The role of histamine in anterior pituitary secretion

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

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].

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Figure 1:

(a-e) Effect of histamine on rat’s pituitary hormones after treatment with chlorpheniramine (H1 blocker) and cimetidine (H2 blocker).

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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.

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.