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

Brain Res. 2013 Sep 5;1529:74-82. doi: 10.1016/j.brainres.2013.07.021. Epub 2013 Jul 21.


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 48 h following gonadectomy. Correspondingly, treatment of intact male rats with the 5α-reductase inhibitor, finasteride, for 48 h, enhanced the CORT and ACTH response to restraint stress. Peripheral injections of gonadectomized male rats with DHT or T for 48 h 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.

Keywords: 3V; 3β-diol; 5-Alpha reductase; 5-alpha androstane 3β,17βdiol; 5-alpha reductase; 5α-dihydroprogesterone; 5αDHP; 5αR; ACTH; Androgen; BnST; CORT; CRH; CSF; DHT; DHTP; Dihydrotestosterone; E; ER; HPA; HPA axis; Hypothalamus; MPOA; PBS; PVN; Stress; T; TP; Testosterone; Veh; adrenocorticotropic hormone; bed nucleus of the stria terminalis; cerebrospinal fluid; corticosterone; corticotropin releasing hormone; dihydrotestosterone; dihydrotestosterone propionate; estradiol; estrogen receptor; hypothalamo-pituitary-adrenal; icv; immunoreactivity; intracerebroventricular; ir; medial preoptic area; paraventricular nucleus; phosphate-buffered saline; s.c; subcutaneous; testosterone; testosterone propionate; third ventricle; vehicle.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 5-alpha Reductase Inhibitors / pharmacology*
  • Adrenocorticotropic Hormone / metabolism
  • Animals
  • Corticosterone / metabolism
  • Dihydrotestosterone / pharmacology
  • Disease Models, Animal
  • Estradiol / pharmacology
  • Finasteride / pharmacology*
  • Hypothalamo-Hypophyseal System / drug effects*
  • Hypothalamo-Hypophyseal System / metabolism
  • Injections, Intra-Articular
  • Male
  • Orchiectomy
  • Pituitary-Adrenal System / drug effects*
  • Pituitary-Adrenal System / metabolism
  • Radioimmunoassay
  • Rats
  • Rats, Sprague-Dawley
  • Restraint, Physical / adverse effects
  • Stress, Physiological / physiology*
  • Testosterone / blood
  • Testosterone / metabolism*
  • Time Factors


  • 5-alpha Reductase Inhibitors
  • Dihydrotestosterone
  • Testosterone
  • Estradiol
  • Finasteride
  • Adrenocorticotropic Hormone
  • Corticosterone