Melatonin anterior pituitary of the female Wistar rat(6)

Melatonin modulates DES effects on the pituitary

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Fig. 2.Electron microscopy on pitu-itary tissues. Accumulated secretiongranules for extrusion into the bloodvessels were observed in the DEStreated rat pituitary gland (A),whereas in the DES treated rat pitu-itary co-administrated with mela-tonin, most of these granules wereseen in the loosened structure of therough endoplasmic reticulum (B).

opment of prolactinoma [16]. Here, we also observedthe accumulation of secretion granules approachingthe blood vessels in the DES treated rat pituitary gland(Fig. 2A). In pituitary tissues of rats co-treated withmelatonin, many premature, abnormally enlarged,medium-density hormone containing granules wereobserved in loosened endoplasmic reticulum, with anaverage diameter of 300 nm (Fig. 2B), suggestingmelatonin may function by inhibiting the granuleextrusion.

Discussion

Prolactinoma is a multi-factorial disease. Althoughdopamine agonists, including bromocriptine,quinagolide, and lisuride, have proved to be effective inmost patients suffering from prolactinoma, there are stillmany patients who show no response to these drugs orwho develop resistance to them [18]. In this investiga-tion, rats were subjected to DES administration with orwithout concurrent melatonin treatment, after whichimmunohistochemistry and electron microscopy wereundertaken to investigate the effects of melatonin on theexpression of VEGF, MMP-9, and AQP-1, as well as itseffect on the ultrastructure of pituitary tissues. Ourresults demonstrate the ability of melatonin to counter-act DES-induced upregulation of VEGF and MMP-9expression and its ability to improve the ultrastructureof DES-treated pituitary tissue.

Although investigations have demonstrated that thepineal body influences PRLrelease, little is knownabout the effects of the pineal body on hyperprolactine-mic diseases, and pineal body activity is usually exclud-ed from clinical investigations of pituitary tissues. Liss-noi et al. [19] investigated the effects of melatonininjection on serum PRLin 19 patients with hyperpro-lactinemia. They found that intramuscular injection ofmelatonin led to the reduction of serum PRLin 3 out of8 patients with congenital hyperprolacthemia. Subse-quent investigation [17] showed that the serum mela-©Polish Histochemical et Cytochemical Society

Folia Histochem Cytobiol. 2010:48(2): 281(278-283) 10.2478/v10042-010-0023-1

tonin level in these patients was significantly lower thanin normal controls. Additionally, patients withacromegaly and pituitary tumors showed no response interms of serum growth hormone or prolactin to acuteadministration of melatonin. Thus, the effects of long-term melatonin treatment need further elucidation.

Xuet al. [9,20] used controllable pumps containingestradiol to induce the development of prolactinoma inrats, which received melatonin treatment from 7 daysbefore implantation to 90 days after implantation. Theresults demonstrated that melatonin could effectivelyabolish the growth of prolactinoma by inhibiting PRLand ER expression and could partially prevent thebinding of ER to ERE.

Melatonin, at an appropriate dose, can also reducemutations in the PRLgene enhancer, preventing over-expression of PRLand resulting in the decreasedgrowth of prolactinomas [10]. Further investigationsdemonstrated that melatonin can increase the activityof caspase-3, increasing the expression of Bcl-2 andfacilitating decreases in mitochondrial membranepotential, which promote apoptosis and reduce tumormass [11,21]. Notably, melatonin treatment was initi-ated before DES induction in previous studies. In con-trast to this preventive mode of treatment, we adminis-tered melatonin after 12 weeks of DES pre-treatment.Co-administration of melatonin with DES couldpromote the re-emergence of the adenoid cavity, espe-cially in the areas approaching the margin of the ante-rior pituitary gland. This may be caused by the rapidretreat of proliferative cells, allowing greater bloodflow and thus leaving a larger cavity. It can be specu-lated that further increases in blood flow might rupturethe vessels. Therefore, an effective dose of melatoninwill need to be determined to optimize vascular stabil-ity during melatonin treatment.

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