DHEA is well known as a “prohormone” due to its precursor role in androgen and estrogen synthesis, as well as its ability to modulate several physiologic processes including metabolism, muscle protein synthesis and cardiovascular function. Emerging research suggests that DHEA may serve as an active hormone in its own right, with far reaching modulatory actions on several physiological processes including the central nervous system (CNS).
DHEA is predominantly synthesized in the zona reticularis of the adrenal cortex in response to stimulation by ACTH. There it is converted to its sulfate, DHEA-S, which represents the majority of circulating DHEA, jointly referred to as DHEA(S). In humans, levels of DHEA change significantly across the life cycle, peaking during the second decade of life. By the third decade, levels begin a slow decline, to as low as 10-20% of peak levels by the eighth decade.
An emerging area of scientific study is that of DHEA’s role in the regulation of brain development and its emerging role as a CNS modulator. DHEA(S) levels have been shown to be positively correlated with cognitive function and improved mood, and seem to display a cognitive-preserving effect through neuroprotective, antioxidant, anti-inflammatory, and antiglucocorticoid actions. While the physiological significance and mechanisms of action are still being defined, there is emerging evidence pointing to roles in neurocognition, the stress response, and emotional regulation.
Stress and Mood:
DHEA administration has been shown to reduce circulating levels of cortisol, with anti-glucocorticoid or modulatory effects, to buffer cortisol’s impact on the hippocampus. Similarly, DHEA elevation seems to serve as a compensatory response to stress, seen in anxiety disorders and PTSD – perhaps serving as a mark of resiliency. DHEA is positively associated with adaptive responses to stress and symptom improvement and coping in PTSD.
The amygdala plays a role in the fight or flight response by detecting threat and activating appropriate behaviors in response to threatening or dangerous stimuli. The hippocampus plays a significant role in learning and memory. During emotional reactions, the two regions interact to translate emotion into particular outcomes. The anterior cingulate cortex (rACC) is positioned between limbic and cortical structures, aids in integrating emotion and cognition and amygdala-dependent learning. In a study with fMRI imaging to explore DHEA’s impact on emotional processing and regulation, compared to placebo the DHEA group reflected reduced activity in brain regions associated with the generation of negative emotion (amygdala and hippocampus), and enhanced activity in the regulatory processing area of the rACC. Since altered activity in these regions are associated with mood and anxiety disorders, results suggest that DHEA may be useful as a pharmacological intervention for these diagnoses, prompting further research.
Neurotransmission:
An increasing body of evidence suggests that DHEA(S) modulate several neurotransmitter systems. Both stimulatory and inhibitory effects have been observed. Regarding dopamine neurotransmission, studies suggest that DHEA(S) may act as dopamine receptor (D2) antagonists, in a similar fashion to antipsychotics, suggesting that increasing DHEA(S) levels may lead to a therapeutic effect. Similarly, the serum DHEA/cortisol ratio has been shown to be inversely correlated to psychopathology in schizophrenic patients.
The effect of DHEA(S) on glutamate neurotransmission is also a potential therapeutic target. The stimulating effect of DHEA(S) may reduce glutamate hypofunction seen in schizophrenia, which could explain the therapeutic effect of DHEA on negative symptoms in this disorder.
While results are contrasting, some data suggest that DHEA might stimulate the serotonin system in a similar fashion as antidepressant drugs, improving mood and well-being. Data regarding GABA is less clear as it binds to GABA-a receptors, which would typically create anxiogenic effects, which is paradoxical to its reported anxiolytic effects. Assuredly, research will continue to emerge further elucidating the roles of DHEA(S) on the neurotransmitter system.
Cognition:
Endogenous DHEA(S) levels have shown a positive correlation with global cognition in women and men; and a positive correlation with working memory, attention and verbal fluency in women. However, studies to date with DHEA replacement have failed to improve cognitive functions including short term memory.
Dosing:
DHEA is often referred to as “the fountain of youth” hormone, perhaps due to low levels associated with many of the medical problems of postmenopausal women. Aside from lack of cognitive improvement, findings to date suggest that DHEA replacement seems to be well-tolerated with an absence of significant side effects. While physiologic doses are not well defined and differ in men and women, clinical studies use a wide range of dosing from 50 mg/day to 450 mg/day. A more conservative strategy for commencing DHEA supplementation, would be 5-10 mg/day for females, and 25mg for males, increasing dosing as tolerated.
Due to DHEA’s prohormone effects, regular hormone testing (every 3-6 months) is essential to monitor estradiol and testosterone levels. Saliva testing is a simple and effective means of measuring DHEA, estradiol and testosterone levels, as well as progesterone and diurnal cortisol. Urine testing will reflect systemic levels of neurotransmitters, including those which may be susceptible to the modulatory effects of DHEA: dopamine, glutamate, serotonin and GABA.
