Quick Summary: DHEA and DHEA-S are the most abundant steroid hormones in the human body and act as neurosteroids — protecting the brain, regulating mood, and supporting cognitive function. Their levels decline with age, making testing and monitoring clinically important. This article explains the biochemical difference between the two, how they work in the nervous system, and what different administration routes mean for testing.
Originally authored by Dr. Kate Placzek, ZRT Laboratory. Reproduced with permission.
Everything we do, feel, think – it all starts with the brain. A balanced, healthy brain helps lay the essential foundation for optimal wellbeing. A small but significant aspect of brain health is regulated by a specific class of steroid molecules called neurosteroids.
That the brain is a steroidogenic organ is widely accepted, and neurosteroids are woven into its very fabric. The term "neurosteroid" refers to cholesterol-derived steroid compounds that play critical roles in the nervous system — its development, maintenance and survival. "Neurosteroids: of the nervous system, by the nervous system, for the nervous system" as Baulieu said a decade and a half following the remarkable discovery of the very first neurosteroid — DHEA-S.
As the levels of DHEA and DHEA-S decline with age, the brain loses their protective properties and becomes more sensitive to the ravages of neurological decline. This article focuses on DHEA and its sulfated form DHEA-S and their relevance to brain health.
What Is DHEA and Why Does It Matter?
Dehydroepiandrosterone (DHEA) is plentiful in the human body — together with its sulfated form (DHEA-S), DHEA comprises the most abundant form of steroid hormones. The average concentration of DHEA(S) in the bloodstream is about 10,000 times higher than the most potent estrogen, estradiol. Derived from cholesterol, DHEA is produced by the adrenal glands, brain, ovaries and testes, and is a precursor for the major sex steroids (oestrogen, progesterone, and testosterone). Sometimes called the "anti-aging hormone," supplementation with DHEA to mid-normal physiologically youthful levels appears to engender a sense of wellbeing.
DHEA(S) levels peak around the mid-twenties and gradually decrease to around 20% by age 70. Once DHEA levels begin to decline, there are no feedback mechanisms to help restore it. As DHEA and downstream metabolites decrease, the brain loses the protective effects of sex steroids and becomes increasingly vulnerable to the neurotoxic effects of cortisol. With declining DHEA(S) levels, cortisol levels remain constant, resulting in an increased cortisol/DHEA(S) ratio — a ratio closely associated with decreased hippocampal function in Alzheimer's disease.
This is why DHEA is commonly prescribed to patients presenting with low androgen symptoms in combination with low circulating DHEA-S and/or low testosterone levels. DHEA replacement therapy can impede the ravages of ageing — adequate levels help ramp up downstream sex steroids, enhance stress adaptation, increase libido, improve body fat ratio, and boost the immune system. However, it is important to monitor sex steroid hormones as well as DHEA-S during supplementation, as too much DHEA can have its own set of distressing symptoms.
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Low Androgen Symptoms
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High Androgen Symptoms
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Why Measure DHEA-S Rather Than DHEA?
At ZRT Laboratory, we test for DHEA-S — the sulfated form of DHEA. Approximately 98% of circulating DHEA in the bloodstream is the sulfated form (DHEA-S). DHEA-S binds more strongly to albumin, its carrier protein, than DHEA, contributing to slower metabolic clearance from circulation. In addition to the longer biological half-life, DHEA-S does not exhibit a strong diurnal rhythm as seen with cortisol and DHEA, nor does it vary significantly from day to day.
DHEA-S represents a more stable index of adrenocortical activity and stress accumulated over time, whereas DHEA may better reflect the response to acute stressors. When we measure DHEA-S, we gain an understanding of the body's systemic biological reservoir of DHEA.
All of the above reasons make DHEA-S the ideal molecular testing candidate. You can test your DHEA-S levels at home with our saliva hormone tests or dried blood spot tests. For a comprehensive adrenal and stress hormone picture including DHEA-S and cortisol, our Adrenal Function Saliva Test Kit (LCMS) is an excellent starting point.
DHEA(S) and the Central Nervous System
For many years, DHEA was regarded as inactive and merely a forerunner of androgens and oestrogens in the periphery. However, more recent evidence reveals DHEA not just as a pro-hormone, but as an active hormone in its own right. Both DHEA and DHEA-S are now recognised for regulating a myriad of biological processes, with a remarkable tropism especially for the central nervous system. Both hormones modulate neurotransmitter synthesis and release, immunity and inflammation, endothelial and cognitive function, and neurogenesis and neuronal survival.
Independent of age, serum levels of DHEA-S appear to be positively correlated with healthier psychological profiles — executive function, working memory, attention, concentration, enjoyment of leisure activities and overall stress-buffering effect. Imbalance in the DHEA pool tends to be associated with distress and psychopathology, such as depression, anxiety, bipolar disorder, eating disorders, PTSD and perceived stress. Specifically, DHEA-S levels are inversely correlated with hyperactivity, suggesting a possible protective role in the aetiology of ADHD.
Mechanisms of Action: How DHEA and DHEA-S Work in the Brain
"Typical" steroid molecules (such as oestradiol, testosterone and progesterone) modulate their effects by entering target cells, binding to their receptors and initiating cascades that either activate or inhibit the expression of various downstream proteins. Neurosteroids work in a slightly different fashion.
DHEA and DHEA-S act directly on neurotransmitter systems to regulate synaptic transmission. Specifically, these neurosteroids modulate neuronal excitability by directly interacting with neurotransmitter systems, such as dopamine, serotonin, glutamate, and GABA. If you are concerned about how your hormone levels may be affecting your neurotransmitter balance, our Neurotransmitter Test Kit (LCMS) measures key neurotransmitters alongside adrenal markers.
DHEA and DHEA-S bind to and both activate and modulate the NMDA glutamate receptor, potentiate dopamine and serotonin signalling, and inhibit GABA-A receptor activity. In essence, DHEA(S) helps keep excitatory neurons firing properly — maintaining the right balance without tipping into excess.
➡️ Related: Learn more about Neurotransmitters and how they affect your health
DHEA vs DHEA-S: Same But Different
Both molecules can stimulate dopamine release — the neurotransmitter well-known as the brain's "pleasure centre." However, the paths to raise dopamine differ. DHEA-S uses genomic, slow, long-lasting mechanisms by upregulating tyrosine hydroxylase levels, the enzyme responsible for dopamine production. DHEA, on the other hand, signals to increase dopamine levels in rapid, intense, short-lived bursts.
DHEA Administration Routes and What They Mean for Testing
Topical DHEA
When administered topically, DHEA restores skin elasticity, relieves symptoms of vaginal dryness and atrophy, and generally improves many low-androgen symptoms. The caveat with topical DHEA administration is that it does not undergo first-pass metabolism through the liver (no liver passage — no sulfation), so although a subsequent increase in salivary and blood spot DHEA is observed, DHEA-S levels remain unchanged. Animal studies show that with topical DHEA treatment, the unsulfated DHEA crosses into the brain and gives rise to DHEA-S on site. If low androgen symptoms persist with topical DHEA treatment, switching to oral dosing may prove more effective.
Oral DHEA
With oral DHEA administration, we see a substantial spike in DHEA-S levels in all commonly tested body fluids (serum, saliva, urine, and blood spot), as it undergoes first-pass metabolism and gets sulfated. Once DHEA becomes sulfated to DHEA-S, it is unable to cross the blood-brain barrier (DHEA is non-polar and crosses easily; DHEA-S is polar and does not). It is plausible that DHEA-S arising from first-pass metabolism after oral DHEA administration contributes to the body's biological reservoir of DHEA, readily converting to DHEA when needed. To monitor DHEA-S levels across all body fluids during oral supplementation, our All Day Cortisol Test (LCMS) can help track the cortisol/DHEA-S ratio throughout the day.
Troche (Sublingual) DHEA
Troche (sublingual) DHEA goes directly into the bloodstream and, because it is not sulfated, crosses directly into the brain and other tissues. Some patients are particularly sensitive even to small amounts (5 mg) of DHEA administered this way — with agitation being a common side effect. In this case, taking DHEA orally could have a more gentle uplifting effect on wellbeing.
Clinical Utility of Neurosteroids
Since the discovery of neurosteroids in the early 1980s, significant efforts have been poured into studying the role they play in brain-related disorders. Gleaning insight into the mechanisms that underlie neurosteroid involvement in mood pathologies may extend their clinical utility to treatment of mood and anxiety disorders, alcoholism, sleep disorders, chronic pain, traumatic brain injury, neurodegenerative disorders and many others. Overall, DHEA is well-poised in clinical development for its therapeutic potential in helping the ageing brain retain its regenerative capacity.
Test Your DHEA-S Levels at Home
If you are concerned about your DHEA-S levels or experiencing symptoms of androgen imbalance, at-home hormone testing offers a convenient and accurate way to gain insight. Explore our most relevant tests:
- Adrenal Function Saliva Test Kit (LCMS) — measures DHEA-S and cortisol across the day; ideal for assessing adrenal reserve and the cortisol/DHEA ratio
- Neurotransmitter Test Kit (LCMS) — measures dopamine, serotonin, GABA, glutamate and more; ideal if mood, focus or sleep are affected
- All Day Cortisol Test (LCMS) — 4-point diurnal cortisol profile to assess the cortisol/DHEA-S ratio and stress burden over time
- Men All-In-One Test – Hormones, Neurotransmitters & Heavy Metals — comprehensive panel covering DHEA-S, sex hormones, neurotransmitters and more
- Women All-In-One Test – Hormones, Neurotransmitters & Heavy Metals — comprehensive panel for women covering DHEA-S, sex hormones, neurotransmitters and more
Frequently Asked Questions About DHEA and DHEA-S
What is the difference between DHEA and DHEA-S?
DHEA (dehydroepiandrosterone) and DHEA-S (DHEA-sulphate) are two forms of the same hormone. DHEA-S is the sulfated, more stable form that circulates in the bloodstream at much higher concentrations. DHEA-S has a longer half-life and does not fluctuate throughout the day, making it the preferred marker for clinical testing.
Why do DHEA and DHEA-S levels decline with age?
DHEA(S) production peaks in the mid-twenties and declines progressively with age, reaching approximately 20% of peak levels by age 70. Unlike cortisol, there is no feedback mechanism to restore DHEA levels, which is why the cortisol-to-DHEA ratio becomes increasingly imbalanced as we age.
Can low DHEA-S affect mood and brain function?
Yes. Low DHEA-S levels are associated with depression, anxiety, ADHD, PTSD, and cognitive decline. DHEA-S acts directly on neurotransmitter systems including dopamine, serotonin, glutamate, and GABA, making it a key regulator of mood and neurological health.
How can I test my DHEA-S levels?
You can test your DHEA-S levels at home using a saliva or dried blood spot test kit. Hormone Lab UK offers a range of hormone balance tests that include DHEA-S measurement alongside other key markers. Our Adrenal Function Saliva Test Kit (LCMS) is the most targeted option for DHEA-S and cortisol assessment.
Does topical DHEA raise DHEA-S levels?
No. Topical DHEA bypasses first-pass liver metabolism, so it does not get sulfated. This means salivary and blood spot DHEA levels rise, but DHEA-S levels remain largely unchanged. Oral DHEA, by contrast, undergoes sulfation in the liver and raises DHEA-S levels in all body fluids.
Hormone Lab UK is an official test provider of ZRT Laboratory.