Sex Differences in Stress Hormone Receptors

An understanding why women experience more stress-related mental disorders like depression and Post Traumatic Stress Disorder (PTSD) has eluded scientists but a new study in rat brains may help explain why women are more prone to mood and anxiety disorders than men.

In order to better understand this study, I found it helpful to look up a few key definitions:

  • stressor:   a stimulus that causes stress, can be physical, emotional or social
  • hormone:  a secretion of an endocrine gland that is transmitted by the blood to the tissue on which it has an effect
  • neurotransmitter:   a chemical that transmits signals from a neuron (nerve system cell) to a cell across an empty space called a “synapse”
  • receptor:   a protein molecule embedded in either the membrane or cytoplasm of a cell, to which one or more specific kinds of signaling molecules, such as a neurotransmitter or hormone may attach. Each cell typically has many receptors, of many different kinds.

Now, back to the study:

Corticotropin releasing factor (CRF), which acts as both a hormone and a neurotransmitter, is likely a key player.   In response to a stressor, CRF binds to receptors on cells in an alarm center deep in the brainstem, called the locus ceruleus.   This telegraphs heightened emotional arousal throughout the brain via the chemical messenger norepinephrine.   Such hyper-arousal can be adaptive for brief periods, but not if it becomes chronic.   Runaway CRF is a core feature of depression.

Previous studies suggested that this alarm system is more sensitive to CRF and stress in the female brain and researchers at Children’s Hospital in Philadelphia developed an experiment to see how CRF receptors responded in male versus female rats, both unstressed and after exposure to a stressor (in this case, a swim).

Even in the absence of any stress, the researchers found the female stress signaling system to be more sensitive from the start.   CRF receptors had stronger connections or coupling in the female rats, so it took lower levels of CRF to activate proteins in the unstressed females compared to males.    CRF levels that had no effect in males turned on cells in female rats.

After stress, CRF receptors remained exposed on the neuronal membranes in the female rat, maintaining the CRF effect.   In the stressed male, the CRF receptors interacted with proteins in the cell that enabled some of the them to retreat and not be available to couple to the CRF.  This helped the male brain adapt its sensitivity to the stressor and thus the stress response was less than in the females.

What is the significance of this experiment?   Certain brain cells in females are more sensitive to CRF  and less able to adapt to too much CRF than male brain cells.

The next step is to examine the male and female CRF receptors for structural differences that might account for the functional differences (e.g., response to stress, depression).   Since most rodent models of mood and anxiety disorders use male animals exclusively, the new findings of sex differences in stress signaling mechanisms call for a more sex- and gender-balanced approach—especially for mental disorders that disproportionately affect females.   This sex-difference should also be factored in as medication treatments based on blocking CRF receptor are developed, say the researchers.

Source: Sex differences in corticotropin-releasing factor receptor signaling and trafficking:   potential role in female vulnerability to stress-related psychopathology.  Mol Psychiatry. 2010 Jun 15. (PMID:  20548297)