Objective:

To investigate the relationship between testosterone and functional brain network connectivity in perimenopausal women. 

Background:

Women are at higher lifetime risk to Alzheimer's disease (AD) and face more rapid progression than men, with evidence implicating hormonal transitions. Perimenopause cognitive symptoms are typically attributed to estrogen fluctuations but largely understudied in relation to testosterone. Androgen receptors are present throughout the salience network (SN), which integrates and processes sensory information and shows early AD disruption. Higher testosterone in women is associated with decreased connectivity between the SN and central executive network, while the opposite is true in males. Further, women exhibit lower within-SN connectivity, whereas men show greater SN connectivity to other networks. Despite these findings, and testosterone's established cognitive role in males, its relationship with SN connectivity during perimenopause remains unexplored.  

Design/Methods:

Healthy women from the Human Connectome Project Aging dataset were classified as being in perimenopause through STRAW+10 staging (n=48, ages 35-55). Seed-based connectivity analysis was completed using a 5mm³ left anterior insula seed to represent the SN. Through AFNI, multivariate approach was used to model the effects of testosterone on SN connectivity, by generating z-score maps (p<0.01, p<0.01). 

Results:

Higher testosterone correlated with reduced within-salience network connectivity (right anterior insula, frontal operculum, and mid-cingulate). It was negatively correlated with posterior DMN regions (posterior cingulate and precuneus) and positively to mid-DMN regions such as the paracingulate and regions of the prefrontal cortex.  

Conclusions:

Higher testosterone was related to reduced SN intraconnectivity and reduced SN connectivity to important posterior DMN hubs that are impacted early in AD. Given the SN's role in autonomic and emotional regulation, these patterns may underlie common perimenopause symptoms. As the DMN subserves short-term memory, future studies should assess the impact of altered SN-DMN connectivity on cognitive outcomes in menopause and the relationship with testosterone.