Introduction

DHEA is touted as a ‘wellness hormone’ and the ‘fountain of youth hormone’ owing to its alleged benefits related to ageing. It is used to try to reverse the effects of ageing including the metabolic syndrome, impaired memory, vaginal dryness, osteoporosis, loss of libido and skin ageing.

Sounds great but is DHEA really the fountain of youth?

What Is DHEA?

Dehydroepiandrosterone (DHEA) is a pro-hormone that belongs to an umbrella class of steroids known as 17-ketosteroids. Just to clarify;

  • DHEA is the abbreviation used for dehydroepiandrosterone (which is the subject of this article)
  • DHEA (S) is the sulphated form of DHEA.
  • DHA is the abbreviation used for docosahexaenoic acid which is an omega- 3 fatty acid which has nothing to do with this article. (I had a patient with dyslexia who was annoyed at not getting the benefits of an expensive ‘DHEA’ supplement but had actually bought DHA).
  • DHEA is secreted by the zona reticulas of the adrenal cortex, the brain and the testes in humans and related species. It accounts for the highest concentration of all steroid hormones in the body. It is the precursor of androgens and estrogens in the body.
  • The peak plasma levels of DHEA and DHEAS occur at approximately age 25 years. The levels then decrease progressively over time and are reduced by 95 per cent around the age of 85 years (the adrenopause). (All downhill from there if you believe the doom and gloom brigade).
  • The true physiological role and mechanism of action (or actions) of DHEA are not fully known or understood. (This in itself is interesting considering the fact that we know so much about human endocrinology in general).
  • DHEA can also be synthesized from chemicals found in wild yams and soy. The human body cannot make DHEA from these chemicals so you cannot increase your DHEA levels by eating wild yams or soy. (I have another patient who was busily sourcing wild yams to get ‘natural DHEA’ for its use as a fertility aid. There is some science connecting wild yams to twin pregnancies but it sure won’t work as a natural DHEA source).
  • Replacement with DHEA is only recommended if levels are below 130mg/dl in women and less than 180mg/dl in men. The usual replacement dose is 5 – 50 mg once to twice daily and it is advisable to monitor levels and follow the hormone levels if supplementation is being undertaken.
  • Salivary testing for DHEA levels is now available.
  • It is recommended that DHEA be taken in the morning to mimic the normal circadian pattern of DHEA release. It is used as tablets, capsules, topically, intravenously for induction of labor or myotonic dystrophy and intramuscularly for psoriasis.
  • Some drugs can increase the levels of DHEA in the body e.g. the BP medication, nifedipine.
  • Other drugs can lower the levels of DHEA in the body e.g. metformin.
  • It is banned by the National Collegiate Athletic Association and the Olympic Committee.
  • There are 364 DHEA products for sale on Amazon and 100mg costs on overage $0.10.

Is There Any Research?

There are 15,918 publications relating to DHEA which include 1,135 clinical trials. Compare that to androgen which has over 86,000 publications and 4,000 clinical trials.

Do DHEA Supplements Lower Inflammation?

Researchers from Washington University School of Medicine studied 50 mg DHEA or placebo once daily in 125 adults aged between 65 to 75 years of age for one year (1). DHEA was associated with a statistically significant decrease in inflammatory markers of TNF-alpha and IL-6. The clinical benefits (if any) of this biochemical inflammatory effect were not followed in this study cohort.

A 2007 Cochrane review was conducted on DHEA for the auto-immune inflammatory condition Systemic Lupus Erythematosis (2). A total of 7 clinical trials with 842 participants showed that DHEA had little clinical effect on disease activity in those with mild/moderate disease but that it had a modest but clinically significant impact on health related quality of life in the short term.

It is hard to deconstruct how DHEA could improve quality of life but not the disease process itself which makes it hard to use this study as definitive proof that DHEA acts as an anti-inflammatory. Surely, if DHEA were improving quality of life by acting as an anti-inflammatory, then we would have seen an effect on the underlying disease process?

Mexican investigators found that DHEA can protect against inflammation induced by urban particulate matter and titanium dioxide nanoparticles in a cell culture model (3).

DHEA inhibited the migration of human peripheral blood neutrophils  and human airway smooth muscle cells in a cell culture experiment which raises the possibility that DHEA might (I said might) have a role to play in airway hypersensitivity syndromes such as asthma (4).

Bottom Line

There is surprisingly little published relating to DHEA and the immune system. The available science is too sparse to make any guesses (if we were the kind of blog which guesses which we are not) on the role of DHEA in immunity or inflammation.

Do They “protect the brain”?

This is an area of huge interest.

Researchers from Oxford, UK carried out a Cochrane review to see if DHEA improves cognitive function (5). Results from five studies were included in the final analysis. The evidence was inconsistent. Of special interest were the results of two particular studies which showed reduced performance in a visual memory recall test in one trial and a significant drop-out rate in favour of placebo emerged in another trial.

All in all, the authors concluded that there was no evidence for an improvement in memory or other aspects of cognitive function in non-demented older people following DHEA supplements.

A more recent meta-analysis of DHEA from a group of Italian investigators reached a similar negative conclusion based on inconsistent and conflicting results from studies (6).

It must be said that studies on DHEA supplementation on cognitive function have an inherent problem. The brain makes its own DHEA and as such it may be difficult to assess the effect of supplemental DHEA with this major confounder in place.

Bottom Line

There is no proof that DHEA ‘protects the brain’ and there are even studies showing negative effects of DHEA on cognitive function. (Maybe my patient with dyslexia inadvertently bought the better product for brain protection by choosing DHA).

Does It Lower Diabetes Risk?

Italian investigators followed 1258 community-dwelling subjects aged ≥65 years without type 2 diabetes for 4.4±1.2 years. This was an observational study. Higher natural serum DHEAS levels revealed a significant protective effect against the onset of type 2 diabetes in older men but not in older women. This is interesting but what this does not tell us is whether supplementing with DHEA would protect against diabetes (7)?  Observational studies are not as powerful as interventional studies.

Investigators from the Mayo Clinic addressed this very question (8). They evaluated the effect of DHEA replacement (versus placebo) on insulin secretion, insulin action, and/or postprandial glucose metabolism in 112 elderly subjects with relative DHEA deficiency. The DHEA group had a decreased post-meal glucose but this was offset by a parallel decrease in insulin sensitivity. Overall, 2 years of replacement of DHEA in elderly men and women did not improve insulin secretion, insulin action, or the pattern of postprandial glucose metabolism.

DHEA 40 mg administered sublingually twice daily for 8 weeks had no positive effect on body weight, body composition, serum lipids, or insulin sensitivity in extremely obese adolescents and young adults according to a study from Cornell University (9).

Two other systematic reviews  failed to show any benefits of DHEA on plasma sugar (10,11). These reviews are of relevance to other sections in this article but will be discussed in detail here.

Researchers from the Mayo Clinic did a systematic review of the risks and benefits of DHEA supplementation in post-menopausal women (11). A total of 23 randomized controlled trials were included in the overview. DHEA was not associated with any improvements in serum lipids, glucose, weight, body’s index, bone mineral density, libido or sexual function.

Italian investigators did a meta-analysis of DHEA in elderly men (11). They identified 220 studies but only 25 were of sufficient quality to be included in the meta-analysis. The data came from 1353 men who were followed for an average of 36 weeks. No effect was noted on plasma glucose, lipids, bone health, sexual function or quality of life. A small but significant reduction in fat mass was noted.

Bottom Line

There is no scientific proof that DHEA supplementation helps with diabetes.

Does It Improve Bone Density and or Muscle Mass?

Faculty from the University of California carried out a placebo controlled randomized trial of DHEA 50mg for one year on mineral density in 225 healthy adults aged 55-85 years (the DAWN trial) (12). The levels of DHEA and DHEA(S) increased to levels that would be typical of a younger aged population in the active arm of the study. At 12 months in women, there was a statistically significant effect on bone mineral density in the lumbar spine but not at the hip, femoral neck. At 12 months in men, there was no significant effect on bone mineral density noted for any site. No effect was noted on body composition in this study.

As mentioned above, two systematic reviews failed to find any effect on bone mineral density (10,11).

Bottom Line

The effect of DHEA on bone mineral density is limited to a single study which only found benefit in women and at a single site (lumbar spine). Systematic reviews failed to find any benefit of DHEA for bone mineral density. DHEA is unconvincing as an anti-osteroporosis agent.

Do They “Improve your sex life?

DHEA is used to help erectile dysfuntion and is believed to act by causing penile dilatation via the nitric oxide pathway.

Austrian investigators studied DHEA for erectile dysfunction ( 50 mg orally for 6 months) in 27 patients with hypertension, 24 patients with diabetes mellitus, 6 patients with neurological disorders and 28 patients with no organic etiology. Results suggest that oral DHEA-treatment may be of benefit to patients with erectile dysfunction who have hypertension or in patients with ED without organic etiology (13). There was no impact of DHEA therapy on patients with diabetes mellitus or with neurological disorders.

DHEA is also used for vaginal dryness which directly affects sexual function in women(14). French Canadian investigators carried out a prospective, randomized, double-blind, and placebo-controlled phase III clinical trial looking at the effect of daily intravaginal 0.50% DHEA (6.5 mg) on four parameters of vulvovaginal atrophy namely percentage of parabasal cells, percentage or superficial cells, vaginal pH, and moderate to severe pain at sexual activity (dyspareunia).

Clinical and statistically significant benefits were seen in the treatment arm of the study for all four parameters measured. The lead author on the study is an employee of a company that is developing a vaginal DHEA product which always a little uncomfortable.

As mentioned above, two systematic analysis failed to show any benefits of DHEA on sexual function (10,11).

Bottom Line

Vaginal dryness is the only indication for DHEA that the American National Institutes of Health classifies as ‘likely effective’. Available studies and systematic reviews looking at DHEA for other parameters of libido or sexual function failed to show any convincing benefits.

Does It Help with Aches and Pains?

A double-blind crossover study of postmenopausal women with fibormyalgia who were randomized to DHEA supplementation (50 mg/day) or placebo for 3 months, with a one-month washout period in between, failed to show any improvement in quality of life, pain, fatigue, cognitive function, mood, or functional impairment (15). As mentioned above, DHEA did not improve the symptoms of SLE which would include aches and pains (2).

Bottom Line

DHEA does not help alleviate aches and pains.

Do they help weight loss or muscle gain?

A study in obese dogs showed that DHEA in combination with caloric restriction results in a faster rate of weight loss than does caloric restriction alone (16).

Spanish investigators carried out a randomized, double-blind placebo-controlled trial involving 61 postmenopausal obese women, who received DHEA-S or placebo for 3 months (17). The study had an unusual design and the effect of DHEA-S treatment in these postmenopausal women was compared with the effects observed in a group of premenopausal women. Both the pre and post menopausal women were noted to loose weight. Of note, improvements in features of the metabolic syndrome were noted in the post menopausal women only which is different to what was found in other studies.

Serbian investigators examined the effects of acute DHEA intake on body composition and serum steroid hormones in young athletes (18). A total of 20 young (19 to 22 years) male soccer players were allocated into two randomly assigned trial groups in a double-blind design to ingest 100-mg daily oral DHEA or as placebo for 28 days. No significant changes in body mass index, waist-to-hip ratio and body fat or total muscle mass for the two groups were detected at the end of the trial (P > 0.05).

Bottom Line

The results are inconclusive for the effects of DHEA on body composition. It is certainly possible that DHEA exerts differentia effects in people with different baseline levels of DHEA.

Is DHEA (and or Supplementation) Safe?

A key concern with DHEA supplementation is the risk of ‘aromatization’ of DHEA which raises the possibility of stimulation of estrogen dependent tumors like breast and endometrial cancer. Aromatization is the term used to describe the conversion of DHEA to estrogen. Generally speaking, androgens are anti-proliferative for breast and endometrial tissue. However these tissues possess aromatase activity which can catalyse the conversion of androgen into estrogen. Use of a 7 keto form of DHEA can minimize the risk of aromatization.

  • DHEA can cause mania, irritability and sexual inappropriateness in people with underlying mood disorders and DHEA should only be used under medical supervision (if at all) in this population.
  • DHEA can worsen polycystic ovarian disease.
  • Care should be taken with the combination of DHEA and liquorice as liquorice can prevent the breakdown of DHEA and increase the levels and prolong the effects of DHEA.
  • DHEA can reduce the response to the TB vaccine.
  • It can exacerbate underlying liver problems and is best avoided in people with liver disorders.
  • DHEA can increase the sedative effects of barbituates.
  • Other less serious but unwanted side effects include acne, hair loss, stomach upset and hypertension.

Conclusion

The National Institutes of Health have rated DHEA as likely effective for vaginal thinning and possibly effective for ageing skin and depression (19). All other possible uses of DHEA fall under possibly ineffective or likely ineffective as per the National Institutes of Health.

Many of the items found in the shelves of your average health food store are backed by relatively little science. DHEA is an interesting anomaly. DHEA comes with a pretty impressive research portfolio (relatively speaking). Admittedly, DHEA has less research than androgens but it has way more research than some other topics we have researched.

Unfortunately, all that research doesn’t amount to the proverbial ‘hill of beans’.

That being said, most people agree that research into DHEA is fraught with difficulties. The reasons for the difficulties encountered by researchers relate to:

  • a lack of clarity concerning the underlying physiological role of DHEA in humans,
  • baseline levels vary between men and women and across the ages so it is not possible to just study ‘adults’ as a single group
  • levels of DHEA are so low in most animals that it is difficult to measure them.

I have never recommended DHEA to any of my patients and having reviewed the research, I don’t think that my prescribing practice will change on this one.

References

1. Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans.
Weiss EP, Villareal DT, Fontana L, Han DH, Holloszy JO.
Aging (Albany NY). 2011 May;3(5):533-42.

2. Dehydroepiandrosterone for systemic lupus erythematosus.
Crosbie D, Black C, McIntyre L, Royle PL, Thomas S.
Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005114. Review.

3. Dehydroepiandrosterone protects endothelial cells against inflammatory events induced by urban particulate matter and titanium dioxide nanoparticles.Huerta-García E, Montiél-Dávalos A, Alfaro-Moreno E, Gutiérrez-Iglesias G, López-Marure R.
Biomed Res Int. 2013;2013:382058. doi: 10.1155/2013/382058. Epub 2013 Jan 14

4. DHEA-S inhibits human neutrophil and human airway smooth muscle migration.
Koziol-White CJ, Goncharova EA, Cao G, Johnson M, Krymskaya VP, Panettieri RA Jr.
Biochim Biophys Acta. 2012 Oct;1822(10):1638-42. doi: 10.1016/j.bbadis.2012.06.012. Epub 2012 Jul 3

5. Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people.
Grimley Evans J, Malouf R, Huppert F, van Niekerk JK.
Cochrane Database Syst Rev. 2006 Oct 18;(4):CD006221. Review

6. DHEA and cognitive function in the elderly.
Maggio M1, De Vita F2, Fisichella A2, Colizzi E2, Provenzano S2, Lauretani F2, Luci M2, Ceresini G3, Dall’Aglio E4, Caffarra P5, Valenti G4, Ceda GP3.
J Steroid Biochem Mol Biol. 2015 Jan;145:281-92. doi: 10.1016/j.jsbmb.2014.03.014. Epub 2014 May 2

7. Serum Dehydroepiandrosterone Sulfate and Risk for Type 2 Diabetes in Older Men and Women: The Pro.V.A Study.

Veronese N, Trevisan C, De Rui M, Bolzetta F, Maggi S, Zambon S, Corti MC, Baggio G, Perissinotto E, Crepaldi G, Manzato E, Sergi G.

Can J Diabetes. 2016 Apr;40(2):158-63. doi: 10.1016/j.jcjd.2015.09.013. Epub 2016 Feb 26

8. Two years of treatment with dehydroepiandrosterone does not improve insulin secretion, insulin action, or postprandial glucose turnover in elderly men or women.
Basu R, Dalla Man C, Campioni M, Basu A, Nair KS, Jensen MD, Khosla S, Klee G, Toffolo G, Cobelli C, Rizza RA.
Diabetes. 2007 Mar;56(3):753-66. Erratum in: Diabetes. 2007 May;56(5):1486

9. Dehydroepiandrosterone in morbidly obese adolescents: effects on weight, body composition, lipids, and insulin resistance.
Vogiatzi MG, Boeck MA, Vlachopapadopoulou E, el-Rashid R, New MI.
Metabolism. 1996 Aug;45(8):1011-5

Dehydroepiandrosterone in the treatment of erectile dysfunction in patients with different organic etiologies.
Reiter WJ, Schatzl G, Märk I, Zeiner A, Pycha A, Marberger M.
Urol Res. 2001 Aug;29(4):278-81

10. Clinical review: The benefits and harms of systemic dehydroepiandrosterone (DHEA) in postmenopausal women with normal adrenal function: a systematic review and meta-analysis.
Elraiyah T, et al.
J Clin Endocrinol Metab. 2014

11. Dehydroepiandrosterone supplementation in elderly men: a meta-analysis study of placebo-controlled trials.
Corona G, et al. J Clin Endocrinol Metab. 2013

12. Effect of dehydroepiandrosterone supplementation on bone mineral density, bone markers, and body composition in older adults: the DAWN trial.
Randomized controlled trial
von Mühlen D, et al. Osteoporos Int. 2008

13. Dehydroepiandrosterone in the treatment of erectile dysfunction in patients with different organic etiologies.
Reiter WJ, Schatzl G, Märk I, Zeiner A, Pycha A, Marberger M.
Urol Res. 2001 Aug;29(4):278-81

14. Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause.
Labrie F, Archer DF, Koltun W, Vachon A, Young D, Frenette L, Portman D, Montesino M, Côté I, Parent J, Lavoie L, Beauregard A, Martel C, Vaillancourt M, Balser J, Moyneur É; VVA Prasterone Research Group.

Menopause. 2016 Mar;23(3):243-56. doi: 10.1097/GME.0000000000000571

15. A randomized controlled trial of dehydroepiandrosterone in postmenopausal women with fibromyalgia.
Finckh A, Berner IC, Aubry-Rozier B, So AK.
J Rheumatol. 2005 Jul;32(7):1336-40

16. The effect of dehydroepiandrosterone combined with a low-fat diet in spontaneously obese dogs: a clinical trial.
Kurzman ID, Panciera DL, Miller JB, MacEwen EG.
Obes Res. 1998 Jan;6(1):20-8

17. Differential effect of oral dehydroepiandrosterone-sulphate on metabolic syndrome features in pre- and postmenopausal obese women.
Gómez-Santos C, Hernández-Morante JJ, Tébar FJ, Granero E, Garaulet M.
Clin Endocrinol (Oxf). 2012 Oct;77(4):548-54. doi: 10.1111/j.1365-2265.2011.04306.x

18. Effects of short-term dehydroepiandrosterone supplementation on body composition in young athletes.
Ostojic SM, Calleja J, Jourkesh M.
Chin J Physiol. 2010 Feb 28;53(1):19-25

19. https://medlineplus.gov/druginfo/natural/331.html