1. 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 androgens 3. 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 aging 4. Much of the research has tested the cause-and-effect relationships between DHEA and the symptoms of aging. 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 species 3. The side effects of DHEA are similar to androgen agonists and replacements, including the development of the secondary sex characteristics of the opposite gender 5. Both genders may also experience electrolyte retention 5. 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 pathway 5. The immune effects, although present in vitro and in mice, were not exhibited in otherwise healthy men 3. 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 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 Excretion DHEA, which is a naturally occurring steroid, is excreted as bile salts and eliminated in the feces. 6 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 Menopausal Women: Barnhart, et al 7 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 al 8 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 old 11. 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 ED 9,12. 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 athletes 13. 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 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. 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. 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.http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/dhe_0094.shtml 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, double- blind, 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 5/14/2006http://www.genome.ad.jp/dbget/ 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/17,20- lyase(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 http://www.emedicine.com/PED/topic1051.htm on 5/6/2006 18.http://www.rxlist.com/cgi/generic/viagra_ad.htmhttp://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 P450c17 Pregnenolone17 Hydroxy PregnenoloneDHEA Testosterone Estradiol (E2) Estrogen Cholesterol P450scc Androsteridione 3 Beta- Hydroxysteroid Dehydrogenase P450c17 Figure 2. Synthetic Pathway of DHEA, Testosterone and Estradiol 14,15,16,17 Table 1. Comparisons of DHEA to Prescription Treatments for various disorders DHEA plasma levels decrease as one’s age decreases, with a peak around 30 years of age (Figure 1) 2. DHEA in Postmenopausal Women Hormone Replacement Therapy in Postmenopausal Women DHEA for Addision’s Disease Hydrocortisone and Cortisone in Addison’s Disease DHEA for erectile dysfunction (males 40- 70) 9,11,12 Sildenafil for erectile dysfunction 18,19 EfficacyPositive results only in hypoadrenal women Some evidence of improved sexual function and mood, decreased fatigue Improveme nt in testosterone blood levels, mood and fatigue 3x/day preferable to 2x/day. Hormone levels improve, but do not reach normal levels Improved symptoms of ED for some populations Effective in 70- 90% of patients, depending on etiology Treatment50 mg dailyEstrogen, Estradiol, progesterone combination 50 mg for 12 weeks Hydrocortisone 20 mg/day Cortisone 25 mg/day 50 mg daily for 6 months 25-50 mg PRN Adverse Effects Hair growth, deepening of voice, male pattern baldness, etc Increased bleeding with high doses Few Side Effects UnknownNo dataHeadache and flushing rates similar to placebo SafetyIncreased risk with high dose and extended use Risk of CVD & cancer Little concern due to lack of secondary effects Concern about effects on bone metabolism No dataContraindicated with Nitrates Costs$9 - $19 per month $15 - $200 per month $9 - $19 per month Hydrocortisone $32, Cortisone $22 per month $9 - $19 per month $25-$35 per month