Foretelling the future with DHEA …

High DHEA Levels
Decrease Heart Disease

… and may increase survival and thus prolong life

By Will Block

B ack in 1993, I reviewed a text book on dehydroepiandrosterone (DHEA) edited by William Regelson, MD.1 The lengthy article that resulted covered much of what was then known about DHEA, which was published in the Life Extension Foundation’s Life Extension Newsletter and later incorporated into their Physicians’ Guide to Life Extension Drugs. The overcast of my report was that, while the data looked promising, more information was needed.

Nevertheless, I wrote, “DHEA may be able to, by its absence or presence, foretell the future of degenerative diseases such as diabetes, cancer, cardiovascular disease, memory disorders, and perhaps aging itself.” I have been continuously interested since then. As an adrenal sex hormone DHEA — present in serum mainly as the sulfate DHEA-S — is the most abundant steroid hormone in human blood. Its levels decline dramatically with age. About its applications there is abundant positive research. For example:

DHEA Levels and Survival

The National Institutes on Aging analyzed data from the Baltimore Longitudinal Study of Aging, they found a profound relationship between DHEA levels and survival.2

Tumor Prevention

“Whenever it has been tested in a model of carcinogenesis and tumor induction, DHEA has preventative effects.”3

Lower Cholesterol

In laboratory animals, DHEA has been shown to lower cholesterol, inhibit the formation of atherosclerotic plaque by 50%, and prevent at least one kind of induced hypertension. DHEAS levels may decrease blood pressure.4

Healthier Heart

DHEA levels have a strong positive correlation with a healthier heart and lowered risks of heart disease.5

Replacement Doses of 25 – 50 mg/Day

“Logic pleads in favor of oral administration of DHEA at a dose that provides so called ‘young’ DHEA levels in the blood and no T/DHT and E2 concentrations superior to those of normal people of 30 to 40 years of age. Calculations based on production rates, interconversion between DHEA and DHEAS, and metabolic studies suggest that replacement doses of 25–50 mg once daily are able to fulfill this double requirement.”6

Low DHEA Levels May Increase Mortality

“Low concentrations of DHEA are associated with immunosenescence, physical frailty, decline in muscle mass, increased mortality, loss of sleep, diminished feelings of well-being and impaired ability to cope, and occur in several common diseases (including cancer, atherosclerosis, hypertension, diabetes, osteoporosis and Alzheimer’s disease.)”7

Normalize Some Effects of Aging

“No potentially harmful accumulation of DHEAS and active steroids was recorded … A number of biological indices confirmed the lack of harmful consequences of this 50 mg/day DHEA administration over one year, also indicating that this kind of replacement therapy normalized some effects of aging.”8

DHEA at 25 – 50 mf/Day Safe in the Elderly

“No accumulation of steroids was observed. No worrying transformation to androgen and estrogen was recorded; indeed, the limited increased estradiol in aged women could be predicted to be beneficial. These results suggested that daily oral administration of DHEA (25/50 mg) is safe in elderly subjects. The 50-mg dose was chosen for a 1 yr, double blind, placebo-controlled trial of daily oral administration of DHEA in 60- to 80-yr-old individuals.”9

May Reduce Cognitive Deficits

“Elevated cortisol-DHEA ratios may be a state marker of depressive illness and may contribute to the associated deficits in learning and memory. Administration of DHEA may reduce neurocognitive deficits in major depression.”10

Greater Survival

“Consistent with the beneficial effects of calorie restriction on aging and life span in other animals, men with lower temperature and insulin and those maintaining higher DHEA levels have greater survival than their respective counterparts.”11

May Reverse Some Age-Associated Conditions

“Oral replacement of DHEA, which does not appear to cause important adverse effects, may prevent, or even reverse, some age-associated conditions.”7

DHEA Supports the Creation of New Neurons

“These results show that DHEA, a steroid prominent in the blood and cerebral environment of humans, but which decreases markedly with age and during major depressive disorder, regulates neurogenesis in the hippocampus and modulates the inhibitory effect of increased corticoids on both the formation of new neurons and their survival.”12

DHEA Helps Parkinsonian Disease and Schizophrenia

“Higher DHEA levels were significantly correlated with lower symptom ratings, better performance on some measures of memory and lower ratings of Parkinsonian symptoms.” A follow-up placebo-controlled human trial published in the Archives of General Psychiatry reports that DHEA supplementation produced significant benefits in patients with schizophrenia.13

Low DHEA-S Associated with Increased Pain and Distress

DHEA-S was negatively associated, and prolactin positively associated with musculo-skeletal pain and psychological distress.14

DHEA Decreases Cholesterol, Insulin, and Glucose

DHEA therapy at 150 mg per day during 40 days in men with DHEA levels < 2000 microg/l decreased total cholesterol concentration, insulin and glucose levels and fasting insulin resistance index. This therapy may be a beneficial against coronary heart disease risk factors.15

DHEA Enhances Muscle Mass in the Elderly

DHEA replacement has the beneficial effects of enhancing the increases in muscle mass and strength induced by heavy resistance exercise in elderly individuals.16

DHEA Restores Sex Hormones of Elders to Younger Subjects

Daily administration of 25 mg DHEA increased the serum DHEA, DHEA-S, androstenedione, and estradiol levels of the subjects of the older group to the same level as that of younger subjects.17

Low DHEA Associated with Gait and Memory

In a cohort of very old individuals, DHEA-S decline tracked with declines in gait speed and memory test scores in women independent of baseline DHEA-S level. DHEA-S decline might be a marker for age-associated performance decline, but its relevance is specific to women.18

Lower DHEA-SL with higher CVD Mortality and All-Cause Mortality

Among postmenopausal women with coronary risk factors undergoing coronary angiography for suspected myocardial ischemia, lower DHEA-S levels were linked with higher cardiovascular disease (CVD) mortality and all-cause mortality.19

DHEA Improves Fertility and Increases Live Births

DHEA supplementation at 75 mg of DHEA once a day before starting the next in vitro fertilization (IVF) cycle and during treatment can have a beneficial effect on ovarian reserves for poor-responder patients on IVF treatment.20 Women taking DHEA improved embryo quality during treatment between first and second cycles. Patients in the DHEA group also had a significantly higher live birth rate compared with controls (23.1% versus 4.0%, respectively). Six of seven deliveries were among patients with secondary infertility.

Inhaled DHEAS Improved Asthma

Inhaled dehydroepiandrosterone-3-sulfate (DHEAS) possesses anti-inflammatory activity in in vitro assays and in models of allergen and lipopolysaccharide challenges.21 An inhaled suspension of DHEAS delivered via nebulizer was found to improve asthma control scores in subjects with poorly controlled moderate-to-severe asthma.

DHEA Lowers Inflammatory Cytokines in Aging Humans

Fifty-seven men and 68 women aged 65 to 75 years were randomly assigned to 50 mg DHEA or placebo once daily.22 Year one was a randomized, double-blind trial. Year 2 was an open label continuation. DHEA replacement improved glucose tolerance in participants who had abnormal glucose tolerance initially, reduced plasma triglycerides, and the inflammatory cytokines IL-6 and TNF-α.

DHEA improves Cognition in Older Women

Twelve women were assigned to receive DHEA 25 mg/day for 6 months. The control group (n = 15) matched for age and cognitive function was followed without hormone replacement.23 Cognitive function was assessed by standard tests along with basic activities of daily living at baseline, 3 and 6 months. Cognitive scores and activities of daily living scores were improved in the DHEA group, but not the control group.

DHEA Improves Pulmonary Hypertension

Eight patients with pulmonary hypertension in chronic obstructive pulmonary disease were treated with DHEA (200 mg daily orally) for 3 months.24 The primary end-point was the change in the 6-minute walk test (6-MWT) distance. Secondary end-points included pulmonary hemodynamics, lung function tests and tolerance of treatment. DHEA treatment significantly improved 6-MWT distance, pulmonary hemodynamics, and diffusing capacity of the lung.


“DHEA may be able to, by its absence
or presence, foretell the future of
degenerative diseases such as
diabetes, cancer, cardiovascular
disease, memory disorders, and
perhaps aging itself.”


DHEA Reverses Arterial Aging and Reduces CVD Risk

A randomized, double-blind trial was conducted to study the effects of 50 mg day DHEA replacement on carotid augmentation index (n = 92) and pulse wave velocity (n=51) in women and men aged 65–75 years.25 The augmentation index decreased in the DHEA group, but not in the placebo group. The reductions in augmentation index and pulse wave velocity were accompanied by decreases in inflammatory cytokines (TNFα and IL-6). In conclusion, DHEA replacement in elderly men and women improves indices of arterial stiffness, which is known to increase with age and is an independent risk factor for CVD.

Discovered: A DHEA Receptor

DHEA affects multiple cellular functions of the endocrine, immune, and nervous systems, while interacting and modulating a variety of membrane, intracellular neurotransmitter, and steroid receptors. However, up to now, no receptor has been described specifically for it, while most of its physiological actions have been attributed to its conversion to either androgens or estrogens.

Intrigued by its ability to produce multiple effects in the nervous system of a variety of species, Greek researchers investigated the ability of DHEA to interact with the two mammalian neurotrophin receptors, the TrkB and TrkC.1 The same researchers had recently reported that DHEA protects neuronal cells against apoptosis, interacting with the TrkA, a high affinity pro-survival receptor of the neurotrophin nerve growth factor.

Amazingly, DHEA binds to all Trk receptors, whatever the species. Trk receptors are a family of tyrosine kinases that regulate synaptic strength and plasticity in the mammalian nervous system. Trk stands for tropomyosin-receptor-kinase.

The researchers hypothesize that early in evolution, DHEA may have acted as a non-specific neurotrophic factor promoting neuronal survival. The interaction of DHEA with all types of neurotrophin receptors offers new insights into the largely unidentified mechanisms of its actions on multiple tissues and organs known to express neurotrophin receptors.

The vast number of experimental and clinical findings involving this multifaceted steroid in the reproductive, immune, endocrine, vascular and cancer cell physiology and dysfunction should be reassessed in view of these findings.

References

  1. Pediaditakis I1, Iliopoulos I, Theologidis I, Delivanoglou N, Margioris AN, Charalampopoulos I, Gravanis A. DHEA: An Ancestral ligand of neurotrophin receptors. Endocrinology. 2014 Oct 20:en20141596. [Epub ahead of print]

DHEA Predicts Major Coronary Heart Disease

The Journal of the American College of Cardiology recently published the findings of researchers at Sweden’s University of Gothenburg of an association between higher levels of DHEA and a reduced risk of coronary heart disease events in elderly men.26 This new study involved a large cohort of elderly men examined under the hypothesis that serum DHEA and DHEA-S are predictors of major coronary heart disease (CHD) and/or cerebrovascular disease (CBD) events.

The new study included 2,614 Swedish subjects between 69 and 80 years of age enrolled in the Osteoporotic Fractures in Men study. Blood samples obtained upon enrollment were analyzed for DHEA and DHEA-S. National register data were used to obtain cardiovascular clinical outcomes over a five-year period.

Over the follow-up period, CHD events occurred among 302 men and 225 men experienced a CBD event. A decline in DHEA as well as DHEA-S was associated with an elevation in the risk of CHD events. The association remained significant following adjustment for cardiovascular risk and other factors.

In a press release, “Endogenous production of DHEA appears to be a protective factor against coronary heart disease,” said lead researcher Åsa Tivesten, of the University of Gothenburg's Wallenberg Laboratory for Cardiovascular and Metabolic Research, who coordinated the study.27 “High DHEA levels may also be a biomarker of generally good health in elderly men.”

Using mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based Osteoporotic Fractures in Men study in Sweden (2,416 men, ages 69 to 81 years), complete cardiovascular clinical outcomes were available from national Swedish registers.

During follow-up lasting 5 years, 302 participants experienced a CHD event, and 225 had a CBD event. Both DHEA and DHEA-S levels were inversely associated with the age-adjusted risk of a CHD event; the higher the level the lower the number of heart attacks and strokes.

However, neither DHEA nor DHEA-S showed any statistically significant association with the risk of CBD events. Moreover, the association between DHEA/-S (both) and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum total testosterone and estradiol, C-reactive protein, and renal function. The association remained unchanged after exclusion of the first 2.6 years of follow-up to reduce reverse causality. Low serum levels of DHEA and its sulfate form predict an increased risk of CHD, but not CBD, events in elderly men.

References

  1. Kalimi M, Regelson W, eds. The Biologic Role of Dehydroepiandrosterone (DHEA). Berlin, New York: Walter de Gruyter, 1990.
  2. Shock NW, et al, eds. Normal Human Aging: the Baltimore Longitudinal Study on Aging. Washington, DC: US Government Printing Office;1984.
  3. Regelson W, Loria R, Kalimi M. Dehydroepiandrosterone (DHEA) I: immunologic action. Ann NY Acad Sci. 1994 May 31;719:553 – 63.
  4. Barbagallo M, Shan J, Pang PK, Resnick LM. Effects of dehydroepiandrosterone sulfate on cellular calcium responsiveness and vascular contractility. Hypertension. 1995;26:1065 – 9.
  5. Herrington DM. Dehydroepiandrosterone and coronary atherosclerosis. Ann NY Acad Sci. 1995;774:271– 80.
  6. Baulieu EE. Dehydroepiandrosterone (DHEA): a fountain of youth? J Clin Endocrinol Metab. 1996 Sep;81(9):3147 – 51.
  7. Steel N. Dehydroepiandrosterone and aging. Age Ageing. 1999 Mar;28(2):89 – 91.
  8. 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 USA. 2000 Apr 11;97(8):4279 – 84.
  9. Legrain S, Massien C, Lahlou N, et al. Dehydroepiandrosterone replacement administration: pharmacokinetic and pharmacodynamic studies in healthy elderly subjects. J Clin Endocrinol Metab. 2000 Sep;85(9):3208 – 17.
  10. Giordano R, DiVito L, Lanfranco F, et al. Elderly subjects show severe impairment of dehydroepiandrosterone sulfate and reduced sensitivity of cortisol and aldosterone response to the stimulatory effect of ACTH. Clin Endocrinol. (Oxf) 2001 Aug;55(2):259 – 65.
  11. Roth GS, Lane MA, Ingram DK, et al. Biomarkers of calorie restriction may predict longevity in humans. Science. 2002 Aug 2; 297(5582):811.
  12. Karishma KK, Herbert J. Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone-induced suppression. Eur J Neurosci. 2002 Aug;16(3):445 – 53.
  13. 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.
  14. Finset A, Øverlie I, Holte A. Musculo-skeletal pain, psychological distress, and hormones during the menopausal transition. Psychoneuroendocrinology. 2004 Jan;29(1):49 – 64.
  15. Rabijewski M, Zgliczyński W. Positive effects of DHEA therapy on insulin resistance and lipids in men with angiographically verified coronary heart disease — preliminary study. Endokrynol Pol. 2005 Nov-Dec;56(6):904 – 10.
  16. Villareal DT, Holloszy JO. DHEA enhances effects of weight training on muscle mass and strength in elderly women and men. Am J Physiol Endocrinol Metab. 2006 Nov;291(5):E1003 – 8.
  17. Yamada Y, Sekihara H, Omura M, et al. Changes in serum sex hormone profiles after short-term low-dose administration of dehydroepiandrosterone (DHEA) to young and elderly persons. Endocr J. 2007 Feb;54(1):153 – 62.
  18. Sanders JL, Cappola AR, Arnold AM, et al. Concurrent change in dehydroepiandrosterone sulfate and functional performance in the oldest old: results from the Cardiovascular Health Study All Stars study. J Gerontol A Biol Sci Med Sci. 2010 Sep;65(9):976 – 81.
  19. Shufelt C, Bretsky P, Almeida CM, et al. DHEA-S levels and cardiovascular disease mortality in postmenopausal women: results from the National Institutes of Health — National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women’s Ischemia Syndrome Evaluation (WISE). J Clin Endocrinol Metab. 2010 Nov;95(11):4985 – 92.
  20. Wiser A, Gonen O, Ghetler Y, et al. Addition of dehydroepiandrosterone (DHEA) for poor-responder patients before and during IVF treatment improves the pregnancy rate: a randomized prospective study. Hum Reprod. 2010 Oct;25(10):2496 – 500.
  21. Wenzel SE, Robinson CB, Leonard JM, Panettieri RA Jr. Nebulized dehydroepiandrosterone-3-sulfate improves asthma control in the moderate-to-severe asthma results of a 6-week, randomized, double-blind, placebo-controlled study. Allergy Asthma Proc. 2010 Nov-Dec;31(6):461 – 71.
  22. Weiss EP, Villareal DT, Fontana L, Han DH, Holloszy JO. Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans. Aging (Albany NY). 2011 May;3(5):533 – 42.
  23. Yamada S, Akishita M, Fukai S, et al. Effects of dehydroepiandrosterone supplementation on cognitive function and activities of daily living in older women with mild to moderate cognitive impairment. Geriatr Gerontol Int. 2010 Oct;10(4):280 – 7.
  24. Dumas de La Roque E, Savineau JP, Metivier AC, Billes MA, Kraemer JP, Doutreleau S, Jougon J, Marthan R, et al. Dehydroepiandrosterone (DHEA) improves pulmonary hypertension in chronic obstructive pulmonary disease (COPD): a pilot study. Ann Endocrinol (Paris). 2012 Feb;73(1):20 – 5.
  25. Weiss EP, Villareal DT, Ehsani AA, Fontana L, Holloszy JO. Dehydroepiandrosterone replacement therapy in older adults improves indices of arterial stiffness. Aging Cell. 2012 Oct;11(5):876 – 84.
  26. Tivesten Å, Vandenput L, Carlzon D, et al. Dehydroepiandrosterone and its sulfate predict the 5-year risk of coronary heart disease events in elderly men. J Am Coll Cardiol. 2014;64(17):1801 – 10.
  27. Svahn K. Low levels of the DHEA prohormone predict coronary heart Disease. Nov. 06, 2014. http://sahlgrenska.gu.se/english/news_and_events/news/News_Detail/low-levels-of-the-dhea-prohormone-predict-coronary-heart-disease.cid1245084. Accessed: Dec 1, 2014.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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