Report New Research Substantiates the Anti-Aging Properties of DHEA

Life Extension Magazine December 2010

New Research Substantiates the Anti-Aging Properties of DHEA

By Kirk Stokel

In 2007, Life Extension® led the battle against Congress’s ill-conceived campaign to re-classify DHEA (dehydroepiandrosterone) as an “anabolic steroid drug”—an act that would have made this life-sustaining compound unavailable to the American public without a prescription.

Thanks in no small part to the efforts of Life Extension® members, the battle was won.

Today, less than three years later, scientists have uncovered even more research substantiating DHEA’s remarkable health-promoting benefits.

Sometimes called the “youth hormone,” DHEA is the most abundant hormone precursor in the human body and a source of the sex hormones.

Its steady and precipitous decline is an inevitable consequence of aging, 1 and contributes to the onset of degenerative disease.

The latest scientific discoveries indicate that as little as 50 mg of DHEA per day may:

1. Inhibit multiple factors implicated in metabolic syndrome by favorably altering gene expression;
2. Boost bone strength and ward off osteoarthritis;
3. Enhance memory.2-5

Daily intake of 90 mg per day and higher has been shown to improve cognitive function and alleviate depression both in the elderly and among individuals suffering from debilitating mental illness.6,7

First introduced to Americans in 1981 by the Life Extension Foundation®, the anti-aging effects of DHEA have been described in medical textbooks starting in the early 1990s.

In this article, you will discover the most up-to-date evidence of DHEA’s profoundly beneficial impact across multiple systems of the body.

Potent Cognitive Support

DHEA deficiency is implicated in numerous age-related conditions, including declines in brain and nervous system function. The latest research suggests that DHEA supplementation may exert powerful neuroprotective effects.

In fact, 2009 witnessed extraordinary advances in our understanding of the cognitive and memory-enhancing benefits of DHEA.

Two large studies showed that levels of DHEA-S in elderly patients correlated significantly and positively with cognitive function. (Chemically similar to DHEA, DHEA-S is the sulfated form of DHEA.)8,9 Prior research had shown that higher DHEA-S levels were directly associated with improved concentration, working memory, and executive (decision-making) function.10

Israeli scientists found that the cognitive dysfunction that occurs in schizophrenia is also partly associated with levels of DHEA-S and other neurosteroids.11 Supplementation with 200 mg per day of DHEA in schizophrenic patients improved attention and motor skills compared with placebo.6 Although the direct symptoms of schizophrenia were unaffected, DHEA’s ability to provide relief from the cognitive deficits associated with this severe psychiatric condition may significantly improve quality of life in these individuals.

The last few years have also yielded new pre-clinical data on DHEA’s neuroprotective, memory-enhancing effects. In one noteworthy study, DHEA significantly improved memory retention and consolidation in mice—especially when the experimental equivalent of an emotional stimulus was involved.12 This may be related to DHEA’s ability to stimulate the proliferation of key brain cell receptors specifically associated with memory processing.13

When given to aging rats, DHEA was shown to enhance brain cell utilization of ATP—the body’s fundamental energy-storage molecule—thereby protecting the cell membranes from age-related damage.14 Impaired energy utilization and reduced production of ATP contribute to the “neuronal energy crises” that underlie Alzheimer’s and other neurodegenerative diseases.15

A landmark 2007 study showed that DHEA supplementation of 150 mg twice daily improved memory recall and mood in healthy young men, specifically increasing activity in the hippocampus, the region of the brain most closely associated with mnemonic function (memory).5

Enhance Your Mood—Naturally

Depression often accompanies aging, frequently emerging in older individuals.16,17 Fortunately, we now recognize depression as an essentially physiological condition—one that can be treated. Low DHEA levels are known to render aging humans more vulnerable to depression in the presence of triggers such as rejection or isolation.18 Negative emotional stimuli have been shown to lower DHEA levels even further.19

Supplementation with DHEA can powerfully mitigate depression and its effects. A National Institute of Mental Health study of depressive men and women aged 45-65 years showed significant improvement over 6 weeks among those who took 90 mg of DHEA per day for 3 weeks and then 450 mg per day for 3 weeks, compared with placebo.7 The study also showed significant improvements in sexual functioning scores in supplemented patients, but not among control patients. In a rare admission from the generally conservative National Institute of Mental Health, their conclusion was, “We find DHEA to be an effective treatment for midlife-onset major and minor depression.”

In a set of studies, DHEA was found to improve both mood and energy while alleviating depression.20-22 Israeli researchers also demonstrated minimal effects on other hormonal profiles, alleviating concerns about adverse events with DHEA.23

A remarkable 2006 study demonstrated reduction in depressive symptoms in an especially challenging population—patients with HIV/AIDS.24

Several 2009 studies revealed associations of low DHEA levels with a number of neuropsychiatric conditions and were able to show that DHEA influences gene expression in the brain.25 For example, DHEA modulates expression of genes directly involved in appetite regulation, energy utilization, and alertness.26 Another study demonstrated that DHEA acted in synergy with the antidepressant fluoxetine (Prozac®), leading researchers to suggest DHEA as “a useful adjunct therapy for depression.”27

Support for Aging Bones and Joints

A 2000 study demonstrated improved bone turnover—more marked in women than in men—during a year-long study of daily 50 mg supplementation with DHEA.28 (Bone turnover is the natural process by which the body replaces old bone from the skeleton and replaces it with new bone.) By 2003, laboratory evidence emerged suggesting that DHEA could potentially enhance joint function and ward off osteoarthritis (OA).2

DHEA treatment of cartilage tissue taken from patients with OA increased production of healthy, flexible type II collagen protein, while reducing production of the less flexible type I collagen associated with scar formation.2 DHEA also modified the imbalance between cartilage-destroying enzymes and those that protect cartilage from damage. These impressive effects were the direct result of DHEA’s capacity to favorably modulate gene expression.

DHEA’s effects on bone structure are no less significant. A double-blind, randomized, controlled trial of 50 mg per day of DHEA administered orally versus placebo for 12 months showed improved hip bone mineral density (BMD) in older men and women with low DHEA-S levels, with additional improvements in spine BMD in women.3,29 A larger study in 2008 showed that DHEA not only improved lumbar spine BMD in women (not men) taking 50 mg per day for a year, but it also reduced blood-borne markers of bone resorption,30 an important measure of overall bone health and bone aging. Not surprisingly, the addition of vitamin D and calcium supplements to a DHEA regimen may afford further benefit.31

What you need to know: DHEA

• DHEA, the most common hormone precursor in the body, is intimately associated with youthful and healthy functioning across a range of physiological systems.
• Levels of DHEA decline steadily with age, and low DHEA levels are associated with increased cardiovascular risk, diabetes, obesity, loss of vigor and sexual energy, depression, and even visible skin aging.
• The most up-to-date scientific research indicates that DHEA can protect brain cells involved in memory function, alleviate depression and enhance mood, strengthen bone health, bolster immunity, lower blood glucose, limit the complications of obesity and diabetes, support healthy cardiovascular function, and enhance sexuality at both the psychological and physical levels.
• As little as 50 mg of DHEA per day may favorably alter gene expression to inhibit multiple factors implicated in metabolic syndrome; boost bone strength; enhance cognitive function and memory; and ward off osteoarthritis.
• DHEA is also available in topical crèmes that has been shown to dramatically enhance the youthful appearance of skin.
• Individuals who have been diagnosed with any type of hormone-related cancer should not supplement with DHEA.

Optimal Immune Strength and Anti-Viral Protection

The precipitous age-related decline in DHEA/DHEA-S levels results in the immune deficiency we call immunosenescence.32 Supplementation with DHEA may beneficially modulate immunity33,34 to help combat debilitating age-related conditions through multiple, complementary pathways.

DHEA has boosted immune function in blood cells taken from patients after major abdominal surgery.35 This action may help to prevent serious infections and promote healing. In the setting of dangerous infections and trauma in laboratory animals, DHEA and its metabolites markedly upregulate host immune responses, modulate inflammation, and improve survival.36-38 In animal models, DHEA’s ability to raise sex hormone concentrations to youthful levels also promoted wound healing.39

DHEA also possesses significant antiviral properties. It has blocked replication of several different, potentially deadly virus families in the laboratory—more effectively and more selectively than the drug ribavirin!40,41

A 2008 study showed that DHEA also increases natural resistance to certain lethal parasites, including Trypanosma cruzi (the cause of Chagas disease),42 a microorganism that causes death from heart disease and brain damage, particularly in immunocompromised patients. Subsequent research conducted in 2009 found that DHEA supplementation reduced parasite levels, raised levels of defensive macrophage white blood cells, and increased levels of immune signalling interferons.43,44

Among individuals stricken with autoimmune disorders such as rheumatoid arthritis or lupus, treatment with conventional corticosteroids not only over-suppresses the immune system, it can also promote bone resorption and catastrophic fractures. DHEA has been shown to reduce expression of cytokines and other factors that lead to bone resorption in steroid-treated tissue, while still suppressing inflammation effectively.45

There’s good news for asthma and allergy patients who respond poorly to regular steroid usage as well. DHEA is now known to suppress allergy-induced inflammatory cytokines in reactive airway cells while increasing the ratio of beneficial interferon to inflammatory cytokines—highly significant advances in the management of this troubling condition.46

Combat Metabolic Disorders

We’ve known for over a decade that DHEA protects against obesity and its consequences in aging and diabetic animals.47,48 In 2009, scientists confirmed that low DHEA levels in men were linked to diabetes and coronary heart disease.49 DHEA powerfully modulates gene expression to shift the metabolic balance in favor of energy utilization and away from storage as fat.50

DHEA also activates gene expression of cellular machinery that affects a cell’s consumption of fats and sugars to remove them from circulation.51,52 These molecules help correct harmful lipid abnormalities and unhealthy body fat distribution—a possible mechanism by which DHEA decreases total body fat.53,54

In 2007, researchers demonstrated in aged rats fed a high-fat diet that DHEA increased body protein, while decreasing total caloric intake, body weight, body fat, and total size and number of fat cells.55 In a related experiment, researchers discovered that DHEA could change the composition of adipose tissue, boosting levels of beneficial omega-3 fatty acids while reducing harmful omega-6 fatty acids.56

A human study showed how powerfully these DHEA effects can modify body composition.4 When 52 elderly men and women took 50 mg per day of DHEA or placebo for 6 months, it reduced stubborn abdominal and subcutaneous body fat. Insulin levels dropped significantly in supplemented patients as well, indicating enhanced insulin sensitivity. The researchers concluded appropriately that “DHEA replacement could play a role in prevention and treatment of the metabolic syndrome associated with abdominal obesity.”

“DHEA replacement could play a role in prevention and treatment of the metabolic syndrome associated with abdominal obesity.”

DHEA is highly protective against diabetes and its complications. In diabetic rats, DHEA prevented increases in oxidant stress and oxidative damage related to the disease. It also significantly improved blood vessel relaxation, improving blood flow.57 DHEA induces genes in muscle tissue that increase uptake and utilization of blood glucose as energy, significantly lowering blood sugar in diabetic animals.58 In humans with type 2 diabetes, DHEA counteracts oxidative imbalance and the formation of deadly advanced glycation end products (AGEs), and downregulates the inflammatory TNF-alpha system—effects that may prevent the onset and slow the progression of deadly diabetes.59

Cardiovascular Disease Defense

The past several years have witnessed extraordinary advances in our understanding of DHEA’s cardioprotective power—and its relationship to cardiovascular disease.

A 2009 study of 153 diabetic men with stable coronary heart disease (CHD) found that 77% were DHEA-S deficient, significantly more than in healthy peers.60 Over the next 19 months of follow-up, 43 of those men died of CHD; the data showed that low DHEA-S and low testostosterone levels were two of the four most significant predictors of death.

Another 2009 study of 247 men with a mean age of 76 years revealed that those with low DHEA-S had a 96% increased risk of diabetes and a 48% increased risk of coronary heart disease.49

A 2009 study from the University of Pennsylvania discovered a surprisingly close relationship between mortality and the trajectory of DHEA-S decline in older adults.61 Specifically, a rapid or erratic decline in DHEA-S predicted earlier death, and both together increased the death rate by nearly threefold! Regular blood testing for healthy DHEA-S levels are the only way to detect these lethal changes in DHEA levels early. It is of paramount importance that you have your DHEA-S levels checked at least once a year.

A Mayo Clinic study found that DHEA supplementation (50 mg per day) in women with low DHEA levels and low adrenal function improved plasma DHEA content, significantly lowered total cholesterol, and tended to reduce triglyceride and low-density lipoprotein (LDL) levels.62 But supplemented patients also had reductions in their beneficial high-density lipoprotein (HDL) levels. This study suggests that long-term studies are needed to determine the impact of DHEA supplementation on cardiovascular risk in women with low adrenal function.

Additional support for DHEA’s benefits in patients suffering from vascular disease came in two remarkable 2009 studies.63,64 The first examined vascular remodeling, a dangerous process that occurs when vessels are injured by atherosclerosis.63 Vascular remodeling can impede blood flow and ultimately worsen cardiovascular disease.65

DHEA significantly inhibited vascular remodeling in a rabbit model of carotid artery injury and limited deadly buildup of smooth muscle in vessel walls.63 Another study of rabbits fed a high-fat diet showed that DHEA supplements restored oxidative balance, lowered lipid levels and inflammatory damage, and prevented heart muscle tissue death and dysfunction, delaying the onset of cardiac damage.64

Enhanced Well-Being and Libido Even in Challenged Populations

Studies as early as 2000 demonstrated how DHEA improved well-being and could help to manage menopause without deleterious effects.28,66 In 2006 it was revealed that 50 mg per day of DHEA could improve psychological well-being even in challenging populations such as those with decreased pituitary function.67

DHEA exerted a remarkably positive effect on health-related quality of life in women taking long-term steroids for lupus (chronic steroid therapy can produce powerful depression and reduction in quality of life measures).68 Of particular importance, the DHEA-supplemented groups also reported improvement in sexuality.

Additional research supports an excitatory effect for DHEA on sexuality—especially in women. In one study, sixteen sexually functional postmenopausal women were randomly given either placebo or a single DHEA supplement of 300 mg, 60 minutes before presentation of an erotic video.69 Women in the supplement group showed significantly greater mental and physical sexual arousal during the video than did the control women. The supplemented women also reported a greater increase in positive affect (generally feeling good) compared to placebo recipients.

A 2009 animal study may shed light on some of the physical causes behind these benefits: DHEA applied to the smooth muscle of rabbit clitoris resulted in significant relaxation,70 allowing the increased blood flow and engorgement that results in enhanced sensitivity during sexual arousal.

Favorable Gene Expression for Youthful, Glowing Skin

A growing body of scientific evidence suggests that DHEA has especially favorable effects on skin health and appearance. In a 2000 laboratory study, DHEA was shown to increase production of collagen—the protein that gives youthful skin its suppleness—while decreasing production of the collagenase enzymes that destroy it.71

It wasn’t until 2008, however, that Canadian scientists discovered more than 50 DHEA-responsive genes in the skin of women using a topical DHEA crème.72 DHEA “switched on” multiple collagen-producing genes and reduced expression of genes associated with production and cornification (hardening) of the tough keratinocytes that form calluses and rough skin. The researchers concluded, “DHEA could exert an anti-aging effect in the skin through stimulation of collagen biosynthesis, improved structural organization of the dermis while modulating keratinocyte metabolism.”

Other unexpected benefits of topical DHEA on aging skin are emerging. DHEA treatment increases production of sebum, or skin oil.73 Sebum not only contributes to smooth, supple skin; it also contains myriad antimicrobial components that prevent infection and irritation. Topical DHEA also improves skin “brightness” and counteracts the “papery” appearance of aging skin, combating the epidermal thinning that is a visible hallmark of aging.73 The study authors note that these are “beneficial effects on skin characteristics that are rarely provided by topical treatments.”

Summary

In the past few years alone, significant scientific substantiation of DHEA’s anti-aging effects has emerged. Its neuroprotective effects are now recognized as being vital in protecting memory and reducing depressive symptoms in older adults. DHEA enhances bone health by improving mineralization to reduce fracture risk. DHEA modulates immunity in a coordinated fashion, boosting resistance to infection while quelling dangerous inflammation. DHEA supports cardiovascular health and activates genes that prevent cardiovascular risk factors, including diabetes and obesity. DHEA is intimately involved in improving quality of life and bolstering sexual arousal, while dramatically improving the appearance of healthy, youthful skin. As little as 50 mg of DHEA per day may favorably alter gene expression to inhibit multiple factors implicated in metabolic syndrome; boost bone strength; enhance cognitive function and memory; and ward off osteoarthritis. DHEA topical crèmes allow ready application of DHEA to the site of action.

Note: Individuals who have been diagnosed with a hormone-dependent cancer should not supplement with DHEA until their cancer is cured.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

REFERENCES:

1. Dharia S, Parker CR Jr. Adrenal androgens and aging. Semin Reprod Med. 2004 Nov;22(4):361-8

2. Jo H, Park JS, Kim EM, et al. The in vitro effects of dehydroepiandrosterone on human osteoarthritic chondrocytes. Osteoarthritis Cartilage. 2003 Aug;11(8):585-94.

3. Jankowski CM, Gozansky WS, Schwartz RS, et al. Effects of dehydroepiandrosterone replacement therapy on bone mineral density in older adults: a randomized, controlled trial. J Clin Endocrinol Metab. 2006 Aug;91(8):2986-93.

4. Villareal DT, Holloszy JO. Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial. JAMA. 2004 Nov 10;292(18):2243-8.

5. Alhaj HA, Massey AE, McAllister-Williams RH. Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study. Psychopharmacology (Berl). 2006 Nov;188(4):541-51.

6. Ritsner MS, Gibel A, Ratner Y, Tsinovoy G, Strous RD. Improvement of sustained attention and visual and movement skills, but not clinical symptoms, after dehydroepiandrosterone augmentation in schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychopharmacol. 2006 Oct;26(5):495-9.

7. Schmidt PJ, Daly RC, Bloch M, et al. Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch Gen Psychiatry. 2005 Feb;62(2):154-62.

8. Fukai S, Akishita M, Yamada S, et al. Association of plasma sex hormone levels with functional decline in elderly men and women. Geriatr Gerontol Int. 2009 Sep;9(3):282-9.

9. Valenti G, Ferrucci L, Lauretani F, et al. Dehydroepiandosterone and cognitive function in the elderly: The InCHIANTI Study. J Endocrinol Invest. 2009 Oct;32(9):766-72.

10. Davis SR, Shah SM, McKenzie DP, Kulkarni J, Davison SL, Bell RJ. Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab. 2008 Mar;93(3):801-8.

11. Ritsner MS, Strous RD. Neurocognitive deficits in schizophrenia are associated with alterations in blood levels of neurosteroids: A multiple regression analysis of findings from a double-blind, randomized, placebo-controlled, crossover trial with DHEA. J Psychiatr Res. 2010 Jan;44(2):75-80.

12. Bazin MA, El Kihel L, Boulouard M, Bouët V, Rault S. The effects of DHEA, 3beta-hydroxy-5alpha-androstane-6,17-dione, and 7-amino-DHEA analogues on short term and long term memory in the mouse. Steroids. 2009 Nov;74(12):931-7.

13. Chen C, Lang S, Zuo P, Yang N, Wang X. Treatment with dehydroepiandrosterone increases peripheral benzodiazepine receptors of mitochondria from cerebral cortex in D-galactose-induced aged rats. Basic Clin Pharmacol Toxicol. 2008 Dec;103(6):493-501.

14. Taha A, Mishra M, Baquer NZ, Sharma D. Na+ K(+)-ATPase activity in response to exogenous dehydroepiandrosterone administration in aging rat brain. Indian J Exp Biol. 2008 Dec;46(12):852-4.

15. de la Torre JC. Pathophysiology of neuronal energy crisis in Alzheimer’s disease. Neurodegener Dis. 2008;5(3-4):126-32.

16. Camus V. Evaluation of the depressive symptomatology in the elderly. Psychol Neuropsychiatr Vieil. 2004 Sep;2 Suppl 1:S13-17.

17. Djernes JK. Prevalence and predictors of depression in populations of elderly: a review. Acta Psychiatr Scand. 2006 May;113(5):372-87.

18. Akinola M, Mendes WB. The dark side of creativity: biological vulnerability and negative emotions lead to greater artistic creativity. Pers Soc Psychol Bull. 2008 Dec;34(12):1677-86.

19. Wang HT, Chen SM, Lee SD, et al. The role of DHEA-S in the mood adjustment against negative competition outcome in golfers. J Sports Sci. 2009 Feb 1;27(3):291-7.

20. Strous RD, Maayan R, Lapidus R, et al. Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry. 2003 Feb;60(2):133-41.

21. Herbert J. Neurosteroids, brain damage, and mental illness. Exp Gerontol. 1998 Nov-Dec;33(7-8):713-27.

22. Bloch M, Schmidt PJ, Danaceau MA, Adams LF, Rubinow DR. Dehydroepiandrosterone treatment of midlife dysthymia. Biol Psychiatry. 1999 Jun 15;45(12):1533-41.

23. Strous RD, Maayan R, Kotler M, Weizman A. Hormonal profile effects following dehydroepiandrosterone (DHEA) administration to schizophrenic patients. Clin Neuropharmacol. 2005 Nov-Dec;28(6):265-9.

24. Rabkin JG, McElhiney MC, Rabkin R, McGrath PJ, Ferrando SJ. Placebo-controlled trial of dehydroepiandrosterone (DHEA) for treatment of nonmajor depression in patients with HIV/AIDS. Am J Psychiatry. 2006 Jan;163(1):59-66.

25. Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol. 2009 Jan;30(1):65-91.

26. Mo Q, Lu S, Garippa C, Brownstein MJ, Simon NG. Genome-wide analysis of DHEA- and DHT-induced gene expression in mouse hypothalamus and hippocampus. J Steroid Biochem Mol Biol. 2009 Apr;114(3-5):135-43.

27. Pinnock SB, Lazic SE, Wong HT, Wong IH, Herbert J. Synergistic effects of dehydroepiandrosterone and fluoxetine on proliferation of progenitor cells in the dentate gyrus of the adult male rat. Neuroscience. 2009 Feb 18;158(4):1644-51.

28. Baulieu EE, Thomas G, Legrain S, et al. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue. Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4279-84.

29. Jankowski CM, Gozansky WS, Kittelson JM, Van Pelt RE, Schwartz RS, Kohrt WM. Increases in bone mineral density in response to oral dehydroepiandrosterone replacement in older adults appear to be mediated by serum estrogens. J Clin Endocrinol Metab. 2008 Dec;93(12):4767-73.

30. von Muhlen D, Laughlin GA, Kritz-Silverstein D, Bergstrom J, Bettencourt R. Effect of dehydroepiandrosterone supplementation on bone mineral density, bone markers, and body composition in older adults: the DAWN trial. Osteoporos Int. 2008 May;19(5):699-707.

31. Weiss EP, Shah K, Fontana L, Lambert CP, Holloszy JO, Villareal DT. Dehydroepiandrosterone replacement therapy in older adults: 1- and 2-y effects on bone. Am J Clin Nutr. 2009 May;89(5):1459-67.

32. Buford TW, Willoughby DS. Impact of DHEA(S) and cortisol on immune function in aging: a brief review. Appl Physiol Nutr Metab. 2008 Jun;33(3):429-33.

33. Kim SK, Shin MS, Jung BK, et al. Effect of dehydroepiandrosterone on lipopolysaccharide-induced interleukin-6 production in DH82 cultured canine macrophage cells. J Reprod Immunol. 2006 Jun;70(1-2):71-81.

34. Nawata H, Yanase T, Goto K, Okabe T, Ashida K. Mechanism of action of anti-aging DHEA-S and the replacement of DHEA-S. Mech Ageing Dev. 2002 Apr 30;123(8):1101-6.

35. Frantz MC, Prix NJ, Wichmann MW, et al. Dehydroepiandrosterone restores depressed peripheral blood mononuclear cell function following major abdominal surgery via the estrogen receptors. Crit Care Med. 2005 Aug;33(8):1779-86.

36. Marcu AC, Paccione KE, Barbee RW, et al. Androstenetriol immunomodulation improves survival in a severe trauma hemorrhage shock model. J Trauma. 2007 Sep;63(3):662-9.

37. Oberbeck R, Deckert H, Bangen J, Kobbe P, Schmitz D. Dehydroepiandrosterone: a modulator of cellular immunity and heat shock protein 70 production during polymicrobial sepsis. Intensive Care Med. 2007 Dec;33(12):2207-13.

38. Burdick NC, Dominguez JA, Welsh TH, Jr., Laurenz JC. Oral administration of dehydroepiandrosterone-sulfate (DHEAS) increases in vitro lymphocyte function and improves in vivo response of pigs to immunization against keyhole limpet hemocyanin (KLH) and ovalbumin. Int Immunopharmacol. 2009 Jul 29.

39. Mills SJ, Ashworth JJ, Gilliver SC, Hardman MJ, Ashcroft GS. The sex steroid precursor DHEA accelerates cutaneous wound healing via the estrogen receptors. J Invest Dermatol. 2005 Nov;125(5):1053-62.

40. Romanutti C, Bruttomesso AC, Castilla V, Bisceglia JA, Galagovsky LR, Wachsman MB. In vitro antiviral activity of dehydroepiandrosterone and its synthetic derivatives against vesicular stomatitis virus. Vet J. 2009 Nov;182(2):327-35.

41. Acosta EG, Bruttomesso AC, Bisceglia JA, Wachsman MB, Galagovsky LR, Castilla V. Dehydroepiandrosterone, epiandrosterone and synthetic derivatives inhibit Junin virus replication in vitro. Virus Res. 2008 Aug;135(2):203-12.

42. Santos CD, Toldo MP, Santello FH, Filipin Mdel V, Brazão V, do Prado Júnior JC. Dehydroepiandrosterone increases resistance to experimental infection by Trypanosoma cruzi. Vet Parasitol. 2008 May 31;153(3-4):238-43.

43. Brazão V, Santello FH, Caetano LC, Del Vecchio Filipin M, Paula Alonso Toldo M, do Prado JC, Jr. Immunomodulatory effects of zinc and DHEA on the Th-1 immune response in rats infected with Trypanosoma cruzi. Immunobiology. 2009 Jul 4.

44. Caetano LC, Santello FH, Del Vecchio Filipin M, et al. Trypanosoma cruzi: dehydroepiandrosterone (DHEA) and immune response during the chronic phase of the experimental Chagas’ disease. Vet Parasitol. 2009 Jul 7;163(1-2):27-32.

45. Harding G, Mak YT, Evans B, Cheung J, MacDonald D, Hampson G. The effects of dexamethasone and dehydroepiandrosterone (DHEA) on cytokines and receptor expression in a human osteoblastic cell line: potential steroid-sparing role for DHEA. Cytokine. 2006 Oct;36(1-2):57-68.

46. Choi IS, Cui Y, Koh YA, Lee HC, Cho YB, Won YH. Effects of dehydroepiandrosterone on Th2 cytokine production in peripheral blood mononuclear cells from asthmatics. Korean J Intern Med. 2008 Dec;23(4):176-81.

47. Hansen PA, Han DH, Nolte LA, Chen M, Holloszy JO. DHEA protects against visceral obesity and muscle insulin resistance in rats fed a high-fat diet. Am J Physiol. 1997 Nov;273(5 Pt 2):R1704-1708.

48. Richards RJ, Porter JR, Svec F. Long-term oral administration of dehydroepiandrosterone has different effects on energy intake of young lean and obese male Zucker rats when compared to controls of similar metabolic body size. Diabetes Obes Metab. 1999 Jul;1(4):233-9.

49. Ponholzer A, Madersbacher S, Rauchenwald M, Jungwirth S, Fischer P, Tragl KH. Vascular risk factors and their association to serum androgen levels in a population-based cohort of 75-year-old men over 5 years: results of the VITA study. World J Urol. 2009 Jun 28.

50. Tagliaferro AR, Davis JR, Truchon S, Van Hamont N. Effects of dehydroepiandrosterone acetate on metabolism, body weight and composition of male and female rats. J Nutr. 1986 Oct;116(10):1977-83.

51. Poczatková H, Bogdanová K, Uherková L, et al. Dehydroepiandrosterone effects on the mRNA levels of peroxisome proliferator-activated receptors and their coactivators in human hepatoma HepG2 cells. Gen Physiol Biophys. 2007 Dec;26(4):268-74.

52. Karbowska J, Kochan Z. Effect of DHEA on endocrine functions of adipose tissue, the involvement of PPAR gamma. Biochem Pharmacol. 2005 Jul 15;70(2):249-57.

53. Smith KJ, Skelton HG. Peroxisomal proliferator-activated ligand therapy for HIV lipodystrophy. Clin Exp Dermatol. 2001 Mar;26(2):155-61.

54. Kochan Z, Karbowska J. Dehydroepiandrosterone up-regulates resistin gene expression in white adipose tissue. Mol Cell Endocrinol. 2004 Apr 15;218(1-2):57-64.

55. de Heredia FP, Cerezo D, Zamora S, Garaulet M. Effect of dehydroepiandrosterone on protein and fat digestibility, body protein and muscular composition in high-fat-diet-fed old rats. Br J Nutr. 2007 Mar;97(3):464-70.

56. de Heredia FP, Larque E, Zamora S, Garaulet M. Dehydroepiandrosterone modifies rat fatty acid composition of serum and different adipose tissue depots and lowers serum insulin levels. J Endocrinol. 2009 Apr;201(1):67-74.

57. Yorek MA, Coppey LJ, Gellett JS, et al. Effect of treatment of diabetic rats with dehydroepiandrosterone on vascular and neural function. Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E1067-1075.

58. Sato K, Iemitsu M, Aizawa K, Ajisaka R. DHEA improves impaired activation of Akt and PKC zeta/lambda-GLUT4 pathway in skeletal muscle and improves hyperglycaemia in streptozotocin-induced diabetes rats. Acta Physiol (Oxf). 2009 Nov;197(3):217-25.

59. Brignardello E, Runzo C, Aragno M, et al. Dehydroepiandrosterone administration counteracts oxidative imbalance and advanced glycation end product formation in type 2 diabetic patients. Diabetes Care. 2007 Nov;30(11):2922-7.

60. Ponikowska B, Jankowska EA, Maj J, et al. Gonadal and adrenal androgen deficiencies as independent predictors of increased cardiovascular mortality in men with type II diabetes mellitus and stable coronary artery disease. Int J Cardiol. 2009 Apr 21.

61. Cappola AR, O’Meara ES, Guo W, Bartz TM, Fried LP, Newman AB. Trajectories of dehydroepiandrosterone sulfate predict mortality in older adults: the cardiovascular health study. J Gerontol A Biol Sci Med Sci. 2009 Dec;64(12):1268-74.

62. Srinivasan M, Irving BA, Dhatariya K, et al. Effect of dehydroepiandrosterone replacement on lipoprotein profile in hypoadrenal women. J Clin Endocrinol Metab. 2009 Mar;94(3):761-4.

63. Ii M, Hoshiga M, Negoro N, et al. Adrenal androgen dehydroepiandrosterone sulfate inhibits vascular remodeling following arterial injury. Atherosclerosis. 2009 Sep;206(1):77-85.

64. Aragno M, Meineri G, Vercellinatto I, et al. Cardiac impairment in rabbits fed a high-fat diet is counteracted by dehydroepiandrosterone supplementation. Life Sci. 2009 Jul 3;85(1-2):77-84.

65. Mitchell GF. Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage. J Appl Physiol. 2008 Nov;105(5):1652-60.

66. Stomati M, Monteleone P, Casarosa E, et al. Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecol Endocrinol. 2000 Oct;14(5):342-63.

67. Brooke AM, Kalingag LA, Miraki-Moud F, et al. Dehydroepiandrosterone improves psychological well-being in male and female hypopituitary patients on maintenance growth hormone replacement. J Clin Endocrinol Metab. 2006 Oct;91(10):3773-9.

68. Nordmark G, Bengtsson C, Larsson A, Karlsson FA, Sturfelt G, Rönnblom L. Effects of dehydroepiandrosterone supplement on health-related quality of life in glucocorticoid treated female patients with systemic lupus erythematosus. Autoimmunity. 2005 Nov;38(7):531-40.

69. Hackbert L, Heiman JR. Acute dehydroepiandrosterone (DHEA) effects on sexual arousal in postmenopausal women. J Womens Health Gend Based Med. 2002 Mar;11(2):155-62.

70. Lee SY, Myung SC, Lee MY, et al. The effects of dehydroepiandrosterone (DHEA)/DHEA-sulfate (DHEAS) on the contraction responses of the clitoral cavernous smooth muscle from female rabbits. J Sex Med. 2009 Oct;6(10):2653-60.

71. Lee KS, Oh KY, Kim BC. Effects of dehydroepiandrosterone on collagen and collagenase gene expression by skin fibroblasts in culture. J Dermatol Sci. 2000 Jun;23(2):103-10.

72. Calvo E, Luu-The V, Morissette J, et al. Pangenomic changes induced by DHEA in the skin of postmenopausal women. J Steroid Biochem Mol Biol. 2008 Dec;112(4-5):186-93