Age‐dependent regulation by androgens of gene expression in the anterior hypothalamus and stress‐induced release of adrenal hormones in adolescent and adult male rats

Abstract

Adolescents show greater and/or more prolonged activation of the hypothalamic-pituitary-adrenal axis in response to stressors than adults, although the basis for such an age difference is not understood. We investigated developmental shifts in the regulation of HPA function by testosterone using androgen replacement in orchiectomised (OCX) pre-pubertal and post-pubertal adolescent rats and in adults, as well as using inhibitors of testosterone synthesis in non-operated rats. The expected dampening effect of testosterone in adult OCX rats did not meet statistical significance in all of the three experiments. Nevertheless, in each, adolescents had higher post-stress concentrations of corticosterone compared to adults despite similar concentrations of testosterone. The effect of testosterone was in the opposite direction in post-pubertal adolescents compared to that in adults, with testosterone replacement leading to increased rather than lower corticosterone concentration.Testosterone replacement decreased arginine vasopressin and corticotrophin-releasing hormone immune-reactive cell counts in the paraventricular nucleus at all ages. In a fourth experiment, we provide evidence that the basis of the age difference in corticosterone release is because of a greater conversion of testosterone to oestradiol in adolescents and a greater conversion of testosterone to dihydrotestosterone in adults: aromatase inhibition had little effect in adults and attenuated the age difference by decreasing stress-induced corticosterone release in adolescents. By contrast, 5α-reductase inhibition or an androgen receptor antagonist had little effect in adolescents and attenuated the age difference by increasing stress-induced corticosterone release in adults. In the adrenal gland, adolescents had reduced 5α-reductase and androgen receptor gene expression. There also were age differences in the regulation of hypothalamic mRNA expression of androgen receptors, oestrogen receptors and aromatase by testosterone. In sum, the results suggest that developmental shifts in the synthesis of testosterone and the regulation of gene expression are factors with respect to age differences in corticosterone release in response to stressors. K E Y W O R D Sadolescence, androgens, corticosterone, glucocorticoids, oestrogens 2 of 20 | GREEN Et al. | INTRODUC TI ONAdolescence in male rats spans from approximately postnatal day (P) 28 to P59, with physical markers of pubertal onset evident at approximately 40-42 days of age. 1 Functional changes in hypothalamic-pituitary-adrenal (HPA) responses to stressors during adolescence are well-documented in rats, although most research has involved pre-pubertal adolescents. 2,3 Pre-pubertal adolescents respond to an acute stressor with a more pronounced release of adrenocorticotrophic hormone (ACTH) and corticosterone than adults.Moreover, concentrations remain elevated for longer in pre-pubertal males, despite similar rates of hormone metabolism, 4,5 which suggests that negative-feedback is maturing during adolescen...

Up to the maximum—testosterone dose‐dependent effects on anabolic and androgen responsive tissues in orchiectomized rats

“…49,50 In addition, the investigation of testosterone dose-response effects in adult rats of older age might be of interest in comparison to the results presented herein, as the androgen receptor expression has been shown to be age-dependent. 51,52 Yet, the lacking gain in wet weight and muscle fiber area of the M. soleus and M. gastrognemicus were consistent with weekly testing for the rats' forelimb grip strength, where no significant differences for muscle strength were observed. 48 However, the observed treatmentindependent increase in grip strength might be due to other factors, such as growth hormone or insulin-like growth factor I, or due to the growth of the young adult rats.…”

“…Testosterone combined with exercise was shown to be effective in weight reduction of obese rats as well as in treating cachexia in HIV‐infected men 49,50 . In addition, the investigation of testosterone dose–response effects in adult rats of older age might be of interest in comparison to the results presented herein, as the androgen receptor expression has been shown to be age‐dependent 51,52 …”

On the role of sex steroids in biological functions by classical and non-classical pathways. An update

“…The T-mediated regulation of the expression of AR, ERs and aromatase in the HYP is age dependent. In adolescence, the corticosterone release is regulated mostly by conversion of T to E 2, while in adulthood greater conversion of T to DHT occurs in male rats ( Green et al, 2019 ).…”

Restricted effects of androgens on glucocorticoid signaling in the mouse prefrontal cortex and midbrain

“…In liver, brown and white adipose tissues, GR-driven gene expression is potentiated when AR is activated, and such potentiation is abolished when an AR antagonist is administered (12,13). AR is expressed in different regions of the brain, and it has been demonstrated that AR agonism in the brain influences hypothalamic pituitary adrenal (HPA) axis activity (14)(15)(16).…”