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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.
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 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
According to our hypothesis, this could be coherent with the poor quality of sleep 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.
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.
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
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
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
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 22640
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)
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
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
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
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 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, supplementary DHEA substitution is advisable.9
This is to be distinguished from the treatment of adrenal hyperactivity, when the excess cortisol is to be downregulated by administering DHEA, as has been successfully used for melancholic depression.7
In our opinion, these contradictory aspects should be taken into account when considering when DHEA administration alone might be appropriate:
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
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.6668 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
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
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
Hypotheses about the relationship between DHEA and cortisol in hypo- and hypercortisolism
Since it is reported that the DHEA response (even more than the DEAH-sulfate response) in healthy people follows the individual characteristics of the cortisol response (which also correlates with the ACTH and prolactin response and heart rate),6 it could 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.
However, it would then no longer make sense for DHEA to be effective in melancholic depression, as has been reported several times. It is therefore questionable whether the DHEA response in non-healthy people, e.g. with existing ADHD or depression, also follows the cortisol stress response pattern.
As DHEA has an anticortisol effect, this anticortisol effect should be able to slow down the rise in cortisol if DHEA increases in parallel with 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 the event of an imbalance in 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 is not sufficiently anticortisolergic to limit a sharp rise in cortisol
An argument against the last hypothesis is that it could explain hypercortisolism, but not hypocortisolism.
These thoughts are reinforced in the light of the studies presented below.
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
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
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
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)
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
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
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
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,33343536 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.
However, our hypothesis is clearly contradicted by the fact that electroconvulsive therapy alone has the same antidepressant effect in the same rat breeding line (FSL rats) as DHEA alone. Statements about the cortisol stress response in FSL rats are rare. An indication of a rather increased cortisol stress response in FSL rats could be an increased cortisol response to the acetylcholine agonist arecoline.106
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.
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)
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
