Transcript Slide 1

Dehydroepiandrosterone (DHEA): is it a safe choice?
Christina Andrade, Scott Nakashimada, Ted D. Williams PharmD Candidates
Oregon State University College of Pharmacy, Corvallis, Oregon 97331
Introduction/History
DHEA is a naturally occurring hormone in the human body identified in 1934 which is
known as Mexican Yam (Dioscoria). The first human study is most likely the study most
responsible for generating the initial interest in supplementation, published in 1994.1 The
results showed an increase in mood, physical and psychological well-being in hypoadrenal
volunteers.
Later that year the 1994 Dietary Supplements Health and Education Act (DSHEA) made it
legal to sell DHEA over-the-counter. Subsequently, popular media reported the
results. Much of what was reported, however, was information from previous studies,
almost all of which were conducted in rodents. Marketing campaigns tout:
• Reversing or slowing the aging process
• Enhancement of mental function
• Improvement of muscle strength/mass
• Improvements in cardiovascular health
• Strengthening of immune function
• Prevention of Osteoporosis
• Increase of libido
DHEA plasma levels decrease as one’s
age decreases, with a peak around 30
years of age (Figure 1)2.
Mechanism of Action
DHEA is a native, cholesterol-derived androgen precursor. The primary metabolic pathway
is shown in Figure 2. Oral dietary supplements have been shown to increase serum DHEA
levels as well as levels of downstream androgens3. This increase in androgens is
foundation for the purported anti-aging, improved immune response, increased libido, etc.
of dietary supplements. Much of the interest and hype regarding DHEA assumes that the
lack of DHEA causes many of the symptoms of aging4. Much of the research has tested
the cause-and-effect relationships between DHEA and the symptoms of aging.
Menopausal Women:
Barnhart, et al7 conducted a study on 60 menopausal women and found no change or
improvement in libido, perimenopausal symptoms, mood, memory or well-being. It did
show a decrease in HDL levels over three months of 50 mg administration in comparison to
placebo. Hunt, et al8 studied DHEA in 36 patients with Addison's Disease (adrenal
insufficiency). Results showed significant enhancement of overall well-being, mood and
fatigue and no effects on cognitive or sexual function, body composition, lipids, or bone
mineral density were observed. These studies suggest that DHEA is effective primarily in
women who are hypoadrenal.
Erectile Dysfunction:
Much of the discussion of the role of DHEA comes from the Massachusetts Male Aging
Study done in 1994. Several studies have subsequently linked lower DHEA levels with
aging and erectile dysfunction (ED)9,10. Serum DHEA levels vary in young patients with
ED, but there is no variation in patients over 60 years old11. Two studies by Reiter, Pycha,
and Schatzl demonstrated that doses of 50mg/day for 6 months reduced ED symptoms in
patients under 60 years old with hypertension or no known etiology for ED9,12. These
studies did not appears to track side effects. These studies did not use placebo, but did
divide patients by etiology, with differing results based on cause of ED. A MedLine search
of the literature found no studies which directly challenged these results.
Young Athletes:
While there are some clinical studies that show slight increases in athletic
performance, most show common agreement that the use of DHEA does not
provide benefits with continuous and long-term usage. These studies showed
that serum testosterone levels increased in males but only for the effect of a
couple hours after use. With regular usage (50-100 mg per/day), no increase
in serum testosterone levels was seen, however increased estrogen levels were
observed the male athletes13. Studies also show no significance difference in improvement
in body composition and overall body strength over the course of the study between the
group of athletes taking DHEA and those taking a placebo.
Conclusion
One important consideration when evaluating potential effects of DHEA supplements is that
animal have limited applicability to humans, as the sources of androgens varies by
species3.
The side effects of DHEA are similar to androgen agonists and replacements, including the
development of the secondary sex characteristics of the opposite gender5. Both genders
may also experience electrolyte retention5.
The full effects of DHEA are being actively researched. There is ongoing research into how
DHEA levels affect Type II Diabetes. At least one study has demonstrated that poorly
controlled Diabetes is linked to low DHEA levels, apparently due to decreased enzyme
activity at multiple points along the DHEA metabolic pathway5. The immune effects,
although present in vitro and in mice, were not exhibited in otherwise healthy men3.
Absorption
Although a literature search revealed no studies specifically on DHEA absorption, it seems
reasonable that DHEA will be absorbed similar to other cholesterol derivatives. In such a
case, oral doses have low bioavailability due to first pass metabolism in the liver. What is
absorbed would be through the intestinal tract via chylomicrons where they will travel to the
lymphatic system. From there they will enter general circulation into the bloodstream and
ultimately body tissues.6
There is evidence to suggest therapeutic uses for DHEA in women that are hypoadrenal or
that have Addison’s Disease. There is limit evidence to suggest non-diabetic men under
60 with erectile dysfunction related to hypertension or unknown physical etiology may
benefit from DHEA therapy. More uses may become accepted as new research is
published.
P450scc
P450c17
Pregnenolone
P450c17
17 Hydroxy Pregnenolone
Distribution
DHEA is normally produced in the Adrenal cortex of the brain. However, under
supplementation, DHEA can is absorbed into the bloodstream and a 100 mg dose can
raise levels of androstenedione (and ultimately testerone and estrogen levels) by up to
700%. 6
Metabolism
DHEA is a steroid precursor or prohormone. In this inactive form it has no observed effect.
However, in the body it is converted to androstenedione, and from there, further converted
to either testosterone or estrogen. 6
Treatment 50 mg daily
Adverse
Effects
Safety
Costs
Hair growth,
deepening of
voice, male
pattern
baldness, etc
Increased risk
with high dose
and extended
use
$9 - $19 per
month
Estrogen,
Estradiol,
progesterone
combination
Increased
bleeding with
high doses
DHEA for
Addision’s
Disease
DHEA for
erectile
dysfunction
(males 4070) 9,11,12
Improveme 3x/day
Improved
nt in
preferable to
symptoms
testosterone 2x/day.
of ED for
blood
Hormone levels some
levels,
improve, but do populations
mood and
not reach
fatigue
normal levels
50 mg for
Hydrocortisone 50 mg
12 weeks
20 mg/day
daily for 6
Cortisone 25
months
mg/day
Few Side
Unknown
No data
Effects
Risk of CVD & Little
cancer
concern due
to lack of
secondary
effects
$15 - $200 per $9 - $19 per
month
month
Hydrocortisone
and Cortisone in
Addison’s
Disease
Sildenafil for
erectile
dysfunction 18,19
Effective in 7090% of patients,
depending on
etiology
25-50 mg PRN
Headache and
flushing rates
similar to
placebo
Concern about
effects on bone
metabolism
No data
Contraindicated
with Nitrates
Hydrocortisone
$32, Cortisone
$22 per month
$9 - $19
per month
$25-$35 per
month
Table 1. Comparisons of DHEA to Prescription Treatments for various disorders
Endogenous DHEA is involved in erectile dysfunction, aging and postmenopausal
symptoms, as well as testosterone levels in young athletes. Current research suggests
that lower DHEA levels coincide with the symptoms of aging, but is not a causative agent.
This is not to say that DHEA does not have potential therapeutic uses. Areas under current
research include DHEA’s role in neuropathic and insulin activity related to Type II diabetes,
some types of rheumatoid arthritis and hormonal replacement in postmenopausal women.
Cholesterol
Efficacy
DHEA in
Hormone
Postmenopausal Replacement
Women
Therapy in
Postmenopausal
Women
Positive results Some evidence
only in
of improved
hypoadrenal
sexual function
women
and mood,
decreased
fatigue
3 BetaHydroxysteroid
Dehydrogenase
Testosterone
Androsteridione
Excretion
DHEA, which is a naturally occurring steroid, is excreted as bile salts and eliminated in the
feces. 6
Estradiol (E2)
Estrogen
Figure 2. Synthetic Pathway of DHEA, Testosterone and Estradiol14,15,16,17
DHEA
References
1. Morales AJ, Nolan JJ, Nelson JC, Yen SS. Effects of replacement dose of dehydroepiandrosterone in men and
women of advancing age. The Journal of Clinical Endocrinology & Metabolism. 1994 Jun;78(6):1360-7
2. Powers, M.E. 2002. The Safety and Efficacy of Anabolic Steroid Precursors: What is the Scientific Evidence?
Journal of Athletic Training 37(3): 300-305
3. Kohut, et al., Ingestion of a Dietary Supplement Containing Dehydroepiandrosterone (DHEA) and
Androstenedione Has Minimal Effect on Immune Function in Middle-Aged Men Journal of the American
College of Nutrition 2003 22:5
4. Feldman, H.A., et al. Age trends in the Level of Serum Testosterone and Other Hormones in Middle-Aged
Men: Longitudinal Results from the Massachusetts Male Aging Study. The Journal of Clinical Endocrinology
& Metabolism 2002: 87(2)
5. Williams, D, Lemke, T, Foye’s Principles of Medicinal Chemistry, 5th edition. 2002 Lippincott Williams and
Wilkins
6. PDR Heath. Retrieved from http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/dhe_0094.shtml
on 5/25/2006.
7. Ueshiba, H. et al Decreased steroidogenic enzyme 17,20-lysase and increased 17-hydrolas activities in type 2
diabetes mellitus. European Journal of Endocrinology 2002 146:375-380
8. Hunt PJ, Gurnell EM, Huppert FA, Richards C, Prevost AT, Wass JA, Herbert J & Chatterjee VK. Improvement
in mood and fatigue after dehydroepiandrosterone replacement in Addison’s disease in a randomized, double
blind trial. Journal of Clinical Endocrinology and Metabolism 2000 85 4650–4656.
9. Reiter, W.J. et. al., Dehydroepiandrosterone in the treatment of erectile dysfunction: a prospective, doubleblind, randomized, placebo-controlled study. Urology 1999 53:3
10.Tomova, A, Kumanov, P. Are dehydroepiandrosterone sulphate and lipids associated with erectile
dysfunction? Maturitas 2004 50:294-299
11.Reiter et. al. Serum Dehydroepiandrosterone sulfate concentrations in men with erectile dysfunction. Urology
2000 55:5
12.Reiter et. al., Dehydroepiandrosterone in the treatment of erectile dysfunction in patients with different organic
etiologies. Urology 2001 29:278-281
13.King D, Sharp L, Yukovich M, Brown G, Reinfenrath T, Uhl N. Effect of Oral Andostenedione on Serum
Testosterone and Adaptations to Resistance Training in Young Men. Journal of the American Medical
Association, 2006 281:2020-2028
14.Chemical Structures retrieved from http://www.genome.ad.jp/dbget/ on 5/14/2006
15.Vogl, Falk, Dorner, Scholmerich, Straub Serum Levels of Pregnenolone and 17-hydroxypregnenolone in
Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus: Relation to Other Adrenal Hormones,
The Journal of Rheumatology 2003 30:2
16.Soucy, Luu-The, Conversion of pregnenolone to DHEA by human 17 alpha-hydroxylase/17,20lyase(P450c17), European Journal of Biochemistry, 2000 267
17.Frindik, J.P.,3-Beta Hydroxysteroid Dehydrogenase Deficiency eMedicine April 2003, Retrieved from
http://www.emedicine.com/PED/topic1051.htm on 5/6/2006
18.http://www.rxlist.com/cgi/generic/viagra_ad.htm
19.Stroberg, P. , Hedelin, H. , Ljunggren C., Prescribing All Phosphodiesterase 5 Inhibitors to a Patient with
Erectile Dysfunction—A Realistic and Feasible Option in Everyday Clinical Practice—Outcomes of a Simple
Treatment Regime European Urology 2006, 49: 900–907