Changes of hypothalamic-pituitary-testicular axis in male rats during cognitive impairment

Abstract

From the previous reports denoting that hypothalamus regulating reproductive function via hypothalamic-pituitary-testicular (HPT) axis, and hippocampus controlling learning and memory capacity can synthesize reproductive hormones, and that cognitive impairment particularly occurs during reproductive senescence, it leads to the following research questions; i) which system first enters the aging stage and ii) how the changes are related. Male rats at the ages of 4, 6, 8, 10 and 12 months old were subjected for this study. Blood samples were collected for serum testosterone (T) and luteinizing hormone (LH) assays by enzyme-linked immunosorbent assay (ELISA) techniques. Testes, seminal vesicle, prostate gland and epididymis were collected and weighed. Hypothalamus (including anteroventral periventricular nucleus (AVPV), arcuate nucleus (ARC), preoptic area (PoA) and median eminence (ME)) and hippocampus were collected, and mRNA expression levels of reproductive hormones related genes were determined by quantitative real-time reverse transcription polymerase chain reaction (qrt-RTPCR) techniques. Learning and memory capacity were tested using Morris water maze test. Serum T level was marginally decreased at 8 months old, but significantly decreased at 12 months old. Serum LH levels were significantly declined from 8 months old. Relative weights of testes, seminal vesicle and prostate gland were significantly lowered at 6 months old, but it occurred at 10 months old for epididymis. Decreases in transcript expression at hypothalamus counted by the controlling pathway were as follows; AVPV-Kiss1 at 12 months old, PoA-Kiss1r and Gnrh1 from 12 and 8 months old, and Ar, Esr1 and Esr2 at AVPV, ARC and ME at 6-12 months old, but no changes in ARC-Esr1, and ME-Esr1 and Esr2 were detected. In hippocampus, Kiss1, Gnrhr, Lhβ, Ar, Esr1 and Esr2 mRNA levels were significantly elevated at 8 months old, but no changes in those of sex steroid synthesis genes. Cognitive impairment was detected when the rats are at the early middle-aged, 8 months old. This study indicates that the reproductive senescence is initiated at the higher (hypothalamus and pituitary) levels of the HPT axis of 6-12 months old male rats which leads to the aging of reproductive (testis) organ when they are middle-aged, 12 months old. In an attempt to retain the cognitive function in response to changes of HPT axis, hippocampus up-regulated sex steroid receptors and locally synthesized reproductive hormone encoding genes (only Kiss1, Gnrhr and Lhβ). In light on the results of this study, it implies that the prevention of cognitive impairment in men should be conducted when they are at the early middle age before a significant reduction of serum T level and a reproductive senescence are detected.