Testosterone in the Bedroom ‐ Not All Good
Authors: Snyder Brina , Duong Phong , Cunningham Rebecca L. 
Published: June 2021

There are no effective therapeutics to prevent the progression of neurodegenerative diseases, such as Alzheimer's disease (AD) or Parkinson's disease (PD). This deficit highlights the need to identify early contributors to neurodegenerative pathophysiology, such as examining common comorbidities. One such comorbidity is sleep apnea. To examine the relationship between sleep apnea and neurodegeneration, we used a rodent model of chronic intermittent hypoxia (CIH) to simulate the hypoxic events experienced by patients with sleep apnea. Interestingly, in male rats CIH causes an increase in oxidative stress and inflammation, along with a decrease in circulating testosterone (T). These findings are consistent with key characteristics of neurodegeneration. Since sex differences can be observed in both sleep apnea and neurodegeneration, it has been hypothesized sex hormones may underlie this sex difference. Currently, studies have been equivocal about the role of the major male sex hormone, T, in neuroprotection and neurodegeneration. It has been proposed that an oxidative stress environment may predispose T to be neurotoxic via androgen receptor activation. To address if oxidative stress is the switch for testosterone's neuroprotective or neurotoxic actions, we used male Long‐Evans rats assigned to different hormone treatment groups: gonadally intact, gonadectomized (GDX – hormone deficient), gonadectomized + T, gonadally intact + T, or gonadectomized + dihydotestosterone (DHT). Two weeks after hormone replacement, rats were exposed to CIH (used as an oxidative stressor) or room air (AHI = 8) for 12 days. During the last 5 days of CIH, cognitive and motor behavioral assessments were conducted. As expected, we observed increased oxidative stress and spatial memory impairments in response to CIH in gonadally intact rats, which is consistent with patients with sleep apnea. In addition to memory impairments, gonadally intact male rats exposed to CIH exhibited fine motor impairments. Although fine motor skills have not been assessed in clinical sleep apnea populations, delayed motor reaction times have been reported. This suggests CIH‐induced oxidative stress results in behavioral deficits associated with early‐stages of neurodegenerative diseases. Since CIH decreases T, we examined the effects of CIH on hormone deficient rats (GDX) and exogenous hormone replacement rats (GDX + T & intact + T). GDX rats exhibited only cognitive impairments, regardless of CIH exposure, indicating sex hormones play a role in memory. Irrespective of CIH exposure, maintaining physiological levels of T prevented oxidative stress generation as well as motor and cognitive impairments. Since T can activate both estrogen and androgen receptors, we wanted to isolate the effects of androgen receptor activation. Therefore, we used DHT, a T metabolite and an androgen receptor specific agonist. CIH induced oxidative stress and cognitive impairments were exacerbated in GDX + DHT male rats, compared to gonadally intact rats. These results indicate that the androgen receptor is involved in T's negative effects in an oxidative stress environment. Since sleep apnea is a common comorbidity of neurodegeneration, the observed sex differences may be due to a negative interaction between oxidative stress and androgen receptor activation. Therefore, men with sleep apnea who have elevated oxidative stress may be susceptible to neurodegenerative pathophysiology.Support or Funding InformationNational Institutes of Health (NIH) R01 NS088514 to RLCNIH training grant T32 AG 020494 to BDSThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.