Efeitos da olanzapina via leite materno sobre o desenvolvimento testicular de ratos Wistar pré-púberes e sua repercussão sobre parâmetros testiculares e endócrinos em adultos

Abstract

Olanzapine (OLNZ) is an atypical antipsychotic that binds to dopamine (D2) and serotonin (5HT2) receptors, widely prescribed for the treatment of schizophrenia and postpartum psychosis. Its transfer through breast milk to newborns has been reported. Consequently, neonates are susceptible to their adverse side effects. In the present study, aims to evaluate the effects of OLNZ administered through breast milk on the testicular development of newborn rats exposed to lactation. The testicular histopathology, the morphometric analysis of the testes, androgen-dependent organs weights and the levels of prolactin and testosterone were the several end points studied. Twenty-four pregnant rats (age 3–4 months) and their pups were used in this study. After birth, forty-eight pup rats were randomly assigned to the following groups: I) control group – saline solution NaCl 0.9% (n = 12), II) treated group with 2.5 mg/kg OLNZ (n = 12), III) treated group with 5 mg/kg (n = 12) and IV) treated group with 10 mg/kg of OLNZ (n = 6). Each mother along with their pups was housed singly in PVC cages. On the 21st day postpartum, the animals were separated from their respective mothers, during which treatment with the antipsychotic was stopped. The pubent rats of each group were randomly selected and processed for stage 1 of the study: to verify the effect of antipsychotic exposure during lactation on the testicular development of pubertal rats at 21 days of age. The remaining half of the male offspring of each group were maintained until adulthood of sexual maturity (90 days) for stage 2 of the study. At stage 1 of this study, Histopathological findings, and changes in testicular morphometric parameters of pubescent rats, with consequent hypogonadism, may be related to OLNZ-induced hyperprolactinemia with negative endocrine repercussions on testosterone, which justifies the atrophy resulting from the use of OLNZ during the critical period of testicular development. At stage 2 of the study (90 days), the histopathologic and histomorphometric analysis of spermatogenesis indicated testicular degeneration. The hypogonadism thus observed might be mediated by OLNZ-induced hyperprolactinemia, which further inhibited secretion of testosterone. Testicular degenerative processes associated with hormonal changes in adult rats have a significance for this irreversible event even after discontinuation of the antipsychotic after weaning. Thus, adverse impact was persistent until adulthood with higher doses of the drug as evidenced by the analysis of testicular weight, histology and hormonal profiles of post-pubertal rat lactationally exposed as neonates and pubescents. The present study thus revealed that the lactational exposure to OLNZ interfered with the pituitary– testicular axis by prominently influencing blood levels of pituitary hormone prolactin and adversely affecting testosterone levels and testicular histopathology.