DHEA

DHEA - dehydroepiandrosterone or prasterone (INN) - is the most common steroid hormone in humans.
DHEA is the precursor for both male (androgens) and female (estrogens) sex hormones. The effect of DHEA is very gender-specific.

DHEA and cortisol are both mainly produced in the adrenal cortex:¹

• DHEA:
  • Zona reticularis (inner layer) of the adrenal cortex
    • Men: 100 %
    • Women: 70 %
  • Ovaries
    • Women: 30 %
  • Testicles
    • Men: low proportion
  • Glial cells in the brain
    • Low proportion
• Cortisol
  • Zona fasciculata (broad middle layer) of the adrenal cortex

While cortisol is a catabolic hormone, DHEA is an anabolic hormone.
Unlike for cortisol, no specific DHEA or DHEA sulphate receptors have yet been found.

• 1. Development of DHEA
  • 1.1. DHEA by age and gender
  • 1.2. DHEA according to daily rhythm
• 2. Absorption of DHEA
• 3. Effect of DHEA
  • 3.1. Effect of DHEA in healthy people
    • 3.1.1. Effects in the body
    • 3.1.2. Effect in the brain
      • 3.1.2.1. DHEA and dopamine
      • 3.1.2.2. DHEA as an agonist
      • 3.1.2.2. DHEA as an antagonist
  • 3.2. Effect on diseases / disorders
    • 3.2.1. Disorders with DHEA deficiency
      • 3.2.1.1. ADHD
      • 3.2.1.2. Stress
        • 3.2.1.2.1. DHEA stress response
        • 3.2.1.2.2. DHEA/cortisol imbalance during stress
        • 3.2.1.2.2.1. Mechanisms of action of cortisol and DHEA/DHEA sulphate
        • 3.2.1.2.2.1.1. Genomic mechanisms (slow)
        • 3.2.1.2.2.1.1.1. Genomic mechanisms of cortisol
        • 3.2.1.2.2.1.1.2. Genomic mechanisms of DHEA and DHEA sulfate
        • 3.2.1.2.2.1.2. Non-genomic effects (fast)
        • 3.2.1.2.2.1.2.1. Non-genomic mechanisms of cortisol
        • 3.2.1.2.2.1.2.2. Non-genomic mechanisms of DHEA/DHEA sulfate
      • 3.2.1.3. Hypertension, cardiac allograft vasculopathy
      • 3.2.1.4. Helplessness, dissatisfaction with life
      • 3.2.1.5. Autoimmune diseases
      • 3.2.1.6. Disorders with unexplained indications of DHEA
    • 3.2.2. Disorders with excess DHEA
    • 3.2.3. When DHEA administration is helpful
      • 3.2.3.1. Adrenal insufficiency in women and men
      • 3.2.3.2. Melancholic (endogenous) depression
      • 5.2.3.3. Midlife dysthymia
      • 3.2.3.4. Fear
      • 3.2.3.5. Muscular dystrophy
      • 3.2.3.6. Erection problems
      • 3.2.3.7. Immunological and protective effect
      • 3.2.3.8. Disorders without improvement due to DHEA
        • 3.2.3.8.1. Perimenopause
        • 3.2.3.8.2. Alzheimer’s disease
• 4. Reduction of DHEA
• 5. Animal examinations not transferable
• 6. Hypothesis: Is DHEA more helpful in ADHD-I / melancholic depression than in ADHD-HI / atypical depression?
  • 6.1. Effects on cortisol stress response decisive?
  • 6.2. DHEA for melancholic depression, electroconvulsive therapy for atypical depression?
• 7. DHEA medication
• 8. Possible interactions of DHEA with other active substances
• 9. Measurement of DHEA

1. Development of DHEA¶

• DHEA is based on a molecular structure of 19 carbon atoms, i.e. it is a C19 steroid
• Cholesterol becomes pregnenolone
• Pregnenolone is metabolized by steroid 17α-hydroxylase (CYP17A1, P450c17) depending on the cell
  • To hydroxy-pregnenolone or to
  • DHEA.

1.1. DHEA by age and gender¶

DHEA is only significantly produced from the age of 6 to 10,² which (possibly purely coincidentally) is the age at which ADHD can be diagnosed. The DHEA level rises until around 25/30 years of age and continues to fall with increasing age, down to 10 to 20 % in old age.² At the beginning of puberty, DHEA or DHEA sulphate rises again sharply.¹ and reaches its highest level in early adulthood.³

DHEA/DHEA-S apparently plays a role in brain development ⁴⁵
This could build a bridge between DHEA deficiency, which is common in ADHD, and the brain developmental delay typically present in ADHD.

The decrease in DHEA that correlates with advancing age is not triggered by lower ACTH production. As the (indirect) cortisol response to ACTH does not decrease with age, this leads to a reduced DHEA/cortisol ratio with age.
Most sources report a higher or equally high basal DHEA level in women⁶ and a higher basal DHEA sulphate level⁶ in men. One source, however, reports a 10 to 20 % higher basal DHEA level in men compared to women.²

The ratio of the conversion of DHEA into male or female sex hormones depends on gender.
In men, DHEA primarily increases the level of oestrogen in the blood; in women, it primarily increases the level of androgen. In men, testosterone is produced in some tissues, but without increasing the testosterone level in the blood. Only increased testosterone degradation products are detectable.⁷

DHEA / DHEA sulphate levels vary greatly from individual to individual and can differ up to threefold in healthy people of the same age and sex, but are more stable than cortisol levels within an individual over a longer period of time.²

DHEA taken orally increases

• For women
  • Androstenedione⁸
  • Testosterone⁸
  • Dihydrotestosterone⁸
• For men
  • Estrone⁸
  • 17-ß-estradiol⁸
  • Androstenedione in Addison’s disease patients (primary adrenal insufficiency)⁹
  • Not testosterone⁸
  • Not dihydrotestosterone⁸

Androgens are lipophilic and non-polar and can therefore pass through the blood-brain barrier.¹⁰

1.2. DHEA according to daily rhythm¶

DHEA levels have the same circadian rhythm as cortisol, as DHEA is stimulated by ACTH, which also stimulates cortisol production within the HPA axis. ACTH also stimulates the formation of DHEA sulphate in the adrenal gland, although unlike DHEA, DHEA sulphate is not subject to a circadian rhythm.²⁶

It is possible that, contrary to previous opinion, DHEA in healthy people is subject to an awakening response (DAR) in the sense of a strong 8-fold increase in levels that occurs immediately upon waking, unlike the cortisol awakening response (CAR), which peaks around 40 minutes after waking. The DAR also appears to be an indicator of the restfulness of sleep.¹¹

2. Absorption of DHEA¶

DHEA sulphate would be largely destroyed by stomach acid if taken orally. It therefore makes sense to take DHEA alone.²
DHEA and DHEA sulfate are balanced by sulfotransferases and sulfatases.⁸ Arylsulfatase C (STS, estrone/dehydroepiandrosterone sulfatase; steroid sulfatase) is a sulfatase that converts DHEAS to DHEA. More on this under Sulfation and ADHD In the article* Dopamine degradation*. The STS gene is a gene candidate for ADHD.

3. Effect of DHEA¶

3.1. Effect of DHEA in healthy people¶

A double-blind placebo-controlled DHEA administration of 50 mg daily to 280 healthy people between 60 and 80 years of age over one year brought about improvements without significant side effects, especially in participants over 70 years of age.¹²

3.1.1. Effects in the body¶

• Reduction of “good” cholesterol (especially in women)⁷
• Antidiabetic results from animal studies were not reproducible in humans
  • No improvement in well-being in older healthy men⁷
  • No change in insulin sensitivity in humans (several studies on healthy participants of all ages)⁷
• Androgen effects on the skin and simultaneous estrogen effects on the vaginal mucosa in older postmenopausal women⁷
• Excess androgen effects in case of overdose in women (reversible)⁷
  • Hirsutism
  • Acne
  • Hair loss
• 25-50 mg DHEA / day⁷
  • Significant reduction in apolipoprotein A1 (only in women)
  • Significant reduction in HDL cholesterol (“good cholesterol”) (only in women)
• 50 mg DHEA / day:
  improved libido (especially in older women, hardly in men)¹²; different: no improvement in libido in a smaller test group.¹³
• 50 mg DHEA / nightly over 6 months¹³
  13 men and 17 women aged 40 to 70 years; randomized, placebo-controlled cross-over study:
  • DHEA and DS serum levels reached the levels of young adults within 2 weeks and maintained them during the intake
  • Increase in androgen serum levels in women by a factor of two
    • Androstenedione
    • Testosterone
    • Dihydrotestosterone
  • Slight increase in androstenedione in men
  • Unchanged levels in men and women of
    • Sex hormone-binding globulin
    • Estrone
    • Estradiol
  • Slight reduction in lipoprotein levels in women
  • No other lipid changes in men and women
  • Insulin sensitivity unchanged
  • Body fat percentage unchanged
  • Mean 24-hour GH and IGFBP-3 levels unchanged
  • IGF-I serum levels increased significantly
  • IGFBP-1 significantly reduced for men and women
    • Indicates increased bioavailability of IGF-I for target tissue
  • Increased mental well-being in men (67%) and women (84%)
  • Improved physical well-being
  • Libido unchanged
• 50 mg DHEA / day:
  slightly elevated levels of testosterone and estrogen (especially in older women)¹²
• 50 mg DHEA / day:
  slightly increased bone density (in women over 70)¹²
  • Mixed study results⁷
• 50 mg DHEA / day:
  Skin improvements (especially in older women)¹²
  • Less dried out
  • Thicker epidermis
  • Improved sebum production
  • Improved pigmentation
• 50 mg DHEA / day⁷
  • No reduction in HDL cholesterol (“good cholesterol”), even in men
  • No decrease in fat mass
  • No increase in muscle mass
• 100 mg DHEA / day⁷
  • Significant reduction in HDL cholesterol (“good cholesterol”), even in men
  • Slight decrease in fat mass (only in men)
  • Slight increase in muscle mass (only in men)
  • Increase in muscle strength (only in men)
• 100 mg DHEA / day¹⁴
  • Increased IGF-I level
  • Increased fat mass in men
  • Increased muscle strength in men
• 400 mg DHEA¹⁵
  • Reduced connectivity between amygdala and periamygdala
  • Reduced connectivity between amygdala and insula
  • Reduced connectivity between amygdala and precuneus
    • The latter was associated with reduced negative sentiment.
  • 400 mg pregnenolone, on the other hand, caused
    • Reduced connectivity between amygdala and dmPFC
    • Reduced connectivity between amygdala and precuneus
    • Reduced connectivity between amygdala and hippocampus.
• 500 mg DHEA / day⁷
  • Recurrence of a prostate carcinoma regressed by androgen suppression (individual case)
  • DHEA is therefore not recommended in cases of suspected hormone-dependent tumors such as
    • Breast cancer
    • Uterine cancer
    • Prostate cancer
• 1600 mg / day in healthy young men ⁷²
  • Significant fat loss
  • Significant decrease in LDL cholesterol (“bad cholesterol”)
  • Unchanged androgen concentration
• 1600 mg DHEA / day in (older) women after menopause⁷
  • Androgens increased tenfold
  • Drop in HDL cholesterol (“good cholesterol”)
  • Fat mass unchanged

3.1.2. Effect in the brain¶

3.1.2.1. DHEA and dopamine¶

• Increased dopamine production
  • Dopamine increase due to DHEA, DHEA sulphate and allopregnanolone, dose-dependent and within 10 to 30 minutes¹⁶
  • DHEA modulated basal and depolarization-induced extracellular DA levels in the striatum¹⁷
    • Increased tyrosine hydroxylase
• Reduced motor activity¹⁷
• Increased DA release¹⁷
  • Possibly effects on phasic and tonic DA release¹⁷
• Reduced DA metabolism in the striatum¹⁷¹⁸
  • Not due to reduced DA release.¹⁷ The statement to the contrary in an earlier study¹⁸ was no longer upheld.
• Influence on MAO (which breaks down dopamine)
  • In vivo
    • No effect on MAO activity in the striatum¹⁷
    • Inhibition of MAO-A and MAO-B activity in the nucleus accumbens by 24 %¹⁹
  • In vitro
    • Inhibition of MAO in the nucleus accumbens and (somewhat weaker) in the striatum¹⁹
• DHEA influences the neonatal development of the dopaminergic system
  Pregnenolone administration to newborns influences the activity of dopamine in the striatum. Pregnenolone is a neurosteroid precursor.²⁰
  Neonatal administration of pregnenolone or DHEA²⁰

• increased synapsin I and neuropeptide Y in the hippocampus.
• increased the immunodensity of synapsin I in the dorsomedial or ventrolateral striatum
  DHEA, but not pregnenolone, increased DAT immunodensity in the striatum and nucleus accumbens and dynorphin A immunodensity in the nucleus accumbens²⁰

It is assumed that DHEA exerts its positive effects in ADHD patients through stimulatory or antagonistic effects on GABA-A receptors and facilitation of NMDA activity.²¹ This could be explained by a DHEA-induced reduction in GABA-mediated inhibition of dopamine synthesis or dopamine firing in the VTA. Alongside the substantia nigra, the VTA is the most important dopamine-producing region of the brain. About half of the dopaminergic VTA neurons are active and fire spontaneously. The other half are inactive and do not fire spontaneously²², because they are constantly hyperpolarized by an inhibitory GABAergic influence from the ventral pallidum and thus kept inactive. By suppressing the pallidal afferents, the neurons are freed from the GABAergic inhibition and fire spontaneously again.²³²⁴

Peripheral dopamine infusion appears to suppress serum DHEAS levels in critically ill patients without affecting their elevated serum cortisol levels. The DHEA-lowering effect of dopamine may be related to the concomitant suppression of circulating prolactin²⁵

3.1.2.2. DHEA as an agonist¶

DHEA/DHEA sulfate act as an excitatory neurosteroid and agonist:

• Sigma-1 receptors
  • Agonist of sigma-1 receptors²²⁶
    • Sigma-1 agonists have an antidepressant effect.²⁷
  • Sigma-1 receptor binding by DHEA sulfate in the hippocampus and prelimbic cortex²⁸
  • DHEA sulphate has the following effects
    • Glutamate release²⁸
      • In the PFC, although there must be other mechanisms by which DHEA sulfate increases glutamate in the PFC.²⁹
      • In the hippocampus, with the sigma-1 receptor appearing to be the only pathway for DHEA sulfate to increase glutamate in the hippocampus.²⁹
    • Protein kinase A in the hippocampus and prelimbic cortex²⁸
    • Acetylcholine release in the hippocampus²⁹
    • Noradrenaline release in the hippocampus when DHAE sulfate was combined with dopamine D2 antagonists or NMDA. Sigma-1 receptor antagonists prevented the noradrenaline increase by DHEA sulfate plus NMDA in the hippocampus²⁹
• Dopamine D1 receptor
  • DHEA sulphate has the following effects
    • Glutamate release²⁸ in the PFC
    • Protein kinase A in the prelimbic cortex²⁸
• Oestrogen alpha and beta receptors (weak)³⁰
  • Androsterone increase due to DHEA³¹
    allopregnanolone, pregnanolone and pregnenolone were not increased
• Noradrenaline production
  • Noradrenaline increase due to DHEA, DHEA sulphate and allopregnanolone, dose-dependent and within 10 to 30 minutes¹⁶
• Serotonin production
  • Increase in serotonin levels in some regions of the brain, as antidepressants do.⁷
  • Inhibition of serotonin degradation³²
  • Increase in the serotonin receptor effect³²
• DHEA increases the T-cell expression of IL2-R²
• DHEA increases the number of natural killer cells²
• DHEA/S (like cortisol) has an anti-inflammatory effect. DHEA/S mediates this through³²
  • With inhibition of ROS formation
    with subsequent
  • Inhibition of NF-kB

3.1.2.2. DHEA as an antagonist¶

• DHEA reduces cortisol levels and the toxic effects of cortisol.^{33343536373839}
• Antagonist of GABA-A receptors, i.e. reduces the effect of the neurotransmitter GABA in the brain ^{2 2640}
  • DHEA influences the serotonin activity controlled by GABA-A receptors⁴¹
  • Only DHEA sulphate, but not DHEA, is a GABA-A receptor antagonist⁴²
  • The TBPS and picrotoxin binding site is inhibited⁴²
  • The benzodiazepine binding side of the receptor for GABA and pentobarbital is not inhibited⁴²
  • The simultaneous administration of the GABA-A agonist muscimol and DHEA eliminated the beneficial effect of DHEA administration alone on depressive behavior. This suggests that the GABA-A receptor is the main target for DHEA in depression.²⁶
• Inhibits the activity of glucose-6-phosphate dehydrogenase (G6PDH)
  • DHEA only (not DHEA sulphate) ²
• DHEA does not bind to androgen receptors²
• Inhibits N-methyl-D-aspartic acid (NMDA) in the hippocampus, which is a glutamate agonist. This means that DHEA and DHEA-S have an indirect glutamate antagonistic effect
  • DHEA as well as DHEA sulphate ³⁸
  • Different: agonist of glutamate NMDA receptors, thus acts like glutamate and enhances its effect.²²⁶
  • Inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the hippocampus
    • DHEA like DHEA sulphate ³⁸
  • Inhibits kainic acid in the hippocampus
    • DHEA like DHEA sulphate ³⁸
• Inhibits the translocation of the stress-activated protein kinase 3 in the hippocampus
  • DHEA ³⁹
  • Reduces pregnenolone and pregnenolone sulphate⁴³
  • DHEA sulphate reacts to positive modulation by androsterone⁴¹

3.2. Effect on diseases / disorders¶

3.2.1. Disorders with DHEA deficiency¶

3.2.1.1. ADHD¶

ADHD sufferers showed reduced serum DHEA-S levels, with unchanged levels of free testosterone and SHBG⁴⁴
In children with ADHD, salivary DHEA levels correlated negatively with distractibility and impulsivity, but not with inattention and hyperactivity⁴⁵

One study found a 25% reduction in salivary DHEA levels and significantly different DHEA to cortisol ratios in ADHD. Salivary DHEA levels and DHEA/cortisol ratios were independently negatively correlated with CPT scores for distractibility and impulsivity. Basal levels of cortisol were not significantly associated with ADHD.⁴⁶
Reduced DHEA and DHEAS serum levels correlated with increased hyperactivity in children with ADHD⁴⁷

One study found only slightly reduced serum DHEAS levels in ADHD, but significantly reduced serum DHEAS levels in ADHD with comorbid conduct disorder.⁴⁸
In children with ADHD, one study found no differences in serum DHEA and serum DHEA-S levels, but did find differences in serum allopregnanolone levels.⁴⁹

Salivary DHEA levels correlated positively with attention as measured by Conners’ Continuous Performance Test (CPT).⁵⁰

In anoxia (which is a common cause of ADHD, e.g. premature birth, birth complications, asthma, sleep apnea), DHEA and DHEAS are able to almost double the survival of neurons in vitro.⁵¹ It is also possible that a DHEA deficiency is associated with an increased risk of ADHD in this way.
DHEAS administration improved 5-choice serial reaction time task (5-CSRTT) performance in mice, while inhibition of steroid sulfatase impaired test performance. Loss of Sts gene expression throughout development in 39,X(Y)*O mice causes deficits in 5-CSRTT performance at short stimulus durations and a reduced anticipatory response. Motor activity remained unchanged in all cases.⁵²

Children with ADHD treated with MPH showed a significant increase in salivary DHEA levels,⁴⁵⁵³ plasma DHEA levels,⁵⁴ or plasma DHEAS levels. ⁵⁴⁵⁵ .
Bupropion also increased plasma DHEAS levels in ADHD.⁵⁵
Lisdexamfetamine and D-amphetamine (in doses above the recommended maximum dose of medication) also increased DHEA in healthy people, as well as other steroid hormones and glucocorticoids.⁵⁶

One study found subtype-specific differences in DHEA:

• In the ADHD-HI subtype, plasma DHEA levels were higher than in ADHD-I before MPH treatment.⁵⁷
• In the ADHD-HI subtype, MPH increased plasma DHEA levels; in ADHD-I, MPH decreased them.⁵⁷

In ADHD-I sufferers without depressive symptoms, MPH doubled allopregnanolone levels.⁵⁷

After 6 months, MPH treatment resulted in an increase in salivary cortisol levels that correlated with the increase in salivary DHEA.⁵³

Treatment with Korean red ginseng extract improved ADHD symptoms without altering DHEA or cortisol⁵⁸

3.2.1.2. Stress¶

Stress states correlate with DHEA deficiency.²

DHEA and DHEA sulphate improve the body’s resistance to stress by changing the

• Steroid metabolites²
• IGF-1 production²
• Cytokine modulation²
• Immune parameter modulation²
• Changes in the brain²

DHEA is not subject to the negative feedback of cortisol, so it is not downregulated by an increased release of cortisol like the HPA axis.²

The DHEA level decreases with age, but the cortisol level does not. As a result, the cortisol-DHEA ratio increases with age. Nevertheless, sensitivity to stress does not appear to generally increase with age.

Oxytocin (given nasally) reduced DHEA levels from before to after stress exposure (TSST). It also reduced anxiety, but not the subjective perception of stress.⁵⁹
Accordingly, oxytocin could possibly be the treatment approach for atypical depression, ADHD or other disorders that are characterized by a reduced cortisol-DHEA ratio. Further studies on this are desirable.

Unlike cortisol levels alone, a high cortisol/DHEA sulfate ratio and a low DHEA sulfate level is a predictor of more frequent imminent death.⁶⁰

3.2.1.2.1. DHEA stress response¶

DHEA and DHEA sulphate levels in healthy men and women are subject to the same response patterns to an acute stressor as cortisol, ACTH, prolactin and heart rate.⁶ This also applies to testosterone.⁶¹

• In the case of adrenal insufficiency (flattened cortisol response) in parallel with simultaneous cortisol substitution in order to maintain the existing cortisol-DHEA balance.
• To limit adrenal overactivation (excessive cortisol response), i.e. to establish a functional cortisol-DHEA balance if DHEA is reduced.

Deviation: during physical stress, DHEA is elevated in women but not in men, while cortisol is elevated in both.⁶²
Based on this assumption, we believe that physical stress should improve melancholic or psychotic depression in women, but leave it unchanged in men.
In both physically trained and untrained older people, sports training increased DHEA sulphate levels in women only and DHEA levels in both men and women. Cortisol levels, on the other hand, decreased.⁶³

An increased DHEA stress response correlated with increased internalizing symptoms of social stress in healthy people.⁶⁴
In our understanding, this can be reconciled with the collapsed DHEA response in melancholic / psychotic depression (which is characterized by an excessive cortisol response in parallel with the strongly internalizing ADHD-I) if one takes into account that the DHEA stress response can differ in healthy people and depressed people. Severe stress leads to an increased cortisol and DHEA response in the first phase (i.e. in people who are still healthy). However, prolonged stress leads to a breakdown of the hormone systems in later stress phases. See here: ⇒ The stress response chain / stress phases.
Depending on which hormone system collapses first due to the long-term stress (cortisol or DHEA), the other will then take over due to the loss of the counterpart. This could explain the different findings of excessive cortisol/DHEA ratios in predominantly internalizing disorders and reduced cortisol/DHEA ratios in predominantly externalizing disorders.
See below.

Measuring the stress responses of different DHEA steroids by ACTH stimulation and insulin stimulation could provide valuable information about the state of the HPA axis, with ACTH stimulation possibly providing more concise results.⁶⁵

3.2.1.2.2. DHEA/cortisol imbalance during stress¶

Cortisol and DHEA and DHEA sulphate influence¹

• Reward processing / motivation
• Attention regulation
• Sensory perception
• Mood
• Emotion
• Executive function (behavior control)

3.2.1.2.2.1. Mechanisms of action of cortisol and DHEA/DHEA sulphate¶

Cortisol and DHEA(S) act via genomic and non-genomic mechanisms.⁶⁶
The following presentation was originally based on Kamin, Kertes (2017).¹

3.2.1.2.2.1.1. Genomic mechanisms (slow)¶

3.2.1.2.2.1.1.1. Genomic mechanisms of cortisol¶

Cortisol exerts genomic effects in the target tissue by binding to mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). There are probably different GR isoforms with different functions.⁶⁷ GR bind 10 times weaker to cortisol than MR.^{66 68} MR are therefore already addressed by the usual cortisol levels within the circadian cortisol level differences, GR only when the cortisol level rises particularly high as a stress response.

If no ligand (e.g. cortisol) is present, MR and GR are located in the cytoplasm of the cells as part of a multimeric complex containing chaperone heat shock proteins.⁶⁹ Upon binding by cortisol, the receptor undergoes a conformational change, causing it to hyperphosphorylate and dissociate from the multidrug resistance p-glycoprotein complex. At this point, MR or GR translocate to the nucleus to bind to DNA recognition sites called glucocorticoid response elements (GREs) in the promoter region of the target genes. There, cortisol influences the activation or inhibition of the transcription of the subsequent gene and thus its expression. Cortisol exerts further e.g. anti-inflammatory, immunosuppressive, anti-allergic and shock-inhibiting effects through indirect genomic mechanisms by influencing membrane receptors and second messengers⁷⁰ and thus e.g. influencing the release of excitatory amino acids and triggering endocannabinoid synthesis.⁷¹

3.2.1.2.2.1.1.2. Genomic mechanisms of DHEA and DHEA sulfate¶

DHEA and DHEA sulfate activate specific transcriptional genetic pathways to directly alter cellular functions. For example, DHEA exerts direct genomic effects on the stimulation of nitric oxide synthesis without the use of estrogen, progesterone, glucocorticoid or androgen receptors.¹
Androgens are lipophilic and non-polar and can therefore not only cross the blood-brain barrier but also the plasma membranes of cells in order to bind to androgen receptors in the cytosol. This ligand-receptor complex then dimerizes, is phosphorylated and migrates into the cell nucleus, where the DNA-binding domain binds to a specific DNA sequence, the so-called hormone response element, and acts as a transcription factor.¹⁰

3.2.1.2.2.1.2. Non-genomic effects (fast)¶

In addition to the slow genomic effects of cortisol and DHEA/DHEA sulfate, rapid non-genomic modes of action exist to mediate behavioral responses to a stressor.

3.2.1.2.2.1.2.1. Non-genomic mechanisms of cortisol¶

Cortisol binds to cytosolic receptors and membrane receptors.⁶⁶⁷²

3.2.1.2.2.1.2.2. Non-genomic mechanisms of DHEA/DHEA sulfate¶

DHEA/DHEA sulphate binds to membrane receptors in various tissues.⁷³⁷⁴⁷⁵

Androgen receptors¹⁰

• can be found
  • in high quantities in
    • Hypothalamus
    • Limbic system
  • moderate to low (in male and female rodents, non-human primates and humans) in
    • VTA
    • NAc
    • mPFC
    • OFC
• regulate
  • homeostatic functions
  • Reproductive behavior
  • Aggression
  • Executive functions

DHEA/DHEA sulfate alters the properties of biophysical plasma membranes,⁷⁶ which influences the release and metabolism of monoamines¹⁶ and exerts modulating effects on voltage-gated ion channels.⁷⁷

Like cortisol, DHEA and DHEA sulphate also have an effect on a variety of psychopathologically relevant processes by modulating pre- and postsynaptic neurotransmitter receptors.⁷⁸⁷⁹

The ratio of cortisol and DHEA represents the balance between catabolic and anabolic activity.⁶⁸⁰

An increased cortisol/DHEA ratio (cortisol high, DHEA low) was found in

• Chronic stress⁸¹
  • Prolonged stress reduces the DEAH sulphate stress response, but not the DEAH stress response⁸²
• Depression,^{8336 84} especially in the stress response⁸⁰
• A 34% reduction in the DHEA sulphate stress response was found in clinical burnout sufferers.⁸⁵
• Dementia³⁶
• Fear
  • In a study⁸⁶ was
    • High anxiety associated with a rise in cortisol
    • Moderate anxiety correlated with an increase in cortisol and DHEA/DHEA sulfate
    • Low levels of anxiety correlated with an exclusive increase in DHEA and DHEA sulfate, without an increase in cortisol
    • An increase in DHEA/DHEA sulfate correlated overall with low anxiety and low anxiety levels
• PTSD
  • At least a high basal cortisol/DHEA ratio predicted the efficacy of EMDR therapy for PTSD.⁸⁷
• Multiple sclerosis⁸⁸
• A massively reduced DHEA sulphate level was found in patients with chronic neck pain.⁸⁹
• Fibromyalgia
  • Here, an unchanged cortisol level and a reduced DHEA sulphate level with higher pain sensitivity were found.⁹⁰

Other cortisol/DHEA abnormalities were seen in other disorders:

• Rheumatoid arthritis sufferers showed⁹¹
  • A flattened cortisol stress response to ACTH
  • A flattened DHEA stress response to ACTH
  • Unchanged androstenedione and OH-progesterone responses to ACTH.
• In hyperthyroidism, cortisol and DHEA/DHEA sulfate stress responses were reduced compared to normal thyroid function⁹²
  • DHEA-S was basally elevated, but not DHEA
  • ACTH was basally elevated
  • Cortisol was unchanged basally
  • The stress response of DHEA to CRH administration was reduced, but unchanged to ACTH administration
  • The stress response of cortisol to CRH and ACTH administration was reduced

In our opinion, the findings of a shift in the ratio of increased cortisol and decreased DHEA levels should not be generalized as a prototype of all forms of a particular disorder.
As the results we have compiled on ADHD and depression show, an elevated cortisol level is only one of several possible variants of cortisol imbalance within one and the same disorder. While in some cases excessive cortisol stress responses can be observed (ADHD-I, melancholic depression, psychotic depression), other forms of expression show flattened cortisol levels (cortisol stress responses) (ADHD-HI, atypical depression). The imbalance between cortisol and DHEA could also be disturbed in the second group mentioned, but probably more in the direction of a DHEA overweight. In this case, we expect that treatment with DHEA would be counterproductive.

This can be seen, for example, in studies that found a relatively increased DHEA sulphate level and an increased DHEA-S/cortisol ratio in correlation with reduced dissociative symptoms in chronic stress³⁷ or post-traumatic stress, in which the DHEA level is also increased.⁹³⁹⁴

Another study found - unfortunately without differentiating between the internalizing and externalizing types of depression - no strong differences within the group of depression sufferers studied and found a reduced DHEA stress response on average.⁸⁰

3.2.1.3. Hypertension, cardiac allograft vasculopathy¶

DHEA deficiency has been reported in hypertension or cardiac allograft vasculopathy.²

3.2.1.4. Helplessness, dissatisfaction with life¶

The DHEA level in people aged 65 and over correlated with their enjoyment of life and decreased with illness and life restrictions. A lower DHEA level correlated with near death.⁹⁵

The more helpless people in need of care at home are, the lower their DHEA levels are.⁹⁶

3.2.1.5. Autoimmune diseases¶

A lower DHEA level is found in the case of serious health problems and especially in autoimmune diseases.²

Examples:

• Lupus erythematosus (butterfly lichen)
• Rheumatoid arthritis
• AIDS

3.2.1.6. Disorders with unexplained indications of DHEA¶

There are unexplained indications of a DHEA deficiency in²

• Arteriosclerosis
• Fatal coronary diseases
• Death from cardiovascular insufficiency

3.2.2. Disorders with excess DHEA¶

Various disorders correlate with an excess of DHEA. Paradoxically, additional DHEA administration can also have therapeutic benefits in these cases.

• Schizophrenia
  • DHEA increased in posterior cingulate cortex and parietal cortex⁹⁷
    • Schizophrenia is characterized by excess dopamine
  • DHEA administration may nevertheless be therapeutically helpful⁹⁸
• Depression
  • DHEA increased⁹⁹
  • Nevertheless, DHEA has an antidepressant effect [29].⁷⁹⁸⁹⁹
• Bipolar
  • DHEA increased in posterior cingulate cortex and parietal cortex⁹⁷
• Conduct disorder in boys¹⁰⁰
• ODD¹⁰¹

3.2.3. When DHEA administration is helpful¶

3.2.3.1. Adrenal insufficiency in women and men¶

Women and men with hypofunction of the adrenal gland benefit significantly from DHEA administration, although the onset of effect was only detectable after 4 months; no change was detectable after 1 month:⁷

• Improved well-being
• Improved mood
• Depressiveness reduced
• Reduced anxiety
• Improved physical correlates of depression and anxiety
• Libido improved (only for women)
• Improves erectile and sexual functions (in men from 40 to 60)
• No improvement in cognitive performance

3.2.3.2. Melancholic (endogenous) depression¶

Significant improvement due to DHEA,⁷ especially in women.⁹⁸

5.2.3.3. Midlife dysthymia¶

Significant improvement due to DHEA.⁷

3.2.3.4. Fear¶

Significant improvement due to DHEA, especially in women.⁹⁸

3.2.3.5. Muscular dystrophy¶

In myotonic dystrophy, DHEA significantly improves the Activity of Daily Living (ADL), unlike in healthy older men.⁷

3.2.3.6. Erection problems¶

DHEA improved erectile function and other aspects of sexuality in men between 40 and 60 years of age with erectile dysfunction and reduced DHEAS blood levels.⁷

3.2.3.7. Immunological and protective effect¶

In vitro experiments indicate an immunological effect of DHEA on HIV and lymphocytes.
In addition, a protective effect of DHEA was observed against:²

• Glucocorticosteroid-induced thymus shrinkage
• An age-related decrease in the immune system and
• A decrease in the immune response to vaccines

3.2.3.8. Disorders without improvement due to DHEA¶

3.2.3.8.1. Perimenopause¶

Women in the one to two years before the onset of menopause did not benefit from DHEA treatment in this respect.⁷

3.2.3.8.2. Alzheimer’s disease¶

The DHEA blood level (which does not necessarily have to correspond to the DHEA level in the brain) is not altered in Alzheimer’s patients compared to subjects of the same age. Treatment with DHEA did not bring any improvement.⁷

4. Reduction of DHEA¶

• DHEA is converted to 4-androstenedione by 3β-hydroxysteroid dehydrogenase (3bHSD).
• 4-Androstenedione is
  • Through 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3, testosterone 17β-dehydrogenase) to testosterone (most important male sex hormone)
    • Testosterone is converted by aromatase (CYP19A1) to 17β-estradiol (most important female sex hormone)
  • Through aromatase to estrone
    • Estrone is converted by 17bHSD to 17β-estradiol (most important female sex hormone)
• DHEA is converted to DHEA sulphate (DHEAS) in the liver

DHEAS is released from the brain into the blood by efflux transport across the blood-brain barrier. This removes DHEAS from the brain. Oatp2 is involved in this process.¹⁰²

5. Animal examinations not transferable¶

Unlike humans, rats and mice cannot produce DHEA in the adrenal gland. The effect of DHEA on tumor growth control, immune stimulation and blood sugar regulation observed in mice and rats could not be reproduced in humans.⁷
Monkeys do have some DHEA, but far less DHEA sulphate than humans in their blood, so an age-related decline is hardly measurable.²

In a mouse model of polycystic ovary syndrome, DHEA administration caused depressive symptoms.¹⁰³

6. Hypothesis: Is DHEA more helpful in ADHD-I / melancholic depression than in ADHD-HI / atypical depression?¶

6.1. Effects on cortisol stress response decisive?¶

In our understanding, the ADHD-I / melancholic depression group represents an internalizing stress phenotype of the disorder (ADHD/depression) associated with an excessive cortisol stress response (compared to healthy individuals), while ADHD-HI / atypical depression each represent expressions of an externalizing stress phenotype associated with a flattened stress response compared to healthy individuals.
ADHD-I / melancholic depression are thus expressions of adrenal cortical overactivity, ADHD-HI / atypical depression expressions of adrenal cortical exhaustion or weakness.

As we understand it, the symptoms of melancholic depression are associated with symptoms that can be attributed to a GABA deficiency.
The studies collected above now report a positive effect of DHEA on melancholic (endogenous) depression, although DHEA is a GABA antagonist and thus, according to our theoretical understanding, should rather worsen the symptoms of melancholic (endogenous) depression.

6.2. DHEA for melancholic depression, electroconvulsive therapy for atypical depression?¶

The fact that depression treatments do not work identically for all depressions is shown by the fact that DHEA and electroconvulsive treatment have the same antidepressant effect, but the simultaneous use of DHEA and electroconvulsive treatment neutralized each other’s antidepressant effect.¹⁰⁴

We believe that the positive effect of DHEA on melancholic depression could be explained by the fact that DHEA reduces cortisol levels and attenuates the toxic effects of cortisol,^{3334 35 36} possibly increases cortisol levels during electroconvulsive therapy.¹⁰⁵

A hypothetical model as to why DHEA is suitable for treating melancholic depression despite GABA antagonism when a particularly intense cortisol stress response is present could be that the normalization of cortisol levels is more significant than the normalization of GABA levels. Nevertheless, the probability of a recurrence of depression can be determined on the basis of the cortisol response to the dexamethasone/CRH test.

If our hypothesis were correct, the stress phenotype (cortisol stress response phenotype) would have to be determined for optimal treatment of depression (and ADHD).

In turn, we believe that electroconvulsive therapy, which raises cortisol levels, should be more useful for atypical depression.

This model shows the importance of differentiating the stress phenotypes within a disorder (be it depression or ADHD) for the choice of a sensible therapeutic agent.

7. DHEA medication¶

In the EU, all prohormones, including DHEA and DHEA sulphate, are subject to authorization and prescription.
In Germany and Switzerland, the DHEA prodrug prasterone antate in combination with estradiol valerate is available as a prescription drug (Gynodian® Depot).¹⁰⁷

In the USA, DHEA has been freely available as a dietary supplement since 1994.

• Studies of dietary supplements containing DHEA have shown the absence of DHEA in some cases and a significantly higher DHEA content than stated in others.
• A vaginal insert for dyspareunia has been approved since 2016 (Intrarosa®).¹⁰⁷

8. Possible interactions of DHEA with other active substances¶

Source: Mayo Foundation for Medical Education and Research (MFMER)¹⁰⁸

DHEA should not be used during pregnancy or breastfeeding.

Interactions could exist in relation to:

• Antipsychotics
  • E.g. Clozapine
  • DHEA can reduce the effectiveness of antipsychotics
• Carbamazepine
  • Carbamazepine is a drug used to treat seizures, nerve pain and bipolar disorder
  • DHEA can impair the efficacy of carbamazepine
• Oestrogen
  • DHEA increases oestrogen levels (especially in men)
  • DHEA can therefore enhance the effect of oestrogen
  • Symptoms of an estrogen overdose include
    • Nausea
    • Headache
    • Insomnia
• Lithium
  • DHEA can impair the effectiveness of lithium
• Phenothiazines
  • DHEA can impair the effectiveness of phenotiazines
  • Phenothiazines are a group of active substances used to treat severe mental and emotional disorders. They are used as

    • Neuroleptics (antipsychotic)

    • Sedatives (tranquilizers)

    • Antihistamines (against allergic reactions)

    • Antiemetics/antivertiginosa (against nausea and dizziness)

    • Types of phenothiazines¹⁰⁹

      • Chlorpromazine type
        weak antipsychotics, e.g. acepromazine
        • Chlorpromazine
        • Levomepromazine
        • Promazine
        • Promethazine
        • Triflupromazine
      • Pecazine type
        weak neuroleptic with a rather high side effect profile, e.g.
        • Thioridazine
      • Perphenazine type
        medium antipsychotic, e.g.
        • Perazine
        • Perphenazine
        • Fluphenazine
      • Azaphenothiazines
        • Prothipendyl
      • Thioxanthenes
        • Chlorprothixene
        • Zuclopenthixol/Clopenthixol
        • Flupentixol
• Selective serotonin reuptake inhibitors (SSRIs)
  • DHEA can enhance the effect of SSRIs
  • DHEA and SSRIs together can trigger manic symptoms
• Testosterone
  • DHEA increases testosterone levels (especially in women)
  • DHEA can therefore enhance the effect of testosterone
  • Symptoms of a testosterone overdose include
    • Low sperm count (oligospermia)
    • Enlarged breasts in men (gynecomastia)
    • Development of typical male characteristics in women
• Triazolam
  • Triazolam is a benzodiazepine derivative
    • Stronger effect than diazepam
    • Side effects more common than with other benzodiazepines
    • Withdrawn from the market in France and England in 1991; withdrawal in Germany was considered
  • DHEA and triazolam together can trigger central nervous system depression, which affects breathing rate and heart rate
• Valproic acid
  • Valproic acid is an anticonvulsant
  • DHEA can reduce the effectiveness of valproic acid

9. Measurement of DHEA¶

The DHEA values in the brain are said to be on average 6.5 times the blood value, but the DHEA values in the cerebrospinal fluid are said to be only 1/20 of the blood values.¹¹⁰