~ The DHEA Debate, Part 2
Naysayer: How can you be sure that DHEA won't cause cancer?
Stephen Cherniske: There are no data to suggest that. In fact, all the evidence is to the contrary. Dr. Marian Laderoute, a pathologist at the Canadian Bureau of Infectious Diseases, reminds us that cancer is associated with low DHEA levels. She and others point out that the specific mutations required for carcinogenesis can be traced to a failure of immunity and cell regulation that takes place as a consequence of falling levels of DHEA.62
Clearly, cancer does not take place due to high levels of DHEA. If that were the case, young people would get cancer, when in fact it is remarkably rare in the young. Declining immunity must be a factor, but we also do not see an increased incidence of cancer among young patients on immunosuppressive therapy (for example, organ transplant recipients). Cancer incidence, it turns out, is tied to numerous aspects of aging, including impaired apoptosis, decreased immune surveillance and decreased number and activity of NK (natural killer) cells. DHEA has been shown to improve every one of these factors.45,55,63,64
Current research also shows that DHEA, like calorie restriction, reduces the inducible generation of nitric oxide, which is yet another way of reducing cancer risk.65 On the gene level, DHEA's anticancer activity includes a reduction in levels of the mutant gene p53.66 Moreover, aging and cancer are associated with the dysregulation of cytokine production in which IL-6 predominates over IL-2. It is known that IL-2 has powerful anticancer activity, and IL-2 injection is presently used in Europe with various stages of cancer. Since optimizing DHEA has been shown to significantly increase IL-2 and normalize cytokine balance, maintaining optimal levels of DHEA appears to be an effective cancer-preventive strategy.
Indeed, animal studies have supported this idea for over 25 years, where DHEA administration has reduced the risk of cancer of the liver, adrenals, pancreas, breast, lung, thyroid, colon, skin, and lymphatic tissue.67-75
In all, there is compelling genomic, biochemical, and biological evidence supporting the ability of DHEA to reduce cancer risk. But perhaps you have data from human trials showing that DHEA somehow stimulates cancer growth.
Naysayer: DHEA has been shown to cause liver cancer in mice.
Stephen Cherniske: Yes, there is a study in which mice were given a massive dose of DHEA—the human equivalent of 10,000 mg per day. And even then, this dose had to be administered continuously for at least 18 months (the human equivalent of 76 years) before they could induce cancer in these poor animals.76
Do you really think that this is relevant, considering that studies using a lower dose (the human equivalent of 2,000 mg per day) did not produce cancer,77 and more than 50 rodent studies show that DHEA reduces cancer risk? Importantly, DHEA administration has reduced cancer risk in every conceivable model, whether the cancers were spontaneous or induced by a virus or carcinogenic chemical.78
Naysayer: Well, there are other studies . . .
Stephen Cherniske: Yes, the study at the University of Oregon where DHEA was fed to trout—an organism that does not even produce DHEA naturally.79 Such data would be useful only if there were indications that the same thing might occur in humans. But in a review of more than 5,500 studies published on DHEA, not one has shown that DHEA stimulates cancer growth. In fact, DHEA has been used successfully in the treatment of cancer.80
Look at the recent research conducted by the National Cancer Institute. They created a reliable animal model for the study of breast cancer and found that DHEA administration significantly reduced both the incidence and multiplicity of tumors.81 Here's the quote that appeared in the Journal of Nutrition (p. 2408S):
"Whenever it has been tested in a model of carcinogenesis and tumor induction, DHEA has preventative effects."82
Another animal study from 2001, also conducted by the National Cancer Institute, showed that DHEA administration reduced breast cancer incidence by 30% and multiplicity by 50%.83 The following year, NCI published a mode-of-action study explaining how DHEA helps to limit cancer growth.84
DHEA has even shown powerful anti-cancer activity in mice selectively bred to be highly susceptible to cancer.85 Researchers have also found the specific genes that confer this advantage (including p53, DHEA ST, and p21) are upregulated by oral administration of DHEA.86,87
DHEA may also be effective in reducing risk for colon cancer. Scientists in Japan exposed mice to a chemical that induces abnormal cellular proliferation in the colon. After this exposure, some of the mice were fed DHEA. At the end of the experiment, the DHEA-supplemented mice had a significant decrease in precancerous lesions compared to controls.88
In another animal study, small doses of DHEA were shown to significantly prevent breast cancer. DHEA treatment resulted in a marked reduction in tumor incidence and a whopping 92% reduction in tumor size compared to controls.89
Naysayer: But these are animal studies. They don't prove that DHEA prevents breast cancer in human beings.
Stephen Cherniske: Agreed. But they certainly disprove your "sky-is-falling" diatribe that DHEA might cause breast cancer. There isn't any evidence whatsoever that DHEA increases risk for breast cancer. In fact, a study published in the prestigious journal The Lancet showed a remarkable correlation between breast cancer and low DHEA levels.
In this longitudinal study, researchers measured DHEA metabolites in 5,000 women, and then followed these subjects for nine years for breast cancer. DHEA levels were significantly lower in cases (women who were subsequently diagnosed with breast cancer) compared to matched controls, leading the researchers to conclude that women with low DHEA levels are at increased risk for breast cancer.90
So the breast cancer scare is a red herring. You also claim that DHEA might cause prostate cancer, when all the evidence is to the contrary.
Naysayer: I disagree. DHEA can be converted to testosterone.
Stephen Cherniske: So? Human studies show that there is no correlation between DHEA or testosterone and prostate cancer.91-95 In-vitro studies show that DHEA actually inhibits prostate cancer,96 and even giving massive amounts of DHEA to animals does not induce abnormal growth in the prostate. A study published in the journal Cancer Research states:
"No effect on the development of prostate cancer precursor lesions was observed when mice were treated with DHEA."83
Naysayer: But I've read in dozens of articles that DHEA might cause prostate cancer. All of those articles can't be wrong.
Stephen Cherniske: Sure they can. Journalists are not scientists. If they believe their source to be accurate, they print the information without checking the medical literature. Then the story is repeated and, as you know, if an error is repeated enough, it appears to be true. If journalists were willing or able to carefully research this topic, they'd find an animal study reported in the European Journal of Urology that concludes:
"DHEA and 9-cis-retinoic acid are the most active [cancer-preventive] agents identified to date. DHEA inhibits prostate cancer induction both when chronic administration is begun prior to carcinogen exposure, and when administration is delayed until preneoplastic pros-tate lesions are present."97
Notice that DHEA administration inhibited prostate cancer when given prior to carcinogen exposure, and was effective even after the initial stages of prostate cancer.
Naysayer: But again, that's an animal study.
Stephen Cherniske: And animal studies are routinely used to establish safety and efficacy, especially when there is no evidence that DHEA might cause or accelerate abnormal prostate growth in humans.
Naysayer: There must be evidence.
Stephen Cherniske: No, there's only inference, speculation. Look, if DHEA caused abnormal prostate growth, high levels of DHEA would be associated with high PSA scores. In fact, low DHEA levels are associated with elevated PSA in men, and the converse is also true: men with higher DHEA levels have lower PSA scores.98
Naysayer: Still, DHEA supplements might raise PSA levels.
Stephen Cherniske: That does not occur. In study after study, supplementation with DHEA—even at high doses—has been shown to have no negative effect on PSA levels.99,100 In private communication, many clinicians have told me that they have observed a gradual decline in PSA levels in patients taking DHEA. Consistent with this are recent findings that prostate cancer patients have higher serum levels of immunosuppressive glucocorticoids95 (DHEA counters that) and that DHEA metabolites can inhibit PSA expression by interrupting androgen binding to the prostate androgen receptor.101 These provide yet more evidence that DHEA may actually reduce prostate cancer risk.
Naysayer: Well, if there is no danger, and DHEA might even help prevent prostate disease, why are there no human trials with DHEA and prostate health?
Stephen Cherniske: Actually, the Division of Cancer Prevention at the National Cancer Institute is planning to study DHEA supplementation as a way to prevent prostate cancer in men.102 DHEA has already been used successfully in the treatment of erectile dysfunction.103,104 Here are the findings from a study that reviewed the effects of DHEA on common age-related ailments:
"Low concentrations of DHEA are associated with immunosenescence, physical frailty, decline in muscle mass, increased mortality, loss of sleep, diminished feelings of well-being and impaired ability to cope, and occur in several common diseases (including cancer, atherosclerosis, hypertension, diabetes, osteoporosis and Alzheimer's disease."105
Naysayer: Still, DHEA stimulates IGF-1, and that promotes cancer.
Stephen Cherniske: First of all, the widely cited association between IGF-1 and prostate cancer has been debunked.106,107 That said, the concern for tumor acceleration does make sense because IGF has angiogenic activity that would favor tumor growth. But IGF-1 has only been shown to accelerate tumor growth in test tubes. Test tubes and petri dishes do not have immune systems, which are upregulated by IGF-1. In fact, the preponderance of the evidence shows that IGF-1 does not promote cancer in any living organism, whether animal or human. Even direct injection of IGF-1 does not promote tumor growth in animals.108 In Europe, IGF-1 is routinely given to cancer patients to help them gain weight.
Aside from this, it is important to note that increases in IGF-1 after DHEA supplementation are significant but modest, and there are no published studies in which DHEA administration caused IGF-1 to rise above the normal range. Moreover, scores of published studies demonstrate the essential role that IGF-1 plays in the repair and regeneration of the brain, skeleton, and cardiovascular and immune systems.109-112 Conversely, low IGF-1 levels have been associated with dementia, atherosclerosis, osteoporosis, and sarcopenia,54,113 and a study in the journal Gerontology shows that men who maintain youthful levels of IGF-1 do not experience the decline in testosterone or muscle mass, or the accumulation of fat, that has been considered an inevitable consequence of aging.114
Naysayer: But DHEA is converted to testosterone and estrogen . . .
Stephen Cherniske: Some DHEA is converted to testosterone and estrogens. But there are enzymes in every tissue of the human body and brain that metabolize DHEA itself. The idea that DHEA is merely a reservoir for sex steroids was debunked decades ago. A recent study in the journal Steroids documents the anticancer effects of DHEA and all of its major metabolites.115 Likewise, the ability of DHEA to reduce risk for cardiovascular disease is independent of its conversion to sex steroids.116 A study with 375 men with a mean age of 60 found that sexual activity and satisfaction was far more closely associated with DHEA levels than testosterone.98
Naysayer: But it is converted to testosterone and estrogen . . .
Stephen Cherniske: Yes it is, but are you saying that is inherently unsafe?
Naysayer: Well, look at the disaster that we just saw with hormone replacement therapy (HRT).
Stephen Cherniske: That was caused by conventional HRT using large doses of synthetic hormones. Yes, that was a disaster, given to more than 80 million women, which actually increased risk for breast cancer, stroke, and pulmonary embolism.117 So, because large amounts of synthetic hormones increased disease risk, you believe that small amounts of a natural hormone will do the same thing, even though we've been over this already and you've seen that there is no evidence that DHEA promotes abnormal growth of any tissue in the human body. Even though studies with human volunteers show that a 50-mg daily dose of DHEA does not elevate systemic or blood levels of estradiol.19 Heck, human studies with 200 mg of DHEA per day have shown no systemic elevation of estradiol.118 On the contrary, conversion of DHEA to sex steroids appears to take place on an as-needed basis, through an inherent self-regulating activity.
The dangers of HRT stem not only from the systemic elevation of estradiol. We now know that HRT lowers DHEA levels.119 Importantly, DHEA supplementation does not raise sex steroid levels above normal. Most of the repair and regenerative benefits of DHEA come from local (or peripheral) anabolic activity such as was recently demonstrated in Mechanisms of Ageing and Development. This important study utilizing genomic technology revealed that DHEA improves bone density, not by raising systemic levels of estradiol but through local conversion to estrone by osteoblasts.120 In other words, DHEA is converted by repair cells in the bone to estrone, which does not promote cancer, while leaving estradiol levels in the breast and uterus unchanged.
In fact, a growing number of endocrinologists are realizing that the solution to maintaining bone density in postmenopausal women was staring us in the face for more than 40 years, but the pharmceutical-based health care system ignored this natural, safe, and effective treatment in favor of prescription drugs, even though those drugs have been known to be unsafe for at least the last 15 years.
Research shows conclusively that DHEA deficiency contributes significantly to age-related bone loss in men and women.42 And a recent study with postmenopausal women demonstrates the significant ana-bolic benefits that can be obtained from DHEA supplementation. Women in the treatment group experienced improvements in virtually all anabolic (repair) hormones, including DHEA, estrone, estradiol, androstenedione, and testosterone. Importantly, none of these steroids rose to levels that would be considered unsafe. What's more, increases in osteocalcin and IGF-1 indicate that 50 mg of DHEA might be more effective in maintaining bone density than high doses of synthetic estrogen and progestins (conventional HRT). The researchers conclude:
"Our data support the hypothesis that DHEA treatment acts similarly to estrogen-progestin replacement therapy on the GHRH-GH-IGF-1 axis. This suggests that DHEA is more than a simple 'antiaging product'; rather it should be considered an effective hormonal replacement treatment."121
One final note on women's health is the ability of DHEA supplements to help balance estrogen and progesterone.
Naysayer: How can that be? DHEA is not converted to progesterone.
Stephen Cherniske: Not directly, but DHEA can raise progesterone levels by inhibiting conversion of pregnenalone to cortisol (via 17-hydroxyprogesterone).122 Thus, by any measure, DHEA appears to be a valuable and safe hormone supplement for women and men.
Naysayer: Men don't need progesterone.
Stephen Cherniske: Of course they do. And a study just published with men suffering from fatigue and depression suggests that improvements in mood, energy, and libido derived from 25 to 50 mg of DHEA resulted from increased progesterone levels, not testosterone.18
Naysayer: There's still no proof that DHEA is safe.
Stephen Cherniske: Yes, there is. You've been trying to persuade the public that safety data do not exist, when there are adequate human clinical trials, including year-long studies with as many as 300 volunteers. Listen to the conclusion of one of these studies published in the Journal of Clinical Endo-crinology and Metabolism. This is a human study with a 25-mg/day group and a 50-mg/day group:
"No accumulation of steroids was observed. No worrying transformation to androgen and estrogen was recorded; indeed, the limited increased estradiol in aged women could be predicted to be beneficial. These results suggested that daily oral administration of DHEA (25/50 mg) is safe in elderly subjects. The 50-mg dose was chosen for a 1 yr, double blind, placebo-controlled trial of daily oral administration of DHEA in 60- to 80-yr-old individuals."123
This was followed by an even larger, year-long evaluation. This landmark project, known as the DHEAge study, was published in the Proceedings of the National Academy of Science. The conclusion:
"No potentially harmful accumulation of DHEAS and active steroids was recorded . . . A number of biological indices confirmed the lack of harmful consequences of this 50 mg/day DHEA administration over one year, also indicating that this kind of replacement therapy normalized some effects of aging."124
Naysayer: Well, what about the well-known side effects that DHEA produces in women?
Stephen Cherniske: Such as?
Naysayer: Oily skin, acne, and growth of facial hair.
Stephen Cherniske: Those are overdose effects, and to produce these effects, a woman would have to take an excessive dose of DHEA for months. Importantly, these effects are obvious and sequential.
In other words, if a woman takes too much DHEA, she may experience side effects from the conversion of DHEA to testosterone. The first sign is oily skin. If she ignores this and does not reduce her dose, she may develop testosterone-related acne. If she ignores the acne and continues to overdose, she may start to see hair growth on her upper lip. Importantly, these side effects are reversible and certainly not life threatening.
Naysayer: Still, such side effects are distressing.
Stephen Cherniske: But you're talking as if side effects are common, when in fact they are rare. At the clinically effective dose of 5 to 25 mg, the incidence of androgen-related side effects is less than 2%.123 Compared to the known benefits, and the ease by which a safe dose can be determined, it is unreasonable and unscientific to harp on side effects that are rare and innocuous. Tremendous health benefits are obtainable from 5 to 25 mg of DHEA. It significantly reduces risk for diabetes and cardiovascular disease at 25 mg per day.3 These two degenerative diseases account for more than 70% of deaths in the U.S. and all you can do is wring your hands about an adverse effect that might occur at four or five times that dose.
Naysayer: Well, DHEA is sold in health food stores. People are naturally going to think that any dose is safe.
Stephen Cherniske: Aspirin is sold in convenience stores and gas stations. Aspirin can cause gastrointestinal bleeding and other side effects.
There is an absurd double standard being used here. You promote the sale and use of high-dose aspirin, which can have serious side effects, because you believe in the principle of informed choice. Yet when it comes to DHEA, you don't think people are capable of making an intelligent decision.
Naysayer: But women do not know how much DHEA they are presently producing.
Stephen Cherniske: Exactly. This is part of the education process that should be in high gear; but the exact opposite is taking place. Instead of encouraging women to measure their DHEA levels, many doctors are telling them that it doesn't matter. Instead of receiving guidance on a critically important aspect of health and wellness, patients are being misled. With what we know about the influence of DHEA on health and disease, this should be a top priority. Women with severe symptoms associated with menopause (known as climacteric syndrome) have DHEA levels that are roughly half those of age-matched controls,125 but few physicians know this.
FACT: For 70% of women, the gynecologist is the only doctor they see.
Naysayer: You keep talking about DHEA supplementation, but couldn't people just exercise and get the same benefit? After all, studies show that individuals who exercise regularly have higher levels of DHEA and IGF-1.126,127
Stephen Cherniske: I agree, but let's look carefully at this correlation. In a recent study with elderly women, DHEA and IGF-1 were directly related to daily activity, physical exercise, muscle strength, and respiratory efficiency. The authors conclude that exercise must therefore have a positive effect on anabolic hormones.128 I call this the Jack LaLanne effect, but it is important to understand that the converse is also true; that some people have a genetic ability to maintain higher levels of DHEA, which stimulates IGF-1, and this maintenance of anabolic drive is what enables them to remain active and to perform physical exercise. The vast majority of Americans do not have this genetic advantage. If people are on the "catabolic" side of life with poor exercise tolerance, telling them to "just exercise more" is unfair and unscientific. Better to improve anabolic drive via DHEA supplementation, and then go to the gym. They will suffer less and achieve better results.
Naysayer: You don't know that.
Stephen Cherniske: Yes, we do. In a study funded by the National Institutes of Health, Dr. Dennis Villareal and his colleagues conducted a double-blind, placebo-controlled human clinical trial using 50 mg of DHEA per day with a group of elderly men and women. After only six months, those taking DHEA experienced improvements in muscle mass and bone density, and a reduction in body fat.2
As I explain in my book, The Metabolic Plan, this is one of the most important keys to living a long and healthy life. As we age, most people lose muscle and gain fat. You have to understand the profound effect this has on quality of life. Beyond the aesthetic effect, which affects our self-esteem and outlook on life, the accumulation of fat and loss of muscle causes a progressive loss of functional ability and a dramatic alteration in glucose metabolism. More than 70% of obese individuals will become diabetic, and the diabetic state is like turbo-aging, producing rapid degeneration throughout the body and brain.
Continued . . .
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