What You Should Know About DHEA

Dear Dr. Dean:

I wonder if you could comment on this, which I found on the Internet:

“For those taking DHEA, if you're not having regular PSA tests, you're committing suicide. Dead serious. If you have any prostate cancer cells in your body, as one in six older men do, the DHEA, which is a precursor for testosterone, will cause the cancer cells to grow and multiply.”

Paul, Gardnerville, NV

Dear Paul,

Thanks. This is an important question, which I will deal with here at some length. Misinformation, such as you have found is all over the Internet — and is unfortunately the prevailing belief shared by many in “mainstream medicine.”

 

Fig 1. Decline of DHEA-S with age.3 (click on thumbnail for full sized image)

DHEA (dehydroepiandrosterone) is the most abundant steroid hormone in the body. It is also one of the most significant age-related biomarkers, which predictably declines with age in even the healthiest of people (Figure 1). Abnormally low levels of DHEA have been reported to be related to a number of diseases, including cancer, diabetes, coronary artery disease, obesity, and Alzheimer’s. Conversely, supplemental DHEA has been reported in study after study to have immunoregulatory, anti-diabetic, anti-cancer, anti-obesity and anti-stress activity, and to be involved in the prevention of atherosclerosis, hypertension, hypercholesterolemia, Alzheimer’s disease and multiple sclerosis.^1-2

 

Nevertheless, a controversy which plagues many physicians, their patients, and consumers who are considering whether to add DHEA to their supplement regimens involves whether men with prostate disease — either benign prostatic hypertrophy (BPH) or prostate cancer—should take DHEA? This question stems from the much-speculated possibility that DHEA could aggravate both conditions, based on the belief that DHEA is converted in the body into testosterone, and that testosterone and/or its metabolite, dihydrotestosterone (DHT), causes or worsens BPH and prostate cancer. Let’s examine each of these issues separately and review some of the laboratory and clinical studies that are relevant to these questions.

Prostate Size (and Incidence of BPH) Increases with Age

 

Fig 2. Incidence of BPH in men with age.4  (click on thumbnail for full sized image)

BPH is a common affliction of men over 50. The incidence of BPH progressively increases with age (Figure 2).⁴ Symptoms that indicate the presence of BPH include (1) hesitation of urination, (2) a reduction in urinary force, (3) dribbling at the end of urination, and (4) nocturia (getting up one or more times during the night to urinate). In severe cases, it can cause complete urinary obstruction! These symptoms are due to compression of the urethra as it passes from the bladder through the prostate gland. Large-scale autopsy studies confirm that prostate size increases significantly with age, in parallel with the severity of symptoms.⁵

 

Is Prostatic Hypertrophy or Prostate Cancer Caused by too Much or too Little Testosterone?

 

Fig 3. Changes in total testosterone levels in men with age.6  (click on thumbnail for full sized image)

Conventional medical dogma holds that both prostatic hypertrophy and prostate cancer are due to androgenic hormones—especially testosterone. Consequently, standard medical therapy for these conditions includes blocking testosterone and dihydrotestosterone formation by drugs, avoiding testosterone replacement, or even orchiectomy in advanced cases of prostate cancer (surgical removal of the testicles).

 

I have never been convinced that testosterone was necessarily the “bad guy.” Testosterone, like DHEA, drops progressively with age in men (Figure 3).⁶ Consequently, it did not seem logical that diseases which increase in incidence with age were caused by a hormone that progressively decreases with age. Dr. William Campbell Douglass, a pioneer in alternative medicine, agreed with me that: “… testosterone has been proven to be protective against cancer [and] it has been suggested that testosterone is contraindicated in men with cancer of the prostate. In view of the hormone’s protective effect in other cancers, I doubt the validity of this supposition.”⁷

A small crack in the time-honored dogma that testosterone was the cause of prostate hypertrophy and prostate cancer was published in 1994.⁸ Dr. Herman M. Behre and colleagues studied nearly 200 hypogonadal men divided into four groups: control; 250 mg testosterone enanthate intramuscular injections every 2–3 weeks; 80–120 mg per day of oral testosterone undecanoate; or a scrotal patch providing 10–15 mg per day of testosterone. After six months’ treatment, the researchers reported that, “No epidemiological data indicate an increased incidence of prostate cancer in testosterone-treated hypogonadal patients compared to normal men. In addition, the present clinical study is the first report showing that testosterone treatment of hypogonadal men even with preparations leading to supraphysiological testosterone serum levels increases prostate volume and PSA levels only to a range comparable to that in age-matched normal men.” They concluded that a testosterone-induced increase in prostate volume should not preclude hypogonadal men from necessary testosterone substitution therapy.

The crack was widened in 1997 with a shocking report in the Journal of the American Medical Association by Dr. Abraham Morgentaler, a Harvard-trained urologist, and his colleagues.⁹ They reported on a surprisingly high incidence of prostate cancer in men (diagnosed by biopsy) who had normal PSA, normal rectal exams, but low testosterone (which should have been protective, if current concepts were correct). Since then, Dr. Morgentaler has published a steady stream of articles in high quality medical journals, to dispel what he terms a modern myth.¹⁰

By 2007, Dr. Morgentaler confidently proclaimed that, “the long-standing fear of stimulating prostate cancer with testosterone is without a scientific basis.” He documented that, “approximately 15% of hypogonadal men with a PSA 4.0 ng/ml or less have biopsy-detectable cancer, and that the risk of cancer increases for men with more severe reductions in testosterone. Low levels of testosterone are also associated with high-grade prostate cancer, higher stage at presentation, and worse prognosis.¹¹[Emphases added]

In a paper in 2009, Dr. Morgentaler reiterated that, “T therapy may not be nearly as risky as once assumed.” In support of this statement, he reviewed more than 20 English language longitudinal studies that investigated the relationship between serum testosterone and the risk of developing prostate cancer. He reviewed a global collaboration of data from 18 of these studies, which comprised approximately 95% of the existent data on this topic. The studies involved 3,886 men with prostate cancer and 6,438 men without cancer as age-matched controls. The results were definitive — “no relationship was seen between prostate cancer risk and serum concentrations of testosterone, free testosterone, DHT, or other androgenic measures (including DHEA).”[Emphasis added]¹²

Is DHEA Converted into Testosterone in Men?

 

Fig 4. Conversion of DHEA into other steroid hormones.  (click on thumbnail for full sized image)

Of course, the major reasons for the concern about DHEA supplements in men is (1) the (apparently erroneous) beliefs that testosterone causes BPH and prostate cancer; and (2) because DHEA is a precursor of testosterone (Figure 4), consuming DHEA supplements in a physiological dose may abnormally raise testosterone levels (and thus cause BPH or prostate cancer).

 

 

Fig 5. Effect of nightly oral dose of 50 mg DHEA on androgen levels (testosterone, dihydrotestosterone, and androstenedione in men and women), compared with placebo. Note the significant increases in androgen levels in women and the lack of effect on these levels in men.13  (click on thumbnail for full sized image)

While DHEA may raise testosterone levels in women, who very efficiently convert it to testosterone, this does not appear to be true for men. Scientists at the University of California, San Diego, performed a study on 13 men and 17 women, ranging from 40–70 years of age. These subjects were given 50 mg of DHEA orally every night for six-months. The scientists reported that testosterone, dihydrotestosterone, and androstenedione were doubledin women—bringing these levels into the physiological range for young women. In men, however, only androstenedione levels increased slightly, while testosterone and dihydrotestosterone levels were unchanged (Figure 5).¹³ Clearly, it appears that physiological doses of DHEA [i.e., doses that restore DHEA and DHEA-S (DHEA-Sulfate) levels to those of youthful men and women] do not significantly elevate testosterone in men.

 

 

Fig 6. Changes in DHEA, DHEA-S, testosterone, dihydrotestosterone, and androstenedione after 400 mg oral DHEA in a 72 year-old man. DHEA-S, mcg/dl. All others, ng/dl.14  (click on thumbnail for full sized image)

On the other hand, when pharmacologic doses of DHEA are administered (i.e., doses that are far in excess of those required to restore levels to those of healthy young adults), testosterone and DHT levels do increase significantly. For example, in one elderly man, to whom 400 mg of DHEA was administered, significant and rapid rises were noted in DHEA, DHEA-S, testosterone and DHT (Figure 6).¹⁴

 

Does DHEA Promote Prostate Cancer Cell Growth?

To answer this question, scientists at the New York University Medical Center, Tuxedo, NY, studied the effect of DHEA on the proliferation of (1) three human prostate cancer cell lines, and (2) cell cultures of rat prostate carcinomas. They reported that DHEA inhibited growth of the human prostate cancer cell lines by approximately 10%, 25%, and 80% at concentrations of 1, 10, and 22.5 µg/ml, respectively. DHEA also inhibited growth of rat prostate carcinoma cultures (media with 50 nM testosterone [T]), by 11–40% at 1 µg/ml, 25–54% at10 ug/ml, and 55–77% at 22.5 µg/ml. The scientists concluded that: (1) DHEA inhibits growth of human and rat prostate cancer cells in a dose-related fashion; (2) DHEA acts as a chemopreventive agent by direct growth inhibition of prostate cancer cells; and (3) DHEA should be considered for further research for prostate cancer chemoprevention in humans.¹⁵

More recently, scientists in Turkey evaluated the effects of long-term administration of DHEA-S on 15 rats, compared to 15 age-matched controls. They administered 5 mg/kgof oral DHEA-S to each rat, 5 days/week, for 6 months (this is equivalent to a whopping pharmacological dose of 350–400 mg per day for 20–30 years for humans). At that high dose, the total testosterone was (not unexpectedly) twice that of the age-matched controls (paralleling the findings of Roberts, and colleagues, above), and DHEA-S levels were 35–38 times higher than the unsupplemented controls. Nevertheless, despite the prolonged administration of these massive doses of DHEA-S to the rats, the scientists found that long-term DHEA-S use did not cause adverse effects on the prostate and testis in rats; and by contrast, it protected the prostate from atrophy.¹⁶

What about Serum DHEA Levels in Patients with Prostate Cancer?

Physicians at the Department of Urology, Institute of Experimental Endocrinology at Humboldt University Medical School in Berlin, Germany, found that DHEA levels in patients with prostate cancer were significantly lower than healthy controls.¹⁷ The authors conceded that similar findings of low DHEA levels in prostate cancer patients had previously been reported by scientists in Hungary more than twenty years prior to their own findings.¹⁸

Dr. George W. Comstock, a professor of the Department of Epidemiology, Johns Hopkins School of Hygiene and Public Health, studied the relationship of DHEA and DHEA-S to cancer of the prostate. This retrospective study involved blood samples taken from 25,000 men from Washington County, Maryland in 1974. Between 1974 and 1987, 103 cases of prostate cancer were diagnosed among the donors to the serum bank who were reported to the Washington County Cancer Registry. Compared to age-matched case controls, the researchers found that those with prostate cancer had levels of DHEA and DHEA-S that were 11% lower than those who did not have prostate cancer. The authors concluded that not only has DHEA been shown to have a protective effect against tumors in animals, but that it is “unlikely that [high] serum levels of DHEA or DHEA-S are important risk factors for prostate cancer.”¹⁹

In a recent review of the still-prevalent but counterintuitive view that high testosterone is risky for prostate cancer, and low testosterone is protective, Morgentaler discussed the more recent work of himself and others. He insisted that the prevailing concept never made much sense, and was contradicted by the inescapable fact that prostate cancer (especially high-grade prostate cancer) becomes increasingly prevalent with age, and age is associated with low testosterone. He added that if BPH were caused by high testosterone, then prostate cancer and BPH would primarily affect men in the teens and twenties, when testosterone is at lifetime highs. Morgentaler proposed that it was time to change the paradigm, and focus on the likelihood that low testosterone is associated with high-risk prostate cancer, and that low testosterone is not protective. He concluded that “After 7 decades of circumstantial evidence pointing us in the wrong direction, it is time to consider the once unthinkable: a testosterone therapy trial of sufficient size and duration to determine whether normalization of serum testosterone in older men may reduce the risk of prostate cancer, particularly high-risk prostate cancer.”²⁰

Summary

From the above review, the following conclusions appear to be clear:

 

1. The incidence of prostate disease increases with age
2. Testosterone and DHEA levels decrease with age.
3. Physiologic replacement doses of DHEA do not raise testosterone levels in men to supraphysiologic levels.
4. DHEA inhibits growth of human and rat prostate cancer cells in a dose-dependent manner— i.e., the higher the concentration of DHEA, the greater the inhibition of growth!
5. Patients with prostate cancer have lower levels of DHEA and DHEA-S than age-matched controls, as confirmed by many independent studies.
6. DHEA and testosterone are not contraindicated, and, in fact, should be considered for the therapy of prostate disease.

 

Bottom line, I believe the benefits far outweigh any potential risks — and recommend that all of us who are growing older include DHEA in our supplement regimens to maintain healthy youthful levels of DHEA.

I hope this answers your question.

Ward Dean, M.D.

References

1. Kalimi M, Regelson W, eds. The Biologic Role of Dehydroepiandrosterone (DHEA). Berlin, New York: Walter de Gruyter, 1990.
2. Bellino FL, Daynes RA, Hornsby PJ, Lavrin DH, Nestler JE, eds. Dehydroepiandrosterone (DHEA) and Aging. Vol 774. New York: NY Acad Sci; 1995.
3. Orentreich N, Brind JL, Rizer RL, Vogelman VH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab. 1984 Sep;59(3):551-5.
4. Oesterling JE. The origin and development of benign prostatic hyperplasia: an age-dependent process. J Androl. 1991: 12(6):348-55.
5. Macfarlane MT. Prevalence, etiology and pathophysiology of benign prostatic hyperplasia. Recent Advances in the Treatment of Benign Prostatic Hyperplasia. 1992, UCLA Extension.
6. Belanger A, Candas B, Dupont A, et al. Changes in serum concentrations of conjugated and unconjugated steroids in 40 to 80 year-old men. J Clin Endocrinol Metab. 1994 Oct;79(4):1086-90.
7. Douglass WC. A neglected hormone—testosterone for men and women, Part I. Second Opinion. 1995;3:1-5.
8. Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf). 1994 Mar;40(3):341-9.
9. Morgentaler A, Bruning CO 3rd, DeWolf WC. Occult prostate cancer in men with low serum testosterone levels. JAMA. 1996 Dec 18;276(23):1904-6.
10. Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol. 2006;50:935-9.
11. Morgentaler A. Commentary: Guideline for male testosterone therapy: A clinician’s perspective. J Clin Endocrinology & Metab. 2007;92(2):416-7.
12. Morgentaler, A. Rapidly Shifting Concepts Regarding Androgens and Prostate Cancer. ScientificWorldJournal. 2009 Jul 27;9:685-90.
13. Yen SSC, Morales,AJ, Khorram O. Replacement of DHEA in aging men and women. In: Bellino FL, Daynes RA, Hornsby PJ, Lavrin DH, Nestler JE, eds. Dehydroepiandrosterone (DHEA) and Aging. Vol 774. New York: NY Acad Sci. 1995:128-42.
14. Roberts E, Fitten LJ. Serum steroid levels in two old men with Alzheimers disease (AD) before, during and after oral administration of dehydroepiandrosterone (DHEA). In: Kalimi M., Regelson W, eds. The Biologic Role of Dehydroepiandrosterone (DHEA). Berlin, New York: Walter de Gruyter;1990:43-63.
15. Voermans C, Condon MS, Bosland MC. Growth inhibition by dehydroepiandrosterone of human prostate cancer cell lines and primary epithelial cultures of rat prostate carcinomas (meeting abstract). Proc Annu Meet Am Assoc Cancer Res. 1996;37:A1933.
16. Sah C, Aridogan I, Izol V, et al. Effects of Long-Term Administration of the Antiaging Hormone Dehydroepiandrosterone Sulfate on Rat Prostates and Testes as Androgen-Dependent Organs. Korean J Urol. 2013 Mar;54(3):199-203.
17. Stahl F, Schnorr D, Pilz C, Dorner G. Dehydroepiandrosterone levels in patients with prostatic cancer, heart diseases and surgery under stress. Exp Clin Endocrinol. 1992;99:68-70.
18. Feher T, Koref O, Szendroi Z, Csellar M. Androgen metabolites in blood of patients with Prostatic Carcinoma. Int Urology and Nephrology. 1970; 2(2):163-9.
19. Comstock GW, Gordon GB, Hsing AW. The Relationship of Serum Dehydroepiandrosterone and its Sulfate to Subsequent Cancer of the Prostate. Cancer Epidemiol Biomarkers Prev. 1993;2(3):219-21.
20. Morgentaler A. Turning conventional wisdom upside-down: low serum testosterone and high-risk prostate cancer. Cancer. 2011 Sep 1;117(17):3885-8.