Dehydroepiandrosterone health benefits


In by Raphikammer

DHEA is the acronym used to designate the hormone “dehydroepiandrosterone,”

also referred to as “prasterone.”

The chemical name forDHEAis 5-androsten-3-ol-17-one

DHEA is available as an over-the-counter dietary

supplement in the United States, as the Food and Drug Administration

did not include it in the 2004 Anabolic Steroid

Control Act, which reclassified other related agents as

anabolic steroids and hence, controlled substances. As

a dietary supplement, it is marketed under different

trade names (e.g., Nature’s Blend DHEA, Nature’s Bounty

DHEA, DHEA Max, DHEA Fuel, etc.). A pharmaceuticalgrade

preparation, currently available only for experimental

use, has been assigned the trade name Prestara (previously

known as Aslera or GL701).

Discovered in 1934, DHEA is the most abundant steroid

hormone, and is produced by the adrenal glands in humans

and other primates.


It acts as a weak androgen and serves as a precursor of other steroids including

more potent androgens and estrogens. To date, however,

the exact functions of this hormone remain unknown.

DHEA is broadly traded on the Internet, under

the claim of being a “marvel hormone.” Despite the

growing popularity of its use, there is insufficient scientific

evidence supporting the purported potential health

benefits, and little information regarding the potential

short- and long-term adverse risks of consuming exogenous

DHEA. Moreover, variations in quality control and

manufacturing practices of dietary supplements result

in differences in concentrations and purity of the marketed

compounds, and insufficient surveillance for side


Biosynthesis and Metabolism

DHEA is primarily produced in the zona reticularis of

the adrenal cortex.

In healthy women, the adrenal gland

is the principal source of this steroid, whereas in men,

10% to 25% of the circulating DHEA is secreted by the

testes (1). It can also be synthesized within the central

nervous system (CNS), and can be considered a “neurosteroid”

(2). Pregnenolone, the immediate precursor of

DHEA, is derived from cholesterol through the action of

the cytochrome P450 side-chain cleavage enzyme (CYPscc).

It is converted into DHEA by cytochrome P450 17-

hydroxylase (CYP17), while hydroxysteroid sulfotransferase

(DHEAST) catalyzes the transformation of DHEA

into its 3-sulfated metabolite DHEAS (Fig. 2). This can be

converted back to DHEA by the action of sulfohydrolases

(DHEASH), located in the adrenal gland and peripheral


Human plasma contains DHEA-fatty esters (DHEAFA),

which are formed fromDHEAby the enzyme lecithincholesterol

acyltransferase. Newly formed DHEA-FA are

incorporated into very low-density lipoproteins (VLDL)

and low-density lipoproteins (LDL) and may be used as

substrates for the synthesis of active oxidized and hydroxylated

metabolites in the periphery, such as 7/-

hydroxy-DHEA in the brain, and androstenedione, androstenediol,

and androstenetriol in the skin and immune

organs (3,4).

Regulation of DHEA Production

Release of DHEA by the adrenals is mostly synchronous

with that of cortisol, under the stimulus of the hypothalamic

corticotropic-releasing hormone (CRH) and pituitary

adrenocorticotropic hormone (ACTH). However, the

finding of dissociation between DHEA and cortisol secretion

during several physiologic and pathophysiologic

states suggests that other non-ACTH-mediated mechanisms

may be involved in the modulation of DHEA secretion.

Estrogens, growth hormone, insulin, and prolactin

stimulate DHEA secretion by human adrenal cells. However,

these findings have not always been replicated in animal

or clinical studies. A complex intra-adrenal network

involving vascular and nervous systems, local growth and

immune factors, and a “cross talk” between cells of the

cortex and medulla, the other component of the adrenal

gland, also regulate DHEA secretion. The existence of

a specific “adrenal androgen-stimulating hormone” has

also been postulated, but remains controversial (5).

Adrenarche and Adrenopause

At birth, DHEAS is the predominant circulating steroid.

However, a dramatic involution of the fetal adrenal zone,

starting in the first postnatal month and continuing

through the first year of life, is paralleled by a sudden

decrease in DHEA/DHEAS, which remains unchanged

for the next six years. By the age of six to eight years,

the adrenal gland matures, culminating in the creation of

Chemical structure of dehydroepiandrosterone (DHEA).

the zona reticularis, followed by an abrupt elevation in

DHEA and DHEAS concentrations, termed the “adrenarche”

(6). Peak concentrations of DHEA (180–800 ng/dL)

and DHEAS (45–450 g/dL) are reached during the third

decade of life. Subsequently, there is a progressive 2% decline

per year in DHEA and DHEAS secretion and excretion,

with concentrations equal to 20% of the peak by the

age of 80, and values lower in women than in men (5,7).

This marked decline has been termed “adrenopause.”

DHEA and DHEAS levels are higher in men than in

women at all ages.

DHEA Mechanisms of Action

Despite the identification of high-affinity binding sites for

DHEA in rat liver, T-lymphocytes, and endothelial cells,

the search for a specific, cognate DHEA receptor has been

unsuccessful. Multiple mechanisms of action have been

proposed for DHEA. Most important among these are that

DHEA can be metabolized into more potent androgens

[testosterone and dihydrotestosterone (T and DHT)] and

estrogens (estradiol and estrone) in the periphery, which

  • Cholesterol
  • Pregnenolone
  • Androstenedione
  • Androsterone DHEAS
  • DHEA
  • 17α−Hydroxypregnenolone
  • 3β-HSD
  • CYP17
  • 5α-R
  • 3α-HSD
  • 17β-HSD
  • CYParo
  • Testosterone
  • Estradiol
  • CYP17

Schematic diagram of DHEA/DHEAS biosynthesis and

metabolism. Abbreviations: CYPscc, cytochrome P450 side-chain cleavage

enzyme; CYP17, cytochrome P450 17 -hydroxylase; 3/17/3-HSD, 3-

/17-/3 hydroxysteroid dehydrogenase; 5-R, 5- reductase; DHEASH,

DHEA sulfohydrolase; DHEAST, DHEA sulfotransferase; CYParo, cytochrome

P450 aromatase.

Table 1 Dissociation of Cortisol and DHEA/DHEAS Secretion During

Physiological and Pathological Conditions

Condition DHEA DHEAS Cortisol

Physiological (age-related)

Fetal stage ↑ N

Birth ↑ N

Infancy and childhood ↓ N

Adrenarche (6–8 yr) ↑ ↑ N

Puberty ↑ ↑ N

Adrenopause (50–60 yr) ↓ ↓ N or ↑


Anorexia nervosa ↓ ↓ ↑

Chronic/severe illness ↓ ↑

Burn trauma ↓ ↑

Cushing disease N N ↑

Congenital adrenal hyperplasia ↑ ↓

Ectopic ACTH syndrome N, ↑, or ↓ N, ↑, or↓ ↑

Idiopathic hirsutism ↑ N

Partial hypopituitarism without

ACTH deficiency

↓ ↓ N

End-stage renal diseases ↓ ↑

Stress ↓ ↓ ↑

N = normal serum levels;↑=increased serum levels;↓=decreased serum

levels. can interact with specific androgen and estrogen receptors.

DHEA itself can bind to the androgen and estrogen receptors,

but its affinity is extremely low compared with those

of the native ligands. It has been estimated that DHEA

and DHEAS function as precursors of 50% of androgens

in men, 75% of active estrogens in premenopausal women,

and 100% of active estrogens in postmenopausal women

(8). Lipophilic DHEA, but not hydrophobic DHEAS, can

be converted into both androgens and estrogens intracellularly

in target tissues by “intracrine” processes (4). This

conversion depends on the levels of different steroidogenic

and metabolizing enzymes, and on the hormonal

milieu. For example, DHEAS and sulfatase are present

in high concentrations in the prostate, and the resultant

metabolism of DHEA to DHT accounts for up to one-sixth

of the intraprostatic DHT (9).

DHEA can also function as a neurosteroid, by modulating

neuronal growth, development, and excitability, the

latter via interaction with -aminobutyric acid (GABAA),

N-methyl-D-aspartate (NMDA), and sigma receptors (10).

It is known to be a potent inhibitor of glucose-6-phosphate

dehydrogenase (G6DPH), thus interfering with the formation

of mitochondrial nicotinamide adenine dinucleotide

phosphate [NADP(H)] and ribose-6-phosphate and inhibiting

DNA synthesis and cell proliferation (11). The

steroid hormone has also been proposed to exert antiglucocorticoid,

cytokine modulatory, potassium channel and

cyclic guanyl monophosphate (cGMP) stimulatory, and

thermogenic effects.


Absorption and Tissue Distribution

While DHEA is marketed as an oral product, it has

also been shown to be absorbed when administered by

the transdermal, intravenous, subcutaneous, and vaginal

routes. Crystalline and micronized formulations result in

higher DHEAS serum concentrations, possibly due to an

enhanced rate of absorption (12). After absorption in the

small intestine, DHEA is mainly sulfated in the liver. The

nonoral route averts first pass liver degradation, resulting

in higher serum levels. DHEA concentrations are high in

the brain, with a brain-to-plasma ratio of 4–6.5:1 (13) and

plasma, spleen, kidney, and liver concentrations follow in

descending order. Cerebrospinal, salivary, and joint fluid

levels are directly related to those of serum.

Bioavailability, Metabolism, and Clearance

Pharmacokinetic studies on DHEA reveal a clearance rate

compatible with a two-compartment model. The initial

volume of distribution is 17.0 °æ 3 L. DHEA disappears

from the first compartment in 17.2 °æ 6.2 minutes and from

the second in 60.2 °æ 12.3 minutes (14). DHEAS follows a

one-compartment model of disappearance. Its volume of

distribution is 4.6 °æ 0.9 L, while the half-life from that

compartment is 13.7 hours (15). In men, 77.8 °æ 17.3% of

the DHEAS that enters the circulation will reappear as

DHEA, while in women, it is 60.5 °æ 8.2%. The opposite

conversion of DHEA to DHEAS is much smaller, 5.2% °æ

0.7% in men, and 6.25% °æ 0.54% in women.

Mean metabolic clearance rates (MCRs) were calculated

using the constant infusion technique: The DHEA

MCRis 2050°æ160 L/day in men and 2040°æ160 L/day in

women, whereas the MCR for DHEAS is 13.8 °æ 2.7 L/day

in men and 12.5 °æ 1.0 L/day in women. The differences

in the clearance rates of DHEA and DHEAS are partly

explained by different binding efficiencies with albumin.

Circulating DHEA is primarily bound to albumin, with

only minimal binding to sex hormone-binding globulin

(SHBG); the remaining small amount is free. There is no

known specific DHEA-binding protein. In comparison,

DHEAS is strongly bound to albumin but not to SHBG,

and an even smaller amount is protein free. Obesity results

in increased MCR for DHEA from 2000 to 4000 L/day in

women. A rise in MCR is also caused by insulin infusion

in men (16).

DHEA Supplementation

Considerations related to the metabolism of DHEA become

more complicated when it is administered as a dietary

supplement (in the United States) or as a drug (in

some other countries). The steroid is usually given orally

in a single morning dose, as its constant interconversion

to DHEAS and the long half-life of DHEAS make multiple

dosing unnecessary. In addition, morning dosing mimics

the natural rhythm of DHEA secretion. Doses ranging

from 25 to 1600 mg/day have been used in different


After an oral dose, the half-lives of DHEA/DHEAS

are longer (24 hours) than those reported in intravenous

tracer studies, which may reflect the conversion ofDHEAS

toDHEA(17). Oral administration of 20 to 50mgofDHEA

in patients with primary or secondary adrenal insufficiency

restores serum DHEA and DHEAS concentrations

to the range observed in normal young individuals, while

a dose of 100 to 200 mg/day results in supraphysiological


Different metabolic pathways for exogenous DHEA

in relation to gender and age have been reported. DHEA

levels after oral administration of 25 or 50 mg DHEA for

eight days were persistently higher in women versus men

(17). Similarly, oral administration of 200mgof micronized

DHEA in single or multiple doses for 15 days in healthy

adult men and women resulted in higher serum concentrations

and bioavailability (measured byDHEACmax and

AUC) in women. The net increase in DHEAS levels was

21-fold in women and 5-fold in men (18). The metabolic

fate of exogenous DHEA also differs by gender and age.

While in pre- and postmenopausal women, DHEA is

mostly transformed into androgens, in men it is preferentially

metabolized into estrogens. Higher serum concentrations

of DHEA, testosterone, and estradiol are achieved

in elderly subjects (19).


DHEA Replacement in Adrenal Insufficiency

Patients with primary (Addison disease) and secondary

adrenal insufficiency, typically exhibit very low, often undetectable,

serum concentrations of DHEA(S) compared

with values in age-matched control subjects. Despite optimal

glucocorticoid and mineralocorticoid replacement,

however, these patients often experience chronic fatigue,

reduced sense of well-being, and lack of sexual interest.

Some studies have suggested that DHEA replacement

exerts a positive effect on mood, vitality, sexuality,

and overall well-being mostly in women and, to a lesser

extent, in men, with chronic adrenal insufficiency (20–23).

For example, oral administration of 50 mg/day of DHEA

for four months to 24womenwith adrenal insufficiency increased

serum levels of DHEAS, androstenedione, testosterone,

and androstenediol glucuronide, and improved

overall well-being, mood, and sexual activity (20). In another

study of 15 men and 24 women with Addison disease,

administration of 50 mg/day of DHEA for three

months corrected the hormonal deficiency and improved

self-esteem, while it tended to enhance overall well-being,

mood, and energy (21). However, other studies have failed

to show similar effects (24–26). Moreover, a meta-analysis

of 10 randomized placebo-controlled studies concluded

that DHEA may improve health-related quality of life and

depression in women with adrenal insufficiency, though

the effect size (0.21; 95% confidence interval, 0.08–0.33;

inconsistency (I2) = 32%) was too small to support the

routine use of DHEA in this patient group (27).

In the earlier studies, a single oral dose of DHEA

(25–50 mg) was sufficient to keep serum concentrations

of DHEA within the normal range, while signs of overreplacement

included acne, hirsutism, or alopecia. Moreover,

concerns have been raised about the effects of DHEA

supplementation on the lipid profile and specifically on

high-density lipoproteins (HDL) levels in hypoadrenal

women (28), though it has been reported to improve their

insulin resistance (29).

Because a pharmaceutically controlled DHEA

preparation, as well as proof of effectiveness and safety

in long-term phase III trials, are still lacking, replacement

of DHEA in patients with adrenal insufficiency should be

220 Alesci et al.

restricted to those individuals whose well-being or libido

is severely impaired despite adequate glucocorticoid and

mineralocorticoid replacement.

DHEA Replacement in Adrenopause and

Age-Related Disorders

As noted, aging is accompanied by profound decreases in

circulating concentrations of DHEA and DHEAS in both

sexes (5,7). Epidemiological studies suggest an association

between the DHEA and DHEAS declines and the adverse

effects of aging, albeit with gender differences.

One large, prospective observational study reported

a small, but significant, inverse correlation between serum

DHEAS concentrations and risk of cardiovascular mortality

in men at 19-year follow-up, whereas in women,

high DHEAS levels were associated with an increased

risk of cardiovascular death at 12-year follow-up, and this

trend lost significance at 19-year follow-up (30). Similar results

were reported in another study of 963 men and 1171

women aged>65 years: all-cause and cardiovascular mortality

were highest in men with DHEAS levels in the lowest

quartile, whereas no significant association between

circulating DHEAS and mortality was found in women

(31). Other studies failed to demonstrate this inverse relationship

in men (32). Positive correlations between low

circulating DHEAS concentrations and depressed mood

and bone loss have been reported in aged women (33).

In comparison, DHEAS levels are reduced in men, with

noninsulin-dependent diabetes mellitus (NIDDM) (34).

Reports of an association between low DHEA levels and

Alzheimer disease are conflicting.

It remains uncertain as to whether the DHEAS decline

is simply a biomarker of aging, or is causally related

to morbidity and mortality in the elderly. One study of

the effects of oral administration of 50 mg/day of DHEA

for six months to 13 men and 17 women aged 40 to

70 years showed restoration of DHEA and DHEAS levels

to young–adult values, with improvement in physical and

psychological sense of well-being, but not sexual interest,

in both genders using a questionnaire for self-assessment.

These effects were accompanied by increased serum levels

of insulinlike growth factor 1 (IGF-I), reduced IGF-I

binding protein-1 (IGFBP-1), and a significant decrease in

apolipoprotein A1 and HDL-cholesterol in women, but

no change in insulin sensitivity and body composition

(35). Another study using 100 mg/day of DHEA for six

months in 9 men and 10 women aged 50 to 65 years reported

decreased fat mass and enhanced muscle strength

in men, whereas increased levels of downstream androgens

were detected in women (36). In a third study of 39

elderly men treated for three months with 100 mg/day

of oral DHEA, no treatment effect on body composition

or subjective well-being was found, whereas a significant

reduction in HDL-cholesterol was reported (37).

In the largest study to date, 280 men and women

aged 60 to 79 years were treated for 12 months with

50 mg/day of oral DHEA. No improvement in wellbeing

was detected using a variety of validated tools.

In addition, there were no significant changes in body

composition, metabolic parameters, or muscle strength.

However, a slight but significant increase in bone mineral

density (BMD) at the femoral neck and the radius,

and an increase in serum testosterone, libido, and sexual

function were observed in women >70 years old (38).

Similar changes were reported in 14 women aged 60–70

years who were treated for 12 months with a 10% DHEA

skin cream. In addition to a 10-fold increase in DHEA

levels, the authors described increased BMD at the hip,

and decreased osteoclastic and increased osteoblastic bone

markers. Other changes included improved well-being,

a reduced skinfold thickness, and lower blood glucose

and insulin levels, with no adverse change in lipid profile

(39). DHEA replacement did not affect BMD in other

studies (36).

Little information is available regarding the effects

of DHEA therapy on cardiovascular function and insulin

sensitivity from interventional studies, other than that

provided in the preceding text. The effects of DHEA treatment

on lipid profile were evaluated in more than a dozen

studies performed in men and women with various doses

and routes of administration. The majority of these studies

showed no effect of DHEA on plasma lipids (40).

In one study of 24 middle-aged men, administration

of 25 mg/day of oral DHEA for 12 weeks decreased the

plasma levels of plasminogen activator inhibitor type 1

(PAI-1), and increased dilatation of the brachial artery after

transient occlusion (41).

In rodent models of NIDDM, dietary administration

of DHEA consistently induced remission of hyperglycemia

and increased insulin sensitivity. Some clinical

studies in aged men andwomenhave shown improved insulin

sensitivity after DHEA replacement (39,42), whereas

others have not confirmed those findings in women


The effects of DHEA supplementation on cognitive

function in healthy elderly people were recently

reviewed in depth by Grimley et al. All randomized

placebo-controlled trials enrolling people aged >50 without

dementia to whom DHEA had been administered for

more than one day were considered for inclusion. Five

studies provided results from adequate parallel-group

data. The authors concluded that findings from these controlled

studies did not support any beneficial effect of

DHEA supplementation on cognitive function in nondemented

elderly people (44).Moreover,DHEAreplacement

did not affect memory in any of the controlled studies in

healthy elderly, as previously discussed. Therefore, the use

of DHEA supplementation to improve cognitive function

should not be recommended in the elderly population at

this time.

Potential Beneficial Effects of DHEA Supplementation

DHEA administration, often in large doses, has been

proposed in the management of numerous disorders,

including obesity, cancer, autoimmune diseases, AIDS,

mood disorders, as well as in enhancing physical performance.

The scientific evidence supporting the benefits

of DHEA therapy in these conditions is, however, very


Pharmacologic treatment with DHEA in mice genetically

predisposed to become obese reduced weight

gain and fat cell size. In obese rats, the steroid decreased

food intake by 50%. In humans, some observational studies

indicate a relationship between circulating DHEA and

Dehydroepiandrosterone 221

DHEAS levels, body mass index (BMI) and weight loss,

whereas others do not confirm this (45). Similar inconsistencies

are encountered in interventional studies. Administration

of a high oral dose of DHEA (1600 mg/

day) decreased body fat and increased muscle mass,

with no net change in body weight, in a small group

of healthy young men. As mentioned earlier, a reduction

in fat mass was also reported in healthy elderly

men after six months administration of 100 mg/day of

DHEA (36), whereas topical application of a 10% DHEA

cream for one year decreased femoral fat and skinfold

thickness in postmenopausal women (39). Other studies

in healthy elderly individuals and in obese men

failed to demonstrate changes in body fat after DHEA

treatment (37,43).

DHEA has been reported to exhibit chemopreventive

activity in mouse and rat models, although it has

also been found to be hepatocarcinogenic in rats. Epidemiological

research has revealed increased DHEA levels

to be associated with a rise in risk of ovarian cancer

and breast cancer in postmenopausal women, whereas

decreased levels are linked with increased risk of bladder,

gastric, and breast cancer in premenopausal women.

To date, we are unaware of clinical studies documenting

the effects of DHEA intervention on cancer initiation or

propagation. Fluorinated DHEA analogs that cannot be

converted into androgens or estrogens appear to have antiproliferative

effects and have been tested in several preclinical

cancers including bowel polyposis (46) and used

without side effects in doses up to 200 mg/day orally for

four weeks (47).

Increased antibody production in response to bacterial

infections and decreased mortality from endotoxic

shock were reported in DHEA-treated mice. In a study

of 71 aged individuals, however, DHEA administration

did not enhance antibody response to influenza vaccine

(48). In contrast, 50 mg/day of oral DHEA increased the

activity of natural killer cells by twofold, with a concomitant

decrease in T-helper cells in postmenopausal

women (49). In 28 women with mild-to-moderate systemic

lupus erythematosus (SLE), oral treatment with

200 mg/day of DHEA for three to six months improved

well-being and decreased disease activity and prednisone

dosage requirements. The same DHEA dose administered

orally for 56 days to patients with Crohn disease

or ulcerative colitis decreased disease activity in a small,

uncontrolled study (50). DHEA did not separate itself

from placebo in a randomized controlled trial in patients

with Sj ¨ogren syndrome (51). The effect of DHEA supplementation

in SLE was recently reviewed more systematically.

Analysis of the results from seven randomized

placebo-controlled trials of at least three months duration

revealed a modest but clinically significant beneficial effect

of DHEA on measures of quality of life in SLE patients,

whereas effects on measures of disease activity were

inconsistent (52).

Serum DHEA and DHEAS levels in patients infected

with HIV are directly related to CD4 cell counts

and disease stage and progression. This observation has

stimulated self-administration of DHEA as an adjunct to

antiviral treatment by AIDS patients. In the only published

placebo-controlled trial of DHEA in patients with

advanced HIV disease, treatment with 50 mg/day orally

for four months resulted in increased DHEAS levels and

improved mental function, with no change in CD4 cell

count (53). These results were consistent with those from

a previous open label study in 32 HIV-positive patients

treated with DHEA doses of 200 to 500 mg/day for eight

weeks (54).

Studies in adults and adolescents with major depressive

disorders have revealed a blunted DHEA circadian

variation, with low DHEA and high cortisol/DHEA ratio

at 8:00 AM. In 22 patients with medication-free or stable

major depression, supplementation with 30 to 90 mg/day

of oral DHEA for six weeks decreased Hamilton depression

scale scores as much as 50% (55). Similar results were

reported in a well-controlled study in 15 patients aged

45 to 63 years with midlife-onset dysthymia who, after a

three-week administration of 90 mg of DHEA, reported

improvements in depressive symptoms (56). In a recent

double-masked trial in schizophrenic patients with predominant

negative symptoms, supplementation with 100

mg/day of DHEA also led to improvement in depression

and anxiety (57). DHEA administration improves memory

test results and decreases serum levels of -amyloid

in aging mice. In contrast, treatment with 100 mg of oral

DHEA did not improve cognitive performance in patients

with Alzheimer disease, similar to the findings reported

in healthy elderly subjects (58).

DHEA is a popular dietary supplement among athletes.

Nevertheless, at 150 mg/day orally, it did not improve

body mass or strength in young male athletes and

weight lifters (59,60). In contrast, increased quadriceps

and lumbar strength were reported in healthy elderly men

on DHEA replacement (36), and an increase in lean body

mass of 4.5 kg was observed in healthy young men taking

1600 mg/day of DHEA for four weeks (61).

A summary of the various potential therapeutic applications

of DHEA replacement/supplementation is presented

in Table 2.

Table 2 Clinical Conditions for Which DHEA Use Has Been Proposed

Condition Effect References



Improved general well-being, mood,

sexual function


No significant effects 24–27

Aging Improved physical well-being, bone

mineral density or sexual function


Decrease in HDL or no effects 36,37



Improved well-being, fatigue, disease

activity in SLE patients, enhanced

immune response


No effect in HIV patients 53,54

Body composition Decreased fat and increased muscle



No changes 37,43

Insulin resistance Improved insulin sensitivity 39

No change 35

Depression Improved mood 55–57

Alzheimer disease No effect on cognitive function 58

Cardiovascular Improved endothelial function

No effect on lipids



222 Alesci et al.


Dietary/Nondietary Sources and Available Preparations

There are no known dietary sources of DHEA, although

it was suggested that the supplement chromium picolinate

could stimulate endogenous DHEA secretion. The

Mexican plant “wild yam” contains some natural DHEA

precursors, which cannot be converted into DHEA. However,

sterol extracts of “wild yam” (such as diosgenin

and dioscorea) are used to produce various forms of synthetic

DHEA, including tablets, capsules, injectable esters

(Gynodian Depot, Schering), sublingual and vaginal

preparations, topical creams, lozenges, and herbal

teas. DHEA is usually sold in tablets of 5 to 50 mg. A

pharmaceutical-grade preparation (Prestara) has been developed

for potential use as a prescription drug. During

the manufacture of DHEA, other steroid-like compounds,

like androstenedione, may be produced and could contaminate

DHEA. Moreover, the real steroid content of the

DHEA preparation sold over the counter may vary from

0% to 150% of the amount claimed (62). In addition, there

is a lack of information about comparability or bioequivalence

among the many products on the market or information

about lot-to-lot variability of any particular product

in terms of characterization (content) and standardization


Dosage and Administration There is no consensus on a recommended dietary allowance

(RDA) or optimal treatment dose for DHEA. Replacement

with oral doses of 20 to 50 mg/day for men and

10 to 30 mg/day for women appears adequate to achieve

DHEA/DHEAS levels similar to those in young adults,

as suggested by most studies in subjects with adrenal or

age-related DHEA/DHEAS deficiency, though oral doses

as low as 5 mg/day have been reported to be effective.

Higher DHEA doses may be necessary for patients with

very low endogenous DHEA levels secondary to glucocorticoid

administration or chronic disease. Doses of 200

to 500 mg and 200 mg/day have been used in patients

with HIV and SLE, respectively. Serum DHEAS levels and

its androgenic and estrogenic metabolites must be closely

monitored during replacement to enable appropriate dose

adjustments. Rigorous dose ranging studies are needed

to determine the optimal doses to achieve a beneficial


Adverse Reactions, Long-Term Effects,

and Contraindications

DHEA appears to elicit few short-term side effects when

used in the recommended doses. Women may experience

mild hirsutism, increased facial sebum production,

and acneiform dermatitis. Circulating concentrations

of downstream androgens rise above young–adult values

in healthy elderly women treated with 100 mg/day

DHEA; however, the long-term consequences of this increase

are unknown. No significant changes in complete

blood count, urinalysis, hepatic, and thyroid indices were

found in women after 28 days of treatment with 1600 mg

DHEA/day (43).Adose escalation study of 750 to 2250mg

oralDHEAconducted in 31 HIV-positive men revealed no

serious dose-limiting toxicity (63).

Because of its potent androgenic and estrogenic

effects, it would appear prudent to avoid DHEA replacement/

supplementation in individuals with a personal

or family history of breast, ovarian, or prostate

cancer. This would seem especially important for postmenopausal

women, considering the demonstrated direct

correlation between circulating concentrations of DHEA

and breast and ovarian cancers in this group (46), and

the reported increase with DHEA supplementation in

free IGF-1 (64). Caution may also be appropriate in HIV

patients, since high DHEA levels have been implicated

in the pathogenesis of Kaposi’s sarcoma. Moreover, increased

insulin resistance and decreased cholesterol and

HDL after administration of a high dose 1600 mg/day

of DHEA for four weeks have been reported in aged

women (43).

DHEA administration is not recommended for people

younger than 40 years of age, unless there is a documented

deficiency state. It should be avoided during pregnancy,

lactation, and in persons younger than 18 years, as

dosage and safety of the treatment under these conditions

have not been evaluated.

Known Drug Interactions

Drugs known to interfere with DHEA and/or DHEAS

include various hormone preparations, drugs acting on

the CNS, cardiovascular drugs, adrenergic and adrenergic

blocking agents, and anti-infective agents. Synthetic

glucocorticoids such as dexamethasone are the most

potent suppressors of DHEA and DHEAS. DHEA and/or

DHEAS levels are known to be decreased in patients

taking aromatase inhibitors, oral contraceptives,

dopaminergic receptor blockers, insulin, troglitazone,

and multivitamins, or fish oil. They are also decreased

due to the induction of the cytochrome P450 enzymes,

by carbamazepin, phenytoin, or rifampicin. Metformin

(a biguanide antihyperglycemic drug) and calcium

channel blockers are shown to increase DHEA and

DHEAS levels. The effect of alcohol is controversial


Compendial/Regulatory Status

In the early 1980s, DHEA was widely advertised and

sold in U.S. health food stores as an “anti-aging,”

“anti-obesity,” and “anti-cancer” nonprescription drug.

However, on the basis of unknown potential long-term

risks, and following the ban by the International Olympic

Committee, in 1985 the U.S. Food and Drug Administration

reclassified DHEA as a prescription drug. In

October 1994, the U.S. Dietary Supplement Health and

Education Act allowed DHEA to be sold again as an

over-the-counter dietary supplement, as long as no claims

are made regarding therapeutic efficacy. DHEA remains

available over the counter in the United States, as it was

not reclassified as an anabolic steroid, and hence a controlled

substance, in the 2004 Anabolic Steroid Control


Dehydroepiandrosterone 223



Despite a considerable amount of research related to

DHEA, and its alleged utility to sustain “eternal youth,”

several key questions remain unanswered. For example,

the physiologic function(s), regulation, and mechanisms

of actions of DHEA remain unknown, and a causal link

between age-related declines in DHEA and adverse effects

of aging has not been proven. Results from clinical

studies suggest that DHEA may be beneficial in some patients

with adrenal insufficiency, whereas data from intervention

studies in healthy older people have been inconclusive,

save for some modest gender differences in

selected outcome measures. Well-characterized and standardized

products need to be evaluated for safety and efficacy,

starting with dose ranging to determine an optimal

dose. Because DHEA can be converted to estrogen and

testosterone, its potential adverse effects in patients with

breast or prostate cancer need to be determined. Longterm,

well-designed clinical studies, with clear end points,

will be necessary before the beneficial and/or detrimental

effects of “replacement” or “pharmacological” DHEA

therapies in human aging and disease can be firmly