RESUMO
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
Gamma-aminobutyric acid (GABA) is involved in the neural control of hypophyseal hormones, including PRL and TSH. In the present work we investigated the ontogeny of the effect of baclofen, a GABA B agonist, on basal PRL and TSH release and in the presence of releasing stimulus which act at two different levels: TRH, at the hypophyseal level, and serotonin, at the central nervous system. Ages studied were 4, 12, 20, 28-29, 37-38 day-old and adult male and female animals. Rats of each age and sex were separated in groups and each group received two intraperitoneally injections, one 45 minutes after the other: saline-saline, saline-TRH, baclofen-saline, baclofen-TRH, saline-serotonin or baclofen-serotonin. Rats were decapitated 15 minutes after the last injection and serum hormones were measured by RIA. Baclofen (7 mg/kg) significantly elevated basal prolactin levels at 4, 12 and 20 days of age and the stimulating effect increased with age. At 28 days of age baclofen significantly inhibited PRL whereas from 38 days of age onwards it had no effect on basal PRL levels. No sex differences were evident. Interaction of TRH (4 microg/kg) and baclofen on PRL secretion resulted in an additive effect on days 4 and 12, this effect was not observed when baclofen was administered with serotonin (10 mg/kg). In 28 day-old and older animals baclofen completely blunted the PRL releasing effect of TRH or serotonin. Again, no sex differences were observed. With regard to TSH, baclofen did not alter either basal or TRH stimulated TSH secretion regardless of sex and age. The present experiments indicate that GABA B receptors are involved in the regulation of basal and stimulated PRL secretion from the first days of life to adulthood. Receptor activation results in stimulation or inhibition of PRL release depending on the age of the animals and the site of action. This GABA B regulation of PRL secretion is sex independent. In contrast, pituitary GABA B receptors do not seem to be involved in the regulation of TSH secretion.
Assuntos
Baclofeno/farmacologia , Prolactina/metabolismo , Serotonina/farmacologia , Hormônio Liberador de Tireotropina/farmacologia , Tireotropina/metabolismo , Animais , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de GABA-B/fisiologiaRESUMO
Recent work from our laboratory has demonstrated that the activation of GABA B adenohypophyseal receptors by baclofen inhibits pituitary hormone secretion under basal (PRL) or stimulated conditions (PRL and LH) in adult female rats, suggesting a hypophyseal site of action in addition to the central site previously described. Since different patterns of hormone secretion are observed in infantile and adult rats, the purpose of the present study was to determine whether GABA B pituitary receptors were involved in endocrine responses at early stages of development. Pituitary cells of 12 day-old female rats were cultured in vitro and the effect of baclofen was determined in the presence or absence of stimulatory factors. Baclofen (1.10(-9), 1.10(-7) and 1.10(-5) M) did not alter basal LH or FSH secretion but significantly inhibited the LHRH induced gonadotropins release after 30 or 60 minutes of incubation (after 60 minutes of incubation LH (%): control: 100 +/- 5.6; BACL(1.10(-7)): 134.5 +/- 25.8; LHRH(1.10(-7)): 596.7 +/- 85.9; LHRH(1.10(-7))-BACL(1.10(-7)): 374.7 +/- 48.0; p<0.01. FSH (%): control: 100 +/- 6.5; BACL(1.10(-7): 103.7 +/- 6.5; LHRH(1.10(-7)): 283.9 +/- 29.3; LHRH(1.10(-7))-BACL(1.10(-7): 183.0 +/- 20.0; p<0.01). Baclofen did not significantly modify either basal or TRH-stimulated PRL or TSH secretion. These results show that baclofen has direct effects on the of adenohypophyseal cells of immature rats and such effects are different from those observed in adult rats, and depend on the stage of development of the neuroendocrine controls of each cellular type.