The Role of DHEA Supplementation
In Age Management Medicine

The Role of DHEA Supplementation In Age Management Medicine 

Dehydroepiandrosterone (DHEA) is a member of the steroid hormone family, produced by the zona reticularis of the adrenal cortex in response to pituitary ACTH stimulatory signaling. Slide 1 DHEA is the hormone present in the greatest abundance in circulation.

DHEA levels peak at around age 20, then decline by approximately 10 percent per decade, with great individual-to-individual variability. By age 70, DHEA levels reach a relatively stable trough level of 10 percent to 20 percent of its young adult levels.  

DHEA was first isolated in 1931, by Dr. Adolf Buternandt, whose data were published in 1934. Publication the DHEA structure preceded that of testosterone by one year. (2)  

In the 1950s, DHEA was isolated from human serum; later in that same decade, the first reports of DHEA demonstrating a decline in level with aging were accounted, for both males and females. Slide 2

In the 1960s, DHEA was found to be an intermediate molecule in the testosterone synthesis pathway—becoming the basis for the initial embrace of DHEA supplementation as a potential body building/performance enhancing aid. DHEA’s utility was generally unspectacular. High-dose DHEA supplementation favored conversion to estradiol in addition to any small benefit in terms of testosterogenic effect—Slide3—which limited its value as an androgenic supplement; subsequently, its use as a high-dose supplement was short lived. By the 1980s, DHEA was universally stocked in nutrition and health stores at lower doses, marketed as a more general aid to good health and function with aging.  

DHEA followed a checkered path in the subsequent decade. In 1986 the FDA reclassified DHEA as a controlled drug, based on the lack of well-delineated dosing data and a paucity of literature, regarding risks of long-term supplementation.

In1994, the U.S. Dietary Supplement Health and Education Act re-reclassified DHEA (based on the lack of data demonstrating long-term supplement risk) as a food supplement, once again allowing it to be sold over the counter, where it has remained. 

When viewing DHEA as a weapon in the medical armamentarium, it is not typically mentioned in the same tones and with the same volume as testosterone, growth hormone, thyroid hormones or estradiol and progesterone. Yet, like a good character actor, it still plays a role in a balanced approach in considering the utility hormone supplementation. Like a vital supporting actor, it’s important in the big picture, integral to the fabric of the film, but not the star. 

Regardless of hormone discussion’s subject matter, the standard caveat applies. We should require more than mere association between the presence or absence of a hormone and an associated finding. We should also require data demonstrating the effect of altering that state. Whenever possible, follow literature based on the association of low or high hormone levels and disease risk—as well as examining outcomes associated with directed intervention. Only meteorologists and economists get the luxury of telling people what has happened. In medicine, data must give an idea of what interventions will do in the future. 

The focus: Use of DHEA in a rational clinical context, targeting DHEA literature and its replacement data in a system-by-system review.

Note:  DHEA Levels 

DHEA, like cortisol, follows a diurnal secretion/level pattern. This makes sense, given DHEA’s secretion is, like that of cortisol, stimulated by pituitary-derived ACTH. Unlike cortisol, DHEA secretion is prolonged rather than pulsatile; DHEA has a longer serum half-life (10 to 20 hours), making for much less exaggerated daily peak and trough levels. It also makes for readily valid measurement, which is not as time-dependent as it is for cortisol. (1) Slide 5

DHEA & Mortality 

A good starting point in the DHEA literature is a 1996 study by Claudine Berr, published in the Proceedings of the National Academy of Science. The study followed 622 adults (average age was 74 upon study entry). Over the proceeding four years, the study population was followed for DHEA levels and total mortality risk, functional status, psychological state and mental status. In women, DHEA levels were directly related to scores of well-being, cognitive function and functional status. In men, DHEA levels were inversely related to total mortality risk. Neither group demonstrated a specific Alzheimer’s Disease (AD) risk, based on DHEA levels. The mortality data for women at the end of 4 years were not significant. (3) Slide 6  Slide 7  

Barrett-Connor, in the New England Journal of Medicine, 1996, published a prospective study of baseline dehydroepiandrosterone sulfate levels and associated risk for mortality and cardiovascular disease: 242 men (ages 50 to 79), followed over a 12-year period. In men with no history of heart disease at base line, the age-adjusted relative risk associated with a DHEAS level below 140 micrograms per deciliter was 3.3 (P less than 0.05) for death from cardiovascular disease and 3.2 (P less than 0.05) for death from ischemic heart disease.

In multivariate analyses, an increase in DHEAS level of 100 micrograms per deciliter was associated with a 36 percent reduction in mortality from any causes (P less than 0.05) and a 48 percent reduction in mortality from cardiovascular disease (P less than 0.05)—after adjustment for age, systolic blood pressure, serum cholesterol level, obesity, fasting plasma glucose level, cigarette smoking status and personal history of heart disease. Of greatest interest is that baseline determination of DHEA levels was associated with long-term health risk, even in subjects with no diagnostic history of previous pathology. (4)

DHEA & Heart Disease 

Several studies demonstrated the relationship between low DHEA levels and heart disease risk. 

The Massachusetts Male Aging Study (MMAS) included DHEA as part of their thorough prospective evaluation of heart disease mortality. The MMAS followed a random sample of 1,709 men (aged 40 to 70 years at baseline) over a 9-year period. Men in the lowest baseline quartile for DHEA levels had a relative CAD risk of 1.6, compared to those in the other three quartiles. The risk was independent of confounding risk factors, including age, obesity, diabetes, hypertension, smoking, serum lipids, alcohol intake and physical activity. (5) Slide 8  

Muller, in the 2003 Journal of Clinical Endocrinology and Metabolism (JCEM), performed a meta-analysis of the androgen/CAD literature, pointing out 21 of 33 cited studies associated low DHEA levels with increased CAD risk. Eleven of the studies were neutral; one study associated higher values of DHEA levels with higher CAD risk. Muller’s conclusion was that higher levels of DHEA are associated with a mild reduction in CAD risk. (6) Slide 9 

Side Note: DHEA & The Heart

Osorio, in Hormone Research (2002), reported that DHEA levels fell after acute myocardial infarction. The study broadly concluded drops in DHEA level were an epiphenomenon of CAD, rather than playing any risk-related role. It only followed subjects nine days post-MI, but it does raise the intriguing point that cardiac tissue may interact with as-yet-to-be elucidated hormone synthesis/inhibition pathways. (9) 

Om 2003, Nakamura in Circulation, demonstrated localized production of DHEA by cardiac tissue, revealing a decline in DHEA production in association with a rise in aldosterone production in the failing heart. His hypothesis is that DHEA exerts a cardioprotective effect and is associated with more favorable non-androgenic hormone levels in healthy hearts. Whether or not this is accurate, its association between hormones and their effects on each other is intriguing. (8) 

In a study published in the May 2005 JCEM, Muller reports the results of a 400-subject study, demonstrating a 1 SD above the mean DHEA level was associated with a 0.76 relative risk for the presence of metabolic syndrome—an important CAD-risk marker. (7)

DHEA & Mood/Well-Being 

For decades, DHEA has been touted as a useful intervention for treating depression or improving mood. In the previously mentioned Berr study, women whose DHEA levels were better maintained scored higher, regarding measures of mood. This correlation has been shown in several articles: 

Cawood, in 1996, evaluated mood in relation to ovarian and adrenal steroids, finding only DHEA was associated with their measurement modality of well-being. (10) 

Barrett-Connor, in a 1999 Journal of the American Geriatric Society, published data from the Rancho Bernardo longitudinal survey database. Measured were plasma levels of estradiol, testosterone, estrone, androstenedione, cortisol and DHEA. A study of 699 women (ages 50 to 90) demonstrated a significant inverse correlation between DHEA levels and mood scores on the Beck Depression Inventory. These findings were age independent. DHEA had better predictive value than any other hormone evaluated in the study. (11) 

Additionally, interventional studies have demonstrated the efficacy of DHEA supplementation and measures of mood. A small prospective pilot study published by Bloch in 1999—examining “mid-life dysthymia”—found 60 percent of their subjects had responded to DHEA monotherapy at the end of the 6-week treatment period, compared with 20 percent in the placebo group. Symptoms improving the most significantly were anaerobia, energy loss, lack of motivation, emotional "numbness" sadness, worry and an inability to cope. (12)

Wolkowitz, in 1999, demonstrated similar findings: Twenty-two patients with major depression (medication-free or on stabilized antidepressant regimens) received either DHEA (maximum dose = 90 mg/day) or placebo for 6 weeks in a double-blind manner. They were rated at baseline and at the end of the 6 weeks with the Hamilton Depression Rating Scale. Results: DHEA was associated with a significantly greater decrease in Hamilton depression scale ratings than the placebo. And 5 of the 11 patients treated with DHEA (compared with none of the 11 given placebo) showed a 50% decrease or greater in depressive symptoms. Conclusion: These results suggest DHEA treatment may have significant antidepressant effects in some patients with major depression. (13) 

Schmidt, in the February 2005 Archives of General Psychiatry, demonstrated DHEA’s monotherapy utility for both major and minor mid-life onset depression in both men and women. DHEA produced a greater than 50% reduction in depression scores for 50% of subjects vs. 23% score reduction rate for placebo. Treatment subjects also outperformed the placebo group, regarding self-reports of sexual function. (14) 

Just as Co-Q10 levels are affected by statin therapy and demonstrate the importance of maintaining levels of endogenous compounds that can be iatrogenically affected, the same may hold true for DHEA, during pharmacologic therapy for depression. One study (Deuschle, Neuropsychobiology, 2004) showed amitryptiline therapy was associated with a 39% reduction in circulating DHEA levels. (15)

DHEA & Autoimmune/Inflammatory Disorders 

The importance of DHEA in disease states outside the typical hormonal realm also has been demonstrated. There are many literature citations dealing with disease state and DHEA levels, in addition to demonstrating some clinical benefit associated with DHEA replacement.  Patients with SLE/Lupus have been shown to have diminished DHEA levels. 

In a clinical 1989 study by Hedman, the blood levels of dehydroepiandrosterone sulphate (DHEAS), pregnenolone sulphate (5-PS), testosterone sulphate (TS) and their respective unconjugated steroids were measured in (a) 20 patients with systemic lupus erythematosus (SLE) who were receiving either no treatment (11 patients) or else treatment with chloroquine (9 patients), in some cases combined with non-steroidal anti-inflammatory drugs (NSAIDs); (b) 26 patients receiving corticosteroid (Prednisolone) treatment; (c) healthy men and women. The patients not on corticosteroid exhibited substantially reduced DHEAS. (16)

DHEA & Neuropsychological Function In Lupus Patients

Kozora E, et al, explored the relationship between inflammatory and hormonal activity plus measures of learning, fluency and attention in systemic lupus erythematosus patients without neuropsychiatric symptoms (non-CNS-SLE), patients with rheumatoid arthritis (RA), and healthy controls (HC). They were compared on tests of cognition, depression and plasma levels of interleukin-6 (IL-6), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S) and cortisol.

Non-CNS-SLE patients demonstrated lower learning and poorer attention. Furthermore, non-CNS-SLE and RA patients had significantly lower levels of DHEA and DHEA-S than HC participants. Hierarchical regression analysis demonstrated DHEA-S and IL-6 accounts for a unique portion of the variance in subject performance on measures of learning and attention after controlling for depression and corticosteroid treatment. (18) 

Low DHEA state also correlates with disease-specific pathophysiology. For example, Liu showed SLE patients demonstrate an increase in terminal differentiation of peripheral blood mononuclear cells, which correlates with disease activity. Exposure to DHEA was associated in vitro with a diminishment in the pathological differentiation patterns. (19) 

SLE patients demonstrate lower DHEA levels than in normal controls. These diminished levels are associated with specific disease-enhancing pathology; low levels are also associated with loss of “pathology-preventing” signaling between immune system cells.

Interferon gamma (IFN g) is associated with negative feedback inhibition of immune response in normal controls. DHEA facilitates this signaling. In SLE, normal DHEA levels and signaling effects are lost, with the subsequent change favoring an exaggerated immune response rather than a normal one. (20)

The above findings would lead to the prediction that DHEA holds a therapeutic role in SLE treatment—which has been shown to be the case. Studies have repeatedly demonstrated the utility of DHEA supplementation, pertaining to the reduction of symptom scores or reduction in accompanying medication requirements. This effect has been greatest in patients with mild or moderate disease. However, DHEA has had clinical value as part of multi-drug therapy in severe cases and may also be associated with mitigating the osteoporosis associated with long-term corticosteroid regimens: Slide 21a  Slide 21b Slide 21c  

DHEA has small utility in severe SLE, but is associated with possible reduction in steroid requirements and decreases steroid related bone loss: Slide 22

DHEA suppresses IL-10 secretion by T-cells in patients with SLE. Slide 23

DHEA’s effect on IL-10 secretion demonstrates the substantial “crossover” seen in the pathophysiology of inflammatory disorders. Also demonstrated: DHEA supplementation has disease score modulating effects on other inflammation-based disorders, such as Crohn’s Disease and ulcerative colitis. Slide 24  

In addition to SLE, DHEA therapy may be of utility in rheumatoid arthritis, polymyalgia rheumatica and some aspects of Sjogren’s Syndrome. There are only preliminary reports of diminished DHEA secretion or function and scattered early speculative reports, regarding DHEA therapy. These are just tidbits and not definitive, in any regard. Slide 25

DHEA may aid in some atopic inflammation regulation. Slide 26

Also, DHEA may be associated with minimizing the negative effects of other therapies. Even low-dose inhaled corticosteroid therapy in the management of asthma can be associated with an increase in osteoporosis risk—these therapies are associated with diminished DHEA levels, as well. Slide 27a Slide 27b

This effect has been shown for other steroid requiring disorders: Slide 27c

DHEA & Bone 

Even in otherwise normal patients, low DHEA levels correlate with lower bone mineral density (BMD) and osteoporosis risk, making it another disease risk
marker for BMD loss. Slide 29 Slide 30 Slide 31

Females in the lowest quartile for DHEA levels have shown to be at increased fracture risk, compared to normal risk. Slide 32

Conversely, well-maintained DHEA levels are associated with retained BMD. Slide 33

Per our usual discussions, an association between level and risk is not sufficient validation for therapy. DHEA supplementation has been shown to improve BMD in men with osteoporosis. Over a 12-month study period, BMD increased in the lumbar spine and femoral neck by nearly 3%. Slide 34

The same types of findings have been seen in female replacement studies, with increases in BMD and decreases in bone resorption markers. Slide 35

The segue between DHEA and bone to other organ systems can be found in the next reference. Interleukin 6 (IL-6) is a pro-inflammatory cytokine whose presence is associated with inhibition of osteoblast function—leading to declines in BMD. IL-6 levels also are associated with other potential disease risk, such as heart disease and dementia. Lower DHEA levels are associated with an elevation in IL-6 levels; replacement is associated with declines in IL-6.  Straub’s 1998 study (in the JCEM) revealed results in terms of a disease-risk marker, which is multi-system regarding risk and risk reduction. Slide 17

Another aside, done sotto voce. There are null result studies for DHEA. When reviewing the literature, it may be best to take search results in an electoral fashion and add up the number of studies or total number of subjects studied. Then determine an opinion. The following references show no effect on BMD of DHEA, reminding us that perhaps universal dosing is not always an optimal method of treating a patient group, nor is treating without titration to a given level vs. using even a dose/weight method. These results also act as a reminder of what is promised—and that not all patients will receive all the benefits of a given intervention. These results point out the lack of any negative outcome, which is useful in determining the safety and efficacy of a given intervention. Slide 47  Slide 11

DHEA & The Brain 

Some studies have demonstrated a correlation between Alzheimer’s Disease (AD) and DHEA levels.  Again, these results exist within the context of multiple risk factors, but there is a statistical inverse correlation between DHEA levels and AD.

Weill-Engerer found a significant negative correlation between the levels of cortical beta-amyloid peptides DHEA in the hypothalamus. Slide 36

Another study found higher cortisol levels, lower DHEA levels and a higher cortisol/DHEA ratio in AD subjects than seen in control subjects. Slide 45

Yet another study demonstrated diminished circulating DHEA levels in AD subjects. Slide 37

In patients with pre-existing AD, those with higher DHEA levels performed better on cognitive function testing. Slide 38

Most importantly—and why having more than a correlation between a finding and an assumption that altering the finding will have an effect is critical—AD patients treated with DHEA showed no improvement on cognitive measures. Slide 39

Neither did studies on normal older people. Slide 46

At present, try not to claim any certain value for DHEA in preventing or treating AD. Given the large variability of lesion number and precise location of AD plaques or pathology, different study results may only be expressing findings for the myriad sites of AD damage and anatomical, rather than metabolic consequences regarding AD and its effect on the brain/HPA/adrenal axis. 

Rat studies demonstrated a neuroprotective effect of DHEA on experimentally induced oxidative damage to neurons. Perhaps one day it will show a role for DHEA in cytoporotection . . . and may also overlap with the clinical benefit of DHEA in autoimmune disorders. Slide 48

DHEA & Erectile Dysfunction 

As a member of the androgen family, DHEA has been examined for its possible usefulness in treatment of erectile dysfunction (ED). The ED studies are not exhaustive in their attention to detail. DHEA has been shown to be lower in men with ED. Keep in mind: Many times, this is in conjunction with low levels of all androgens or may have been measured without consideration for other androgen levels. Needless to say, if monotherapy works, then effective is still effective. Slide 40

DHEA supplementation was shown to improve ED in subjects with hypertension, but no mention was made as to which, if any, medications were also involved. Nor was there mention of whether any specific class of anti-hypertensive was more or less likely to contribute to the incidence of ED or the outcome of DHEA intervention.  Slide 49

DHEA & The Elderly

A study by Nair, et al, published in the NEJM, October 2006, concluded that DHEA in elderly people has no physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity or quality of life.(50)  

This two-year, placebo-controlled, randomized, double-blind study involved 87 elderly men and 57 elderly women with low levels of sulfated DHEA.  Among the men, 29 received 75mg/day DHEA and 31 received placebo; 27 women received 50mg/day DHEA and 30 received placebo.  Results: All subjects who received DHEA for 2 years had a significant increase in plasma levels of sulfated DHEA.  A separate analysis of men and women showed no significant effect of DHEA on body-composition measurements, nor did it alter the peak volume of oxygen consumed per minute, muscle strength or insulin sensitivity.  Men in the treatment group had an increase in BMD at the femoral neck. Women who received DHEA had an increase in BMD at the ultradistal radius.  Neither treatment improved the quality of life, as measured by the Health Status Questionnaire, or had major adverse effects.  

In an editorial in the same NEJM issue, Stewart felt these findings confirmed the French DHEAge study, published in 2000. (51) He stated that the QOL results by the Health Status Questionnaire were underpowered.   

Further comments on the article appeared in the February. 5, 2007 NEJM issue.  Yasuda and Horie felt that the findings of Nair et al cannot be generalized.  The subjects appeared to be relatively healthy adults.  The average baseline scores for the QOL on the HSQ of all subjects were above 50 for both the physical and mental components.  The average score in the general US population is 50.  The high scores of these subjects suggest the study included healthier elderly persons than those who would be representative of the general elderly population. (52)

DHEA: General Considerations 

DHEA levels in patients who subsequently developed prostate cancer over a 12-year period had DHEA levels 11 percent to 12 percent below those of controls. Slide 42

Today’s final words on DHEA belong to women. In one 12-month study on postmenopausal women, DHEA supplementation was shown to increase HDL by 11 percent, decrease LDL by 11 percent and improve insulin sensitivity (at a dose of 25 mg/day). Again, global reduction in disease risk markers. Slide 43

Clinical Applications

Dosing for DHEA supplementation is based on patient history and lab values. 

Gender-neutral target levels are 350- 500 mcg/dl. (Upper 40^th percentile for ages 30 to 39.)

Diurnal peak/trough – dose as qam. 

Male:
<100 mcg/dl, start 75mg po qam
>100 mcg/dl, start 50 mg po qam 

Female:
<100mcg/dl, start 50 mg po qam
>100mcg/dl, start 25 mg po qam

The Future 

Finally, a “what will this mean for the future” study on the effects of DHEA on postmenopausal women showed a change in T-cell profile from CD4+ to CD56+ (NK) cell profiles in association with inhibition of IL-6 and T cell mitogenic responses with a simultaneous dramatic increase in NK cell cytotoxicity. These effects were consistent with an “antioncogenic” profile. Slide 44

As laboratory markers become more available and their utility assigned actuarial weight, DHEA may be found to have a role in disease prevention, which can be objectively measured and intervened with outcomes altered. 

References

Post Test