Central 5-alpha reduction of testosterone is required for testosterone's inhibition of the hypothalamo-pituitary–adrenal axis response to restraint stress in adult male rats

Abstract

In rodents, the hypothalamo-pituitary-adrenal (HPA) axis is controlled by a precise regulatory mechanism that is influenced by circulating gonadal and adrenal hormones. In males, gonadectomy increases the adrenocorticotropic hormone (ACTH) and corticosterone (CORT) response to stressors, and androgen replacement returns the response to that of the intact male. Testosterone (T) actions in regulating HPA activity may be through aromatization to estradiol, or by 5α-reduction to the more potent androgen, dihydrotestosterone (DHT). To determine if the latter pathway is involved, we assessed the function of the HPA axis response to restraint stress following hormone treatments, or after peripheral or central treatment with the 5α-reductase inhibitor, finasteride. Initially, we examined the timecourse whereby gonadectomy alters the CORT response to restraint stress. Enhanced CORT responses were evident within 48hrs following gonadectomy. Correspondingly, treatment of intact male rats with the 5α-reductase inhibitor, finasteride, for 48 hrs, enhanced the CORT and ACTH response to restraint stress. Peripheral injections of gonadectomized male rats with DHT or T for 48 hrs reduced the ACTH and CORT response to restraint stress. The effects of T, but not DHT, could be blocked by the third ventricle administration of finasteride prior to stress application. These data indicate that the actions of T in modulating HPA axis activity involve 5α-reductase within the central nervous system. These results further our understanding of how T acts to modulate the neuroendocrine stress responses and indicate that 5α reduction to DHT is a necessary step for T action.

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

“…Indeed, during development, 5α-Rs participates in the generation of T-induced sex differences in the brain by the generation of 5α-DHT [45]. In the adult brain, 5α-Rs may mediate some of the rewarding effects of androgens [46] and is required for the inhibition exerted by T on the response of the hypothalamo-pituitary-axis to stress [47].…”

Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain

“…Indeed, to our knowledge, the effects of finasteride have so far generally been explored after the administration of very high doses [2,8,9,10,11,12,13,14,15,16,17,18]. We demonstrated that, in agreement with the well-known effect of finasteride in the prostate [35], a significant decrease in its relative weight was observed at the end of the subchronic treatment with the drug.…”

“…However, despite of the wide therapeutic use of this inhibitor (e.g., human benign prostatic hyperplasia and androgenic alopecia), the effects of finasteride per se in the nervous system have been poorly explored. The effects of short exposures (i.e., a few days) to high doses (i.e., 50 mg/kg) of finasteride have been assessed in experimental models [2,8,9,10,11,12,13,14,15,16,17,18]. However, the effects of subchronic treatments with finasteride at low doses, more similar to those used in clinical practice, and the consequences of its withdrawal have yet to be clarified.…”

“…Indeed, the metabolites of PROG and T are involved in the regulation of neuroendocrine events, behavior, affection, learning and memory, synaptic and glial plasticity and adult hippocampal neurogenesis as well as in the response of brain tissue to injury and neurodegeneration (i.e., regulating neuronal survival, axonal regeneration and gliosis) [1,5,6,7]. Finasteride has been used as a tool to evaluate whether the effects of PROG or T in the nervous tissue could be ascribed to their conversion into 5α-reduced metabolites [2,8,9,10,11,12,13,14,15,16,17,18]. However, despite of the wide therapeutic use of this inhibitor (e.g., human benign prostatic hyperplasia and androgenic alopecia), the effects of finasteride per se in the nervous system have been poorly explored.…”

Analytical challenges for measuring steroid responses to stress, neurodegeneration and injury in the central nervous system

“…Systemic treatment of adrenalectomized rats with allopregnanolone indeed reduced expression of corticotropin-releasing hormone (CRH) within the hypothalamic periventricular nuclei. On the other hand, treatment of rats with the the 5α-reductase inhibitor finasteride increased their ACTH and corticosterone responses to acute stress [118,119]. Allopregnanolone and THDOC may thus be considered 22 as endogenous stress-protective hormones.…”