Evaluation of DHEA Levels in Multiple Sclerosis
Dehydroepiandrosterone (DHEA) is an androgenic steroidal hormone produced by the adrenal gland. Its specific physiological functions, other than serving as a precursor to other steroid hormones (such as testosterone), are not yet established. It is possible that DHEA plays an important role in physical development during puberty. The amount of circulating DHEA in the blood varies considerably with age and sex. DHEA levels begin to increase several years prior to puberty (at about age 7) and reach their maximum level at around ages 20–25. In young adults, plasma DHEA levels are about 10 times higher than plasma cortisol levels. With aging, cortisol levels remain about the same, while DHEA declines; at age 50, it is typically only about half the peak level, and by age 75 it declines to about 10% the peak level.
Low levels of DHEA in adults have been found to correlate with increased incidence of cardiovascular disease, breast and endometrial cancer, Alzheimer’s Disease, and progression of HIV disease. DHEA levels have been found to decline during illness, with major depressive disorders, and with prolonged stress.
Laboratory animal studies suggest that DHEA regulates immune functions (influences production of interleukin-2 and regulates cellular immune responses); has antidiabetic, antiatherosclerotic, and antiobesity effects; protects against autoimmune nephritis, and inhibits neoplasms.
Relatively little is currently
known about potential clinical benefits of administering DHEA, especially over
a prolonged period. Dr. Samuel Yen
(University of California, San Diego), who first reported on the correlation of
DHEA and cardiovascular disease, has since administered DHEA to elderly
patients and reported that it increases mobility, reduces joint discomfort, and
improves sleep. Preliminary work with
systemic lupus erythematosus (SLE) patients showed low baseline levels of DHEA
and symptom improvement with DHEA administration; a phase III trial of a
synthetic DHEA for treatment of lupus has been approved and is now enrolling
participants.
Based on these findings, one might hypothesize that persons with multiple sclerosis have low DHEA levels. As with autoimmune nephritis and SLE, they suffer from an autoimmune disorder; they also tend to suffer from stress and depression, and they have frequent illnesses. Persons with MS who have low DHEA levels might experience benefits from normalizing those levels, since restricted mobility and poor sleep are common complaints.
In a preliminary 1990 study by Roberts and Faubile (1), persons with MS were found to have low DHEA levels which were improved by DHEA administration. It was also noted that the majority of these patients had discernible improvement, after DHEA administration, in their quality of life, including increased energy levels, better dexterity, greater limb strength, decreased sensations of numbness, and an increase in libido. In a non-randomized 1990 study by Calabrese (2), it was concluded that DHEA administration helped to improve fatigue symptoms in those with MS.
Orally administered DHEA is reported to be readily absorbed, and is converted by the liver to DHEA sulfate (DHEA-S), which is the form usually monitored. DHEA-S must be desulfinated again in order to become physiologically active. The daily adrenal production of DHEA is roughly 30 mg, and typical blood levels of DHEA-S for healthy middle-age female adults are on the order of 150–200 mg/dl (for males, about 200–400 mg/dl).
Currently, DHEA and/or DHEA-S testing is usually not suggested by neurologists working with MS patients; in fact, it is rarely recommended by other physicians. The cost of testing is somewhat high (about $90/test for each component). DHEA supplementation is sometimes recommended to patients by naturopathic physicians, but it is rarely recommended by medical doctors.
DHEA is currently available as
a non-prescription oral supplement in the U.S.
This unusual status arises because DHEA is not currently used as a drug:
it is a natural component of the body (a derivative of cholesterol), it is
found in foods, and demand for it has been generated on the basis of studies
conducted during the past 30 years suggesting anti-aging effects and other
benefits. Unfortunately, products on
the market are of varying quality, from pharmaceutical grade DHEA to herbal
extracts claimed, incorrectly, to contain “natural DHEA.”
Common recommendations for taking supplemental DHEA, found in the popular literature that cites its potential benefits, is 25–50 mg daily (sometimes higher; with some sources recommending 50–150 mg/day). DHEA has been utilized as an experimental viral inhibitor for persons with HIV infection at doses of 600 mg/day or higher. While DHEA appears to be generally safe for short-term use, it may cause general androgenic responses (which can be more easily noted in females) and little is known about the impact of long-term administration of the very high levels that have been suggested by some proponents. Further, there is concern that large doses of DHEA may increase testosterone levels in men with testosterone-dependent prostate cancers. Therefore, it is important to learn more about the effects of DHEA administration on circulating DHEA levels.
For this preliminary evaluation, 7 female patients with multiple sclerosis and 1 male patient with an MS-like disorder (originally diagnosed as MS) were selected from participants of the MS treatment at the ITM clinic (Lovejoy facility; see separate report for details). Selection was based on the following criteria:
1. Not currently or recently taking DHEA as a supplement.
2. A regular ITM program participant for at least 9 months.
3. Willing and able to cooperate with study (including three blood draws).
No health parameters were considered in the selection process. The first two criteria eliminated about one-third the potential participants (we required 9 month participation time to assure compliance and to eliminate variables associated with program start-up; some patients were prescribed DHEA at our clinic prior to the study), and most of the others were eliminated by the third criteria. All but one of the MS patients had a relapsing/remitting type of disease; average participation time in our program was 23 months.
An initial blood draw was taken to determine baseline DHEA-S levels. Since the laboratory reference range for DHEA-S levels vary by age and sex (example: female, age 56, reference range 26–200 mg/dl; male, age 34, reference range 120–520 mg/dl), a single comparison scale was developed for this study. The scale was set as follows:
1. The laboratories highest normal DHEA-S level for the patient age and sex was set at 100.
2. The lowest normal DHEA-S level for the patient was set as 0.
3. The measured value was then adjusted to the scale as follows:
[Measured value–lowest normal value]/[Highest normal value–lowest normal value]
Using this method, a scale value of 50 represents the middle of the laboratory reference range for the patient. A negative reading means the patient’s DHEA-S level was below the lowest value given for the reference range.
After obtaining the baseline value for DHEA-S, patients were instructed to take encapsulated DHEA at a dosage of 15 mg/day, one time per day (morning). The one male patient was instructed to use 30 mg/day (one time per day), based on usual higher DHEA levels in males than females. A retest of DHEA-S levels was scheduled for approximately six weeks after DHEA dosing began. For the second test, patients were instructed to skip their morning dose of DHEA, get the blood draw, and then take their daily dose. In that way, the DHEA-S level would reflect the combination of underlying DHEA production and the remainder of the previous dose, somewhat more than 24 hours after it was taken.
DHEA laboratory testing (conducted by Rhein Consulting Laboratories, in Portland) and prescription of DHEA (obtained from Diosynth in Holland via Flanders Pharmacy, a compounding pharmacy, in Portland) was managed by Edythe Vickers, N.D., L.Ac.
The baseline values of DHEA, both laboratory reported values and using our 100 point scale, were as follows:
|
I.D. |
mg/dl |
scale value |
|
Patient 1: |
59.4 |
6.4 |
|
Patient 2: |
111.0 |
29.3 |
|
Patient 3: |
40.5 |
–2.0 |
|
Patient 4: |
62.5 |
–14.3 [male] |
|
Patient 5: |
140.0 |
51.9 |
|
Patient 6: |
32.9 |
0.4 |
|
Patient 7: |
77.8 |
22.0 |
|
Patient 8: |
33.7 |
4.4 |
|
Average: |
69.7 |
12.3 |
Since the average scale value for a random selection of healthy individuals is expected to be about 50, these values reveal low levels of DHEA.
For the retest at six weeks, 2 patients (with results described below under the heading Pharmacokinetics) did not comply properly with the retest protocol. Of the 6 who did comply, the initial and retest data, converted to our 100 point scale, is as follows:
|
I.D. |
baseline |
6 weeks |
change |
|
Patient 1: |
6.4 |
28.4 |
+22.0 |
|
Patient 3: |
–2.0 |
62.2 |
+64.2 |
|
Patient 4: |
–14.3 |
11.3 |
+25.6 [male; took 30 mg/day] |
|
Patient 5: |
51.9 |
79.3 |
+27.4 |
|
Patient 7: |
22.0 |
52.0 |
+30.0 |
|
Patient 8: |
4.4 |
19.7 |
+15.3 |
|
Average: |
11.4 |
42.2 |
+30.8 |
This data indicates that DHEA is absorbed from the gastrointestinal tract, and that some of it remains in the blood for at least the 24 hours after the last oral dose. Patient 3 had taken a course of prednisone in the interval between the two tests, not for treatment of MS, but for bronchial inflammation, and this may have affected the outcome (hers was the only unusual change, notably greater than the others). On follow-up questioning, she did not report a deviation from the protocol of getting a blood draw in the morning after skipping the morning DHEA dose. During the two weeks prior to the second test, this patient showed a sign of possible excess androgen (chin acne), though it is not possible to directly attribute the symptom to this particular combination of steroid interventions.
One patient took her morning dose of DHEA the day of the second test (about four hours between oral dosing and the blood draw). Her DHEA-S baseline value was 40.5 mg/dl (on our scale, 29.5), but her retest value was 394 mg/dl (on our scale, 155), demonstrating that the DHEA is readily absorbed and reaches relatively high values in the blood within four hours after administration. In fact, 15 mg of DHEA distributed in 5 liters of blood would yield a level of 300 mg/dl, which corresponds closely to the change in DHEA-S level observed in this individual.
As observed from the other participants, who took morning doses of DHEA regularly but did not take it the day of the second blood draw, about one day after the DHEA level in the blood reaches its peak value (due to exogenous supply) the amount declines to a level that is in the normal range. In our group, the result of ingesting 15 mg was that the average DHEA level a day after administration was still somewhat below the mid-point of the normal range.
To give an idea of the clearance of exogenous DHEA, for patient #7, as a representative example, the initial DHEA-S level was 78 mg/dl, and the retest value was 140 mg/dl; an increase of 62 mg/dl. If her blood level soon after DHEA ingestion was about 300 mg/dl higher than her baseline value (15 mg in 5 liters of blood), then 80% of the extra DHEA was eliminated in somewhat more than 24 hours. This corresponds, roughly, to a DHEA-S serum half-life of about 12 hours.
One patient did not take her morning dose of DHEA for the two days prior to the test. Her DHEA level at the second test was almost identical to the baseline level (32.9 mg/dl versus 32.6 mg/dl for the second test), indicating that the orally consumed DHEA was completely removed by that time. Further, there was no evidence of decline in her usual DHEA production level as a result of six weeks of daily ingestion of 15 mg.
As an interpretation of this limited preliminary data, the following tentative conclusions might be drawn:
1. Patients with MS tend to have low DHEA levels, generally falling in the lower part of the laboratory’s reference range (7 of 8 patients tested), and sometimes below the normal range (2 of 8 patients tested). This is consistent with other reports that DHEA levels are low in persons with SLE, MS, and with illness in general. The measured levels also suggest that the medical therapies that had been offered to the patients at our clinical facility up to this time (for at least nine months), including nutritional supplements, Chinese herbs, and acupuncture, do not raise DHEA levels substantially.
2. Orally administered DHEA is readily absorbed in patients with MS. At about four hours after ingestion, the DHEA-S level measured in one patient corresponded to full absorption of the DHEA dose. In order to maintain DHEA levels roughly within the normal range for a middle aged adult, a single daily dose of DHEA should not exceed about 10 mg in women (adding about 200 mg/dl to the baseline at its peak) or 20 mg in men (adding about 400 mg/dl to the baseline at its peak). Recommendations in the popular literature often exceed these amounts.
3. The supplemental DHEA remains in the bloodstream for more than 24 hours, its level decreasing over time. The extra DHEA is cleared from the system within about two days. In order to maintain levels in the upper part of the reference range for the individual, dosing two or three times per day, or using time-released DHEA, appears necessary.
4. It is possible that other exogenous steroids influence DHEA levels. In one patient who undertook a course of prednisone therapy for bronchial inflammation, the DHEA levels measured on the second test were considerably raised compared to the other participants.
This study does not establish whether or not supplemental DHEA will have a health benefit for persons with multiple sclerosis, due to the short period of administration. However, DHEA is believed to have several potentially beneficial effects, including immune regulation and antiviral activity; as a steroid hormone, it can reduce inflammation. Earlier investigations, though informal, have suggested a benefit of DHEA for those with MS.
Our small study further confirms the proposal that persons with autoimmune disorders, and MS in particular, tend to have low DHEA-S levels. Other participants in our MS program have been administered DHEA in the past after finding low DHEA-S levels (data not presented). It is possible that the wide range of DHEA-S values reported in the laboratory reference range includes many low values from patients who suffer from various chronic diseases or who have higher risk for serious diseases. Thus, the desirable level of DHEA may actually be in the upper half of the laboratory’s reference range. Considering what is known about DHEA, normalization of levels in these patients would not be expected to cause adverse reactions.
The next step in this ongoing study, based on these initial findings, is to adjust the dosage schedule from 15 mg one time per day to 7.5 mg each time, two times per day. In this way, the DHEA levels are expected to be more constant and maintained closer to the desired range. If full absorption occurs, a 7.5 mg single dose should raise the DHEA levels in most patients to the upper part of the reference range, while the twice per day dosing will help maintain the desired higher levels in the blood throughout the day and night. The dosage that is being administered is about half that normally produced by a healthy middle-aged adult, so that any potential problems of excessive levels of this substance can be avoided. Further testing will reveal the actual DHEA-S levels attained by this amended protocol.
If additional testing confirms the findings of the current preliminary study, our clinic will plan to treat most enrolled MS patients with this modest dose of DHEA over a period of six months or longer in an attempt to determine possible clinical benefits. Since DHEA could easily be subjected to a randomized placebo controlled study, it is further proposed that major MS clinics with adequate patient populations consider conducting a careful evaluation of the clinical effects. In this way, if there are any substantial benefits, patients are more likely to receive this therapy.
1.
Roberts
E and Fauble TJ, Oral DHEA in multiple
sclerosis: results of a phase one, open study, in The Biologic Role of DHEA by Kalimi, M. and Regelson, W., Editors.
New York: Walter De Gruyter, 1990, pp. 81–93.
2.
Calabrese
VP, et al., DHEA in multiple sclerosis:
positive effects on the fatigue syndrome in a non-randomized study, in The Biologic Role of DHEA by Kalimi, M.
and Regelson, W., Editors. New York: Walter De Gruyter, 1990, pp. 95–100.
Funding for this study was received from the McKenzie River Gathering Foundation (Eugene and Portland, Oregon), the National Multiple Sclerosis Foundation (Fort Lauderdale, Florida), and the Institute for Traditional Medicine (Portland). Rhein Consulting Laboratories provided discounted DHEA-S tests and Flanders Pharmacy provided discounted encapsulated DHEA.
September 1997