DHEA And Anti-Aging MedicineJune 2002
By Ivy Greenwell
Bone building effects and other benefits
The role of DHEA in helping fight osteoporosis in both men and women deserves special discussion. The bone-density increasing action of DHEA has been explained in terms of its two-fold mechanism: anabolic and anti-osteolytic.
For anabolic (tissue-building) purposes, the bone tissue uses the enzyme aromatase to convert DHEA to estrone. Estrone in turn stimulates osteoblasts, or bone-building cells, to produce more bone tissue. Estrone promotes bone formation in both men and women; testosterone can also be easily converted to estradiol, which is then turned into estrone. The current thinking about sex steroids and bone formation emphasizes the importance of estrogens for both sexes. Ravaglia and Forti, for instance, state, "In contrast to traditional belief, estrogens may be more important than androgens and IGF-1 in male bone metabolism." DHEA is a significant source of estrogens for both men and women. Women in the lowest quartile of estradiol or DHEA-S have been found to have twice the risk of fractures. A French study found that low levels of DHEA-S in women were also related to low muscle strength, independent of age.
IGF-1 is also involved in bone building, and some studies have found a significant positive correlation between the levels of DHEA-S and IGF-1, as well as an increase in IGF-1 with DHEA use. Finally, some studies have shown that DHEA can lower sex hormone-binding globulin, which leads to higher levels of "free" or bioavailable sex hormones.
The anti-osteolytic mechanism derives from the ability of DHEA to inhibit pro-inflammatory cytokines such as TNF and IL-6. The levels of these cytokines increase with age. Pro-inflammatory cytokines cause a release of free radicals, which in turn stimulate osteoclasts (bone-destroying cells) to step up the dissolution of existing bone. By inhibiting cytokines such as IL-6, DHEA is able to slow the process of bone breakdown.
Another established benefit of DHEA is its ability to maintain youthfulness of skin cells. A recent in vitro study confirmed that DHEA can increase collagen production while inhibiting its breakdown by the enzyme collagenase. Increased collagen production benefits all connective tissue, including blood vessels and joints. A French study using 50 mg of oral DHEA/day for a year found an improvement in skin thickness, hydration, pigmentation and sebum production, especially in older women.
Overall, the best argument for inclusion of DHEA in hormone replacement regimens stems from its role as a precursor for both androgen and estrogen production in various kinds of tissue, including bone. Primates, including humans, are unique in producing large quantities of adrenal DHEA and DHEA-S. These are converted to androstenedione, and then into other sex steroids according to local need. Postmenopausal women are particularly dependent on the peripheral conversion of precursor hormones for their supply of essential sex steroids. Because DHEA production dramatically drops with age, with a profound drop in women at menopause, women's peripheral tissue may suffer the effects of hormone deficiency especially acutely, unless replacement is provided. Even more important, there is a significant drop in beta endorphins after menopause, with consequent decrease in the sense of well-being. Sufficient DHEA increases beta endorphins and improves mood.
There are even those who favor replacement with DHEA alone (or with DHEA and pregnenolone), arguing that providing hormone precursors is best, and that conversion into estrogens and androgens as needed should be left to the wisdom of the body. A practical advantage of using DHEA (or DHEA combined with pregnenolone) instead of typical hormone replacement for women is that, according to repeated studies, there is no effect on the endometrium-even if the dose of DHEA is large enough to cause changes in the lining of the vagina. Thus, the woman who uses only DHEA need not worry about balancing her estrogen dose with just the right dose of progesterone. Sore breasts are also unlikely. The most typical side effects are androgenic rather than estrogenic: acne and more abundant facial and body hair. Women who are sensitive to the effects of a dramatic rise in androgen levels (chiefly DHT) often drop DHEA after a few months, chiefly due to acne. Many other women, however, find that they have no side effects, and are satisfied with the increased energy, improved sense of physical and mental well-being, and other benefits of DHEA as a postmenopausal hormone replacement. For those women who benefit from DHEA, but produce too much DHT, taking the prescription drug Proscar every other day might be advisable. Proscar inhibits an enzyme (5-alpha reductase) that converts testosterone into excess DHT.
A note of caution should be sounded here: those postmenopausal women who are abdominally obese ("apple-shaped") may be hyperandrogenic and already have high levels of DHEA. High natural levels of DHEA in premenopausal women are not associated with higher risk of breast cancer. High natural DHEA levels in postmenopausal women, however, have been found to raise breast cancer risk (Stoll 1999). Abdominally obese postmenopausal women are known to be at a higher risk of breast cancer, and should not take DHEA supplements unless a blood test indicates a deficiency.
The precautions regarding DHEA and breast cancer risk may be surprising and confusing to those women who remember the first enthusiastic reports about DHEA several years ago. Both in-vitro and animal studies appeared to indicate that DHEA actually inhibited the growth of breast tumor cells. Such growth inhibition does take place, but only in the presence of high concentrations of estrogens. When the levels of estrogens are low, DHEA has been found to stimulate tumor growth, possibly through tissue conversion to estradiol and estrone, and possibly also by raising IGF-1, a known promoter of tissue proliferation. Thus, postmenopausal women who wish to take DHEA (or DHEA and pregnenolone) as their sole hormone replacement are also urged to protect themselves by taking melatonin, palm-oil tocotrienols, indole-3-carbinol (I3C) and vitamin D3.
Women diagnosed with breast cancer and men with prostate cancer should not take DHEA, unless under strict medical supervision.
DHEA may help reduce diabetes damage
Kidneys are one of the organs severely damaged by the high serum glucose characteristic of diabetes. DHEA has been shown to have antioxidant activity that is also protective against lipid peroxidation caused by excess glucose. A recent in-vitro study found that DHEA could reverse glucose-induced impairment of growth in kidney cells, as well as reduce the lipid peroxidation and preserve the cellular reduced glutathione. An animal study done at the University of Louisiana found that DHEA protected the kidneys of diabetic rats against the development of fibrosis in a way that resembled the benefits of calorie restriction.
Essentially the same protective effects were observed in neural tissue, including also the restoration of normal alpha-tocopherol levels and healthy levels of unsaturated fatty acids in cell membranes. Another study found an increase in the antioxidant enzyme catalase in brain tissue treated with DHEA. In liver and kidney tissue, DHEA also raised the levels of reduced glutathione, and enhanced the activity of superoxide dismutase, glutathione-peroxidase and catalase, reducing free radical levels. DHEA was also protective in an animal model of diabetes and stroke: the multi-targeted antioxidant action of DHEA significantly reduced free radical concentrations in the neural tissue. Because DHEA can enhance glucose disposal, it is regarded as a fat-reducing hormone. It is also known to increase resting metabolic rate and lipid oxidation. While not as powerful as growth hormone and testosterone in preventing obesity, DHEA also plays a role. Unfortunately, it seems that it takes pharmacological doses of DHEA to make it work for significant body fat loss in humans.
A prospective nested case-control study using serum samples from blood donors in Washington County, Maryland, compared serum DHEA and DHEA-S between 117 cases and controls matched for age, sex and race. The authors found that men in the highest quartile of DHEA-S levels had only about one-fourth (.26) the risk of developing colon cancer compared to men in the lowest quartile. The mean serum DHEA-S concentration of cases (before the cancer diagnosis) was 13% lower than in healthy controls. Statistical significance was not reached, however. Before we can conclude that DHEA-S may protect against colon cancer in men, a larger study needs to be done.
Overall, previous findings about DHEA continue to be upheld, with more knowledge being gained on various aspects of its benefits. Study after study has found that DHEA can lower levels of tumor necrosis factor alpha (TNF-alpha), thus reducing the damage produced by excess inflammation. It has also been confirmed that DHEA has immunoenhancing properties, and is a promising adjunct therapy not only in chronic inflammatory diseases, but also during various acute bacterial and viral infections, including those that often accompany traumatic injury. The cardioprotective effects of DHEA in males also appear to be reasonably well-established, although we do not fully understand their mechanism.
Maintaining a youthful hormonal balance is an essential part of an anti-aging regimen. This includes trying to maintain youthful levels of DHEA. Unless supplemented, DHEA levels decrease dramatically due to the aging process, with harmful consequences.
DHEA is an important neurosteroid, protecting the neural tissue against various kinds of damage. Nothing is so important in anti-aging medicine as protecting the brain against the ravages of aging. Maintaining the correct ratio of DHEA-S to cortisol appears to be crucial to this protection. It seems to be especially important for
diabetics, since DHEA replacement appears to be able to counteract the damage arising from high blood sugar in critical organs such as the brain and the kidneys. But past a certain age, essentially everyone could use more DHEA as protection against Alzheimer's disease and other degenerative brain diseases.
Maintaining a youthful hormonal balance is an essential part of an anti-aging regimen. This includes trying to maintain youthful levels of DHEA. Unless supplemented, DHEA levels decrease dramatically due to the aging process, with harmful consequences such as impaired immune function and more chronic inflammation. DHEA users generally report more energy and an improved state of well-being, as well as greater ability to cope with stress.
Last but not least, stress of all types (emotional, physical, infection-induced, etc.) remains our great enemy, an accelerator of aging. DHEA has been shown to be a versatile anti-stress hormone, an antiglucocorticoid-an antagonist of cortisol, our main "stress hormone." In many ways the action of DHEA is the opposite to that of cortisol. While cortisol is catabolic, causing loss of muscle and bone, DHEA is an anabolic hormone: it helps the body build new tissue. DHEA also protects us against the immune failure due to aging. In particular, maintaining a normal DHEA/cortisol ratio appears to be critical in trying to prevent the degenerative changes of aging.
Some questions about DHEA remain to be elucidated. Large-scale, long-term human studies are needed. Because DHEA is an over-the-counter supplement rather than a drug such as Premarin, getting funding for such studies would be enormously difficult. Nevertheless, evidence from short-term studies has been accumulating. DHEA's anti-stress, immmunoenhancing and neuroprotective benefits are not in doubt. In men, the cardiovascular benefits of DHEA also appear to be well established. Due to its multiple benefits, DHEA has a firm place in any anti-aging protocol.
Alberg AJ et al. Serum DHEA and DHEA-S and the subsequent risk of developing colon cancer. Cancer Epidemiol Biomarkers Prevention 2000; 9:517-21.
Aoki K et al. DHEA suppresses elevated hepatic glucose-6-phosphatase mRNA levels in C57BL/KsJ-db/db mice: comparison with troglitazone. Endocr J 2000; 47:799-804.
Aragno M et al. Oxidative derangement in rat synaptosomes induced by hyperglycemia: restorative effect of DHEA treatment. Biochem Pharmacol 2000; 60:389-95.
Aragno M et al. DHEA protects tissues of streptozotocin-treated rats against oxidative stress. Free Radic Biol Med 1999; 26:1467-74.
Aragno M et al. DHEA prevents oxidative injury induced by transient ischemia/reperfusion in the brain of diabetic rats. Diabetes 2000;40:1924-31.
Arlt W et al. DHEA replacement in women with adrenal insufficiency. N Engl J Med 1999; 341:1013-20.
Barret-Connor E et al. Endogenous levels of DHEA-S, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo Study. J Am Geriatr Soc 1999; 47:685-91.
Baulieu EE et al. DHEA, DHEA-S, and aging: contribution of the DHEA Age Study to sociobiomedical issue. Proc Natural Acad Sci USA 2000 97:4279-84.
Brignardello E et al. DHEA prevents lipid peroxidation and cell growth inhibition produced by high glucose concentration in cultured rat mesangial cells. J Endocrinol 2000; 166:401-406.
Boudou P et al. Effects of a single bout of exercise and exercise training on steroid levels in middle-aged type 2 diabetic men: relationship to abdominal adipose tissue distribution and metabolic status. Diabetes Metab 2000; 26:450-57.
de Pergola G. The adipose tissue metabolism: role of testosterone and DHEA. Int J Obes Relat Metab Disord 2000; 24 Suppl 2: S59-63.
Dillon JS et al. DHEA-S and beta-cell function: enhanced glucose-induced insulin secretion and altered gene expression in rodent pancreatic beta cells. Diabetes 2000; 49: 1012-20.
Ferrari E et al. Age-related changes of the hypothalamic-pituitary-adrenal axis: pathophysiological correlates. Eur J Endocrinol 2001; 144:319-29.
Garnero P et al. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res 2000; 15: 1526-36.
Haden ST et al. Effects of age on serum DHEA-S, IGF-1, and IL-6 levels in women. Calcif Tissue Int 2000; 66:414-18.
Kostka T et al. Leg extensor power and DHEA-S, IGF-1 and testosterone in healthy active elderly people. Eur J Appl Physiol 2000; 82:83-90.
Labrie, F et al. DHEA and the intracrine formation of androgens and estrogens in peripheral target tissue: its role during aging. Steroids 1998; 63: 322-38.
Laughlin GA, Barrett-Connor E. Sexual dimorphism in the influence of advanced aging on adrenal hormone levels: the Rancho Bernardo Study. J Clin Endocrinol Metab 2000; 85: 3561-68.
Lee KS et al. Effects of DHEA on collagen and collagenase gene expression by skin fibroblasts in culture. J Dermatol Sci 2000; 23: 103-10.
Legrain S et al. DHEA replacement administration: pharmacokinetic and pharmacodynamic studies in healthy elderly subjects. J Clin Endocrinol Metabolism 2000; 85: 3208-17.
McCormick DL, Rao KV. Chemoprevention of hormone-dependent prostate cancer in the Wistar-Unilever rat. Eur Urol 1999; 35:464-7.
Morley JE et al. Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, DHEA-S, and the ratio of IGF-1 to growth hormone. Proc Natural Acad Sci USA 1997; 94: 7537-42.
Nagata C et al. Serum concentrations of estradiol and DHEA-S and soy product intake in relation to psychologic well-being in peri- and postmenopausal Japanese women. Metabolism 2000; 49:1561-64.
Ravaglia G, Forti P et al. Body composition, sex steroids, IGF-1, and bone mineral status in aging men. IJ Gerontol A Biol Sci Medicine Sci 2000; 55: M516-21.
Reiter WJ et al. DHEA in the treatment of erectile dysfunction: a prospective, double-blind, randomized, placebo-controlled study. Urology 1999; 53:590-94.
Richards RJ et al. Effects of DHEA and quinapril on nephropathy in obese Zucker rats. Kidney Int 2001;59:37-43.
Rubino S et al. Neuroendocrine effects of a short-term treatment with DHEA in postmenopausal women. Maturitas 1998; 28:251-57.
Schatzl G. Endocrine patterns in patients with benign and malignant prostatic diseases. Prostate 2000; 44:219-24.
Stoll BA. Dietary supplements of DHEA in relation to breast cancer risk. Eur J Clin Nutr 1999; 53:771-75.
Stomati M et al. Six-month oral DHEA supplementation in early and late postmenopause. Gynecol Endocrinol 2000;14:342-63.
Straub RH et al. Serum DHEA and DHEA-S are negatively correlated with serum IL-6, and DHEA inhibits secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence. J Clin Endocrinol Metab 1998; 83:2012-17.
Sulcova J et at. Effects of transdermal application of DHEA on the levels of steroids, gonadotropins, and lipids in men. Physiol Res 2000; 49:685-93.
Villareal DT et al. Effects of DHEA replacement on bone mineral density and body composition in elderly women and men. Clin Endocrinol 2000; 53:561-68.
Whitnall MH et al. Androstenediol stimulates myelopoiesis and enhances resistance to infection in gamma-irradiated mice. Int J Immunopharmacol 2000; 22:1-14.
Yang JV et al. Inhibition of HIV-1 latency reactivation by DHEA and an analog of DHEA. AIDS Res Hum Retroviruses 1993; 9:747-54.
Yang N et al. DHEA inhibits cell growth and induces apoptosis in BV-2 cells and the effects are inversely associated with glucose concentration in the medium. J Steroid Biochem Mol Biol 2000; 75:159-66.
Wang M et al. Growth of HPV-18 immortalized human prostatic intraepithelial neoplasia cell lines. Influence of IL-10, follistatin, activin-A, and DHT. Int J Oncol 1999;14:1185-95.