DHEA-S

DHEA-S is the sulfated form of DHEA.  Unless indicated otherwise, the discussion of DHEA in this article includes DHEA-S.  

As both an adrenal and a sex hormone, Dehydroepiandrosterone (DHEA) emerges as a vital player in the world of hormone balance.  As with all hormones, healthy DHEA levels are all about balance.   

As an adrenal hormone, DHEA plays a role in anabolic processes such as energy production; cell repair; bone, brain and muscle health; and immune function.  Its ability to convert into androgenic and estrogenic hormones demonstrates additional functions in reproduction, libido and sexual response, mood regulation, sleep, and more.   

It is important to understand the nuanced interplay between DHEA levels and health outcomes, to elucidate the symptoms of imbalanced DHEA levels and appropriate testing for DHEA levels.   Then, one can unlock avenues for optimization through natural interventions and targeted supplementation.

What is DHEA-S?

DHEA-S is the sulfated form of DHEA.  The overwhelming majority of circulating DHEA in the blood is the sulfated form, DHEA-S.  Its actions are very similar to DHEA, although some of its mechanisms, or how it performs those actions, are different.  [19.]  Additionally, because it binds more strongly to its carrier protein albumin, DHEA-S has a longer half-life and it does not exhibit the same diurnal variations that cortisol and DHEA do.  [9., 20.]

Because of its longer half-life, DHEA-S serves as a reliable marker of adrenocortical activity and chronic stress levels, offering insight into long-term stress accumulation.  In contrast, DHEA levels may provide a glimpse into the body's immediate response to acute stressors. By assessing DHEA-S levels, we gain valuable insight into the systemic biological reservoir of DHEA within the body.

Dehydroepiandrosterone (DHEA) is a steroid hormone primarily produced by the adrenal glands, though it is also synthesized in smaller quantities by the ovaries, testes, and brain. Considered the most abundant steroid hormone in the human body, DHEA serves as a precursor to both androgens and estrogens, including testosterone and estradiol. 

Dehydroepiandrosterone (DHEA) is primarily produced from cholesterol, a precursor molecule synthesized by the body. Cholesterol undergoes a series of enzymatic reactions in the adrenal glands, where it is converted into pregnenolone. Pregnenolone is then further metabolized to form DHEA through a sequence of enzymatic steps. 

This process primarily occurs in the zona reticularis, the innermost layer of the adrenal cortex, although smaller amounts of DHEA are synthesized in other tissues such as the ovaries, testes, and brain.

When it enters circulation, most DHEA will be sulfated by the liver, meaning that a sulfur group is added to the DHEA molecule; this is DHEA-S.  

DHEA-S levels peak around the mid-twenties and gradually decline to approximately 20% by age 70. Unfortunately, there are no feedback mechanisms to restore DHEA levels once they begin to decrease. 

As DHEA-S and its downstream metabolites decline the brain loses the protective effects of sex steroids, becoming more susceptible to the neurotoxic effects of cortisol and other damaging factors. This decline in DHEA-S levels leads to a constant cortisol level, resulting in an elevated cortisol/DHEA-S ratio.  [5.] 

The imbalance between high cortisol and low DHEA-S levels can create adverse conditions for the hippocampus, potentially contributing to neurodegenerative diseases. Brain imaging studies have shown a close association between decreased DHEA-S levels and reduced hippocampal function in Alzheimer's disease.  [16.]

What Does DHEA-S do?

DHEA-S has many health and wellness benefits.  Some of its main functions include:

Precursor to sex hormones: DHEA-S serves as a precursor to both androgens (such as testosterone) and estrogens (such as estradiol), playing a vital role in reproductive health and sexual development and contributing to the pool of available anti-aging hormones.

Hormonal balance: DHEA-S helps maintain hormonal equilibrium by modulating the activities of other hormones, including cortisol, androstenedione, and progesterone.

Metabolism: DHEA-S influences metabolism by promoting fat breakdown, enhancing insulin sensitivity, and supporting glucose utilization, thereby affecting energy production and storage.  [10., 15. ]

Immune function: DHEA-S has immunomodulatory effects, regulating the activity of immune cells and cytokines to support immune responses and protect against infections.  [3.]

Brain function: DHEA plays a role in cognitive health and mental well-being, with potential effects on memory, mood regulation, and neuroprotection. [29.]

Bone density: DHEA-S contributes to bone health by stimulating osteoblast activity and collagen synthesis, thereby maintaining bone density and strength.  [13.]

Anti-aging effects: DHEA has been associated with anti-aging properties, including its potential to enhance skin health, improve muscle mass and strength, and support overall vitality and longevity.  [25.]

Role in Hormonal Balance

DHEA-S, the sulfated form of DHEA, is the most abundant steroid hormone in the body, and a precursor to both androgens and estrogens including testosterone and estradiol, so it can be considered a “prohormone pool” from which the body can make more androgens and estrogens in times of depletion. 

DHEA exerts a modulating influence on various hormonal pathways. In addition to its function as an androgen and estrogen prohormone, it helps regulate the synthesis and metabolism of other hormones including pregnenolone, often considered “the mother hormone” because it is the first steroid hormone produced from cholesterol.  [17.]

 By acting as a buffer against the effects of stress and aging, the effects of DHEA can counterbalance the activity of cortisol, the body's primary stress hormone.  This intricate interplay between DHEA-S and other hormones underscores its significance in maintaining optimal health and well-being.

How is DHEA-S Metabolized, or Used, in the Body?

DHEA-S is taken up by local tissues and metabolized into other steroid hormones including estrogen and testosterone.  DHEA-S has its own functional properties, and also exerts its effects through its metabolite steroid hormones.  [25.]

Testing Methods and Clinical Utility:

Laboratory Testing Procedures:

DHEA-S is commonly tested in blood, although saliva and urine tests are also widely available.  Each has its benefits and drawbacks:

Blood Testing:  [1.]

Blood testing for DHEA involves collecting a blood sample from a vein in the arm, typically in the morning when DHEA levels are highest. The sample is then sent to a laboratory for analysis. Blood testing offers a direct measurement of circulating DHEA-S levels, providing a comprehensive assessment of hormonal status.

It is important to understand that serum tests assess levels of DHEA-S, or the sulfated form of DHEA, in the blood. 

The secretion rate of DHEA-S into the bloodstream is only slightly higher than that of DHEA. However, due to its longer half-life of approximately one day, DHEA-S levels are approximately a thousand-fold higher. 

DHEA-S predominantly binds to albumin, with only a small fraction being unbound to proteins and none bound to sex hormone-binding globulin (SHBG). 

Because of its high concentration and minimal variability, DHEA-S serves as an excellent indicator of adrenal cortex androgen production. Alongside testosterone, DHEA-S assays are preferred for initial screening tests to assess elevated androgen levels in hirsutism, with approximately 84% of affected women exhibiting elevated androgen levels. 

Benefits: Blood testing is considered the gold standard for assessing DHEA-S levels, offering accurate and reliable results with a relatively simple sample process. It allows for precise quantification and enables healthcare providers to monitor changes in hormone levels over time.

Drawbacks: Blood testing via venipuncture can be invasive and uncomfortable for some individuals.  Additionally, DHEA levels reported in blood testing do not always differentiate between free and bound hormones, which may be misleading for clinicians when patients present with symptoms of DHEA deficiency with normal blood test results.  

Saliva Testing:

In contrast to serum samples, saliva testing may assess DHEA and/or DHEA-S levels, although DHEA-S levels are preferred due to their stability and higher concentration in saliva.  [5.]  Saliva testing involves collecting a saliva sample using a swab or collection device. [26.]

Saliva testing is often preferred for assessing bioavailable (free) hormone levels, as it reflects the active fraction of hormones available at local tissue levels. 

‍Benefits: Saliva testing is non-invasive and easy to perform, making it convenient for patients. It provides a snapshot of bioavailable DHEA levels, which may offer insights into hormone activity at the tissue level.

Because of the stability of steroid hormones in saliva samples, the timing of sample retrieval may matter less than with blood testing.  [11.]

Drawbacks: Saliva testing may be less accurate than blood testing for quantifying total DHEA levels. Factors such as oral contamination and variability in saliva flow rates can affect test results. Standardization of saliva testing protocols is essential to ensure consistency and reliability.

Urine Testing:

Urine testing involves collecting a urine sample, typically over a 24-hour period, to assess DHEA-S levels.  Urine testing captures free, or unbound, hormones, which are bioavailable.   Because urine testing highlights the metabolites of steroid hormones, it can demonstrate a more comprehensive picture of hormone production and breakdown. 

Benefits: Urine testing offers a non-invasive and convenient method for assessing overall DHEA-S production and clearance. It provides information on DHEA-S metabolism and can be useful for evaluating long-term hormone balance.  It also offers insight into the dynamic balance between steroid hormones. 

Drawbacks: Urine testing may be less sensitive than blood testing for detecting subtle changes in DHEA levels. It requires proper collection and handling of urine samples to ensure accuracy, and results may be influenced by factors such as hydration status and kidney function.

Interpretation of Results and Clinical Relevance

The interpretation of DHEA test results depends on various factors, including the testing method used, reference ranges provided by the lab, and individual patient characteristics. In general, higher DHEA levels may indicate increased adrenal gland activity or supplementation, while lower levels may suggest adrenal insufficiency or aging-related decline.

Clinically, DHEA testing is often used to assess adrenal function, diagnose adrenal disorders such as adrenal insufficiency or adrenal hyperplasia, and monitor hormone replacement therapy. 

However, it's essential to interpret DHEA test results in the context of the patient's clinical presentation, medical history, and other hormone levels. Additional testing and clinical evaluation may be necessary to confirm diagnosis and guide treatment decisions.

High DHEA-S Levels

Signs and Symptoms of Elevated DHEA-S

Signs and symptoms of high DHEA-S levels may include:

• Excessive hair growth (hirsutism), particularly on the face, chest, back, or abdomen
• Acne or oily skin
• Male-pattern baldness or hair thinning in women
• Irregular menstrual periods or absent periods (amenorrhea)
• Deepening voice
• Enlarged clitoris (clitoromegaly) in females
• Increased muscle mass
• Mood changes, such as irritability or aggression
• Insulin resistance and weight gain
• Decreased breast size in females

Causes of High DHEA-S Levels

High DHEA-S can occur due to pathology, or disease, as well as from functional causes.  Some causes of high DHEA-S include: 

Adrenal tumors: Adrenal tumors, such as adrenal adenomas or adrenal carcinomas, can lead to excess production of DHEA and other androgens.

Polycystic ovary syndrome (PCOS): PCOS is a common hormonal disorder characterized by enlarged ovaries with multiple small cysts. It often results in elevated levels of androgens, including DHEA.

Congenital adrenal hyperplasia (CAH): CAH is a group of genetic disorders that affect the adrenal glands' ability to produce cortisol and aldosterone. It can lead to overproduction of androgens, including DHEA.

Adrenal hyperplasia: Adrenal hyperplasia refers to the excessive growth of adrenal tissue, which can result in increased production of adrenal hormones, including DHEA.

Medications: Certain medications, such as corticosteroids or androgenic steroids, can lead to elevated DHEA levels as a side effect.  Over-supplementation of DHEA can also cause elevated levels.  

Rare disorders: Rare conditions, such as Cushing's syndrome or androgen-secreting tumors outside the adrenal glands (e.g., ovarian or testicular tumors), can also cause high DHEA levels.

Stress: acute stress can cause an elevation in DHEA levels; studies have shown that chronic stress may cause an increase or a deficiency in DHEA over time.  [6., 14.]

Management of High DHEA-S Levels in Females

PCOS is a common cause of elevated DHEA-S levels in women, although CAH or an adrenal tumor are less-common causes.  

Polycystic ovary syndrome (PCOS) is a hormonal disorder characterized by imbalanced hormone levels, including elevated androgens (such as testosterone) in women of reproductive age. It often leads to irregular menstrual cycles, ovarian cysts, and symptoms like acne, hirsutism (excess hair growth), and infertility.

Due to the complex interactions between hormones and metabolism, PCOS is often accompanied by metabolic issues including insulin resistance, which predisposes individuals to a higher risk of type 2 diabetes and metabolic syndrome.

Many women with PCOS who have high androgens including elevated DHEA levels benefit from foundational treatments including diet and lifestyle modifications, and targeted supplement or medication therapy, to restore hormone balance.  

Diet:

• Emphasize a low-glycemic index diet rich in whole grains, fruits, vegetables, and lean proteins to help regulate blood sugar levels.
• Incorporate healthy fats such as omega-3 fatty acids found in fish, flaxseeds, and walnuts to support hormone balance.
• Limit intake of refined carbohydrates, sugary foods, and processed snacks to manage insulin resistance.
• The Mediterranean diet and ample hydration have shown benefit for women struggling with PCOS.  [27.]

Lifestyle:

• Engage in regular physical activity, including both aerobic exercises and strength training, to improve insulin sensitivity and support weight management.  [18., 27.]
• Prioritize stress management techniques such as yoga, meditation, deep breathing exercises, or mindfulness practices to reduce cortisol levels and mitigate stress-induced hormonal imbalances.  [2.]
• Ensure adequate sleep hygiene with consistent sleep schedules and sufficient rest to optimize hormonal regulation and overall well-being.

Supplements:

• Consider supplementation with inositol, a B-vitamin-like compound, which has shown promising results in improving insulin sensitivity and ovarian function in women with PCOS.  [22.]
• NAC (N-acetyl cysteine)  supplementation may help reduce inflammation, support metabolic health, and restore ovulation.  [21.]
• Vitamin D supplementation, if deficient, may be beneficial for improving insulin sensitivity and menstrual regularity in women with PCOS.  [12.]

Medications:

• Metformin, commonly prescribed for PCOS, helps improve insulin sensitivity, regulate menstrual cycles, and may aid in ovulation induction, particularly in women with insulin resistance or metabolic dysfunction.

It is important to consult a healthcare provider prior to initiating supplement or medication therapy for high or low DHEA levels.

Low DHEA-S Levels

Manifestations of DHEA-S Deficiency

DHEA plays a pivotal role in various physiological functions, but its levels naturally decline with age. Manifestations of DHEA deficiency can encompass a range of symptoms reflecting its influence on hormone balance and overall well-being.

Symptoms Associated with DHEA-S Deficiency:

• Fatigue and decreased energy levels
• Mood disturbances, including depression and anxiety
• Reduced libido and sexual dysfunction
• Impaired memory and cognitive function
• Muscle weakness and loss of muscle mass
• Weight gain, particularly around the abdomen
• Dry skin and hair, brittle nails
• Insulin resistance and impaired glucose metabolism
• Increased susceptibility to infections and immune dysfunction
• Irregular menstrual cycles and fertility issues (in women)
• Decreased bone density and increased risk of osteoporosis
• Accelerated aging and compromised stress resilience

Note: While DHEA levels naturally decline along the lifespan, individuals experiencing symptoms of deficiency should consult healthcare professionals for proper evaluation and management.

Strategies for Addressing Low DHEA-S Levels in Females

Strategies for addressing low DHEA levels in women should involve a multifaceted approach aimed at optimizing overall hormone balance and supporting adrenal function.  Diet, lifestyle, and supplementation are all potential factors that can promote healthy DHEA levels in women.  

Diet:

• Consume a nutrient-dense diet rich in whole foods, including fruits, vegetables, lean proteins, and healthy fats, to provide essential nutrients for hormone synthesis.
• Incorporate foods high in specific nutrients beneficial for adrenal health, such as zinc, magnesium, vitamin B5 (pantothenic acid), and vitamin C.
• Limit intake of processed foods, refined carbohydrates, and sugars to help regulate blood sugar levels and reduce inflammation.

Lifestyle:

• Regular physical activity, including both aerobic exercises and strength training, can increase DHEA-S levels in women.  [7.]
• Prioritize stress management techniques such as meditation, yoga, deep breathing exercises, or relaxation techniques to reduce cortisol levels and support adrenal function.
• Ensure adequate sleep duration and quality to promote hormonal balance and overall well-being.

Supplements:

• Consider supplementation with adaptogenic herbs such as ashwagandha, rhodiola, or licorice root, which may help regulate cortisol levels and support adrenal function.
• DHEA is available as a supplement, although this should be used only under the guidance of a licensed medical professional.  

Consult with a healthcare professional before starting any supplementation regimen to ensure safety and efficacy, especially if there are underlying health conditions or medication interactions.

DHEA-S and Weight Loss for Women

DHEA, a precursor hormone produced by the adrenal glands, has been implicated in weight management and metabolism in women. 

While research on the direct relationship between DHEA levels and weight loss is limited, some studies suggest that DHEA supplementation may promote reductions in abdominal body fat and improvements in body composition by enhancing metabolic rate and insulin sensitivity. [23., 24.]  Specifically, resistance training may offer the most benefit.  [4.]

However, individual responses to DHEA supplementation vary, and its efficacy as a standalone weight loss aid remains inconclusive. It's important for women considering DHEA supplementation for weight management to consult with a healthcare professional to determine its appropriateness and ensure safe and effective use.

Optimizing DHEA Supplementation

What Type of DHEA Should I Take?

DHEA is available as an over the counter supplement, although it is important to note that  DHEA is banned for use by the National Collegiate Athletic Association, the International Olympic Committee, and the World Anti-Doping Agency (WADA) because of its androgenic effects.

Different types of DHEA supplements are available: DHEA, DHEA-S (the sulfated form of DHEA), and 7-keto DHEA.  

DHEA vs. DHEA-S

DHEA-S is the sulfated form of DHEA.  When it comes to which supplement to take, DHEA or DHEA-S, there is probably not much difference between the two because oral DHEA supplements are readily sulfated in the liver to DHEA-S via first-pass metabolism.  Both forms contribute to the overall prohormone pool in the body, and may contribute to raising levels of DHEA-S, estrogen, and testosterone in the blood.  

7-Keto DHEA

7-keto DHEA is a metabolite of DHEA, and it is also available as an oral supplement.  It’s been marketed as a weight loss supplement, although research is mixed regarding its ability to stimulate weight loss.  [8.]

Unlike DHEA and DHEA-S, 7-Keto DHEA does not convert into steroid hormones such as testosterone and estrogen. Along with its purported benefits on metabolism, It's also thought to enhance memory and boost the immune system. As we age, the levels of 7-Keto DHEA in our bodies decrease.

Dosage Recommendations and Timing

Dosage recommendations for DHEA-S vary widely, and depend on many factors including age, sex, and health status.  Dosages tend to start at 5 mg orally and may go as high as 100-200 mg daily.  Because DHEA-S is a hormone that can have many downstream effects, it is essential to work with a healthcare professional who can utilize appropriate testing and assessment to determine the best dose for an individual.  

There is controversy regarding the best time of day to take DHEA-S supplements.  Because DHEA-S is an adrenal hormone, and adrenal glands tend to make the most hormones in the morning, taking DHEA-S in the morning mimics the body’s natural hormonal rhythm and may be preferred.  However, it should be noted that some research studies recommend nighttime dosing of DHEA-S.  [28.]