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Original Article
65 (
4
); 211-216
doi:
10.25259/IJPP_73_2020

The role of histamine in anterior pituitary secretion

Department of Biology, College of Medicine, University of Thi-Qar University, Nasiriyah, Iraq
Department of Pharmacology, College of Medicine, University of Thi-Qar University, Nasiriyah, Iraq
Corresponding author: Ali Esmail Al-Snafi, Department of Pharmacology, College of Medicine, University of Thi-Qar, Nasiriyah, Iraq. aboahmad61@yahoo.com
Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Faris AN, Al-Fartosi KG, Al-Snafi AE. The role of histamine in anterior pituitary secretion. Indian J Physiol Pharmacol 2021;65:211-6.

Abstract

Objectives:

The aim of the present study was to determine the effects of histamine on the anterior pituitary secretion in rats.

Materials and Methods:

In the first experiments rats were injected with histamine 5 mg/kg i.p., and blood samples were collected to determine the effect of histamine on serum level of adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), prolactin, FSH, and luteinizing hormone (LH) after 10, 20, and 30 min of histamine injection. In the second experiments, rats were treated with (H 1 blocker), chlorphenramine 10 mg/kg, i.p. or (H 2 blocker), cimetidine 80 mg/kg, i.p. respectively, and after 30 min they were injected with histamine and blood samples were taken 30 min after the injection of histamine to determine the same hormones.

Results:

Histamine significantly elevated serum ACTH and LH level, and these stimulatory effects were inhibited by both H1 and H2 receptor blockers. However, histamine significantly inhibited the serum level of thyroid-stimulating hormone and this inhibitory effect was blocked by H2 receptor blocker, while it showed no effect on the secretion of both prolactin and FSH, although H2 blocker significantly decreased prolactin level and H1 blocker significantly elevated FSH level.

Conclusion:

The results clearly indicated that histaminergic pathways were involved in the anterior pituitary secretion.

Keywords

Histamine
Pituitary
Adrenocorticotropic hormone
Follicle-stimulating hormone
Prolactin
Luteinizing hormone

INTRODUCTION

Histamine is an effective biogenic monoammine synthesized from the primary amino acid histidine. It is stored in special granules inside the basophiles or mast cells and is secreted in cases of inflammation or allergies when a reaction occurs between the antibody and the IgE.[1] Histamine is found in the brain in abundant quantities and in smaller quantities in other tissues such as skin, lung, small intestine, white blood cells, liver, kidney, placenta, and neurons in the posterior part of the hypothalamus.[2]

The level of histamine in the brain tissue is lower than the rest of the biological amines, but its metabolic rate is much faster (within minutes), depending on the functional condition, as the half-life of histamine is 30 min,[1,3] histamine reaches the highest level in the anterior segment or anterior lobes of the hypothalamus during the waking period, and its lowest levels during the sleep period. The synthesis and release of histamine are controlled by the H3 auto-receptors located in the presynaptic membrane, in addition to other receptors such as M1 and α2 receptors.[4,5]

It was found that the content of histamine in the brain regions, approximately 50 nanogram histamine per gram.[2] The number of neurons that make up histamine in rats is approximately 2000 neurons located in the tuberomammillary nucleus.[6] There is a similar structure in humans located in the posterior part of the hypothalamus, where the number of histamine-forming neurons is about 64,000 neurons, and from this region a network of nerve fibers branches from these cells to the cerebral cortex.[7]

There are two ascending pathways of the histamine cells that can be distinguished in the brain of rats, one of these paths is comes from the middle bundle of the anterior brain, from which the fibers of the nerve cells are spread in the posterior brain, and the second pathway is in the region around the third ventricle, peri-ventricular, and the nerve connections to these two ascending pathways end in some regions. From the brain, including olfactory bulb, hippocampus, caudate putamen, globus pallidus, and amygdaloid complex, and besides, there are descending pathways of cells that spread from the hypothalamus to the brain areas.[8-10]

Brain histamine is considered as neuro-endocrine transmitter. Histamine possessed stimulatory effect on growth hormone secretion in man mediated by both H1 and H2 receptors.[11,12] It also increased both basal and stimulated plasma level of adrenacorticotrophic hormone and corticosteroids through H1 and H2 receptors, while it possessed inhibitory effects through H3 receptors. However, histamine possessed inhibitory effect on the secretion of prolactin through H2 receptors,[13,14] while histamine stimulated both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion.[15]

The present study aims to determine the effects of histamine on the anterior pituitary secretion in rats. In addition, it aims to investigate the type of receptor responsible for the stimulatory or inhibitory effect of histamine, to know if the H1 and H2 receptor blocker (extensively used) could interfere with the endocrine control especially when used in critical hormonal conditions such as ovulation (such as in patients with peptic ulcers who used H2 blocker, or patients with allergic conditions who used H1 blocker for long period).

MATERIALS AND METHODS

Animals

Sixty male rats (Rattus norvegicus) were used in this study; they were obtained from the animal house of the Department of Biology - College of Education, Thi-Qar University, aged 10–14 weeks and weighted 250–300 g. They were placed in plastic cages, 25 ± 3°C and 14 h light/10 h darkness and were given water and food ad libitum. The study was approved by the ethical committee of the postgraduate studies of Thi-Qar University- Iraq.

Drugs used

Histamine HCl, chlorpheniramine, and cimetidine were purchased from Sigma.

Acute effect of histamine on the secretion of hormones of anterior pituitary

In this experiment, 24 rats were used, and the animals were divided into four subgroups, as follows: First (control group): rats were injected with distilled water and blood samples were taken 10 min after injection. In the second, third, and fourth groups rats were injected with histamine and then blood samples were taken 10, 20, and 30 min after injection of histamine, respectively. Histamine was used in a dose of 5 mg/kg i.p.[16]

Determining the type of receptors mediating the histamine action

This experiment was conducted to determine the type of receptor by which histamine stimulating or inhibiting the anterior pituitary hormones. Eighteen rats were used in the experiment, and the animals were divided into three subgroups, as follows: First (control group): Was injected with distilled water and after 30 min rats were injected with histamine and blood samples were taken 30 min after the injection of histamine. The second and third groups: Were treated with (H 1 blocker), chlorpheniramine 10 mg/kg, i.p. or (H 2 blocker), cimetidine 80 mg/kg, i.p.,[17] respectively, and after 30 min they were injected with histamine. Rats were anaesthetized with chloroform and venous blood samples were collected by cardiac puncture, sera were stored in a deep freezer.[18] LH, FSH, prolactin, thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH) were determined using radioimmunoassay as described by Al-Tahan et al.[19] The significance among groups was determine using student-t-test.[20]

RESULTS

The results of histamine administration to male rats revealed that histamine significantly (P < 0.05) declined the level of TSH (0.29 ± 0.13 vs. 0.82 ± 0.28 IU/l) and significantly (P < 0.05) increased the level of prolactin (1.8 ± 0.38 vs. 0.9 ± 0.23 ng/ml) after 10 min of injection. When serum hormones were estimated after 20 min of histamine injection, the ACTH level was significantly (P < 0.01) increased (90.75 ± 10.53 vs. 48.00 ± 4.78 pg/ml), while prolactin level which significantly increased after 10 min of histamine injection, was significantly (P < 0.05) declined below the normal limit (0.49 ± 2.05 vs. 0.9 ± 0.23 ng/ml) after 20 min of injection. However, after 20 min of injection, histamine also significantly *(P < 0.05) elevated the serum level of LH (2.58 ± 0.86 vs. 1.41 ± 0.55 IU/l). On the other hand, after 30 min of injection, histamine elevated both ACTH (62.00 ± 5.82 vs. 48.00 ± 4.78 pg/ml) (P < 0.05) and LH level (4.03 ± 1.15 vs. 1.41 ± 0.55 IU/l) (P < 0.01). Histamine did not affect the level of FSH after 10, 20, and 30 min of administration [ Table 1 ], [Figure 1].

Table 1:: The effect of histamine (5 mg/kg) on the levels of pituitary hormones in male rats.
Groups Hormonal levels ( mean±SD)
ACTH pg/ml TSH m IU/l PRL ng/ml FSH IU/l LH IU/l
Control group 48.00±4.78 0.82±0.28 0.9±0.23 6.42±0.61 1.41±0.55
First group after 10 minutes of histamine injection 50.75±2.05 0.29±0.13* 1.8±0.38* 6.32±1.02 2.05 0.43
Second group after 20 minutes of histamine injection 90.75±10.53** 0.42±0.20 0.49±2.05* 6.18±1.30 2.58±0.86*
Third group after 30 minutes of histamine injection 62.00±5.82* 0.46±0.10* 1.32±0.17 6.14±1.20 4.03±1.15**
(P<0.05), **(P<0.01), ACTH: Adrenocorticotropic hormone, FSH: Follicle-stimulating hormone, LH: Luteinizing hormone, TSH: Thyroid-stimulating hormone
Figure 1:: (a-e) Effect of histamine on rat’s pituitary hormones after treatment with chlorpheniramine (H1 blocker) and cimetidine (H2 blocker).

As shown in [Table 2], both chlorpheniramine (H 1 blocker) and cimetidine (H 2 blocker) inhibited the stimulatory effect of histamine on ACTH secretion, but it appeared that chlorpheniramine was more potent (P < 0.01) than cimetidine (P < 0.05) in blocking the histamine effect on ACTH. Histamine induced significant decline in the serum level of TSH (P < 0.05), chlorpheniramine did not affected the inhibitory effect of histamine, while, cimetidine blocked this effect, and restored the TSH level to the normal limit. Prolactin level was not affected by histamine after 30 min of injection, and also after injection of chlorpheniramine, but it significantly declined after cimetidine injection (P < 0.05). Neither histamine nor cimetidine affected the FSH level, but chlorpheniramine significantly elevated serum FSH level (P < 0.01). Histamine significantly (P < 0.05) elevated serum LH level and this elevation was inhibited by both chlorpheniramine and cimetidine.

Table 2:: Effect of histamine injection on rat’s pituitary hormones after treatment with chlorpheniramine (H1 blocker) and cimetidine (H2 blocker).
Groups Hormonal levels ( mean±SD)
ACTH pg/ml TSH m IU/l PRL ng/ml FSH IU/l LH IU/l
First group (control): Treatment with distilled water 48.00±4.78 0.82±0.28 0.9±0.23 6.42±0.61 1.41±0.55
Second group treatment with distilled water+histamine 64.00±5.90* 0.45±0.07* 1.20±0.19 6.43±1.97 3.38±0.30*
Third group treated with chlorpheniramine+histamine 24.16±4.34** 0.47±0.07* 1.32±0.42 18.36±4.83** 1.70±0.25*
Fourth group treated with cimetidine+histamine 49.00±1.50* 0.81±0.11 * 0.32±0.16* 6.75±1.75 1.80±0.47*

The second group was compared with the first group, while the third and fourth groups were compared with the second group: *(P<0.05), **(P<0.01), ACTH: Adrenocorticotropic hormone, FSH: Follicle-stimulating hormone, LH: Luteinizing hormone, TSH: Thyroid-stimulating hormone

DISCUSSION

The aim of the present study was to determine the effects of histamine on the anterior pituitary secretion, and to investigate the role of H1 and H2 receptors in the histaminergic effects on the endocrine hormones. The H1 and H2 blockers were used extensively in patients with allergic conditions and peptic ulcer disease, respectively. Their prolong use could interfered with normal physiological role of histamine and may resulted in public health problems.

The study revealed that histamine significantly elevated serum ACTH level, and this stimulatory effect was inhibited by both H1 and H2 receptor blockers. Previously, it was recorded that intracerebroventricular injection of histamine in dogs increased ACTH secretion. Histamine stimulated both the primary and stimulating ACTH secretion through H1 and H2 receptors,[21,22] while it exerted a depressing effect and can neutralize the induced stimulation of ACTH hormone through H3 receptors.[14]

Our study showed that histamine induced insignificant elevation of prolactin serum level. However, H2 blocker caused significant decline in the serum prolactin level. In rats and dogs, histamine released prolactin hormone when given intracerebroventricularly.[23-26]

The effect of histamine on TSH secretion in the resent study, which antagonized by H2 receptor blocker, could be attributed to its effect at hypothalamic level, so histamine inhibited TRH which stimulated pituitary secretion of TSH. The inhibitory effect of histamine on the secretion of TSH in male rats was mediated through H2 receptors located in median eminence. H2 agonist drugs possessed strong inhibitory effect on TSH secretion.[27] Our study also showed that histamine induced insignificant elevation of serum prolactin level. However, H2 blocker caused significant decline in the serum prolactin level. In rats, histamine released prolactin hormone when given intracerebroventricularly.[23,25,26]

The results of the current study also revealed that histamine significantly elevated serum LH level, and this stimulatory effect was inhibited by both H1 and H2 receptor blockers. The same results were recorded by Horno and Alvarez,[28] who mentioned that the stimulatory action of histamine in secretion of LH in female rats occurred, indirectly by stimulating the GnRH release, and both H2 and H1 receptors participated in this stimulatory action. Incubation of the pituitary gland of female rats with histamine resulted in stimulation of the secretion of GnRH and LH.[29] Many histaminergic neurons contain estrogen receptors, project to luteinizing hormone (LH)–releasing hormone neurons in preoptic and infundibular regions, and may constitute, an important relay in the estradiol-induced preovulatory LH surge.[30,31]

However, histamine significantly elevated serum LH level, but it did not affected FSH secretion. On the other hand, FSH secretion was significantly enhanced by H 1 blockers. This could be attributed to the different sensitivity of LH and FSH receptors for the fluctuation in the GnRH, so LH receptors were more sensitive, and responded more early than FSH receptors.[32]

The elevation of FSH level with the using of H1 blocker could be attributed to anticholinergic effects of H 1 blocker, which enhance the secretion of FSH.[33]

These results clearly indicated that histaminergic innervation of hypothalamic and pituitary glands was involved in the anterior pituitary secretion.

CONCLUSION

It appeared that histamine significantly elevated serum ACTH and LH level, and these stimulatory effects were inhibited by both H1 and H2 receptor blockers. However, histamine significantly inhibited serum level of TSH and this inhibitory effect was blocked by H2 receptor blocker, while it showed no effect on the secretion of both prolactin and FSH, although H2 blocker significantly decreased prolactin level and H1 blocker significantly elevated FSH level. According to these results, histamine represented one of the neuroendocrine factors which affected the endocrine secretion. These results indicated that histaminergic pathways were involved in the anterior pituitary secretion.

Declaration of patient consent

Patient’s consent not required as there are no patients in this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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