The Anti-Aging Properties of DHEA
16th International Congress of Endocrinology & The Endocrine 96th Annual Meeting & Expo
Karina Danilowicz MD, PhDDivision of Endocrinology, Hospital de Clínicas,
University of Buenos Aires, Argentina
Disclosure
Nothing to disclose.
Endocrine Myths: Truth versus the Internet
•The Internet is probably the main worldwide channel for easy access to drugs and other substances
•The Web is the primary source of non-medical information
Objectives
•Physiological aspects
•Aging
•DHEA supplementation in the Web
•Scientific evidence
•Main conclusions
Physiology
• Symington et al first identified the adrenal cortex as the key site of DHEA production
• Daily production rate: 8 to 16 mg
• The physiological function remains poorly known
• DHEAS is a circulating reserve of DHEA; they are enzymatically interconvertible
Zona Reticularis 3βHSD
Aging
Aging per se should not be considered as a disease state.
Increased age is associated with an increased demand in healthcare in general.
AgingBjornerem et al, J Clin End Metab 2004
MF
• Plasma samples from 1555 men and 1952 women, 25 to 84 yr of age in 1994-1995, the Tromso Study
• DHEA was negatively correlated with age in both sexes (P<0.001)
• The DHEA levels at 70 yr were 32% and 29% of the levels at 40, among men and women, respectively
Youth
If age-related changes could be prevented or delayed, then this could result in improved well being and quality of
life among the elderly.
DHEA in the Web“The hormonal fountain of youth”
• DHEA is available over-the-counter
• To date, the terms “DHEA supplement” and “antiaging” revealed 931.000 hits on the internet by a Google search
DHEA supplementation
• DHEA is considered by the FDA as a nutritional supplement
• There is little control over the contents of DHEA • There is little control over the contents of DHEA supplements or their manufacturing procedures
• A study showed that 7 of 16 tested preparations had DHEA content within 90-110% of the labelled claim (Parasrampuria J et al, JAMA 1998)
Improves function of the immune system
Epidemiological data
Straub et al, J Clin Endocrinol Metab 1998.
Epidemiological data
•DHEA has beneficial effects in LES(Van Vollenhoven et al, Arthritis Rheum 1995)
•The age associated-increase in IL-6 can be reversed by the administration of DHEA(S) in mice (not by the administration of DHEA(S) in mice (not confirmed in human spleen mononuclear cell suspensions)(Young et al, Clin Exp Immunol 2001)
The routine use of DHEA to reverse cytokine imbalances in the aging population is probably
premature and needs to be carefully monitored.
Cognitive enhancement
Epidemiological data
• Low DHEA has been associated with Alzheimer’s disease, memory, and cognitive impairment
(Nasman et al, Biol Psychiatry 1991; Davis et al, J Clin Endocrinol Metab 2008;
Kalmijn et al, J Clin Endocrinol Metab 1998)Kalmijn et al, J Clin Endocrinol Metab 1998)
• DHEA has been observed to be neuroprotectiveand effective at enhancing neurogenesis (Kaazik et al,
Neuroscience 2001; Suzuki et al, Proc Natl Acad Sci USA 2004)
Authors Duration (wk)
Dose (mg/d)
Total no.
F/M
Effect on cognitive performance
Wolf, 1997 2 50 15/25 No effect
Kudielka, 1998 2 50 36/39 No effect
Wolf, 1998 2 50 37/38 Visual verbal recall reduced, attention increasedincreased
Van Niekerk, 2001
13 50 -/46 No effect
Hirshman, 2003
4 50 30 Enhanced memory discrimination
Kritz S, 2008 52 50 115/110 No effect
Epidemiological data on mortality
Ohlsson et al, J Clin Endocrinol Metab 2010.
Authors Subjects/FU Risk
Barrett-Connor, 1987 242M/289W/ 12 years
Low DHEA(S), increased riskof death in M
Barrett-Connor, 1994 1029M/942W/
19 years
No association
Mazat, 2001 171M/119W/
10 years
Low DHEA(S), increased riskof death for M under 70 yo
Trivedi, 2001 963M/1171W/
7.4 years
Low DHEA(S), increased riskof death in M7.4 years of death in M
Feldman, 2001 1709M/9 years No association except with IHD events
Shufelt, 2010 270W Low DHEA(S), increased risk
Cappola, 2006 539W/5 years High DHEA(S), increasedcancer mortality; low levels, cardiovascular mortality
Ohlsson, 2010 2644M/
4.5 years
Low DHEA(S), increased riskof death
Metabolic and vascular effects
• DHEA tends to have a HDL-cholesterol-lowering effect, with modest effects on plasma lipids in women(Flynn et al, J Clin Endocrinol Metab 1999; Nestler et al, J Clin Endocrinol Metab
1988; Nair et al, N Engl J Med 2006; Lasco et al, Eur J Endocrinol 2001)1988; Nair et al, N Engl J Med 2006; Lasco et al, Eur J Endocrinol 2001)
• Most of the studies indicate no influence on insulin sensitivity or glycometabolic profile
(Nair et al, N Engl J Med 2006 ; Jankowski et al, Clin End (Oxf) 2011)
• DHEA may improve indices of arterial stiffness (Weiss et al, Aging Cell 2012; Iwasaki et al, Am J Physiol 2005)
Epidemiological data
• DHEAS levels below the 10th centile are associated with increased likelihood of low sexual functionin both pre- and post-menopausal women in both pre- and post-menopausal women (Davis et al, JAMA 2005)
•Basar et al. reported significantly lower DHEAand free T levels in men with sexual dysfunction (Basar et al, Urology 2005)
Authors Duration(wk)
Dose(mg/d)
Total no.
F/M
Significant effect onsexual function
Mortola, 1990 1 1600 6 No change
Morales, 1994 12 50 15/13 No change
Wolf, 1997 2 50 15/25 No change
Barnhart, 1999 12 50 60 No change
Reiter, 1999 24 50 -/20 ImprovementReiter, 1999 24 50 -/20 Improvement
Baulieu, 2000 52 50 140/140 Improvement
Hackbert, 2002 1 300 16 Improvement
Schmidt, 2005 6 90-450 23/23 Improvement
Kritz S, 2008 52 50 115/110 No change
Labrie, 2009 52 1.0% 14 Improvement
Panjari, 2009 52 50 93 No change
Morales, 2009 16 100 -/28 No change
Adaptated from Panjari et al, Human Reproduction Update 2007.
DHEA Improves Sense of Well-Being
Epidemiological data•DHEAS levels were found to be inversely correlated with depressed mood in a study of 699 women(Barrett-Connor et al, J Am Geriatr Soc 2007)
•In adrenal insufficiency, DHEA replacement led to a significant improvement on well-being (Arlt et al, N Engl J Med 1999; Hunt et al, Clin Endocrinol Metab 2000)
•In men, low endogenous DHEAS concentrations were associated with normal well-being scores at baseline (Arlt et al, J Clin Endocrinol Metab 2001)
Authors Duration (wk)
Dose (mg/d)
Total no.
F/M
Significant effect on well-
being/mood
Morales, 1994 12 50 15/13 Improvement
Labrie, 1997 52 1.0% 14 Improvement
Wolf, 1997 2 50 15/25 Trend to improve
Bloch, 1999 6 90/450 3/12 Improvement
Van Niekerk, 13 50 -/46 No changeVan Niekerk, 2001
13 50 -/46 No change
Arlt, 2001 16 50 -/22 No change
Schmidt, 2005 6 90-450 11/23 Improvement
Nair, 2006 56 50/75 27/29 No change
Kritz S, 2008 52 50 115/110 No change
Panjari, 2009 52 50 93 No change
Effect on well-being
Allolio B and Arlt W, Trends in Endocrinol and Metab 2002 from Arlt et al, N Engl J Med 1999 and Arlt et al, J Clin Endocrinol Metab 2001.
Elderly men Women with adrenal
insufficiency
Supplement from House Of Muscle
Epidemiological data
• A positive association was found between DHEA and physical measures (Physical Performance Test, PPT score)(O´Donnell et al, J Clin Endocrinol Metab 2006)
• However, the effects of DHEA on body composition and physical performance are modest and often inconsistent (Igwebuike et al, J Clin Endocrinol Metab 2008)
Effect on fat mass
Corona et al, J Clin Endocrinol Metab 2013.
Authors Duration (wk)
Dose (mg/d)
Total no.F/M
Significant muscular effect
Yen, 1995 24 100 8/8 Increased strength (S), fat free mass (FFM) (M)
Diamond, 1996 48 3-5g 10%
15 F Increased muscle area
Morales, 1998 24 100 10/9 Increased FFM and S
Percheron, 2003
48 50 140/140 No effect on S
Igwebuike, 2008
12 50 31 F No effect on physical performance
Kenny, 2010 24 50 88 F Increased in S+exercise
Jancowski, 2011 48 50 58/61 No effect
DHEA:The Missing Link Long-termBone Metabolism and Health
Epidemiological data
• A correlation between DHEA levels and bone mass has been reported by some (low hormone less bone)less bone)(Spector et al, Clin Endocrinol 1991)
but not all studies
(Nordin et al, J Clin Endocrinol Metab 1985)
Authors Duration (wk)
Dose (mg/d)
Total no.
(M/F)
Significant effect on BMD
Kenny, 2010 26 50 99 F No change
Weiss, 2009 56 50 58/55 Increase in BMD (F)
Von Muhlen, 2008
52 50 115/110 Small increase in BMD (F)
Jankowski, 2008 52 50 58/61 Increase in BMDJankowski, 2008 52 50 58/61 Increase in BMD
Nair, 2006 56 50/75 27/29 Increase in BMD
Jankowski, 2006 52 50 70/70 Increase in BMD
Villarreal, 2000 26 50 10/8 Increase in BMD
Baulieu, 2000 52 50 140/140 Increase in BMD (F)
Labrie, 1997 24 10% cream
14 F Increase in BMD (F)
Adaptated from Davies et al, J Clin Endocrinol Metab 2011.
Risks
You must read this article
about DHEA side effects
Risks
• Acne and hirsutism
• Decline in HDL and apoA1
• Potential risks include direct adverse metabolic • Potential risks include direct adverse metabolic effects and effects of the estrogenic and androgenic actions of DHEA metabolites
•There is insufficient documentation of the use of DHEA regarding effects on the breast and uterus
Authors Type of cancer
Risk
Zumoff, 1981 Breast cancer High DHEA(S), increased risk
Gordon, 1990 Breast cancer High DHEA(S), increased risk
Barrett-Connor, 1990
Breast cancer No risk
Dorgan, 1997 Breast cancer High DHEA(S), increased risk
Hanjinson, 1998 Breast cancer High DHEA(S), increased risk (ns)
Zeleniuch-J, 2004 Breast cancer High DHEA(S), increased risk
Baglietto, 2010 Breast cancer High DHEA(S), increased risk
Fourkala, 2012 Breast cancer No risk
Zhang, 2013 Breast cancer High DHEA(S), increased risk
Closing remarks
• At present there is insufficient evidence to recommend DHEA supplementation to improve health status of older individuals
• There are safety concerns associated with long-term hormone therapy
• There is no evidence of DHEA for rejuvenation
Closing remarks
• The lack of quality control of the substances currently marketed is also a concern
• In the Web, information about benefits and therapeutic uses are in general very limited and misleading
Closing remarks
Simple interventions:Exercise, a balanced diet, and not smoking
THANKS FOR YOUR ATTENTION!
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