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 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 27  |  Issue : 3  |  Page : 165-168

Cimetidine-induced Hyperprolactinemia


Department of Pharmacology, J. N. Institute of Medical Sciences, Porompat, Imphal, Manipur, India

Date of Web Publication19-Feb-2014

Correspondence Address:
Oinam Joychandra Singh
Department of Pharmacology, J. N. Institute of Medical Sciences, Porompat, Imphal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-4958.127383

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  Abstract 

Pharmacologic hyperprolactinemia is a problem of underestimated prevalence. This is due to lack of externally visible symptoms, patients' reluctance for embarrassing disturbs, and/or clinicians' lack of awareness. The secretion of prolactin is mainly controlled by hypothalamus over lactotrophs of anterior pituitary through D2 receptor along with many inhibitory and excitatory transmitters particularly serotonin, histamine, and estrogen. Here, the role of histamine receptors (H1 and H2) and their antagonists in the change of serum prolactin level with special reference to the mechanism of action of cimetidine is discussed. It may also conclude with the modifying role of histamine in inducing prolactin secretion through dopamine- GABA-serotoninergic system or modifying PRFs or other unknown mechanism. Therefore, proper evaluation of the hyperprolactinemia, particularly in infertile women, is recommended before extensive diagnosis and therapeutic procedures as hyperprolactinemia may be associated with normal pituitary function. Based on this basic idea, the role of histamine receptor (H 1 and H 2) and cimetidine is discussed. It is concluded that cimetidine may be acting on modifying the role of histamine-induced prolactin secretion, which in term is through dopamine GABA-serotoninergic system/modifying PRFs/other unknown mechanism.

Keywords: Dopamine, Histamine and cimetidine, Hypothalamus, Inhibitory and stimulatory factors, Pituitary


How to cite this article:
Singh OJ, Singh TI, Valte V. Cimetidine-induced Hyperprolactinemia. J Med Soc 2013;27:165-8

How to cite this URL:
Singh OJ, Singh TI, Valte V. Cimetidine-induced Hyperprolactinemia. J Med Soc [serial online] 2013 [cited 2020 Oct 25];27:165-8. Available from: https://www.jmedsoc.org/text.asp?2013/27/3/165/127383


  Introduction Top


Hyperprolactinemia, which is occurred during cimetidine therapy, is associated with sexual dysfunction, galactorrhea, and gynecomastia. But, the cause for hyperprolactinemia is not clearly understood as hyperprolactinemia is determined with many physiological (breast feeding, food intake) and pathological (peptic ulcer, psychosis) conditions. Therefore, it is necessary to find out a possible mechanism of action of cimetidine for the hyperprolactinemia.

Accurate definition of normal prolactin serum concentration can be difficult because of high inter individual variability, [1] and frequent occurrence of macroprolactinemia that can be revealed by poly ethylene glycol precipitation of serum prolactin. [1] Hyperprolactinemia is usually defined as fasting levels at least two hours after waking above 20 ng per ml in man and above 25 ng per ml in woman. [2] Prolactin is released with a circadian trend. Its secretion responds to physiological stimuli i.e. increase after food intake and breast mechanical stimulation. Hyperprolactinemia may be a benign condition without clinical implication for many therapeutic interventions. [3] Hyperprolactinemia can be happened with many conditions i.e. during pregnancy, lactation, and stress. The frequent occurrence of macroprolactinemia can be revealed by polyethylene glycol precipitation of serum sample during circadian trend also. Hyperprolactinemia is being observed during chemotherapy etc. with less frequent impairment of hypothalamic-pituitary gonad /thyroid axis. [4] Therefore, evaluation of hyperprolactinemia, particularly in infertile woman, is recommended before extensive diagnosis and therapeutic procedure as hyperprolactinemia may be associated with normal pituitary function [2],[5]


  Background Top


The main control of prolactin secretion is exerted through the system known as Tuberoinfundibular dopamine pathway (TIDA). Dopamine secreted in hypothalamic peri-ventricular zone (peri-ventricular nucleus and arcuta nucleus) and released from neuronal projections in the median eminence reaches the anterior pituitary gland through portal system, and inhibition of prolactin secretion occurs through D 2 receptor on lactotroph cells of anterior pituitary resulting in inhibition of prolactin gene transcription, reduction of prolactin synthesis and release [Diagram 1]. [6]



Other prolactin inhibiting factors of CNS derivation including GABA, somastatin, acetyldehyde, and noradrenaline and prolactin itself causes an autoregulation of prolactin secretion with the stimulation of TIDA cells through prolactin receptor, GH, TGFB1, and endothelin at pituitary level. Prolactin-releasing factors (PRFs) act mostly through the removal of dopamine inhibiting pathway with the stimulation on lactotrophs and any other unknown mechanism.

Serotonin mediates nocturnal surges and suckled induces prolactin probably through the mediation of GABA producing interneuronal cells. The serotoninergic neurons scattering from the dorsal raphe nucleus to the medial basal hypothalamus paraventricular nucleus (one of the prominent nuclei of the medial hypothalamus) are to contain different population of neurosecretory cells, producing oxytocin, vasopressin, VIP, TRH, and other neuropeptides.

It is known that serotonin affects prolactin level through one or more of these PRFs. Among these, VIP pathway is best studied. VIP acts via hypothalamic afferents and direct paracrine. Autocrine mechanism, through lactotroph receptors increase adenylyl cyclase activity. Oxytocin seems to participate in VIP-induced prolactin release and may act through the inhibition of TIDA. There is little synaptic contact between serotonic fiber and dopaminergic cell. GABAergic neurons in vicinity of DOPA cell has been shown to modulate prolactin secretion. In human, serotonergic stimulation of GABA interneurons results in inhibition of TIDA cells, which increase in prolactin secretion.

Estrogen does the amplification of mitotic activity of lactotrophs enhancement of prolactin gene transcription and translation though ERF receptor binding indirect stimulation of prolactin, stimulation of prolactin synthesis indirectly through VP and OT gene expression. Estrogen also stimulates prolactin release through the inhibition of dopamine synthesis in hypothalamus, the reduction of number of D 2 receptors in pituitary.


  Discussion Top


Considering the role of the above mentioned controlling factors, a discussion is proposed. The complex mechanism which interplays between H1 and H2 receptors and cimetidine in prolactin secretion and release is also highlighted.

Cimetidine was developed [7] and used in the treatment of gastric hyperacidity and peptic ulcer. [8],[9] According to the analytical result of pharmaco-epidemiological and pharmaco-vigilance data, in which, out of 182836 adverse reactions, [10] only 159 cases of hyperprolactinemia due to cimetidine were reported. Therefore, the association of hyperprolactinemia with reproductive dysfunction, sexual impairment, and organic dysfunction was reviewed in favor of cimetidine. [2],[3] But, this condition is usually happened with prolactin-induced reduction of gonadotrophin release and subsequent reduction of estrogen release in female and also testosterone level in male resulting to gynecomastia, galactorrhea, and impotence. The reason behind this condition is the direct feedback mechanism of prolactin causing to hyperprolactinemia.

Intravenous cimetidine [11],[12],[13],[14],[15],[16] is definitely stimulate prolactin secretion and also oral cimetidine. Again, there is the report of significantly raise of prolactin level in the patients who are taking cimetidine in acute and chronic ways. [14],[17]

Cimetidine directly antagonizes the effect of exogenous testosterone at androgen target tissue (e.g. prostate) by inhibiting DHT binding to its cytoplasmic receptor, thereby producing hyperprolactinemia along with gynecomastia. [1] It is also reported that H1 receptor antagonist and H2 receptor agonist suppress prolactin release in lactating mother while H1 agonist and H2 antagonist release prolactin in non-suckled mother.

But, there are many conflicting reports about the role of histamine H2 agonist i.e. some workers' reports in decreasing prolactin secretion [18] and others' reports in increasing prolactin release. [19] Further, the role of H2 agonist is more confusing because the role of histamine receptor H1 (through IP3, DAG, Ca++) and H2 (through Gs, cAMP) at the level of hypothalamus in a feedback mechanism for regulating gonodtrophin, prolactin, vasopressin is also reported. [5] Some workers have strongly opined the role of histamine H2 agonist in increased prolactin release. It is again strictly opined by one worker [20] that histamine-induced prolactin secretion is inhibited by cimetidine and not by H1 receptor antagonist, anti-cholinergic, and anti-serotoninergic agent; [20] but, according to other workers, H1 and H2 antagonist inhibit the prolactin release. [19]

According the latest report, histamine has both inhibiting (minor) and predominantly stimulating effect (major). This predominant action is mediated through the inhibition of dopamine release via H2 receptor following central administration, which is interpreted as intra-cerebroventricular or intra-arterial administration (probably) and via H1 receptor following systemic infusion. During the blockade of the receptors, there is stimulating effect mediated through TIDA, which is exerted by histamine with a minor inhibitory action on prolactin secretion. This effect involves with many transmitters, which is mediated via H1 receptor following central and via H2 receptor following system administration.

As there is no change in plasma level of TSH before and after administration of cimetidine, cimetidine does not potentiate the release of hypothalamic TRH in the hypothalamo-infundibular portal vessels. So, cimetidine seems to produce no change in prolactin level through increasing TRH. H2 receptor in hypothalamus has a role of increasing dopamine secretion and as such, H2 antagonist, which plays the inhibitory role in dopamine secretion, causes increase in prolactin release. H2 antagonist with the prior administration of bromocriptine (D2 agonist) inhibits the increase of prolactin secretion. Therefore, it can be assumed that cimetidine does not have direct effect on pituitary.

The inhibitory action of CB-154, (a dopaminergic drug), on increased prolactin level after IV cimetidine shows that cimetidine does not have anti-dopaminergic activity. [21] Again, the failure of cimetidine to elicit an increase in prolactin release after priming with metoclopromide (which has dopamine receptor blocking properties) indicates that cimetidine under normal condition stimulate prolactin release via reduced dopaminergic inhibition of prolactin on lactotrophs. [22],[23]

The probable mechanism for the hypersecretion of prolactin is due to the blockade of H2 receptor. [24] Inability of impromide (a potent and more specific H2 agonist) to counter cimetidine-induced hypersecretion of prolactin but successful protection of the increase of prolactin secretion by benzodiazepine and GABA (to a less extent) proved that cimetidine does not produce hypersecretion of prolactin by its action on H2 receptor. Therefore, it may be through other pharmacological action such as GABAergic system in the pituitary.

Cimetidine and ranitidine increase the prolactin concentration compared to the placebo treated group, showing that H 2 receptor takes part in reducing prolactin concentration probably by increasing release of dopamine, which, in its turn, reduces prolactin secretion though D 2 receptor on lactotrophs. There is significant increase of prolactin level in cimetidine and ranitidine group followed by TRH (which can directly stimulate prolactin secretion) acting on lactotrophs when compared with group, which is under placebo treatment followed by TRH. Cimetidine also increases prolactin level by inhibiting hepatic metabolism also.


  Conclusion Top


The presence of non-mast cells liberating histamine and the role of histamine as a central neurotransmitter are well-known. Both of the H 1 receptor (through Ca ++ , IP/DAG) and H 2 (Gs, increase cAMP) receptors mediate secretion of various types of secretion histamine that might have stimulated GABAergic neuron through H 2 receptors (major action) near Dopamine cell, just like Serotonin, and various other neurosecretory cells [25] via H 1 receptor (as a minor action) for the secretion of P.R.Fs like TRH, Vasopressin, Oxytocin etc., which may act through the disinhibition of TIDA and directly stimulate lactotroph for the prolactin secretion through the central administration. Through systemic administration, histamine might have stimulate prolactin secretion [19] through H 1 receptor on lactotroph, (predominant action) and inhibit prolactin secretion indirectly through GABA-ergic interneuron and GABA receptors on lactotrophs [Flowchart 1].



 
  References Top

1.Reynolds LR, Rubel AM, Nikitovitch-Winer MB. Cimetidine inhibits the histamine induced prolactin released in male rats. Proc Soc Exp Biol Med 1980;163:322-5.  Back to cited text no. 1
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2.Gibney J, Smith TP, McKenna TJ. The impact of clinical practice of routine screening for macroprolactinemia. J Clin Endocrinol Metab 2005;90:3927-32.  Back to cited text no. 2
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3.Irene VL, Olga DD, Stathis AT, Panayiotis S, Argyris BA, et al. Macroprolactineamia is treatment necessary: Int J Endocrinol Metab 2003;2:185.  Back to cited text no. 3
    
4.Torre DL, Falorni A. Pharmacological causes of hyperprolactineamia. Ther Clin Risk Manag 2007;3:3929-51.  Back to cited text no. 4
    
5.Taghavi M, Allahi HA, Khadjeh MD, Evaluation the prevelance of macroprolactineamia. J Reprod Fertil 2007;8:31.  Back to cited text no. 5
    
6.Rojdmark S. Prolactin release in man: Influence of cimetidine, thyrotrophine-releasing formone and Acute Hypercalcaenua. Acta Endocrinol (Copenh) 1983;102:81-5.  Back to cited text no. 6
    
7.Brimblecomb RW, Durant GJ, Duncan WAM Cimetidine-a non-thiourea H2 receptor Antagonists. J Int Med Res 1975;3:86-92.  Back to cited text no. 7
    
8.Burland WL, Gleadle RI, Lee RM, Rowley Jonee D, Groom GV Symposium on H2 receptor antagonists. Excerpta Med 1977a;1:392.  Back to cited text no. 8
    
9.Durant GJ, Ganelin CR, Person ME. Chemical differentiation of histamine H1 and H2 receptor antagonists. J Med Chem 1975;18:905.  Back to cited text no. 9
    
10.Morosini PP, Campanella N, Ghirelli S, Pellegrini F, Testa I, De Martinis C. Cimetidine and hyper prolactinemia. Boll Soc Ital Biol Sper 1979;55:14-7.  Back to cited text no. 10
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11.Bateson MC, Browning MC, Maconnachie A. Galactorrhoea with cimetidine. Lancet 1977;2:247-8.   Back to cited text no. 11
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12.Burland WL, Lee RM, Rowley Jonee D, Groom GV Pharmacological evaluation of cimetidine. Br J Clin Pharmac 1979;7:19-21.  Back to cited text no. 12
    
13.Carlson HE, Drenick EJ, Chopra IJ, Hershman JM. Alteration in basal and TRH stimulated serum level of thyrotropin, prolactin, and thyroid hormone in starved obese. J Clin Endo Metab 1977;45:707-13.  Back to cited text no. 13
    
14.Carlson HE, Drenick EJ. Cimetidine H2 antagonist stimulation prolactin secretion in man. J Clin Endocrinol Metab 1979;45:367-70.  Back to cited text no. 14
    
15.Knigge UP. Histaminergic Regulation of prolactin secretion. Dan Med Bull 1990;37:109-24.  Back to cited text no. 15
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16.Macaron C, Kyncl M, Singh SP. Cimetidine induced prolactin (PRL) release in thyroid disease. Clin Endocrinol 1979;11:371-5.  Back to cited text no. 16
    
17.Kruss DM, Littman A. Safety of cimetidine. Gastroenterology 1978;74:478-83.  Back to cited text no. 17
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18.Kinon BJ, Gilmore JA, Liu H, Halbreich UM. Hyperprolactinemia in response to antipsychotic drugs; characterization across comparative clinical trials. Psychoneuroendocrinology 2003;28(Suppl 2):S69-82.  Back to cited text no. 18
    
19.Donoso AO, Banzan AM. H1 and H2 receptors antagonists and induced release prolactin in male rats. Neuroendocrinology 1980;30:11-40.  Back to cited text no. 19
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20.Petrillo M, Prada A, Porro GB, Bevilacqua M, Raggi V, Norbiato G. Plasma prolactin and cimetidine. Lancet 1977;2:761.  Back to cited text no. 20
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21.Rojdmark S, Andersson DE. Cimetidine effect of Dopaminergic modulation of prolactin release in healthy woman. Metabolism: 1982;10:1042-5.  Back to cited text no. 21
    
22.Petit A, Piednoir D, Germain ML, Trenque T. Drug-induced hyperprolactinemia: A case-non-case study from the national pharmacovigilance database. Therapie 2003;58:159-61.  Back to cited text no. 22
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23.Portaleone P, Di Carlo F, Genazzani E. Hypothamic H1 and H2 receptors: A tool to investigate the neoroendocrine role of histamine. Pharmacol Res Commun 1980;12:365-73.  Back to cited text no. 23
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24.Cavallini G, Lo Cascio V, Angelini G, Bovo P, Galvanini G, Vaona B, et al. Serum prolactin response to acute and chronic cimetidine administration in man. Acta Hepatogastroenterol (Stuttg) 1979; 26:482-5.  Back to cited text no. 24
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25.Halbreich U, Kahn LS. Hyperprolactinemia and schizophrenia: Mechanisms and clinical aspects. J Psychiar Pract 2003;9:344-53.  Back to cited text no. 25
    



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