DHEA (Dehydroepiandrosterone)

DHEA (Dehydroepiandrosterone)

"DHEA is a natural sterone produced by the adrenal gland. DHEA is the most common sterone in human blood, but amounts decline rapidly with age. Secretions are highest during the early twenties and begin to decline at around age 25, by the time we reach 70 years of age, DHEA production is only a small fraction of what it was 50 years earlier. Research has shown a correlation between low DHEA levels and a declining immune system, and DHEA is being used in the fight against HIV, cancer and senile dementia. It is also been clinically shown that DHEA helps brain neurons establish contact. Further, it is known that Alzheimer patients have low DHEA levels, when compared to their healthy counterparts. It is also known that a small amount of sulphate DHEA and micronized DHEA can convert into testosterone [which is a treatment for prostate cancer]."


Women's Health Update: DHEA, Women, Cancer and More

In the October, 1996 Townsend Letter we reviewed the role of dehydroepiandrosterone (DHEA) in cancer prevention. As I discussed, there are many animal studies which demonstrate a protective role for DHEA in the development of cancer and a few studies in which higher levels of DHEA appeared to increase the incidence of malignancy. In this issue we will quickly review its role in cancer development and discuss the use of DHEA in the treatment of cancer; contraindications for use in women with cancer and its use for other conditions.

DHEA, a steroid hormone, is synthesized in the adrenal gland via cholesterol to pregnenolone. It can then be converted in peripheral tissue to either estrogen or testosterone in both men and women, depending on the hormonal milieu. In premenopausal women DHEA is either an estrogen anatagonist, perhaps through competitive binding of its metabolite 5-androsterone-3-beta, 17 beta-diol (ADIOL) to estrogen receptors or an androgen through its metabolism to androstenedione and testosterone. In postmenopausal women DHEA is more likely to act as an estrogen.

DHEA has been shown to inhibit the development of breast, skin, colon and liver cancers in animals.( 1-3) Long-term administration of high doses of DHEA to rats, however, can act as a hepatocarcinogen. Liver neoplasms developed in 44% of the female rats and 11% of the male rats after 70 weeks of administration. The authors suggest that mitochondrial proliferation by DHEA may result in hepatocarcinogenesis.( 4) Another study found a protective effect by DHEA in rats with chemically induced cancers, including decreased occurrences of preneoplasias in the urinary bladder and seminal vesicles and neoplasms in the thyroid and small intestine. Liver tumors in these same rats increased with DHEA administration.

Circulating levels of DHEA similar to those found in normal premenopausal women exert a potent inhibitory effect on the development of mammary tumors in the rat, which might suggest the possibility of using DHEA in the prevention of breast cancer in premenopausal women.( 6) The effect of DHEA in cancer prevention or development may be explained by the flexibility DHEA demonstrates in conversion to other hormones, depending on how much estrogen is present. Research in the 1980's found that in premenopausal women, low levels of DHEA were associated with a higher incidence of breast cancer, while postmenopausal women with breast cancer had elevated levels of DHEA.( 7, 8) This makes sense because in the premenopausal women, if DHEA acts as an estrogen antagonist, it may help prevent the consequence of excess estrogen levels in the development of breast cancer. In postmenopausal women DHEA may promote malignancy if it acts as an estrogen. More study is clearly needed because of the con flicting data. Review of recent studies have found that the amount of DHEA and DHEA-sulfate (DHEA-S) are not significantly different in normal women from those with breast cancer.( 9)

In a prospective case-control study, individuals with low levels of serum DHEA and DHEA-S levels were more likely to develop bladder cancer than those with normal levels? Serum levels of DHEA in men with prostate cancer were found to be 11% lower among cases than controls.( 11) Incremental decreases in DHEA levels were also found to be associated with increased risk of gastric cancer in men.( 12)

Other human studies haven't been as clear-cut. In a nested case-control study of 31 women with ovarian cancer, researchers found that the women who developed ovarian cancer had higher DHEA (15.9 nmol/L vs 9.7 nmol/L; PO=.02) and androstenedione levels (4.5 nmol/L vs 3.3 nmol: P=.03) prior to diagnosis. The risk of ovarian cancer increased with higher levels of androstenedione and DHEA sulfate (P for trend = .008 and .11, respectively). These associations were not materially different between premenopausal and postmenopausal women?

DHEA and Cancer Treatment

DHEA has an estradiol-like effect in a low estrogen milieu and can stimulate tumor growth. When there is an estradiol abundance, DHEA antagonizes the growth-stimulating effect of estradiol.( 14) Recently it was found that estradiol in breast cancer tissues originated from estrone sulfate as the precursor. At this time it isn't known how much DHEA contributes to the levels of estrogens. A point of further interest is that a series of authors have demonstrated that the administration of DHEA to experimental animals with breast cancer significantly decreased the evolution of the disease.
Finally, it has been suggested that androgens, in their capacity as anti-estrogens, can be used to substitute for anti-estrogens in cases where treatment with classical anti-estrogens has no response. More information concerning the plasma and tissue concentrations of androgens, their contribution as estrogen precursors and their biological response(s), is needed in order to have a clearer idea of the role of these steroids in breast cancer.( 15) If a woman is receiving tamoxifen for the treatment and prophylaxis for breast cancer, the administration of DHEA would clearly be contrindicated because of its competitive binding with tamoxifen for the estrogen receptors.

But what about the use of DHEA in non-hormone sensitive cancers? There is much evidence that DHEA produces its antiproliferative and tumor preventive effects by inhibiting glucose-6-phosphate dehydrogenase and the pentose phosphate pathway. This pathway is an important source of NADPH, a critical reductant for many biochemical reactions that generate oxygen free radicals, which may act as second messengers in stimulating hyperplasia.( 16, 17)
Fifteen weeks of DHEA administration arrested the growth and progression of persistent cancerous liver nodule in rats. Our purpose was to evaluate whether DHEA can also arrest the growth and progression of late lesions, such as persistent nodules (PNs) of rat liver. Within 16 hours after feeding with DHEA the level of glucose-6-phosphate dehydrogenase (G6PD) in liver tissue and the cancerous nodules decreased and the size and number of the nodules decreased.( 18) Why DHEA increased liver cancers in some studies and exactly what other effects it has on the liver must be answered before DHEA can be suggested for prevention or treatment of cancer.

In one study long-term DHEA treatment of mice reduced weight gain (apparently by enhancing thermogenesis), and appeared to produce many of the beneficial effects of food restriction, which have been shown to inhibit the development of many age-associated diseases, including cancer.( 19)

Another proposed mechanism for DHEA's effect against cancer is its effect on the immune system. As we age we experience a dysregulation of the immune system; increased autoantibodies, decreased production of antibodies to most foreign antigens and dysregulation of cytokine production with an increased production of IL-4, IL-5 and IL-6 associated with a decreased production of IL-2. When old mice were treated with DHEA or lymphocytes from aged donors were cultured with DHEA, the antibody response to foreign antigens increased and the dysregulated cytokine production by T cells normalized?

DHEA - Other Possible Effects/Uses

DHEA may be effective in preventing cardiovascular disease. This adrenal hormone appears to be antiatherogenic. In one study DHEA inhibited platelet aggregation in vitro in plasma by reduction of platelet thromboxane B2 production. In a randomized double-blind study, DHEA prevented platelet aggregation in the men studied.( 21) Another possible mechanism is that in men with an androgenic milieu DHEA may act like an estrogen and protect against cardiovascular disease.( 22)

While DHEA in animal studies appears to offer protection against diabetes and obesity, a study in women demonstrated the opposite effect. A large study of postmenopausal women not using estrogen therapy or antidiabetic medicine measured fasting morning levels of DHEA. DHEA levels were positively associated with central obesity as measured by waist-hip ratio, diabetes and impaired glucose tolerance. The study wasn't able to determine if the DHEA levels were raised by the central obesity or vice versa.( 23)

DHEA increased the lifespans of mice an amazing 50%.( 24) and protected rats from osteoporosis after ovary removal.( 25) Studies need to see if these effects hold up in humans.

What effect does DHEA have on postmenopausal women with low endogenous DHEA? In a double blind, cross-over study 1600 mg/day was administered for 28 days. Serum androgens increased which was maximal at 2 weeks. DHEA increased 15-fold, 9-fold for testosterone and 20-fold for DS androstenedione and dihydrotestosterone. Both estrone and estradiol showed a progressive increase to double the basal value at 4 weeks. Sex hormone binding globulin and thyroid binding globulin levels decreased during DHEA treatment. However, LH, FSH, body weight and percent body fat remained unchanged. A marked decline of 11.3% in serum cholesterol and 20.0% in high density lipoprotein persisted for the length of the study and was accompanied by a nonsignificant downward trend in low density lipoprotein, very low density lipoprotein, and triglycerides. Peak insulin levels during the 3-h oral glucose tolerance test were significantly higher after the 28 days of DHEA (1126+/- 165 vs. 746 +/- 165 pmol/L) and were accompanied by a 50% increase in the integrated insulin response (P less than 0.01) without a significant change in fasting glucose insulin or glucose-6-phosphate dehydrogenase level.( 26) The amount of DHEA used in this study is extremely high and 64 to 320 times the conventional dose of 5mg to 25mg per day. The effects of DHEA at more commonly used dosage still need to be determined.

The study of DHEA promises to be intense into the 21st century. While the popular press holds this adrenal hormone up as the fountain of youth and minimizes any side effects as minor, much additional research needs to be completed before its safe applications can be determined for women with cancer and its possible use in cancer prevention demonstrated. Many people are using DHEA without medical guidance and the effects of DHEA, both positive and negative, may be demonstrated in our patients before the definitive laboratory and population studies are published.

References

(1.) Hursting SD, Perkins SN, et al. Chemoprevention of spontaneons tumorgenesis in p53-knockout mice. Cancer Res. 1995;55:3949-3953.

(2.) Simile M, Pascale RM, et al. Inhibition by dehydroepiandrosterone of growth and progression of persistent liver nodule in experimental rat liver carcinogenesis. Int J Cancer 1995;62:210-215.

(3.) Inano H, lshii-Ohba H, et al. Chemoprevention by dietary dehydroepiandrosterone against promotion/progression phase of radiation-induced mammary tumorigenesis in rats. J Steroid Biochem Möl Biol 1995;54:47-53.

(4.). Metzger C, Mayer D, et al. Sequential appearance and ultrastructure of amphophilic cell foci, adenomas and carcinomas in the liver of male and female rats treated with dehydroepiandrosterone. Toxicol Pathol 1995;23:591-605.
(5.) Shibata M, Hasegawa R, et al. Chemoprevention by dehydroepiandrosterne and indomethacin in a rat multiorgan carcinogenesis model Cancer Res 1995;55:4870-4874.

(6.) Li S, Yan X, et al. Prevention by dehydroepiandrosterone of the development of mammary carcinoma induced by 7.12-dimethylbenz(a)anthracene (DMBA) in the rat. Breast Cancer Res Treat 1994;29:203-217.

(7). Bulbrook RD, Hayward JL, Spicer CC. Abnormal urinary steroid secretion and subsequent breast cancer. Lancet 1971;1:519-522.

(8.) Zumoff B, Levin J, et al. Abnormal 24-hour mean plasma concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate in women with primary operable breast cancer. Cancer Res 1981;41:3360-3363.
(9.) Pasqualini JR. Role of androgens in breast cancer. J Steroid Biochem Mol Biol 1993;5 (1-3):167-72.

(10.) Gordon GB, Helzlsouer KJ, Comstock GW. Serum levels of dehydroepiandrosterone and its sulfate and the risk of developing bladder cancer. Cancer Res 1991;51:13661369.

(11.) Comstock GW, Gordon GB, Hsing AW. The relationship of serum dehydroepiandrosterene and its sulfate to subsequent cancer of the prostate. Cancer Epidemiol Biomarkers Prey 1993;2:219-221.

(12.) Gordon GB, Helzlsouer KJ, et al. Serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate and the risk of developing gastric cancer. Cancer Epidemiol Biomarkers Prev. 1993;2:33-35.

(13.) Helzlsouer KJ, Alberg AJ, Gordon GB et al. Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995;274:1926-1930.

(14.) Ebeling P, Koivisto VA. Physiological importance of dehydroepiandrosterone. Lancet 1994;343:1479-81.
(15.) Pesqualini JR. Role of androgens in breast cancer. J Steroid Biochem Mol Biol 1993;45(1-3); 167-72.
(16.) Gordon, GB, Shantz, LM Talelay, P. Inhibitory effects of dehydroepiandrosterone on cell proliferation, differentiation, and carcinogenesis: Role of glucose-6-phosphate dehydrogenase. Hormones, Thermogenesis, and Obesity, Lardy H, Stratman, F eds. Elsevier Science Publishin Co., Inc 1989;339-354.

(17.) Schwartz AG, Pashko LL. Cancer prevention with dehydroepiandrosterone and non-adrogenic structural analogs. J Cell Biochem Suppl. 195;22:210-217.

(18.) Simile M, Pascale RM, et al. Inhibition by dehydroepiandrosterone of growth and progression of persistent liver nodules in experimental rat liver carcinogenesis. Int J Cancer 1995;62:210-215.

(19.) Schwartz AG, Pashko LL. Cancer chemoprevention with the adrenocortical steroid dehydroepiandrosterone and structural analogs. J Cell Biochem Suppl. 1993;17G:73-79.

(20.) Weksler ME. Immune senescence and adrenal steroids; immune dysregulation and the action Of dehydroepiandrosterone (DHEA) in old animals. Eur J Clin Pharmacol 1993;45 Suppl 1:S21-3; discussion S43-4.
(21.) Jesse RL, Loesser K, et al. Dehydroepiandrosterone inhibits human platelet aggregation in vitro and in vivo. Ann NY Acad Sci. 1995;29:281-290.

(22.) Ebeling P, Koivisto VA. Physiological importance of dehydroepiandrosterone. Lancet 1994;343:1479-51.
(23.) Barrett-Conner E, Ferrara A. Dehydroepiandrosterone, dehydroepiandrosterone sulfate, obesity, waist-hip ratio, and noninsulin-dependent diabetes in postmenopausal women: the Rancho Bernardo Study. J Clin Endocrinol Metab. 1996;81:59-54.

(24.) Schwartz AG, Pashko LL. Cancer chemoprevention with the adrenocortical steroid dehydroepiandrosterone and structural analogs. J Cell Biochem Suppl 1993;17G:73-79.
(25.) Turner RT, Lifrak ET. Dehydroepiandrosterone reduces cancerous bone osteopenia in ovarectomized rats. Am J Physiol 1990;258:E673-E677.

(26.) Mortola JF, Yen SS. The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrin Metab 1990;71:696-704.
Article copyright Townsend Letter for Doctors & Patients.
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By Tori Hudson

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CAN DHEA PREVENT BPH AND PROSTATE CANCER?
?
The effect of DHEA supplementation on preventing benign prostatic hypertrophy (BPH) and prostate cancer is showing great promise according to leading anti-aging expert Ward Dean, MD. His surprising conclusion, which is contrary to recent media reports of DHEA supplementation causing cancer risk, was reached after a thorough review of both cellular and human studies with DHEA and was published in a research article in VRP Nutritional News.

From cited studies, he concluded: In vitro growth of both human and rat prostate cancer cells is inhibited by DHEA -- and the higher the concentration of DHEA, the greater the inhibition of growth! Patients with prostate cancer have lower levels of DHEA and DHEA-S than age-matched controls, as confirmed by three independent studies. DHEA (and perhaps testosterone) are not contraindicated and, in fact, should be considered for the therapy of prostate disease.

He based his conclusions on several published research reports as well as two presentations given at the Proceedings of the Annual Meeting of the American Association for Cancer Research.

In Vitro Effects of DHEA on Prostate Cancer Cell Growth

Scientists at the New York University Medical Center, Tuxedo, New York, 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 æg/ml, respectively. DHEA also inhibited growth of rat prostate carcinoma cultures (media with 50nM testosterone [T]), by 40%, 54% and 77% at concentrations of 1, 10, and 22.5 æg/ml, respectively. The scientists concluded that DHEA inhibits growth of human and rat prostate cancer cells in a dose-related fashion, that DHEA acts as a chemopreventive agent by direct growth inhibition of prostate cancer cells, and that DHEA should be considered for further research for prostate cancer chemoprevention in humans.

DHEA Levels in Patients with Prostate Cancer

In a human study, 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. Their findings confirm DHEA-S levels decrease in patients with prostate cancer.
A retrospective study conducted at Johns Hopkins University involved the analysis of DHEA and DHEA-S levels in blood serum that was collected and frozen in 1974 and the relationship of these levels to the subsequent development of prostate cancer. DHEA and DHEA-S levels for 81 men who were subsequently diagnosed with prostate cancer were found to have 11% lower levels of DHEA and 12% lower levels of DHEA-S compared to age-matched controls who did not develop prostate cancer. The authors concluded that it seems unlikely that serum levels of DHEA or DHEA-S are important risk factors for prostate cancer.

Ward Dean, MD, is the Director of Research & Development for Vitamin Research Products and is the founder and director of the Center for Bio-Gerontology. He is also the author of the Neuroendocrine Theory of Aging. Dr. Dean is a prominent figure in the field of anti-aging and life extension medicine. A free copy of his full 2,200 word research article on this subject may be obtained from Vitamin Research Products, 800-877-2447.

Correspondence:

Vitamin Research Products
3579 Highway 50 East
Carson City, Nevada 89701 USA
702-884-1300/Fax 702-884-1331

References

Dean, Ward. Is DHEA Contraindicated in Men with Benign Prostate Hypertrophy (BPH) or Prostate Cancer? VRP Nutritional News. 1997, 11 (10).

McCormick, DL, Rao, KV, Bosland, MD, Steele, VE, et al. Inhibition of rat prostate carcinogenesis by dietary dehydroepiandrosterone but not by N-(4-hydroxyphenyl)-all-trans-retinamide. Proc Annu Meet Am Assoc Cancer Res, 6:A746, 1995.

Voermans, C, Condon, MS, and 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.

Stahl, F, Schnorr, D, Pilz, C, and Dorner, G. Dehydroepiandrosterone levels in patients with prostatic cancer, heart diseases and surgery under stress. Exp Clin Endocrinol. 1992, 99:68-70.

Comstock, GW, Gordon, GB, and Hsing, AW. The relationship of serum dehydroepiandrosterone and its sulfate to subsequent cancer of the prostate. Cancer Epidemiol Biomarkers Prev. 1993, 2:3, 219-221.
Article copyright Townsend Letter for Doctors & Patients.