Aspectos morfofisiológicos e comportamentais da gestação de camundongos após tratamento prévio com Danazol

Abstract

Danazol, a synthetic androgen, developed in 1970 for the treatment of endometriosis, has a controversial application on the pre-treatment of women with unexplained infertility, recurrent miscarriage, and the ones that would undergo fertilization with embryo transfer. The knowledge about the way this compound works after its administration on the incidence of uNK cells, uterine morphology and cognitive functions is still incomplete and inconclusive. Our objectives were to evaluate the effects of different concentrations of danazol on the behavior of pregnant mice, as well as possible changes in implantation, viability, embryonic loss, morphology of the uterus and the incidence of DBA lectin-reactive uNK cell subtype. Ninety-three Swiss female mice from Universidade Federal de Alfenas vivarium were treated for 14 days by gavage with either distilled water + 1% Tween (control) or distilled water + 1% Tween + 0.75, 7.5 or 75 mg/kg of danazol. Females were mated with males after suspension of treatment during four days. Day 1 of gestation was established as the day when the presence of vaginal plug was detected. Behavioral tests were performed and the animals were sacrificed at 6th, 8th, 10th, 12th and 15th gestation days (gd). The data showed that 0.75 mg/kg of danazol caused an anxiogenic effect on mice and decreased the retention of short-term memory in the 10th gd. 7.5 mg/kg of this drug increased the retention of short-term memory and developed a depression-like state on the animals. The fact that gradual increase on hormone concentration caused gradual decrease on the global exploration time suggests a dose-dependent effect of danazol on establishing a state of somnolence and apathy in mice in the 10th ddg. Danazol caused a delay on time of successful mating, however, it increased the rate of pregnancy without reducing the number of corpus luteum in all dosages used. In mice treated with 7.5 mg/kg of danazol, many large cells with a trophoblast-like morphology were observed around vessels that nourish the decidua and the embryo starting at 10th gd, what suggests that this drug increases the invasiveness of the trophoblast starting in the middle period of pregnancy. 7.5 mg/kg of danazol increased the number of uNK cells, whereas the lowest (0.75 mg/ kg) and the highest (75 mg / kg) doses caused a decrease in this number, demonstrating a dose dependent effect of danazol on the number of uNK cells. The analysis of different subtypes of uNK cells in the uterus showed that danazol increases the migration of these cells and can also impair cell proliferation on higher doses. It also suggests that danazol can stimulate cell differentiation in areas close to the embryo. The major changes related to anxiety and memory observed in the 10th gd, associated with morphological changes in the sites of embryo implantation and increase in proliferation of uterine natural killer cells in this period, demonstrate the integration between the nervous, endocrine and immune systems during pregnancy and the dose-dependent action of danazol in the modulation of these systems.