|Year : 2013 | Volume
| Issue : 3 | Page : 165-168
Oinam Joychandra Singh, Thokchom Imoba Singh, Varkung Valte
Department of Pharmacology, J. N. Institute of Medical Sciences, Porompat, Imphal, Manipur, India
|Date of Web Publication||19-Feb-2014|
Oinam Joychandra Singh
Department of Pharmacology, J. N. Institute of Medical Sciences, Porompat, Imphal
Source of Support: None, Conflict of Interest: None
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
| Introduction|| |
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,  and frequent occurrence of macroprolactinemia that can be revealed by poly ethylene glycol precipitation of serum prolactin.  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.  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.  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.  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 ,
| Background|| |
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]. 
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|| |
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  and used in the treatment of gastric hyperacidity and peptic ulcer. , According to the analytical result of pharmaco-epidemiological and pharmaco-vigilance data, in which, out of 182836 adverse reactions,  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. , 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 ,,,,, 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. ,
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.  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  and others' reports in increasing prolactin release.  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.  Some workers have strongly opined the role of histamine H2 agonist in increased prolactin release. It is again strictly opined by one worker  that histamine-induced prolactin secretion is inhibited by cimetidine and not by H1 receptor antagonist, anti-cholinergic, and anti-serotoninergic agent;  but, according to other workers, H1 and H2 antagonist inhibit the prolactin release. 
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.  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. ,
The probable mechanism for the hypersecretion of prolactin is due to the blockade of H2 receptor.  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|| |
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  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  through H 1 receptor on lactotroph, (predominant action) and inhibit prolactin secretion indirectly through GABA-ergic interneuron and GABA receptors on lactotrophs [Flowchart 1].
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