Dehydroepiandrosterone

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DHEA is a naturally occurring hormone and either exerts benefits on its own, or can convert into both testosterone or estrogen depending on the body's need. DHEA supplementation is potent for reducing the 'effects of aging', but appears quite unreliable in its benefits.

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For usage after the age of 40 to preserve steroid hormone levels to 'youthful' levels, a dose of 25-50mg daily appears to be the lowest effective dose whereas 100mg tends to not be associated with any chronic harm in either gender.

The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Dehydroepiandrosterone has in your body, and how strong these effects are.

Level of Evidence	Effect	Change	Magnitude of Effect Size	Scientific Consensus	Comments
A	Testosterone		Notable	66% See all 18 studies	There appears to be an increase in testosterone following DHEA supplementation, but the vast majority of literature is in menopausal women (where testosterone contributes... show to libido). There is variability in the results, and DHEA is unreliable in increasing testosterone, but this unreliability extends to all demographics and subjects (with limited evidence of DHEA increasing testosterone in all studies including youthful athletes, which are less studied).
A	Estrogen		Notable	69% See all 14 studies	There appears to be a notable and unreliable increase in estrogen following DHEA supplementation, with most research being conducted in menopausal women. This increase... show in estrogen has been noted in men as well, although similarly unreliable.
A	DHEA		Strong	100% See all 13 studies	DHEA supplementation strongly and reliably increases serum levels of both DHEA and DHEA sulfate
B	Bone Mineral Density			71% See all 7 studies	Most evidence suggests no increase in bone mineral density, but this may be due to short trials (6 months). Longer trials note a small but unreliable increase in bone mineral... show density, so there may be a role of DHEA in bone health
B	Functionality in Elderly or Injured			66% See all 3 studies	Most evidence measuring functionality in elderly persons have not found any improvement with DHEA supplementation, although it is possible that DHEA may play a role
B	Sex Hormone Binding Globulin		Minor	66% See all 4 studies	There appears to be a decrease in SHBG concentrations in older individuals who also experience an increase in androgen/estrogen concentrations, but this is similarly unreliable
B	Libido			100% See all 3 studies	Insufficient evidence to support an increase in libido despite increases in androgen status
B	Fat Mass			100% See all 8 studies	No significant influence on fat mass appears to exist with DHEA supplementation in youth or in elderly persons
B	Lean Mass			100% See all 8 studies	Perhaps due to a lack of studies pairing DHEA with a prolonged resistance training program, there is no evidence to support DHEA supplementation to increase muscular or lean mass
B	IGF-1		Minor	75% See all 6 studies	An increase in IGF-1 hormone levels may exist following DHEA supplementation, although this has only been investigated in older persons.
B	Subjective Well-being			66% See all 4 studies	No significant influence on well being is noted with DHEA per se, although it may come secondary to other changes occurring during DHEA supplementation (such as improved... show functionality in elderly persons)
B	LDL-C			66% See all 4 studies	Although there is some counter evidence, usually DHEA supplementation does not alter LDL-C concentrations
B	HDL-C			75% See all 5 studies	Most of the evidence leans towards no significant influence of DHEA on HDL-C levels
B	Triglycerides			66% See all 3 studies	Mixed evidence, but it seems that DHEA doesn't have a significant influence on triglycerides
B	Cortisol		Minor	50% See all 5 studies	Highly unreliable influences on cortisol, with decreases seen in studies where androgens and estrogens are also increased (with no significant influence or possibly an... show increase in other studies)
B	Blood glucose			66% See all 3 studies	Most evidence suggests no alterations to fasting blood glucose levels
B	Power Output			100% See all 3 studies	No significant improvement in power output has been noted with DHEA supplementation (studies mostly in older individuals)
C	Stress			100% See study	No significant influence on parameters of stress
C	Fertility		Minor	100% See 2 studies	An increase in fertility has been noted with DHEA supplementation
C	Cognitive Decline		Minor	50% See 2 studies	May attenuate the rate of cognitive decline in persons at higher risk, but this protective effect does not seem to be overly remarkable
C	Prostate Specific Antigen			100% See 2 studies	No significant influence on PSA levels
C	Erections			100% See study	No significant influence on erectile properties in persons with sexual dysfunction
C	Weight			100% See study	No significant influence on weight noted with DHEA supplementation
C	Free Testosterone		Minor	100% See 2 studies	Increases in free testosterone have been noted to coincide with testosterone increases (which are unreliable)
C	Cognition			100% See study	Overall cognition not affected by DHEA supplementation
C	Depression			100% See study	No significant interactions with depression noted
C	Insulin Sensitivity			100% See all 3 studies	No significant influences on insulin sensitivity seem apparent with DHEA supplementation
C	Oxidation of LDL		Minor	100% See study	One study has noted less small particles of LDL, indicative of less LDL oxidation; possibly protective effects
C	IGF Binding Protein			100% See study	There may be an influence (study noted both increases and decreases with high variability) but this does not appear to be a clinical concern
C	Nitric Oxide		Minor	100% See study	Has been detected to increase nitric oxide concentrations in serum, needs to be replicated to investigate mechanisms
C	Insulin			100% See study	No significant alterations in fasting glucose levels
C	Sleep Quality			100% See study	No significant influence on sleep quality in menopausal women
C	Total Cholesterol		Minor	50% See all 3 studies	There may be a decrease in cholesterol seen with DHEA in hypercholesterolemics, but it is not overly reliable
C	Luteinizing Hormone			100% See 2 studies	No significant alterations detected in luteinizing hormone levels
C	Follicle-Stimulating Hormone			100% See 2 studies	No significant alterations in follicle-stimulating hormone levels
C	DHT		Minor	100% See 2 studies	May increase DHT levels alongside testosterone levels, but this has only been observed in postmenopausal women
C	Progesterone			100% See 2 studies	Mixed effects on progesterone (and 17-hydroxyprogesterone) leaning towards no significant influence (athough increases have been noted)
C	Blood Flow		Minor	100% See study	Possible increases in blood flow associated with DHEA supplementation
C	Liver Enzymes			100% See study	No detectable alteration in serum liver enzymes (biomarker of liver damage) seen with DHEA supplementation
D	Symptoms of Menopause		Minor	100% See 2 studies	Decreases in menopausal symptoms have been noted with DHEA supplementation
D	Serum T3			100% See study	No significant influence on serum T3 has been noted
D	Growth Hormone		Minor	50% See 2 studies	May increase growth hormone concentrations, but this appears to be unreliable
D	Plasma Endorphins		Minor	100% See study	An increase in plasma endorphins has been noted with DHEA supplementation

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Edit1. Origin and Structure

1.1. Origin

DHEA was first discovered as a urine metabolite in 1934 by Adolf Buteiiandt and Hans Dannenbaum from Germany, reaffirmed as a urinary metabolite in 1943 and isolated from serum in 1954.^[3]

Dehydroepiandrosterone, or DHEA, is the second most abundant circulating steroid in humans and serves as the substrate (precursor) for other androgens such as testosterone and dihydrotestosterone (DHT) as well as estrogens like Estrogen and 17β-Estradiol.^[4] It exists as a relatively balanced pool of DHEA and its sulfated conjugate, DHEAS (Dehydroepiandrosterone Sulfate, the most abundant circulating steroid) for further metabolism into more potent molecules.

As a supplement, it is aimed towards alleviating symptoms associated with a decreased DHEA pool (either aging in which DHEA declines after the age of 30-40, or adrenal insufficiency where DHEA synthesis declines) and sometimes it is used when the user wants to increase the DHEA pool and downstream metabolites, such as testosterone, for a short period of time.

1.2. Structure

DHEA has the official name of 3β-Hydroxy-5-Androstene-17-one and has a similar skeletal backbone to cholesterol, except without the side-chain (dissociated in the first step of metabolism, from cholesterol into pregnenolone), the remnants of the side-chain are replaced with a ketone group (double-bonded oxygen at the top right of the below structures).

1.3. Properties

DHEA's molecular formula is C₁₉H₂₈O₂, and with a molecular weight of 288.43.^[3]

Edit2. Biological Significance

2.1. Synthesis and Metabolism

Dietary cholesterol is converted into pregnenolone via the CYP11A1 enzyme, and then converted into DHEA via the CYP17 enzyme (P450c17) also known as 17 alpha-hydroxylase 17,20-lyase.^[5] DHEA converts to DHEAS via sulfotransferases and can be converted back via sulfatases, creating a large interchangeable 'pool' of DHEA:DHEAS circulating in the body for further metabolism.^[6] DHEA synthesis is usually referred to occur in the adrenal cortex (small glands above the kidneys) due to a high localized expression of the second enzyme mentioned (CYP17),^[7][8] yet synthesis of DHEA can occur in the testes,^[7] ovaries,^[9] and the brain where circulating levels of DHEA are synthesized locally independent of the rest of the body can can reach concentrations 6-8 times higher than systemic serum.^[10]

DHEA is made from cholesterol naturally via two enzymes, and is highly localized to the Adrenal Glands although not limited to them

Starting from the DHEA:DHEAS pool DHEA tends to be converted into androstenedione directly via the 3β-HSD enzyme, and then multiple paths can be taken. Androstenedione can be directed towards the most potent androgenic hormone 5α-Dihydrotestosterone (DHT) via either turning into testosterone and then becoming substrate for the 5α-Reductase enzyme, or by being substrate to the 5α-Reductase enzyme (to turn into 5α-Androstenedione) and then being converted to DHT. Either route requires one pass via the 5α-Reductase enzyme and one pass by the 17β-HSD enzyme (converting androstenedione to testosterone, and 5α-androstenedione to DHT).^[6][5]

If one of these androgens mentioned has not yet been substrate for the 5α-Reductase enzyme, they can instead be substrate for the Aromatase enzyme and be converted to estrogens. Androstenedione will be converted to Estrone, and Testosterone will be converted to Estrogen; both hormones with 5α in front of them cannot be converted to Estrogen, and Estrone can be converted to Estrogen via the same 17β-HSD enzyme mentioned before.^[6][5]

In a sense, androstenedione and testosterone are bidirectional hormones and can turn into more potent androgens (via 5α-Reductase) or more potent estrogens (via Aromatase). Androstenedione forms the start of this multidirectional pathway, but DHEA forms the pool from which Androsterone is derived from

DHEA, completely independent of the classical steroid pathways mentioned above, can be turned into bioactive DHEA derivatives; demonstrating another possible route for DHEA metabolism.

DHEA can turn into 7α-hydroxyDHEA via an enzyme Oxysterol 7α-hydroxylase (CYP3A4/5 has also been implicated^[11]), and this molecule can be converted into a beta form (7β-hydroxyDHEA) via 11β-HSD type 1.^[6][12] This is the same enzyme pathway that can take androstenedione and, after isomeration into epiandrosterone, create 7α-hydroxyepiandrosterone and 7β-hydroxyepiandrosterone. Conversion of DHEA into the 7α and 7β oxygenated metabolites mentioned above is not limited to steroidogenic tissues (testes, ovaries) nor the adrenals, and can occur in brain, spleen, thymus, perianal skin, ventral skin, intestine, colon, coecum and muscle tissues.^[13][14] Both 7α and 7β hydroxyDHEA can be further converted into 7-Oxo DHEA, which is sometimes referred to as 7-Keto (brand name) via the same 11β-HSD enzymes.^[15][16]

Simply put, DHEA can be metabolized into derivatives via CYP7B1 and this is irreversible. The 7α and 7β conjugates can covert to and from each other, using 7-Oxo (also known as 7-Keto) as an intermediate.

These DHEA metabolites are more involved with the immunological and inflammation aspects of DHEA supplementation, and some neurological aspects.

DHEA can form bioactive metabolites independent of classical steroid synthesis, and not through androstenedione

2.2. Excretion

Androgens tend to be converted to Androsterone Glucuronide, a water-soluble derivative of testosterone and DHT, and then are excreted in the urine.^[17] This is not the only urinary metabolite, as most steroid molecules can be excreted in the urine as well as DHEA.

2.3. Mechanisms of Action

Aside from DHEA acting as a pool for steroid hormones (which would exert metabolic effects vicariously through other hormones), DHEA may have direct actions as well.^[6] It has been shown to, by itself, active a cytosolic G-coupled membrane protein^[18][19] that, when incubated with endothelial cells, can increase cGMP and NO levels^[20] via PI3K/Akt.^[19] This effect (cGMP and NO increasing) has been seen in men after supplementation of 50mg DHEA daily, and may be a mechanism of cardioprotective effects.^[21] When coincubated with androgenic, estrogenic, and progesteronic antagonists (to see if the effects were vicariously through these hormones) no antagonism inhibited the effects, suggesting DHEA is a direct agonist/activator although metabolites of DHEA (7α-hydroxy, 7β-hydroxy, 7-Oxo) have not been ruled out.^[18][19]

This receptor has a good affinity for DHEA at 48.7 pM and is saturated in the range of 1-10uM.^[20]

This same G-coupled receptor can phosphorylated ERK 1/2^[22] and has been implicated in stabilizing Bcl-2.^[19] Phosphorylation of ERK1/2 led to increased angiogenesis, and this was seen with incubated DHEA and albumin-bound DHEA.^[22]

In immune cells, DHEA-S (sulfated version) has also been shown to dose-dependently increase superoxide generation in human neutrophils directly and via PKC activation.^[23] The metabolite of DHEA known as 7β-hydroxy DHEA has also been shown to possess anti-inflammatory effects in vitro by attenuating a pro-inflammatory response to TNF-α and modulating prostaglandin synthesis^[12] thus alleviating subsequent inflammation.^[24]

DHEA also exerts androgenic and estrogenic activity directly, without needing to metabolize into androgens or estrogens; however, its actions on these receptors are weak relative to androgens and estrogens.^[25] Metabolites of DHEA may also modulate these effects.^[26][6]

2.4. Depletion in Adrenal Fatigue

Endogenous levels of DHEA and DHEAS, the sulfur conjugate of DHEA, appear to be significantly reduce in situations of adrenal 'fatigue'.

2.5. Relation to Age

DHEA and its cojugate DHEAS appear to be related to age, declining in both men and females during the aging process.^[27][4] DHEA levels are relatively high after birth, and the descend rapidly until puberty where they return to seemingly supraphysiological levels, remaining stable until around 25-35 years of age, and steadily decline thereforth. At the age of 70, DHEA levels are approximately 20% that of the average 25 year old.^[28][27]

A circulating level of 4.1umol/L, or 1500ng/mL, is commonly seen as near the lower range of average DHEA concentrations for young (15-39) men.^[4] Many studies noting 'DHEA deficiency' in older men will use this level to define the deficiency.

Supplementing DHEA at a level which restores serum DHEA levels (50-100mg daily) does not appear to counter common 'side-effects' of aging such as libido loss or bone metabolism, for the most part DHEA levels and the symptoms we call 'aging' are unrelated.^[29] The decrease of circulating DHEA with aging, unlike decreases in circulating levels of L-Carnitine or Creatine seen in some populations, does not appear to be indicative of a DHEA deficiency state that needs to be corrected.^[30]

Edit3. Pharmacology

3.1. Bioavailability of Topical Administration

DHEA is commonly sold as a cream to be applied on the skin. For most purposes, this is because the product is catered to aiding the skin quality yet topical administration still influences the blood and the rest of the body.

In 36 healthy older women (60-70yrs), 4g of DHEA cream (10%) or gel (10%) applied on a 30x30cm area were compared against oral administration of 100mg DHEA. Oral administration had a C_max of 15.6+/-2.5ng/ml (from baseline of 2.3+/-0.3) at a T_max of an hour, measuring 5.7+/-0.5ng/ml at 6 hours and hitting baseline at 24 hours. The application of a gel or cream reached levels of 8.2+/-2.0nmol/l and 8.0+/-1.2nmol/l at 12 hours, and progressively rose up to 24 hours when the study ceased (higher than baseline values); serum concentrations appeared to cross at 18 hours.^[31] Interestingly, no differences were seen in circulating DHEA, testosterone or estrogen levels between the cream or gel yet the cream resulted in significantly higher androstenedione concentration at 24 hours and topical administration in general favored androgen metabolism more than oral administration.^[31] Over 14 days of application, the cream appeared to raise hormones better than the gel and no influene was seen on DHEA-S levels with topical application.^[31]

Topical administration also shows larger blood values of hormones over a period of days; although suggestive of a potentiating effect, this may be due to the effects of DHEA applied topically lasting more than 24 hours.^[31] Over a period of 12 months, serum levels of daily application are similar to those seem when measured at 28 days.^[32]

Despite the differences seen in kinetics, the overall bioavailability of topical administration and oral administration in reaching the serum is comparable with minimal differences in AUC, with exception to DHEAS which does not appear to be significantly spiked with topical application; it is to a degree, just minimally.^[31][32]

Higher levels of androgens seen with topical administration may be due to bypassing enzymatic digestion of androgens by UDP-Glucuronosyltransferase enzymes^[33][34] which are more prevalent in the gastrointestinal tract and liver.^[35] When measured in the blood, the most prevalent androgen is actually the metabolite ADT-G (Androsterone Glucuronide) consisting of up to 90% of all androgens after application or post-menopausal females, and reaches 70% the value of controls.^[32][36] ADT-G is important to note in women as the majority of androgen synthesis from DHEA in women exists in peripheral tissue, and may be a more reliable biomarker of androgenic effects than circulating testosterone.^[17]

Topical administration appears to have comparable overall bioavailability (percent hitting the bloodstream) when compared to oral ingestion. Topical seems to influence androgens like testosterone more than oral ingestion, and although there are no differences in the short term DHEA cream appears to be better than DHEA gel

3.2. Oral Administration

The T_max of DHEA supplementation, orally, fluctuates wildly. Many studies suggest large acute boluses have a T_max around 1-3 hours,^[31][37] but T_max values of up to 7-12 have been reported at times.^[37]

In young men (18-42), DHEA supplementation at 50mg is insufficient to significantly change circulating DHEA/DHEAS levels whereas 200mg appears to be able to.^[37] In this same population, plasma testosterone and DHT from DHEA did not significantly increase while serum ADT-G (metabolite of androgens) rose dose-dependently from an average 24h AUC of 198ng/h/mL to 603 (after 200mg administration).^[37]

3.3. Metabolism and Metabolites

A metabolite of DHEA that exerts notable anti-inflammatory properties is β-AET, otherwise known as Androstene-3β,7β,17β-triol.^[38]

Edit4. Interactions with Hormones

4.1. Cortisol

DHEA exists in a pseudo-balance with cortisol, as the two opposing hormones of the Hypothalamic-Pituitary-Adrenal stress axis. Both hormones share a common pre-requisite, as they both have their release stimulated by adrenocorticotropic hormone (ACTH).^[39] This relation tends to surface in circulating levels of the two, as cortisol has a morning 'spike' in activity and declines throughout the day, whereas DHEA is seen as more stable but also experiences a decline; the two are positively correlated in serum concentrations, with one tending to increase alongside the other in healthy individuals.^[40][41][42] Interestingly, the decline of DHEA seen with age is met with a decline in cortisol and maintainence of this balance; thus age may not per se cause an abnormal balance.^[43] Due to DHEA being less volatile than cortisol, it is seen as a better biomarker of adrenaline activity.^[40][44]

The two exist in a ratio, and aberrations in this ratio are seen in disease states. Higher cortisol:DHEA ratios (more cortisol, less DHEA) are seen in resistant depression,^[45][46][47] anorexia nervosa,^[48] bipolar disorder,^[49] and to a lesser extent, schizophrenia.^[49][50] DHEA supplementation at 100mg for 6 weeks has actually been shown to help schizophrenic symptoms, although not as potent as a curative compound;^[51][52] it is a contested area of research.^[53] The opposite side of the relation holds true as well, with a high DHEA to cortisol ratio being implicated in chronic fatigue syndrome.^[54]

The Cortisol/DHEA ratio may underlie variability in responses to DHEA. One study in schizophrenics noted that more beneficial effects were seen in persons with higher cortisol levels relative to DHEA, and less in those with more stable ratios.^[55]

Other compounds that have been implicated in the Cortisol:DHEA ratio are Melatonin, which has been shown to increase DHEA relative to cortisol^[56] and L-Theanine may be more effective in schizophrenics that have elevated cortisol to DHEA.^[57]

A balance is supposed to exist between these two hormones, and DHEA may have quite a few of its benefits associated with 'correcting' an abnormal ratio of these two in instances of hypercortisolemia (high blood cortisol)

4.2. Testosterone (and Androgens)

Acute supplementation of 50mg DHEA prior to exercise is able to increase free testosterone in middle-aged men and prevent the subsequent decline during high intensity training.^[58]

4.3. Estrogen (and related Estrogens)

Edit5. Interactions with Lipid Metabolism and Cardiac Health

5.1. Endothelium and Vessel Health

DHEA has been found to interact with a G-protein coupled receptor on the cytosol, which can induce a cascade via MAPK and PI3K/Akt, resulting in increased cGMP and NO.^[20][59] This receptor has a good affinity for DHEA at 48.7 pM and is saturated in the range of 1-10uM, and its activation confers cardioprotective effects.^[20] The biomarkers of this receptor have been seen in vivo after 50mg DHEA ingestion, and confer cardioprotective effects.^[21]

May exert direct protective effects on the endothelium (blood vessel wall) and help maintain vessel health and functionality

5.2. Artherosclerosis and Cholesterol

DHEA has been suggested to reduce lipoprotein levels via its conversion to estrogen^[60]

In interventions in both humans and animals, DHEA supplementation appears to reduce lipoprotein levels. However, it reduces total cholesterol and both LDL and HDL fragments of total cholesterol, and seems to be fairly independent of prior disease state or condition.^{[61][62][63][64][21]}

Some studies do not note decreases in lipoproteins, and these studies either note no decrease in both lipoproteins (theoretically) secondary to no reductions in estrogen^[65] or do not measure estrogen.^[66] A few studies note the inconsistencies in the literature, and note a rise in estrogen with no changes in lipoproteins.^[67]

However, prospective studies on artherosclerosis have not found a relationship between DHEA/DHEAS levels and pathogenesis of atherosclerosis, suggesting no relation between the two.^[68]

There is evidence that DHEA reduces lipoproteins potently, and this may be vicarious through the actions of estrogen. LDL and HDL both experience declines, however, and the clinical significance of DHEA being cardioprotective in this manner is in disrepute

Edit6. Interactions with Longevity

6.1. Telomeres

One study has been put forth suggesting telomere lengthening at a dose of 5-12.5mg DHEA daily, whereas higher dosages shortened telomeres;^[3] however, analysis was via a Bi-Directional O-Ring test and has not been shown to be reliable as validation on the BDORT test has only been published in one journal, by one author.^[69][70] Beyond this information, no other studies have investigated supplemental DHEA and telomere length.

Edit7. Interactions with Glucose Metabolism

7.1. Human Interventions

Studies that are for the notion that DHEA improves insulin sensitivity find improvements at 50mg daily for 6 months or longer in aged (65+) individuals with abnormal glucose disposal, where glucose AUC and disposal rate decline with no significant effects on insulin; indicative of insulin sensitivity.^[71][72] This dose in women with impaired glucose tolerance for 3 months has been shown to attenuate adverse effects with time, although not benefit insulin sensitivity.^[73] One study at 25mg daily has shown benefit on insulin sensitivity in persons without glucose impairment,^[74] and a short term study looking at mechanisms noted increased insulin sensitivity (but no improvements in glucose disposal) via increasing T-lymphocyte binding to insulin.^[75] One study using a 10% DHEA cream noted that it was able to reduce insulin levels (-17%) and fasting glucose (-11%).^[76]

25mg DHEA daily in men with hypercholesterolemia has also shown benefit on insulin sensitivity.^[77]

Beneficial results do not appear to be related to dose, as superloading 1600mg DHEA daily in men does not force insulin sensitizing effects.^[78]

Some studies do not report back significant improvements in insulin sensitivity have used 50mg daily for 3 months in otherwise healthy overweight aged men with low (less than 1500ng/mL) DHEA; DHEA did not even trend towards significance, and appeared to have no directional effect.^[65] This lack of efficacy resulting in no trend towards significance has been noted elsewhere with doses that should normally work.^[79][80] In post-menopausal women where DHEA would not show efficacy, the combination of DHEA and mixed exercises did not create efficacy of DHEA.^[81]

Some studies noting null results do note trends towards significance, reducing insulin levels and AUC,^[63]

At least two studies have noted a slight increase in insulin levels with no changes in serum glucose levels at 50-75mg daily, suggesting a trend towards insulin resistance as well, although the degree of resistance was minimal.^[82][83]

Effects of supplemental DHEA on insulin sensitivity is dubious

7.2. Sexual Dimorphism

It is possible that insulin sensitizing effects may be more present in men, due to higher circulating androgen status after DHEA supplementation. Androgens are reduced with aging and inversely related to insulin sensitivity^[72] and studies in insulin sensitivity after DHEA supplementation, despite not having consensus, appear to be more promising in men rather than women (although this may be secondary to less studies existing in men).^[77][71] This is somewhat strengthened by better results being seen with topical DHEA supplementation (cream) in women,^[76] and topical administration favoring androgen metabolism in peripheral tissue to a greater extent than oral administration.^[31]

Edit8. Interactions with Muscle Mass

8.1. In Youth

In regards to the trials conducted on youth with DHEA, one trial conducted on 9 men aged 23+/-4 years found that DHEA at 150mg daily for 6 out of 8 weeks (1-2, 4-5, 7-8) was unable to increase circulating testosterone and estrogen levels, and due to a loss of samples DHEA levels in serum could not be measured.^[84] 100mg DHEA in 19+/-1 year old males increased circulating DHEA by 2.5-fold, increased testosterone, and decreased circulating markers of muscle breakdown.^[85] Another study in 19-22 year old men using 100mg DHEA daily for 28 days noted increases in circulating testosterone from 18.2+/-6.8nM to 25.4+/-8.1nM, a 39% increase (free testosterone increased by 4%) but this increase, when paired with soccer training, was unable to influence skeletal muscle mass.^[86]

Beyond these studies, 40mg DHEA in obese adolescents confers no benefits to skeletal muscle mass,^[87] 25mg DHEA didn't raise testosterone in youth and muscle mass was not measured,^[88] but an obscene dose of 1600mg per day for 28 days was able to reduce fat mass without changes in weight, signifying muscle hypertrophy, without affecting testosterone.^[78]

100-150mg DHEA appears to increase testosterone levels in most studies (no consensus) but this does not per se translate into increases in skeletal muscle mass. Studies combining effective doses of DHEA and weight lifting in youth are lacking

Edit9. Interactions with Fat Mass and Obesity

9.1. Food Intake

Several studies measuring food intake of rats given DHEA find that DHEA ingestion is associated with less food intake at 0.3% feed weight,^[89] 0.4%,^[90] and 0.6%^[91][92]. Interestingly, DHEA has been implicated in reducing the intake of fatty foods specifically, at doses as low as 25mg/kg bodyweight^[93] which is 4mg/kg bodyweight after Body-Surface Area conversion to humans.

The conjugate, DHEAS, appears to be related to satiety after feeding in humans.^[94]

It is possible that DHEA may independently reduce caloric intake, especially from fat, which may contribute to any observed reductions in body fat

9.2. Mechanisms

In a study on castrated and non-castrated rats that found no differences in anti-obesity effects, it was suggested that DHEA itself exerted anti-obesity effects rather than conversion into testosterone.^[89]

DHEA has been implicated in reducing the protein content of the PPARy receptor in fat cells, as well as sterol regulatory element-binding protein and adipocyte lipid-binding protein.^[90] DHEA has also been shown in rats to increase uncoupling protein expression in adipocytes.^[95]

9.3. Interventions

One study investigating a very large dose of DHEA (1600mg) noted a 31% reduction in fat mass when compared to baseline, with no significant alterations in body weight.^[78]

Edit10. Interactions with the Digestive Tract

10.1. Nutrient Digestibility

A study in aged rats with 0.5% DHEA content of food for 13 weeks found a slight decrease in absorption of protein in the intestines at 2 weeks (-4%) whereas at 6 weeks this reduction was attenuated.^[96]

Fatty acid absorption does not appear to be influenced with DHEA supplementation.^[96]

10.2. Colon Cancer

DHEA status in the blood has been correlated with colon cancer risk, in where confirmed cases of colon cancer had 13% lower circulating DHEA and 21% lower DHEAS relative to age and cohort matched controls, suggesting a relation between DHEA and colonic cancer risk reduction.^[97]

DHEA's oxygenated metabolites (metabolites that are not androgenic or estrogenic steroids) have been noted, in Caco-2 cells (in vitro model for intestinal cells) to have anti-proliferative properties and may suppress carcinogenic growth.^[98]

Edit11. Interactions with Neurology

11.1. Mood and Well-Being

A few studies conducted in the past, usually open label, associated DHEA supplementation with improvements in mood when given to older individuals with lower circulating DHEA levels.^{[99][80][100]} When double-blind placebo studies are run, an increase in well-being is seen in both DHEA supplemented groups as well as placebo groups; suggesting that there is no treatment effect in otherwise healthy individuals.^{[30][101][102][103]} This is not the consensus, as some studies do not an increase in otherwise healthy males but require an androgen deficiency as pre-requisite.^[104]

DHEA is thought to increase well-being due to the ability of DHEA supplementation to increase circulating levels of beta-endorphins and other neurosteroids assocaited with happiness in the body^[104][72] and the brain.^[105]

This is in contrast to any state of adrenal insufficiency, where low circulating levels of DHEA are due to low-activity adrenal glands rather than the age-associated decline. In this state, DHEA supplementation is effective at increasing mood and well-being more than placebo.^[106][107] One study suggested that this may extend to stable HIV patients as well.^[108]

Seems pretty reliable as a mood increasing agent in those with adrenal insufficiency, but in otherwise healthy individuals it does not appear to be effective. In older men with androgen deficiency there is no consensus on the effects of DHEA on mood as it appears mixed

Edit12. Prostatic Implications

12.1. Prostate Specific Antigen (PSA)

PSA is a biomarker used to measure prostatic hypertrophy and risk for prostate cancer.^[109] When PSA levels increase in the blood, it suggests that risk for prostate cancer may be increased.

Studies on DHEA supplementation in men measuring PSA note either no increases in circulating PSA levels at 100mg daily for a year^[110] or 6 months^[111] and at 50mg over the short-term^[112][65] or 6 months.^[113]

In vitro, DHEA appears to be able to increase PSA secretion from prostate cells only if cancerous and to a lesser potency than that of other androgens like testosterone.^[112][114]

Although there is biological basis for DHEA and its metabolites (testosterone, dihydrotestosterone) to increase prostate-specific antigen (PSA) levels and increase risk of prostate cancer, it does not appear to do this at moderate doses when taken by men above the age of 40 without prostate cancer

12.2. Prostate weight

In rat studies where the prostate is measured, low dose DHEA over a long period of time is not associated with an increase in prostate weight despite increases in circulating testosterone and DHEA/DHEAS.^[115]

Edit13. Intervention Studies (Humans) at a Glance

This section is mostly thanks to a thorough 2011 review that compiled many studies, although further studies have been added.^[6]

13.1. In men

Said review^[6] noted 28 studies conducted with DHEA in men, and found that the reseacher's hypothesis' came back neutral 7 times (31%) and came back positive the other 15 (69%) times; no investigated study noted harmful effects.^[6]

The neutral studies found no benefit to DHEA supplementation in augmenting Growth Hormone supplementation in men,^[116] no influence on bone mineral metabolism or bone mass,^[117] no influence on skeletal muscle mass,^[118][119] and no significant benefit to cognition.^[30][120] One neutral study was conducted in a model of Multiple Sclerosis, presented at a conference in Berlin showing no significant benefit, but the presentation noted in the review cannot be retrieved online.^[6] Beyond this, further additions that were not mentioned in the review include no effects seen on insulin sensitivity^[78][82] and mood.^[121]

The beneficial trials noted were conducted in regards to hormonal status (androgens),^[122] lipid profiles,^{[78][123][124]} mood^[104][80] and depression,^[125] joint pain,^[104] endothelial function (heart health),^[77] bone mineral density (only in the hip, however)^[126][111] immunity,^[127] apparent insulin sensitivity,^[77][71] and body composition.^{[100][121][128][71]}

Of these trials, a few were conducted in adrenal fatigue/insufficiency and excluded from the above amalgamation as this is treating a deficiency rather than supraphysiological supplementation.^{[129][106][130][101]} One study showed benefit in the disease state of hereditary angioedema.^[131]

Without analyzing the details of Human Interventions (done in other sections), basic supplementation of DHEA at 50-100mg daily is able to alleviate almost all aspects of 'aging', but is contested on most of them. The only topics that appears to both be substantially researched and uncontested are treatment of Adrenal Insufficiency being beneficial and DHEA at 50-100mg conferring a cardioprotective effect (on the level of the endothelium and reducing lipid levels) in men above 40

13.2. In women

Said review^[6] compiled 63 studies investigating DHEA supplementation in women, and found no significant effects with 11 studies (17%) and benefit with 52 of them (83%). No negative findings were reported in this review.

Neutral studies (those that found no statistically significant benefit) included body composition,^{[83][132][100][81][76][118][133]} exercise capacity,^[132][121] menopausal symptoms,^[64] bone mass,^[134][100] insulin sensitivity,^[82][80][81] mood,^[121] immunology,^[135] cognition,^[120] and sexuality in adrenal failure^[136]. The aforementioned study on Multiple Sclerosis (in the section on men) also investigated women with the same null results.

Benefit has been found with skin treatment when applied topically or orally,^[137][122] lipid profiles,^{[83][74][76][64][123]} cardiac health,^[138] bone mineral density,^{[121][122][126][117][139]} body composition,^[139] sexuality,^[140][122] mood,^[80][141] depression,^[125] apparent insulin sensitivity,^{[74][71][76][75]} and menopausal symptoms such as hot flashes.^[142]

Some studies were omitted from the above paragraph due to being in specific disease states, such as adrenal insufficiency,^{[143][106][101][144][129][107][145]} Anorexia Nervosa,^[146] hypopituitary persons,^{[147][116][148]} or lupus.^{[149][150][151][152][153][154][155]}

For women, the notion that DHEA benefits heart health does carry over but with less evidence relative to men. However, much more evidence exists for the beneficial effects of DHEA on Bone Mineral Density suggesting that it may be a good preventative measure for osteopenia and osteoporosis risk.

Edit14. Notable Related Compounds

14.1. Androst-3,5-dien-7,17-dione

This is a further metabolite of 7-Keto DHEA, and is the result when a single bond on the A ring between carbons 3 and 4 is turned into a double bond. This turns the 5-Androstene designation into 3,5-dien, as the -en refers to a double bond and the di refers to two. Surprisingly, it is a natural metabolite found in the urine as this change from 7-Oxo (the addition of a double bond) appears to occur in the body somewhere^[156] perhaps in the liver.^[157] Sometimes this metabolite is also referred to as 3-desoxy-7-keto DHEA. Regardless of the colloquial name given, the elongated chemical name of this molecule is (8R,9S,10R,13S,14S)-10,13-dimethyl-2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta{a}phenanthrene-7,17-dione

Two separate 'common' names to refer to the same molecule

This conjugate appears to possess competitive aromatase inhibiting activities, with an IC₅₀ of 1.8uM and a K_i of 0.22uM.^[158] The inhibition was time-dependent in pseudo-first order manner, with a K_inact min^-1 of 0.119.^[158]

Not yet scientifically tested in humans, but appears to be a potent aromatase inhibitor

Edit15. Nutrient-Nutrient Interactions

15.1. Aromatase Inhibitors

Since DHEA is the metabolic precursor for both androgens and estrogens, pairing DHEA with an anti-aromatase theoretically directs DHEA as substrate towards androgen status.

One study investiating DHEA inconjunction with an aromatase inhibitor (AI) found that the combination was more potent at increasing testosterone than either in isolation (8.5nmol/L increase in combination, 3.5nmol/L with DHEA, 4.9nmol/L with the AI atamestane); pairing DHEA with an AI also reduced the inevitable spike in estrogen to 2/3rds that seen with DHEA alone.^[159]

Edit16. Safety and Toxicity

50mg DHEA daily for 52 weeks in postmenopausal women is not associated with any significant toxic or adverse effects^[79] and is generally seen as a therapeutically effective dose to avoid side-effects over the long-term.^[160] Lower doses (25mg) for longer periods of time (2 years) are also seen as safe.^[72]

16.1. Androgenicity in Women

DHEA side effects inducing 'androgenic' side-effects in women appear to be rare, but exist. A few studies note increased occurrence of acne when DHEA is taken orally, but this does not appear to affect all persons.^[79]

Even rarer, but still reported, are instances of increased facial hair growth in women.^[79]

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