RESUMO
Membrane progesterone receptors are known to mediate rapid nongenomic progesterone effects in different cell types. Recent evidence revealed that mPRα is highly expressed in the rat pituitary, being primarily localized in lactotrophs, acting as an intermediary of P4-inhibitory actions on prolactin secretion. The role of mPRs in prolactinoma development remains unclear. We hypothesize that mPR agonists represent a novel tool for hyperprolactinemia treatment. To this end, pituitary expression of mPRs was studied in three animal models of prolactinoma. Expression of mPRs and nuclear receptor was significantly decreased in tumoral pituitaries compared to normal ones. However, the relative proportion of mPRα and mPRß was highly increased in prolactinomas. Interestingly, the selective mPR agonist (Org OD 02-0) significantly inhibited PRL release in both normal and tumoral pituitary explants, displaying a more pronounced effect in tumoral tissues. As P4 also regulates PRL secretion indirectly, by acting on dopaminergic neurons, we studied mPR involvement in this effect. We found that the hypothalamus has a high expression of mPRs. Interestingly, both P4 and OrgOD 02-0 increased dopamine release in hypothalamus explants. Moreover, in an in vivo treatment, that allows both, pituitary and hypothalamus actions, the mPR agonist strongly reduced the hyperprolactinemia in transgenic females carrying prolactinoma. Finally, we also found and interesting gender difference: males express higher levels of pituitary mPRα/ß, a sex that does not develop prolactinoma in these mice models. Taken together, these findings suggest mPRs activation could represent a novel tool for hyperprolactinemic patients, especially those that present resistance to dopaminergic drugs.
Assuntos
Neoplasias Hipofisárias/prevenção & controle , Progesterona/farmacologia , Prolactina/metabolismo , Prolactinoma/prevenção & controle , Receptores de Dopamina D2/fisiologia , Receptores de Progesterona/agonistas , Animais , Gonadotropina Coriônica Humana Subunidade beta/genética , Gonadotropina Coriônica Humana Subunidade beta/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Hipofisárias/etiologia , Neoplasias Hipofisárias/patologia , Prolactinoma/etiologia , Prolactinoma/patologia , Ratos , Transdução de SinaisRESUMO
INTRODUCTION. Craniopharyngioma is an embrionary tumor of the sellar and/suprasellar region derived from fusiform cells of Rathke´s cleft. Although locoregional relapse is the way classically proposed for relapse after treatment, it has been described, in a few cases, the possibility of ectopic relapse out of the sellar-suprasellar region, by direct seeding of cells during surgery on the surgical field, or by cell dissemination in the cerebrospinal fluid (CSF). It is proposed to report the case of a patient with relapse of a craniopharyngioma in the frontal lobe, who was previously operated ten years after, as well as to review the similar cases reported in the literature to the date. RESULTS. A systematic review of the literature has allowed to find 21 cases previously reported. Direct cellular seeding was the most frequent implantation mechanism. In all cases, the preferred treatment was radical surgical removal when this was possible. The time of latency between first surgery and relapse differed from 1 to 21 years. CONCLUSIONS. It is interesting, in the differential diagnosis, to bear in mind the possibility of ectopic relapse of craniopharyngioma in patients who have been operated because of this type of tumor and who present a new mass in nervous central system (CNS). In view of the long time of latency that can pass between the resection of a craniopharyngioma and his relapse, there becomes necessary a long follow-up of these patients by periodic imaging tests.
Assuntos
Craniofaringioma , Recidiva Local de Neoplasia , Neoplasias Hipofisárias , Idoso , Craniofaringioma/patologia , Craniofaringioma/prevenção & controle , Craniofaringioma/cirurgia , Diagnóstico Diferencial , Lobo Frontal/patologia , Lobo Frontal/cirurgia , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/prevenção & controle , Neoplasias Hipofisárias/cirurgia , RecidivaRESUMO
Using both IN VITRO and IN VIVO approaches, we studied the antagonism exerted by the synthetic progestin levonorgestrel on estrogen-induced prolactinomas, considering that levonorgestrel shows partial androgenic properties and that androgens inhibit estrogen-induced prolactin synthesis and secretion. In the tumors, binding of estrogens to their receptors was competed neither by progesterone receptor ligands nor by androgen receptor ligands, ruling out direct inhibitory effects of these drugs on tumor development. Progestin binding was competed by the progesterone receptor agonists progesterone and levonorgestrel, by the antagonist mifepristone, and also by the androgen dihydrotestosterone, whereas the androgen receptor antagonist hydroxyflutamide was a weak competitor. In addition, both progesterone receptor and androgen receptor ligands competed for binding to androgen receptors. In primary cultures of pituitary tumors, levonorgestrel decreased prolactin secretion, an effect that was blocked by mifepristone but not by hydroxyflutamide. IN VIVO results indicated that levonorgestrel inhibition of both estrogen-induced pituitary weight increment and hyperprolactinemia was reduced by mifepristone, whereas flutamide was unable to block levonorgestrel effects. Our results suggest that even when an interaction of levonorgestrel with androgen receptors in the tumors is possible, the antagonistic effects of levonorgestrel on tumor development and functionality are mediated by progesterone receptors.
Assuntos
Carcinógenos , Dietilestilbestrol , Levanogestrel/farmacologia , Neoplasias Hipofisárias/induzido quimicamente , Neoplasias Hipofisárias/prevenção & controle , Congêneres da Progesterona/farmacologia , Receptores de Progesterona/antagonistas & inibidores , Animais , Ligação Competitiva/efeitos dos fármacos , Antagonistas de Hormônios/farmacologia , Masculino , Mifepristona/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Adeno-Hipófise/efeitos dos fármacos , Prolactina/metabolismo , Ratos , Ratos Endogâmicos F344 , Receptores Androgênicos/efeitos dos fármacosRESUMO
Chronic exposure of F344 rats to diethylstilbestrol (DES) induces pituitary tumors (DES-T) composed of proliferating lactotrophs. Presently, we studied the effect of progestins on parameters related to tumor growth and function, due to previous evidences of progesterone antagonism of pituitary tumorigenesis acting at pituitary and hypothalamic levels [Piroli, G., Grillo, C., Ferrini, M., Lux-Lantos, V. and De Nicola, A. F., Antagonism by progesterone of diethylstilbestrol-induced pituitary tumorigenesis in Fischer 344 rats: Effects on sex steroid receptors and tyrosine hydroxylase mRNA, Neuroendocrinology, 1996, 63, 530-539]. In search of a quantitatively more important effect, animals bearing DES-T were treated with synthetic progestins. Competition assays using DES-T as source of progestin receptors indicated that levonorgestrel (LNG), gestodene and R5020 showed higher affinities (IC50 1-2 nM) than progesterone, norethisterone and medroxyprogesterone (IC50 10-25 nM). Treatment with LNG reduced DES-T weight by 45%, and serum PRL by one half. Small (monomeric) and big (polymeric) PRL increased 5- and 2.5-fold, respectively, in DES-T in comparison with pituitaries of ovariectomized (OVX) rats. However, LNG produced no changes indicating that synthesis and storage of PRL was conserved in rats receiving both hormonal treatments. DES induced a 15-fold increase in cell proliferation, measured as bromodeoxyuridine incorporation into cell nuclei, in comparison to OVX rats, while LNG treatment of DES-T bearing rats reduced this index by 72%. Electron microscopic images showed that LNG markedly reduced hypertrophy and hyperplasia of lactotropes, increasing the proportions of degenerating cells and cells of high electronic density with alterations of cytoplasmic organelles. However, histopathological signs of apoptosis were absent. Therefore, reduced cell proliferation and non-apoptotic cell death are part of the mechanisms employed by progestins to antagonize tumorigenesis at the pituitary level. The results may open a new therapeutic strategy for treatment of PRL secreting adenoma in humans.