estradiol-3-benzoate and Hyperplasia

Estrogens and thyroid hormones contribute importantly to cell proliferation and tumor transformation in the pituitary gland. We found that methylene blue antagonized estrogen-promoted adenohypophyseal enlargement and the enhancement of prolactin secretion. The purpose of the present article is to provide a review about neurotransmitters and their receptors involved in estrogen-induced anterior pituitary growth and in the antagonistic effects of triiodothyronine (T3) and methylene blue (MB). Central dopaminergic and noradrenergic systems are the most important factors regulating pituitary growth and function. Recently nitric oxide (NO) was added to the list of the neurotransmitters and neuropeptides involved in the control of the anterior pituitary secretion. Our data suggest that estrogen-induced anterior pituitary growth is associated with decreased synthesis and metabolism of central catecholamines, reduction of adenohypophyseal beta-adrenergic receptors and increase of dopamine DA-2 receptors. We found that the treatment with T3 or MB prevented both estrogen-induced catecholaminergic inhibition and dopamine DA-2 receptor increment in the anterior pituitary. In contrast to T3, MB given alone also slightly decreased the anterior pituitary weight. Serum levels and anterior pituitary content of prolactin were increased after treatment with estradiol benzoate (EB), whereas T3 or MB partially attenuated prolactin hypersecretion after estrogen administration. This is in accord with the attenuation of EB-induced inhibition of dopaminergic system by T3 and MB. MB given in combination with EB also partially attenuated EB-promoted rise of adenohypohyseal NO synthase activity which plays an important role in the regulation of prolactin secretion. Further studies on central catecholaminergic systems, pituitary receptors, the nitrergic system and mechanisms of intracellular signal transduction are necessary for better understanding of pituitary tumor transformation and possibly for the discovery of new approaches towards treating patients with these diseases.

Topics: Adrenergic beta-Agonists; Animals; Dopamine; Estradiol; Estrogens; Hyperplasia; Methylene Blue; Nitric Oxide; Pituitary Gland, Anterior; Prolactin; Rats; Triiodothyronine

Recently, we demonstrated that methylene blue partially inhibited estradiol-benzoate-induced anterior pituitary hyperplasia in rats. Since central dopaminergic systems participate in the regulation of estrogen-induced anterior pituitary growth and tumor transformation, this study examined whether a 3-week treatment with methylene blue could affect anterior pituitary levels of dopamine (DA), dihydroxyphenylalanine (DOPA), and dihydroxyphenylacetic acid and dopamine (D-2) receptors in male rats. Compared to controls, methylene blue significantly decreased anterior pituitary weight, increased basal anterior pituitary DA levels, and inhibited estradiol benzoate-induced decreases in anterior pituitary DA concentrations. Furthermore, we found that methylene blue alone decreased anterior pituitary D-2 receptor number. Methylene blue given in combination with estradiol benzoate partially inhibited estradiol benzoate-induced anterior pituitary growth and estradiol benzoate-induced increases in D-2 receptor number. Estradiol benzoate-treated rats had significantly lower anterior pituitary DOPA accumulation after intraperitoneal administration of 3,4-hydroxybenzyl-hydrazine dihydrochloride (NSD-1015), an irreversible inhibitor of L-aromatic amino acid decarboxylase whereas methylene blue did not affect anterior pituitary DOPA accumulation when compared to controls. Methylene blue decreased anterior pituitary prolactin levels and inhibited increases in anterior pituitary prolactin after estradiol benzoate administration. The present results suggest that anterior pituitary DA may play an important role in estrogen-induced anterior pituitary hyperplasia and tumor formation and that antioxidant drugs such as methylene blue may attenuate estrogen-induced pituitary growth. This may occur via increases in anterior pituitary DA levels associated with down-regulation of anterior pituitary D-2 receptors.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Aromatic Amino Acid Decarboxylase Inhibitors; Dihydroxyphenylalanine; Dopamine; Enzyme Inhibitors; Estradiol; Hydrazines; Hyperplasia; Male; Methylene Blue; Organ Size; Pituitary Gland, Anterior; Rats; Rats, Wistar; Receptors, Dopamine D2; Reference Values