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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