Testosterone rapidly increases neural reactivity to threat in healthy men: a novel two-step pharmacological challenge paradigm

Biol Psychiatry. 2014 Aug 15;76(4):324-31. doi: 10.1016/j.biopsych.2014.01.016. Epub 2014 Jan 29.


Background: Previous research suggests that testosterone (T) plays a key role in shaping competitive and aggressive behavior in humans, possibly by modulating threat-related neural circuitry. However, this research has been limited by the use of T augmentation that fails to account for baseline differences and has been conducted exclusively in women. Thus, the extent to which normal physiologic concentrations of T affect threat-related brain function in men remains unknown.

Methods: In the current study, we use a novel two-step pharmacologic challenge protocol to overcome these limitations and to evaluate causal modulation of threat- and aggression-related neural circuits by T in healthy young men (n = 16). First, we controlled for baseline differences in T through administration of a gonadotropin releasing hormone antagonist. Once a common baseline was established across participants, we then administered T to within the normal physiologic range. During this second step of the protocol we acquired functional neuroimaging data to examine the impact of T augmentation on neural circuitry supporting threat and aggression.

Results: Gonadotropin releasing hormone antagonism successfully reduced circulating concentrations of T and brought subjects to a common baseline. Administration of T rapidly increased circulating T concentrations and was associated with heightened reactivity of the amygdala, hypothalamus, and periaqueductal grey to angry facial expressions.

Conclusions: These findings provide novel causal evidence that T rapidly potentiates the response of neural circuits mediating threat processing and aggressive behavior in men.

Keywords: Aggression; amygdala; androgens; anger; emotion; fMRI; testosterone.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aggression / drug effects
  • Aggression / physiology*
  • Blood Chemical Analysis
  • Brain / drug effects
  • Brain / physiology*
  • Cross-Over Studies
  • Double-Blind Method
  • Facial Expression*
  • Gonadotropin-Releasing Hormone / antagonists & inhibitors
  • Gonadotropin-Releasing Hormone / metabolism
  • Hormone Antagonists / administration & dosage
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Neuropsychological Tests
  • Oxygen / blood
  • Photic Stimulation
  • Signal Processing, Computer-Assisted
  • Testosterone / administration & dosage
  • Testosterone / metabolism*
  • Visual Perception / drug effects
  • Visual Perception / physiology*
  • Young Adult


  • Hormone Antagonists
  • Gonadotropin-Releasing Hormone
  • Testosterone
  • Oxygen