Level of monoamine neurotransmitters in the central nervous system and kisspeptin in blood in the offsprings of experimentally induced model hyperandrogenisation in female rats

Abstract

Background. An important role in the mechanisms of the formation of the sexual differentiation of the brain and sexual behavior assign interneuronal signaling and interaction of neurotransmitter systems in the brain. However, PDM physiology and pathology are the least understood and requires further research, in the aspects of new discoveries neuroendocrine regulation of gonadal axis by kiss / kiss1R system. The purpose. To study the profile of monoamine neurotransmitters in the central nervous system, in association with blood levels of kisspeptin in female offspring with prenatal hyperandrogenisation at different stages of gestation in female rats. Methods. The experimental model was created in female Wistar rats (total 50 rats). Prenatal hyperandrogenisation model was created by intraperitoneal injection of testosterone to pregnant females at 11 and 18 days of gestation. Next, the resulting offspring was investigated. During the experiment set up control groups — prepubertal female rats aged 2 months (5 individuals) and pubertal female rats aged 4 months (5 individuals), those born in a physiological pregnancy. Experimental group were female rats aged 2 and 4 months with hyperandrogenisation in 2 and 3 trimester (5 individuals). In all groups the serum levels of testosterone, kisspeptin and the concentration of norepinephrine and serotonin in the brain structures were measured. Processing of the data was performed by analysis of variance, non-parametric analysis (Me) by using the Wilkokson criterion. Results. In the hypothalamic nuclei a significant increase of NE concentration was found, compared to a control group (median (Me), respectively 3,642 ng/ml and 2,132 ng/ml, p<0.001 in the 2nd trimester, 3,685 ng/ml and 2,132 ng/ml, p<0.001 3 trimester). In the hippocampus a significant increase of NE was revealed in comparison with controls (median (Me) respectively 1,517 ng/ml and 0.068 ng/ml, p<0.05 in the 2nd trimester; 2,068 ng/ml and 0.068 ng/ml, p<0.05 in the 3rd trimester). In the amygdala NE-level changes in comparison to a control group was not revealed. In the hypothalamus there was a significant decrease of SER concentration in rats with hyperandrogenisation in 3 trimester (1,294 ng/ml versus 1.637 ng/ml in the controls (p<0.05). In the amygdala SER level decreased in group with androgenisation in 3rd trimester — a median, respectively, 1.428 ng/ml in the control and 0.885 ng/ml in the experimental group, p<0.05). The study did not found significant differences in the level of testosterone in the blood of female rats hyperandrogenised at different stages of gestation, compared with age-matched controls and within groups. Kisspeptin level was significantly increased in both experimental groups (2 months and 4 months) at androgenisation in 3rd trimester. Kisspeptin median in 2-month aged rats androgenised in the 3rd trimester compared with the 2-month control group was 0.67 ng/ml and 0.17 ng/ml (p<0.05); 4-month aged rats with androgenisation in the same period compared to 4-month controlgroup — 0.64 ng/ml and 0.31 ng/ml, respectively (p<0.05). Conclusions. An excess of testosterone in early gestation has teratogenic effects in the offspring. Opposite changes in neurotransmitter signaling, arising on a background of prenatal hyperandrogenisation in the later stages of gestation, may indirectly lead to inversions of sexual differentiation and sexual behavior. Prenatal hyperandrogenisation is associated with higher levels of kisspeptin in blood, what suggesting an indirect effect of androgenisation in the later stages of gestation on activation kisspeptin signaling and activation of the gonadal axis. Continuation of the study of the association profile changes of monoamine neurotransmitters and dynamics of kisspeptin able to expand the understanding of the mechanisms of sexual differentiation of the brain and translate the findings into clinical practice.