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DHEA, Testosterone and Age-Related Cognitive Decline and Dementia

September 30 2019

By James Lake, MD

In this article:

 

Dehydroepiandrosterone (DHEA) is a precursor of testosterone and other androgenic hormones and has many important roles in physiology including modulation of cognition, appetite and sexual behavior. Serum levels of DHEA and its sulfate form DHEA-S gradually decline with aging and reach their lowest levels in the 7th decade. A gradual decline in serum DHEA levels results in reduced synthesis of testosterone, which is associated with a variety of physical, emotional and cognitive symptoms such as fatigue, weight loss, depressed mood, irritability and memory problems. These symptoms are caused by decreases in beneficial effects of testosterone on different parts of the brain that modulate cognitive and emotional function including the amygdala and hypothalamus. 

Animal studies have established that exogenous DHEA and DHEA-S have beneficial effects on the immune and cardiovascular systems. Both prohormones also have neuroprotective, antioxidant and anti-inflammatory effects in the brain, promote neurogenesis and increase the synthesis and release of the catecholamine neurotransmitters norepinephrine and dopamine. DHEA is widely used in Western medicine to self-treat decline in cognitive functioning associated with normal aging. 

What Does the Research Have to say About DHEA and Cognitive Function?

Many studies have reported improvements in working memory, visual awareness, visuomotor dexterity and attention in healthy adults in response to DHEA. These beneficial effects may be mediated by DHEA-induced cortical plasticity that enhances neural processes underlying visual attention. However, research findings on the effects of DHEA on memory in healthy and cognitively impaired adults are inconsistent. DHEA may improve memory in elderly patients who have low DHEA serum levels more than in younger adults with normal DHEA levels. 

In a small human clinical trial (N=10) adult males administered DHEA 500mg experienced significant increases in rapid eye movement (REM) sleep soon following sleep onset. This finding suggests that neurosteroid changes in the brain induced by DHEA have effects on GABA (Gamma-aminobutyric acid). In fact, DHEA binds to both γ-aminobutyric acid (GABA) receptors and N-methyl-D-aspartate (NMDA) receptors, however, it is not clear whether these receptor affinities are related to its cognitive-enhancing effects. 

A systematic review and meta-analysis found no support for DHEA as a cognitive enhancer in healthy older individuals. The significance of findings was limited by the fact that only three studies met inclusion criteria, all studies reviewed were 3 months in duration or shorter, and doses tested ranged between 25 and 50 mg only. A separate systematic review and meta-analysis found that individuals with Alzheimer’s Disease had consistently low serum DHEA-S levels but normal DHEA levels. The authors argue that this finding is consistent with the role of DHEA as a substrate for DHEA-S synthesis and that activity of sulfatase or other molecular mechanisms of DHEA-S bioconversion may be impaired in individuals with Alzheimer’s Disease. A decline in serum DHEA-S levels may be associated with different stages of progression or levels of severity of Alzheimer’s Disease, such that lower DHEA-S levels predispose to more severe cognitive impairment. Further studies are needed to determine whether DHEA-S levels provide a reliable diagnostic tool for Alzheimer's Disease risk. 

In a 6-month randomized placebo-controlled study unmedicated male patients with Alzheimer’s Disease were randomized to DHEA alone (50 mg twice daily) vs placebo. At 3 months the DHEA group showed a trend toward superior cognitive performance compared to the placebo group which persisted until the end of the study. In a small 4-week open study, 7 individuals with multi-infarct dementia who received daily intravenous administration of 200 mg DHEA-S exhibited significant increases in serum and CSF levels of DHEA-S, improvements in activities of daily living and less frequent emotional disturbances. The significance of the findings of both studies is limited by their small size. 

Lower circulating testosterone levels in older men are associated with an increased risk of developing Alzheimer’s Disease. In a 6-month double-blind, placebo-controlled study, 16 males with Alzheimer’s Disease and 22 healthy adult males were randomized to receive testosterone 75 mg (in the form of a dermal gel) versus placebo together with their usual medications. Global quality of life improved in both the demented group and healthy controls. No significant group differences were found at the end of the study however mildly demented patients who received testosterone experienced less decline in visuospatial abilities.

Side Effects and Safety Concerns of DHEA and Testosterone

Exogenous DHEA and testosterone are associated with safety concerns. Mild insomnia is an infrequent side effect of DHEA, which should be dosed in the morning. It is prudent to avoid DHEA when there is a history of benign prostatic hypertrophy or prostate cancer. Testosterone supplementation may increase the risk of cardiovascular disease, stroke, and prostate cancer. It is prudent to consult with your physician before starting DHEA or testosterone.

A Promising Start but More studies are Needed

Large prospective placebo-controlled studies are needed to further characterize the potential cognitive-enhancing effects of DHEA in both healthy individuals and individuals with Alzheimer’s Disease or multi-infarct dementia to determine safe, optimal dosing strategies.

References:

  1. Martínez-Mota, L., Relationship between androgen deficiency and memory impairment in aging and Alzheimer’s disease. Actas Esp Psiquiatr, 2017. 45(5): p. 227-47.
  2. Friess, E., et al., DHEA administration increases rapid eye movement sleep and EEG power in the sigma frequency range. American Journal of Physiology-Endocrinology And Metabolism, 1995. 268(1): p. E107-E113.
  3. Nguyen, T.-V., et al., Dehydroepiandrosterone impacts working memory by shaping cortico-hippocampal structural covariance during development. Psychoneuroendocrinology, 2017. 86: p. 110-121.
  4. Evans, J.G., et al., Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people. Cochrane Database of Systematic Reviews, 2006(4).
  5. Pan, X., et al., Dehydroepiandrosterone and dehydroepiandrosterone sulfate in Alzheimer’s disease: a systematic review and meta-analysis. Frontiers in aging neuroscience, 2019. 11: p. 61.
  6. Wolkowitz, O.M., et al., DHEA treatment of Alzheimer’s disease: a randomized, double-blind, placebo-controlled study. Neurology, 2003. 60(7): p. 1071-1076.
  7. Azuma, T., et al., The effect of dehydroepiandrosterone sulfate administration to patients with multi-infarct dementia. Journal of the neurological sciences, 1999. 162(1): p. 69-73.
  8. Lv, W., et al., Low testosterone level and risk of Alzheimer’s disease in the elderly men: a systematic review and meta-analysis. Molecular neurobiology, 2016. 53(4): p. 2679-2684.
  9. Ford, A.H., et al., Sex hormones and incident dementia in older men: The health in men study. Psychoneuroendocrinology, 2018. 98: p. 139-147.
  10. Lu, P.H., et al., Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Archives of neurology, 2006. 63(2): p. 177-185.
  11. Sheridan, PJ. Androgen receptors in the brain: what are we measuring? Endocr Rev. 1983;4(2):171-8.

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