoxapine elevates serum prolactin in depressed men. Amoxapine as an atypical antipsychotic: a comparative study versus risperidone. Exaggerated hyperprolactinemia in response to thiothixene. Arch Neurol. Quetiapine is not associated with increase in prolactin secretion in contrast to haloperidol.
Arch Med Res. Prolactin stimulation by intravenous labetalol is mediated inside CNS. Clin Endocrinol Oxf ; 16 — Suppressed prolactin response to dynorphin A in methadone-maintained versus control subjects. J Pharmacol Exp Ther. Effects of short and long term lithium treatment on serum prolactin levels in patients with bipolar affective disorder. Prog Neuropsychopharmacol Biol Psychiatry. Prolactin in patients with major depressive disorder and in healthy subjects.
Longitudinal study of basal prolactin and post-TRH-stimulated prolactin levels. Biol Psychiatry. Control of prolactin secretion.
Klin Wochenschr. Usefulness of bromocriptine in the treatment of amisulpride-induced hyperprolactinemia: a case report. Effects of carbamazepine on prolactin secretion in normal subjects and in epileptic subjects. Clin Neuropharmacol. Psychopharmachology Berl ; — Plasma prolactin levels after acute and subchronic oral administration of domperidone and of metoclopramide: a cross-over study in healthy volounteers. Clin Endocrinol Oxf ; 12 — Differential profile of antipsychotics at serotonin 5-HT1A and dopamine D 2 S receptors coupled to extracellular signal-regulated kinase.
Eur J Pharmacol. Aripipazole: efficacy and tolerability profile of a novel acting atypical antipsychotic. Drugs Today Barc ; 39 — Attenuation of antipsychotic-induced hyperprolactinemia with clozapine.
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