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DHEA

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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 markedly gender-specific.

DHEA and cortisol are both predominantly 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
      • Small 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 sulfate receptors have been found so far.

1. Origin of DHEA

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

2. DHEA degradation

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

DHEA sulfate would be largely destroyed by stomach acid if taken orally. Therefore, taking DHEA alone makes sense.2
DHEA and DHEA sulfate are balanced by sulfotransferases and sulfatases.3 Arylsulfatase C (STS, estrone/dehydroepiandrosterone sulfatase; steroid sulfatase) is a sulfatase that converts DHEAS to DHEA. More about this Sulfation and ADHD In the article* Dopamine degradation*. The STS gene is a candidate gene for ADHD.

3. DHEA by age and gender

DHEA is not produced to any significant extent until the age of 6 to 10 years,2 which (possibly merely by chance) is the age at which ADHD becomes diagnosable. DHEA levels increase until about 25/30 years of age and continue to decrease with age, down to 10-20% at older ages.2 At the onset of puberty, DHEA or DHEA sulfate rises sharply again.1 We hypothesize that the cortisol reduction triggered by the DHEA increase (which correlates with externalizing behaviors) may be a contributor to the puberty-typical behavioral changes.

The decrease in DHEA correlated with further age is not triggered by lower ACTH production. Since the (indirect) cortisol response to ACTH does not decrease with age, this leads to a decreased DHEA/cortisol ratio with age.
Most sources report a higher or equal basal DHEA level in women4 and a higher basal DHEA sulfate level4 in men. One source divergently reports a 10 to 20% higher basal DHEA level in men compared to women.2

The ratio of conversion of DHEA to male or female sex hormones depends on gender.
In men, DHEA predominantly increases estrogen levels in the blood, in women it predominantly increases androgen levels. In men, testosterone is formed in some tissues, but without increasing the testosterone level in the blood. Only increased testosterone degradation products are detectable.5

DHEA / DHEA sulfate levels vary greatly among individuals and can vary by as much as threefold in healthy individuals of the same age and sex, but are more stable within an individual over time than cortisol levels.2

Orally ingested DHEA increases

  • For women
    • Androstenedione3
    • Testosterone3
    • Dihydrotestosterone3
  • For men
    • Östron3
    • 17-ß-estradiol3
    • Androstenedione in Addison’s disease patients (primary adrenal insufficiency)6
    • Not testosterone3
    • Not dihydrotestosterone3

3. DHEA according to daily rhythm

The DHEA level has the same circadian rhythm as cortisol, since DHEA is stimulated by ACTH, which also stimulates cortisol formation within the HPA axis. ACTH simultaneously stimulates DHEA sulfate formation in the adrenal gland, whereas DHEA sulfate, unlike DHEA, is not subject to a circadian rhythm.24

It is possible that, contrary to previous belief, DHEA in healthy individuals does undergo a wake-up response (DAR) in the sense of a sharp level increase to 8-fold that occurs immediately upon awakening, unlike the cortisol wake-up response (CAR), whose maximum occurs about 40 minutes after awakening. The DAR also appears to be an indicator of sleep restfulness.7

According to our hypothesis, this could be coherently related to the poor sleep quality in melancholic and psychotic depression (especially in the second half of the night). Melancholic and psychotic depression are characterized by an excessive cortisol/DHEA ratio. It would be interesting to verify whether DAR is decreased in melancholic and psychotic depression (and increased in atypical depression) and whether DHEA treatment would restore DAR in melancholic and psychotic depression, as we hypothesize.

4. DHEA and stress

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

DHEA levels decrease with age, but cortisol levels do not. As a result, the cortisol-DHEA ratio increases with age. Nevertheless, stress sensitivity does not appear to be generally increased in old age.

Oxytocin (given nasally) reduced DHEA levels from before to after stress exposure (TSST). It also reduced anxiety but not subjective stress perception.8
Accordingly, oxytocin could possibly be the treatment approach for atypical depression, ADHD, or other disorders characterized by a decreased cortisol-DHEA ratio. Further studies are desirable in this regard.

Unlike cortisol levels alone, a high cortisol/DHEA sulfate ratio and a low DHEA sulfate level are predictors of more frequent approaching death.9

4.1. DHEA stress response

DHEA and DHEA sulfate levels underlie the same response patterns to an acute stressor as cortisol, ACTH, prolactin, and heart rate in healthy men and women.4 This also affects testosterone.10

In adrenal insufficiency (Addison’s disease), which is characterized by insufficient cortisol production (without a change in the sensitivity balance between the MR and GR receptors, but with an expected shift towards weakened GR addressing due to the existing cortisol deficiency), the level of DHEA, which is also produced in the adrenal gland, is usually reduced at the same time. In the case of cortisol substitution in adrenal insufficiency, supplemental DHEA substitution is useful.6
This must be distinguished from treatment of adrenal hyperactivity, when the excess cortisol is to be down-regulated by DHEA administration, as has been successfully used in melancholic depression.5
In our opinion, these conflicting aspects should be taken into account when considering when DHEA administration alone might be appropriate:

  • In adrenal insufficiency (flattened cortisol response), parallel to concurrent cortisol supplementation to maintain existing cortisol-DHEA balance.
  • In case of adrenal overactivation (excessive cortisol response) to limit it, i.e. to establish a functional cortisol-DHEA balance, if DHEA is decreased.

Differently, during physical stress, DHEA is elevated in women but not in men, whereas cortisol is elevated in both.11
Under this assumption, our understanding is that physical stress should improve melancholic or psychotic depression in women but leave it unchanged in men.
In both physically trained and untrained elderly, exercise training increased DHEA sulfate levels in women only and DHEA levels in both men and women. Cortisol levels, on the other hand, decreased.12

Increased DHEA stress response correlated with increased internalizing symptoms to social stress in healthy individuals.13
According to our understanding, this can be reconciled with the collapsed DHEA response in melancholic / psychotic depression (which are characterized by an exaggerated cortisol response in parallel with the strongly internalizing ADHD-I) if one includes that the DHEA stress response may differ in healthy people and depressives. Severe stress leads to an increased cortisol and DHEA response in the first phase (i.e., in people who are still healthy). Prolonged stress, meanwhile, leads to a breakdown of hormonal systems in later phases of stress. See in this regard: The stress response chain / stress phases.
Depending on which hormonal system collapses first (cortisol or DHEA) due to the permanent stress, the other will then take over due to the omission of the counterpart. This could explain the different findings of excessive cortisol/DHEA ratios in predominantly internalizing and decreased cortisol/DHEA ratios in predominantly externalizing disorders.
See belowg.

Measurement of the stress responses of various DHEA steroids by ACTH stimulation and insulin stimulation could provide valuable information about the state of the HPA axis, with ACTH stimulation possibly yielding more concise results.14

4.2. DHEA/Cortisol Imbalance in Stress

Cortisol and DHEA and DHEA sulfate influence1

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

4.2.1. Mechanisms of action of cortisol and DHEA/DHEA sulfate

Cortisol and DHEA(S) act through genomic and non-genomic mechanisms.15
The following presentation is based on Kamin, Kertes (2017).1

4.2.1.1. Genomic mechanisms (slow)
4.2.1.1.1. Genomic mechanisms of cortisol

Cortisol exerts genomic effects in target tissues by binding to mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Different GR isoforms with different functions are thought to exist.16 GR bind 10 times weaker to cortisol than MR.15 17 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.

In the absence of a ligand (e.g., cortisol), MR and GR reside in the cytoplasm of cells as part of a multimeric complex containing chaperone heat shock proteins.18 After 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 translocates to the nucleus to bind to DNA recognition sites called glucocorticoid response elements (GREs) in the promoter region of target genes. There, cortisol influences the activation or inhibition of transcription of the downstream gene and thus its expression. Cortisol exerts further e.g. anti-inflammatory, immunosuppressive, anti-allergic and shock-inhibitory effects through indirect genomic mechanisms by affecting membrane receptors and second messengers19 and thus e.g. influencing the release of excitatory amino acids and triggering endocannabinoid synthesis.20

4.2.1.1.2. 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 immediate genomic effects on the stimulation of nitric oxide synthesis without the use of estrogen, progesterone, glucocorticoid, or androgen receptors.1

4.2.1.2. 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.

4.2.1.2.1. Non-genomic mechanisms of cortisol

Cortisol binds to cytosolic receptors and membrane receptors.1521

4.2.1.2.2. Non-genomic mechanisms of DHEA/DHEA sulfate

DHEA/DHEA sulfate binds to membrane receptors in various tissues.222324

DHEA/DHEA sulfate alters the properties of plasma biophysical membranes,25 which affects the release and metabolism of monoamines26 and exerts modulatory effects on voltage-gated ion channels.27

Like cortisol, DHEA and DHEA sulfate affect a variety of psychopathologically relevant processes by modulating pre- and postsynaptic neurotransmitter receptors.2829

Hypotheses on the relationship between DHEA and cortisol in hypo- and hypercortisolism

Since it is reported that the DHEA response (more so than the DEAH sulfate response) in healthy individuals follows the individual characteristics of the cortisol response (which also correlates with the ACTH and prolactin response and heart rate),4 it might initially be concluded that there would tend to be an exaggerated DHEA response in ADHD-I and melancholic depression and a flattened DHEA response in ADHD-HI / atypical depression.
Then, however, it would no longer make sense that DHEA should be effective especially in melancholic depression, as it is reported several times. It is therefore questionable whether the DHEA response in non-healthy people, e.g. with an existing ADHD or depression, also follows the cortisol stress response pattern.
Since DHEA has an anticortisolergic effect, this anticortisolergic effect should be able to slow down the cortisol increase in case of a parallel increase of DHEA to cortisol. This is apparently not (sufficiently) the case in ADHD-I and melancholic and psychotic depression. Purely hypothetical plausible explanations of the cortisolergic imbalance could be that in case of an imbalance of the cortisol balance

  • The DHEA level no longer rises and falls synchronously or even inversely proportional to that of cortisol as a stress response and/or
  • DHEA does not have sufficient anticortisolergic effects to limit a sharp rise in cortisol

The argument against the last hypothesis is that it could explain hypercortisolism but not hypocortisolism.

These thoughts prove to be true in the light of the research found in the following.

The ratio of cortisol and DHEA represents the balance between catabolic and anabolic activity.430

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

  • Chronic stress31
    • Prolonged stress reduces the DEAH sulfate stress response, but not the DEAH stress response32
  • Depression,3334 35 especially in stress response30
  • Clinical burnout sufferers were found to have a 34% decreased DHEA sulfate stress response.36
  • Dementia34
  • Fear
    • In a study37 was
      • High anxiety associated with a rise in cortisol
      • Mean anxiety levels correlated with increases in cortisol and DHEA/DHEA sulfate
      • Low anxiety correlated with an exclusive increase in DHEA and DHEA sulfate, with no 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.38
  • Multiple sclerosis39
  • A massively reduced DHEA sulfate level has been found in sufferers with chronic neck pain.40
  • Fibromyalgia
    • Here, an unchanged cortisol level and a reduced DHEA sulfate level with higher pain sensitivity were found.41

Other cortisol/DHEA abnormalities were seen in other disorders:

  • Rheumatoid arthritis sufferers showed42
    • A flattened cortisol stress response to ACTH
    • A flattened DHEA stress response to ACTH
    • Unchanged androstenedione and OH-progesterone responses to ACTH.
  • In hyperthyroidism (hyperthyroidism), cortisol and DHEA/DHEA sulfate stress responses were reduced compared to normal thyroid function.43
    • DHEA-S was basally elevated, but DHEA was not
    • ACTH was basally elevated
    • Cortisol was basally unchanged
    • The stress response of DHEA to CRH administration was decreased, whereas to ACTH administration it was unchanged
    • The stress response of cortisol to CRH and ACTH administration was reduced

In our opinion, the findings of a ratio shift toward increased cortisol and decreased DHEA levels should not be generalized unseen as a prototype of all forms of a particular disorder.
As the results we have compiled on ADHD and depression show, elevated cortisol levels are only one of several possible variants of cortisol imbalance within one and the same disorder. While in some cases excessive cortisol stress responses are found (ADHD-I, melancholic depression, psychotic depression), in other expressions flattened cortisol levels (cortisol stress responses) are found (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 DHEA overbalance. In this case, treatment with DHEA would be counterproductive according to our expectation.

This is evident, for example, in studies that found relatively elevated DHEA sulfate levels and increased DHEA S/cortisol ratios correlated with reduced dissociative symptoms in chronic stress44 or with post-traumatic stress, in which DHEA levels are also elevated.4546

Another study, unfortunately without differentiating between the internalizing and externalizing types of depression, found no strong differences within the group of depression sufferers studied and found a reduced DHEA stress response on average.30

5. Effect of DHEA

5.1. 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 for one year produced improvements without significant side effects, especially in participants over 70 years of age.47

5.1.1. Effects in the body

  • Reduction of “good” cholesterol (especially in women)5
  • Antidiabetic results from animal studies were not reproducible in humans
    • No improvement in well-being in older healthy men5
    • No change in insulin sensitivity in humans (multiple studies in healthy participants of all ages)5
  • Androgen effects on the skin and at the same time estrogen effects on the vaginal mucosa in older postmenopausal women5
  • Androgen excess effects of overdose in women (reversible)5
    • Hirsutism
    • Acne
    • Hair loss
  • 25-50 mg DHEA / day:5
    • Significant reduction of apolipoprotein A1 (only in women)
    • Significant reduction of HDL cholesterol (“good cholesterol”) (only in women)
  • 50 mg DHEA / day:
    improved libido (mainly in older women, hardly in men)47; different: no improvement of libido in a smaller test group.48
  • 50 mg DHEA / nightly for 6 months48
    13 men and 17 women aged 40 to 70 years; randomized, placebo-controlled cross-over trial
    • DHEA and DS serum levels reached young adult levels within 2 weeks and maintained these levels during dosing
    • Two-fold increase in androgen serum levels in women
      • Androstenedione
      • Testosterone
      • Dihydrotestosterone
    • Small increase in androstenedione in men
    • Unchanged levels in men and women of
      • Sex hormone binding globulin
      • Estrone
      • Estradiol
    • Slight reduction of 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 significantly increased
    • IGFBP-1 significantly decreased for men and women
      • Indicates increased bioavailability of IGF-I to target tissues
    • Mental well-being increased in men (67%) and women (84%)
    • Physical well-being improved
    • Libido unchanged
  • 50 mg DHEA / day:
    slightly elevated levels of testosterone and estrogen (especially in older women)47
  • 50 mg DHEA / day:
    slightly increased bone density (in women over 70)47
    • Study results inconsistent5
  • 50 mg DHEA / day:
    Skin improvements (especially in older women)47
    • Less dried out
    • Thicker epidermis
    • Improved sebum production
    • Improved pigmentation
  • 50 mg DHEA / day:5
    • No reduction in HDL cholesterol (“good cholesterol”) even in men
    • No decrease in fat mass
    • No increase in muscle mass
  • 100 mg DHEA / day:5
    • Significant reduction of HDL cholesterol (“good cholesterol”) also 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 / day:49
    • Increased IGF-I level
    • Increased fat mass in men
    • Increased muscle strength in men
  • 400 mg DHEA:50
    • 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 / day:5
    • Recurrence of prostate carcinoma regressed by androgen suppression (single 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:52
    • Significant fat loss
    • Significant decrease of LDL cholesterol (“bad cholesterol”)
    • Unchanged androgen concentration
  • 1600 mg DHEA / day in (older) women after menupause:5
    • Androgens increased tenfold
    • Drop in HDL cholesterol (“good cholesterol”)
    • Fat mass unchanged

5.1.2. Effect in the brain

5.1.2.2. DHEA as agonist

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

  • Sigma-1 receptors
    • Agonist of sigma-1 receptors251
      • Sigma-1 agonists show antidepressant activity.52
    • Sigma-1 receptor binding by DHEA sulfate in hippocampus and prelimbic cortex53
    • DHEA sulfate thereby causes
      • Glutamate release53
        • In the PFC, although other mechanisms must exist for how DHEA sulfate increases glutamate in the PFC.54
        • In the hippocampus, with the sigma-1 receptor appearing to be the only pathway for DHEA sulfate to increase glutamate in the hippocampus.54
      • Protein kinase A in the hippocampus and prelimbic cortex53
      • Acetylcholine release in the hippocampus54
      • Norepinephrine release in the hippocampus when DHAE sulfate coincided with dopamine D2 antagonists or NMDA. Sigma-1 receptor antagonists prevented norepinephrine elevation by DHEA sulfate plus NMDA in the hippocampus54
  • Dopamine D1 receptor
    • DHEA sulfate thereby causes
      • Glutamate release53 in PFC
      • Protein kinase A in the prelimbic cortex53
  • Estrogen alpha and beta receptors (weak)55
    • Androsterone increase due to DHEA56
      not increased were allopregnanolone, pregnanolone and pregnenolone
  • Norepinephrine production
    • Noradrenaline increase by DHEA, DHEA sulfate, and allopregnanolone dose-dependently and within 10 to 30 min26
  • Dopamine production
    • Dopamine increase due to DHEA, DHEA sulfate, and allopregnanolone dose-dependent and within 10 to 30 min26
  • Serotonin production
    • Increase serotonin levels in some brain regions, as antidepressants do.5
    • Inhibition of serotonin degradation57
    • Enhancement of serotonin receptor action57
  • DHEA increases T-cell expression of IL2-R2
  • DHEA increases the number of natural killer cells2
  • DHEA/S (like cortisol) have an anti-inflammatory effect. DHEA/S mediates this through57
    • With inhibition of ROS formation
      with subsequent
    • Inhibition of NF-kB
5.1.2.2. DHEA as antagonist
  • DHEA reduces cortisol levels and the toxic effects of cortisol.58596034446162
  • Antagonist of GABA-A receptors, thus reduces the effect of the neurotransmitter GABA in the brain.251 63
    • DHEA influences serotonin activity controlled by GABA-A receptors64
    • Only DHEA sulfate, but not DHEA, is GABA-A receptor antagonist65
    • The TBPS and picrotoxin binding side is inhibited65
    • Does not inhibit the benzodiazepine binding side of the receptor for GABA and pentobarbital65
    • 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.51
  • Inhibits the activity of glucose-6-phosphate dehydrogenase (G6PDH)
    • DHEA only (not DHEA sulfate) 2
  • DHEA does not bind to androgen receptors2
  • Inhibits N-methyl-D-aspartic acid (NMDA) in the hippocampus, which is a glutamate agonist. Thus, DHEA and DHEA-S have an indirect glutamate antagonistic effect
    • DHEA as well as DHEA sulfate 61

    • Different: Agonist of glutamate NMDA receptors, thus acts like glutamate and enhances its effect.251

    • Inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the hippocampus

      • DHEA like DHEA sulfate 61
    • Inhibits kainic acid in the hippocampus

      • DHEA like DHEA sulfate 61
  • Inhibits the translocation of the stress-activated protein kinase 3 in the hippocampus
    • DHEA 62
    • Reduces pregnenolone and pregnenolone sulfate66
    • DHEA sulfate responds to positive modulation by androsterone64

5.2. Effect in diseases / disorders

5.2.1. DHEA Deficiency

5.2.1.1. Stress

Stress states correlate with DHEA deficiency.2

DHEA and DHEA sulfate improve the stress resistance of the body by changing the

  • Steroid Metabolites2
  • IGF-1 production2
  • Cytokine modulation2
  • Immune Parameter Modulation2
  • Changes in the brain2
5.2.1.2. Hypertension, cardiac allograft vasculopathy

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

5.2.1.3. Helplessness, dissatisfaction with life

DHEA levels in people aged 65 and older correlated with their enjoyment of life and decreased with illness and life limitations. A lower DHEA level correlated with a near death.67

The more helpless people in need of care at home are, the lower their DHEA level.68

5.2.1.4. Health problems

In cases of severe health problems and especially autoimmune diseases, a lower level of DHEA is detected.2

Examples:

  • Lupus erythematosus (butterfly lichen)
  • Rheumatoid arthritis
  • AIDS
5.2.1.5. Disorders with unexplained indications to DHEA

There is unexplained evidence of DHEA deficiency in the following2

  • Arteriosclerosis
  • Fatal coronary diseases
  • Death due to cardiovascular deficiency

5.2.2. DHEA administration

5.2.2.1. Adrenal insufficiency in women and men

Both women and men with adrenal hypofunction benefit significantly from DHEA administration, although the onset of effect was not detectable until after 4 months; no change was detectable after 1 month:5

  • Wellbeing improved
  • Mood improved
  • Depressiveness reduced
  • Anxiety reduced
  • Physical correlates of depression and anxiety improved
  • Libido improved (only in women)
  • Erectile and sexual functions improved (in men from 40 to 60)
  • No improvement in cognitive performance
5.2.2.2. Melancholic (endogenous) depression

Significant improvement with DHEA.5

5.2.2.3. Midlife Dysthymia

Significant improvement with DHEA.5

5.2.2.4. Muscular dystrophy

In myotonic dystrophy, DHEA significantly improves Activity of Daily Living (ADL), unlike in healthy older men.5

5.2.2.5. Erection problems

DHEA improved erectile function as well as other sexuality aspects in men between 40 and 60 years of age with erectile dysfunction and decreased blood DHEAS levels.5

5.2.2.6. Immunological action and protective effect

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

  • Glucocorticosteroid-induced thymic shrinkage
  • An age-related decrease in the immune defense and
  • A decrease in the immune response to vaccines
5.2.2.7. Disorders without improvement by DHEA
5.2.2.7.1. Perimenopause

Women in the one to two years before the onset of menopause did not benefit from DHEA treatment in this regard.5

5.2.2.7.2. Alzheimer

The DHEA blood level (which does not necessarily have to correspond to the DHEA level in the brain) is not changed in Alzheimer’s compared to comparison subjects of the same age. Treatment with DHEA did not bring any improvement.5

6. Animal examinations not transferable

Rats and mice - unlike humans - cannot produce DHEA in the adrenal gland. The effect of DHEA observed in mice and rats on tumor growth control, immune stimulation and blood glucose regulation could not be reproduced in humans.5
Monkeys have some DHEA but far less DHEA sulfate in their blood than humans, so an age-related decline is hard to measure.2

7. Hypothesis: is DHEA more helpful in ADHD-I / melancholic depression than in ADHD-HI / atypical depression?

7.1. Effects on cortisol stress response crucial?

In our understanding, the ADHD-I / melancholic depression group represents an internalizing stress phenotype of the disorder (ADHD/depression) associated with an exaggerated cortisol stress response (compared to healthy individuals), whereas 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 adrenocortical overactivity, ADHD-HI / atypical depression expressions of adrenocortical exhaustion or weakness.

In our understanding, the symptomatology of melancholic depression is associated with symptoms attributable to 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 aggravate the symptoms of melancholic (endogenous) depression.

7.2. DHEA for melancholic depression, electroconvulsive therapy for atypical depression?

That depression treatments do not work identically for all depression is shown by the fact that DHEA and electroconvulsive treatment were equally antidepressant, but simultaneous use of DHEA and electroconvulsive treatment mutually neutralized the antidepressant effect.69

The beneficial effect of DHEA on melancholic depression could be explained, in our understanding, by the fact that DHEA decreases cortisol levels and attenuates the toxic effects of cortisol,5859 60 34 during electroconvulsive therapy possibly increases cortisol levels.70

A hypothetical model for why DHEA is useful for treating melancholic depression despite GABA antagonism when a particularly intense cortisol stress response is present might be that normalization of cortisol levels is more significant than normalization of GABA levels. After all, the likelihood of recurrence of depression can be determined by the cortisol response to the dexamethasone/CRH test.

However, a clear argument against our hypothesis is that electroconvulsive therapy alone is as antidepressant as DHEA alone in the same rat breeding line (FSL rats). Statements about the cortisol stress response in FSL rats are rare. An indication of a rather increased cortisol stress response of FSL rats could be an increased cortisol response to the acetylchlinagonist arecoline.71

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

In turn, our understanding is that electroconvulsive therapy, which raises cortisol levels, should be more useful in atypical depression.

This model demonstrates the importance of distinguishing stress phenotypes within a disorder (be it depression or ADHD) for choosing a meaningful therapeutic agent.

8. DHEA medications

In the EU, all prohormones, including DHEA and DHEA sulfate, are subject to approval and prescription.
In Germany and Switzerland, the DHEA prodrug prasterone antate is available in combination with estradiol valerate as (Gynodian® Depot) as a prescription drug.72

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

  • Studies of dietary supplements containing DHEA showed partly the absence, partly a considerably higher DHEA content than indicated.
  • A vaginal insert for dyspareunia has been approved since 2016 (Intrarosa®).72

9. Possible interactions of DHEA with other active substances

Source: Mayo Foundation for Medical Education and Research (MFMER)73

DHEA should generally not be used during pregnancy or breastfeeding.

Interactions could exist with respect to:

  • Antipsychotics
    • E.g. clozapine
    • DHEA may reduce the effectiveness of antipsychotics
  • Carbamazepine
    • Carbamazepine is a drug used to treat seizures, nerve pain, and bipolar disorder
    • DHEA may interfere with the efficacy of carbamazepine
  • Estrogen
    • DHEA increases estrogen levels (especially in men)
    • DHEA can therefore enhance the effect of estrogen
    • Symptoms of estrogen overdose include
      • Nausea
      • Headache
      • Insomnia
  • Lithium
    • DHEA may interfere with the efficacy of lithium
  • Phenothiazine
    • DHEA may interfere with the efficacy of phenotiazines
    • Phenothiazines are a group of drugs 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 phenothiazines74

        • Chlorpromazine type
          weak antipsychotics, e.g. acepromazine
          • Chlorpromazine
          • Levomepromazine
          • Promazine
          • Promethazine
          • Triflupromazine
        • Pecazine type
          weak neuroleptic with rather high side effect profile, e.g
          • Thioridazine
        • Perphenazine type
          medium antipsychotic, e.g.
          • Perazine
          • Perphenazine
          • Fluphenazine
        • Azaphenothiazine
          • Prothipendyl
        • Thioxanthene
          • Chlorprothixene
          • Zuclopenthixol/Clopenthixol
          • Flupentixol
  • Selective serotonin reuptake inhibitors (SSRIs)
    • DHEA may enhance the effect of SSRIs
    • DHEA and SSRI together can trigger manic symptoms
  • Testosterone
    • DHEA increases testosterone levels (especially in women)
    • DHEA may therefore may enhance the effect of testosterone
    • Symptoms of 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
      • Effect stronger than diazepam
      • Side effects more common than with other benzodiazepines
      • Withdrawn from the market in France and England in 1991; withdrawal considered in Germany
    • DHEA and triazolam together can cause central nervous system depression, which affects respiratory rate and heart rate
  • Valproic acid
    • Valproic acid is an anticonvulsant drug
    • DHEA may reduce the efficacy of valproic acid

10. DHEA measurement

DHEA levels in the brain are reported to average 6.5 times blood levels, but DHEA levels in cerebrospinal fluid are reported to be only 1/20 of blood levels.75


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