FIRST THE RAGE WAS ANTIOXIDANTS, NOW IT'S...

THE
HORMONE
THERAPY
REVOLUTION

When you're young and in your physical prime, your bones, joints, and muscles are strong and resilient. Your heart responds to every stress without missing a beat. Your immune system is capable of warding off just about anything you (or anyone else) can throw at it, including cancer. And your sex life is active and fulfilling.

But gradually, imperceptibly, as the years add up to 40, 50, and beyond, things start to change. "You're getting older," the doctor tells you. "What do you expect?" Well, if you're reading this magazine, you undoubtedly expect a lot more than that doctor does. For one thing, you expect to know why you don't feel as good now as you did in your 20s. For another, you want to know what you can do about it.

The Antioxidant Revolution

The answer to the "Why?" question is extremely complex; we're just beginning to scratch its surface. One of the first important pieces of the aging puzzle to fall into place was the concept of free radical-induced destruction of cell membranes, DNA, and other vital structures. Continued destruction is thought to add up over a lifetime, making you increasingly vulnerable to breakdowns in essential systems. As we've come to understand the damaging effects of free-radical oxidation, we've learned to counter these effects with powerful antioxidants, like vitamins C and E, beta carotene, coenzyme Q10, alpha lipoic acid, and Ginkgo biloba.

It seems as though once or twice a week, yet another study is published confirming the life-enhancing benefits of antioxidant nutrient supplements. One recent article reported on the results of a National Institute of Aging (NIA) study of 11,178 people (aged 67-105 years) who took high-dose (400 IU) vitamin E supplements for 9 years. Supplement use was associated with a 27% reduction in all-cause mortality, a 41% reduction in heart disease risk, and a 22% reduction in death from cancer.¹

It's hard to argue with figures like those coming from a source like the American Journal of Clinical Nutrition. A leading editorial voice at this prestigious publication is none other than that of Victor Herbert, MD, JD, the New York physician/attorney/"vitamin expert" know-nothing who is routinely trotted out by the American news media whenever they find the need to debunk a pro-vitamin/nutrient supplement story that may find its way onto the front pages. (Herbert was on the food and drug board of the National Academy of Sciences that was dismissed by president Frank Press when they recommended that the RDAs [Recommended Daily Amounts] be decreased in opposition to the latest research findings.) It's funny, but for some reason, we haven't seen Herbert out advocating the widespread use of high-dose vitamin E supplements. He must not have gotten around to reading this article yet.

The Hormone Revolution

If antioxidants were the first significant piece of the anti-aging puzzle, the second, equally-significant piece is hormones. It's well known that the levels of several important hormones usually peak during the third decade of life (in the 20s) and then begin a slow decline that eventually ends with death.

Figure 1 shows the typical pattern for the adrenal steroid hormone, DHEA (dehydroepiandrosterone). The daily production of DHEA drops from about 30 mg at age 20 to less than 6 mg at age 80. In some people, DHEA levels decline 95% during their lifetime-the largest decline of an important biochemical yet documented. ² Similar curves could be drawn for melatonin, pregnenolone (PREG), growth hormone (GH), testosterone, and probably many others. In women, estrogen and progesterone levels remain fairly constant until the perimenopause (at age 40-50 years), when they begin a sharp decline until age 50 to 55, at which time the ovaries discontinue their production of these two hormones. (The ovaries continue to produce some testosterone after menopause, however.)

Biomarkers of Age

It's no coincidence that you could draw a similar curve to plot the general state of health of most human beings over the course of their lifetimes. These hormones play an absolutely essential regulatory role in the life of every cell in the body. It would be surprising if your body didn't start to break down as the hormonal tide begins going out in the later decades of life.

Because DHEA, melatonin, and other hormones all peak during youth and then begin a long slow decline with age, they are often considered "biomarkers" of aging. This means that, by measuring the level of these markers at any given point during a person's lifetime, it is often possible to make an educated guess as to the person's age, like counting the rings on a tree (except that hormones levels can be determined for a living person). This is all described in Dr. Ward Dean's book, Biological Aging Measurement - Clinical Applications, which was the first (and is still the only) compendium of aging measurement systems ever to be published. William Regelson, MD, who may be the world's leading expert on the varied roles of biomarker hormones in health and disease, thinks they are so important in determining how and how rapidly we age that he calls them "superhormones" in his best selling book, The Superhormone Promise. ³

It is a mistake, argues Regelson, to think of aging as a normal process. Rather, it is a disease in and of itself, and the isolated ailments we commonly associate with aging are merely symptoms of the underlying disease, which is essentially a loss of superhormones.

If Regelson is right, it's no great leap to the treatment of the disease of aging - simply restore the missing hormones to the levels they held when you were in your twenties. "Our aim is to simply replenish the hormones that occur naturally in your body and boost them back up to the appropriate, medically-sound levels necessary to maintain youthful health and vigor," writes Regelson. Just as we've been replacing estrogen in women for the last generation, he recommends an "individualized hormone cocktail" tailored to each person's unique needs at a given point in their life.

Hormone Therapy in Action

What can hormone therapy do for you? A lot depends on which hormones you may be deficient in and which symptoms of aging you experience. That's why physicians who treat people with hormone replacement therapy usually recommend that they first have their hormone levels tested. Some health care professionals, however, think that this testing is unnecessary or optional, especially for hormones such as melatonin, pregnenolone, and probably DHEA. Nevertheless, testing can highlight current deficiencies, predict future ones, and establish a baseline to help determine proper doses. A baseline also provides a gauge with which to measure treatment success. Although blood tests are the traditional means of testing hormone levels, many experts now prefer saliva testing and serial urine testing, because these tests are more accurate, more informative, and easier for the person being tested. (See LEN Issue 29, January, 1997.) Once you know your hormone levels, you can begin replenishing the hormones that are deficient. Experts like Willliam Regelson, MD, Ward Dean, MD, Jonathan V. Wright, MD, and John R. Lee, MD, all recommend that you try to bring your hormone levels back to those that would be normal for a person in their 20s or 30s. It's important that you don't take too much. Natural hormones are typically very safe, but as with anything else, including pure water, you may be adversely affected if you take too much.

DHEA: Superstar of the Superhormones

Regelson calls DHEA the "superstar of the superhormones." He points out that DHEA not only helps rejuvenate virtually every organ system, but "actually makes you look, feel, and think better." Studies have shown that taking supplemental DHEA, a steroid hormone produced primarily in the adrenal glands, may help increase your energy level, enhance your sex drive, improve your immunity to diseases - including cancer, reduce the ill effects of stress, enhance your memory and cognitive functions, decrease your body fat, and perhaps even extend your life.

In humans, DHEA levels have also been directly correlated with mortality (the probability of dying). In a 12-year study of over 240 men aged 50 to 79 years, researchers found that DHEA levels were inversely correlated with mortality from all causes. This finding suggests that measurements of DHEA levels can become a standard diagnostic predictor of disease, mortality and lifespan. Furthermore, if animal tests hold true for humans, supplemental DHEA may help prevent disease, reduce mortality, and extend life span.

DHEA and cancer

Regelson reports that Dr. Arthur Schwartz, a leading DHEA researcher from Temple University, is developing a DHEA-based anti-cancer drug that could wind up being the first anti-cancer pill. "What other scientists and I find so exciting about DHEA," writes Regelson, "is that it appears to be an entirely different type of anti-cancer drug - perhaps the ultimate cancer fighter - that is, a true anticarcinogen in that it can actually prevent the onset of this deadly disease." ³

Several studies suggest an association between DHEA levels and cancer. The most important comes from the close observation of the people of the island of Guernsey in Great Britain. Like the population of Framingham, Massachusetts, the people of Guernsey have been under constant medical observation for years. Of the 5,000 women followed in the study, 27 developed cancer, and most of these were found to have abnormally low levels of DHEA as early as nine years before it was diagnosed. In fact, every woman living on Guernsey who had a serum level of DHEA of less than 10% of the expected concentration over 10 years or more developed and died of breast cancer. ^4,5 A similar relationship was found in Guernsey women for ovarian cancer, ⁶ although this result has been contradicted by a later study in the US. ⁷

In contrast to estrogen, DHEA shows promise as an anti-cancer agent. Schwartz has found that DHEA significantly protects laboratory animals from cancers of the breast, lung, colon, liver, skin, and lymphatic tissue. ⁷ Schwartz has hypothesized that DHEA's protective mechanism may be analogous to similar protective effects produced by food restriction, which results in the compensatory or overproduction of adrenocortical steroids, including DHEA. ^8,9

According to Dr. William Regelson, "Whenever it has been tested in a model of carcinogenesis and tumor induction, DHEA has preventative effects." Human tests of DHEA in cancer are in their early stages, and it will probably be several years before we know whether the successes achieved in animals will be realized in humans.

Brain function, depression and DHEA

In one of the most dramatic behavioral effects of DHEA seen in humans, researchers at the University of California School of Medicine, La Jolla, gave DHEA to 13 men and 17 women aged 40 to 70 years. Using a randomized, double-blind, crossover experimental design, the subjects took 50 mg of DHEA (or placebo) every night for 6 months. They found "a remarkable increase in perceived physical and psychological well-being" in 67% of men and 84% of women taking DHEA compared to placebo. The participants reported increased energy, deeper sleep, improved mood, more relaxed feelings, and an improved ability to deal with stressful situations. ¹⁰ Researchers at the University of California, San Francisco, have reported that 30 to 90 mg of DHEA given to six depressed patients with low DHEA/DHEAS levels resulted in improvements in memory and mood. ¹¹

Nor are such central nervous system effects limited to the sick or the elderly. In a study of 10 healthy young men, DHEA administration induced a significant increase in rapid eye movement (REM) sleep, which is associated with memory enhancement. ¹²

DHEA (as well as pregnenolone) has been shown to enhance long-term memory in mice undergoing shock-avoidance training. Some anticipate that DHEA may be found to have similar effects on human brain function. ^{13, 14}

DHEA and heart disease

DHEA levels have a strong positive correlation with a healthier heart and lowered risks of heart disease.15 In laboratory animals, DHEA has been shown to lower cholesterol, inhibit the formation of atherosclerotic plaque by 50%, and prevent at least one kind of induced hypertension. DHEAS levels may decrease blood pressure. ¹⁶

In one study of men with healthy hearts, those who had low levels of DHEA were 3.3 times more likely to die of heart disease during the next 12 years than were those with "normal" DHEA levels. ¹⁷ In a recent update of that study, however, this protective effect of DHEA and DHEAS seemed less clear. Barrett-Conner now says that DHEA/DHEAS supplementation may be good for men, but clinical trials are needed to confirm this. ¹⁸ Regelson believes that DHEA and other superhormones are key factors in the progression of heart disease. "I do not mean to suggest that DHEA is a cure for heart disease," he says, "but what many other researchers and I now believe is that the age-related decline in DHEA levels creates an environment in which heart disease is permitted to take hold." ³

DHEA and diabetes

DHEA has been shown to increase the sensitivity of human cells to insulin. ^{19, 20} This is very important, because noninsulin-dependent (Type II) diabetes, which is the most common form, is usually characterized by the loss of sensitivity of cells to insulin. This results in abnormally high blood sugar and insulin levels, which, in turn, promotes atherosclerosis, hypertension, and other chronic illnesses. Regelson thinks that at least part of the link between diabetes and heart disease may be a relative lack of DHEA. "It seems logical to me that DHEA must somehow buffer or shield us from the harmful effects of insulin," he writes. As DHEA levels drop, its balance with insulin is upset, and the relative excess of insulin is then free to do its damage. ³

Some clinicians believe DHEA shows signs of becoming an important treatment for diabetes. Some have even reported that DHEA supplementation reduces the need for insulin in humans. However, we caution diabetics to consult closely with their doctors before using DHEA or modifying their doses of insulin or other diabetes medication.

Pregnenolone: Be Smarter and Happier

Pregnenolone (PREG) is another steroid hormone that the body normally manufactures using cholesterol as the primary raw material. It is converted into a multitude of steroids and neurosteroids. Although all these substances have been found to have intelligence-enhancing capabilities, pregnenolone seems to have truly extraordinary activity. In a recent study, ²¹ pregnenolone was found to be 100 times more effective for memory enhancement than other steroids or steroid- precursors in laboratory mice. Eugene Roberts, PhD, Distinguished Scientist at the City of Hope, and probably the world's leading expert on pregnenolone, calls this result "just amazing." Noting that just 150 molecules of PREG were required to enhance retention of the correct response in mice, Roberts contends that PREG "appears to be the most potent memory enhancer yet reported in animals."

These benefits of PREG are not just limited to mice, either. Regelson says that PREG appears to make people "not only smarter but happier." This is because evidence suggests that PREG "enhances our ability to perform on the job while heightening feelings of well-being." ³ Some of the human studies of pregnenolone date back more than 50 years. ²²

The results of other studies suggest that PREG may also have a significant ameliorative effect in people with rheumatoid arthritis. In fact, it was a primary treatment for this disease from the 1940s to 1950s, when powerful (but dangerous) synthetic cortisone and nonsteroidal anti- inflammatory drugs pushed it into the background. Other studies indicate that PREG helps reduce fatigue, especially in people under high stress. ²²

Melatonin: The Age- reversing Hormone

Melatonin is a naturally-occurring hormone produced in the body primarily by the pineal gland, which is located at the base of the brain, not far from such vital regions as the pituitary gland, the hypothalamus, and the amygdala. A significant amount of melatonin is also produced in the gastrointestinal tract under certain conditions.

Regelson, along with Walter Pierpaoli, MD, PhD, literally wrote the book on melatonin:The Melatonin Miracle, ²³ which was the spark that set off the current wildfire of interest in hormone replacement therapy. This book discusses melatonin's variety of beneficial effects, including maintaining youthful health and vigor, enhancing sexual vitality, strengthening the immune system, scavenging oxygen-free radicals, protecting against stress, protecting against cancer, preventing heart disease, restoring normal sleep patterns, curing jet lag, and of, course, extending life. While some would argue that there is no direct evidence that melatonin extends the human lifespan, it should be pointed out, first, that serious research on this aspect of melatonin has been going on for almost a decade. Second, experiments performed in animals have evaluated this question, and the results have been extremely encouraging. In one crucial study conducted by Pierpaoli and colleagues, pineal glands of young (3- to 4-month-old) mice were transplanted to old (16-22- month-old) mice. They found that the older mice, with the young pineal glands, lived 12% longer than controls. Conversely, when the pineal gland of old mice was transplanted into young mice, the life span of the young mice was shortened significantly. ^{24, 25}

Some researchers have hypothesized that aging occurs because of the slowdown in pineal secretion of melatonin. Because of the widespread integrative and regenerative effects of melatonin, its reduction or desynchronization in old age may be at least partly responsible for the onset of age-related diseases, including heart disease, Alzheimer's disease, cancer, and various degenerative processes. ^{26, 27}

Enhancing sleep

While some aspects of melatonin use are still in dispute, its sleep- enhancing ability is not. Because it helps drive the body's internal clock, melatonin can have a profound effect on sleep. It should come as no surprise that the high incidence of insomnia found in elderly people is associated with low levels of melatonin. This fact was recently confirmed by British researchers, who measured melatonin levels in 20 people (mean age, 54 years) with long-standing insomnia (mean, 18 years duration) and in matched control subjects with no insomnia. The insomniacs had significantly lower levels of melatonin. ²⁸

In a recent clinical study of melatonin's effects on sleep, a team of Israeli researchers gave tablets containing either melatonin or a placebo to a population of elderly insomniacs. The subjects who received the melatonin experienced significant improvement in their ability to fall asleep and stay asleep. ^{29, 30}

Researchers at MIT gave melatonin or placebo to volunteers and found that the melatonin decreased the time it took them to fall asleep and to reach stage-two sleep without suppressing or delaying REM sleep or causing a "hangover" the next morning. They found that the volunteers who received melatonin could clearly distinguish its effects before falling asleep. ³¹

Beating jet lag and shift work syndrome

This is the aspect of melatonin that really catches the attention of many people who travel by air a lot or who work odd hours. Jet lag occurs when your body's internal clock gets out of sync with your current environment. Your body's clock, set where you came from, tells you that it's time to sleep, but the clock on the wall says, "It's time to eat." As a result you may feel irritable, headachy, tired, even depressed.

Taking melatonin at the right time can help get you back in step after long airplane flights across several time zones, resulting in significantly faster recovery of energy and alertness. ³² If you have to take "red-eye" flights, taking melatonin at the start of the flight can help you feel awake and refreshed when you arrive.

The same time-shifting ability of melatonin comes in handy if you work nights. In a study of police officers who worked a week of night shifts, compared with those who received a placebo, those who took melatonin for seven days at their bedtime (in the morning) had slept better, were in a better mood, and were more alert during their working hours at night. ³³

Extraordinary antioxidant

For all its popularity as a sleep enhancer, no aspect of melatonin gets researchers' blood flowing so much as melatonin's extraordinary abilities as an antioxidant. If you could take only one antioxidant supplement, it should be one that could scavenge the most damaging free radical in the body, the hydroxyl (OH) radical. It should also be the one that helps protect against oxidative damage in your brain and DNA.

That antioxidant is melatonin. Notes Russell J. Reiter, PhD, of the University of Texas, Health Science Center, in San Antonio, "We've tested it in every conceivable system that we can assemble, and melatonin continues to perform as well [as] or better than any other antioxidant." Reiter and his colleagues have convincingly shown that melatonin is taken up rapidly into the brain, where it can penetrate every type of cell and has been shown to be highly effective as a scavenger for toxic OH radicals and is more effective than vitamin E in neutralizing the peroxyl free radical. This is fortunate because the brain's high metabolism and use of oxygen makes it extremely vulnerable to free-radical attack. ^34-36

Several recent in vitro studies have confirmed melatonin's ability to fight off powerful toxic antioxidants in brain tissue. These experiments have shown that melatonin can protect cells, proteins, lipids, and DNA against the toxic effects of hydrogen peroxide (H2O2), carbon tetrachloride, ionizing radiation, and some chemical carcinogens and herbicides. ^36-41 In addition to its own antioxidant activity, melatonin also helps protect the brain by stimulating neural tissue to produce glutathione peroxidase, which helps convert the endogenous oxidizing agent H2O2 to harmless water. ^34-36

Progesterone: Protection Against Cancer and Heart Disease

For women during the years just prior to and after menopause, natural progesterone can literally be a life saver. Among its most important functions are building new bone tissue and countering the tendency of estrogen to induce excess growth in the endometrial lining of the uterus. In extreme cases, this growth can turn cancerous.

One of the great fears women have as they approach menopause is osteoporosis, the disease in which bones become thinner, weaker, and prone to fracture. The most vulnerable bones include those in the hip (femoral neck), wrist, shoulder, ribs, and spine, which contain relatively large amounts of sponge-like cancellous bone. Many years of osteoporosis are responsible for the "dowager's hump" or hunch back in some elderly women, due to the fracture and subsequent compression of their vertebrae. A broken hip due to a severely weakened femoral neck too often marks the beginning of the end for many people with osteoporosis.

In women, bone mass reaches its peak during their early to mid-30s, after which it begins a slow decline at a rate of 1% to 1.5% per year until menopause. After menopause, there is an acceleration of bone loss to about 3 to 5% per year for about 5 years. Thereafter, bone loss continues at a rate of about 1.5% per year. One of the prevailing myths in US medicine today is that osteoporosis can be treated by replacing estrogen. In fact, estrogen replacement therapy may temporarily slow bone loss and may decrease the risk of fractures by as much as 50%, but it does nothing to restore bone that has already been lost. ⁴² Moreover, Dr. John Lee, who has done much of the crucial research on natural progesterone and osteoporosis, contends that even this conclusion may be questionable, because, in nearly every study that has examined the role of estrogen in preventing or slowing postmenopausal bone loss, the women also received a synthetic progestin. ⁴³

Evidence from many in vitro, epidemiologic, and clinical studies support the view that progesterone is the hormone primarily responsible for building new bone. ⁴² Lee conducted the primary study linking natural progesterone (not synthetic progestins, like the drug Provera) and reversal of osteoporosis. ^{43, 44} He treated 100 postmenopausal women (mean age, 65.2 years) for a minimum of three years with a program that included natural progesterone skin cream. Of these women, Lee was able to carry out serial bone density testing on 63. Over three years, the women would have been expected to lose about 4.5% of their bone density with no treatment. In fact, the women's bone density increased by 15.4%. Lee reports, "It was not uncommon to observe increases of 10% to 15% within six months and 20% to 25% in three years."

Lee found that advanced age was no hindrance to improved bone density, since those women who were older than age 70 had the same gains as those who were younger. The only factor that did seem to make a difference was the women's bone density at the start of therapy. Those with the lowest density at the start of treatment had the largest percentage increases after three years. Whether or not the women were also taking estrogen supplements made no difference. Progesterone treatment had no side effects, which probably contributed to a high rate of compliance, Dr. Lee notes. The cost of the progesterone cream, about 10% of the cost of an equivalent dose of Provera, was also an important advantage.

Preventing heart disease and cancer

Estrogen seems to help control lipid levels, blood pressure, carbohydrate metabolism, coagulation factors, and endothelial function. Thus, the increase in heart disease risk following menopause is thought to be due, at least in part, to a reduction in estrogen levels. Replacement of estrogen in postmenopausal women increases the levels of HDL (the "good") cholesterol and decreases levels of LDL (the "bad") cholesterol. ⁴⁵ That's the good news. The bad news is that when a woman takes estrogen by itself, she increases her risk of endometrial cancer. Estrogen is an excellent and important stimulator of cell proliferation in uterine tissue. Unfortunately, if this proliferation is not checked, it can get out of hand, possibly leading to cancer.

Nature harnesses estrogen's carcinogenic potential by "opposing" it with progesterone. Premenopausal women with normal levels of estrogen and progesterone almost never get endometrial cancer. But women who take "unopposed" estrogen (estrogen without progesterone) may have a risk of endometrial cancer that may be as much as 14% higher. ⁴⁶ The addition of a synthetic progestin to an estrogen replacement therapy regimen significantly reduces the risk of endometrial cancer. But again, there's a price to be paid. Taking a synthetic drug like Provera significantly reduces the heart-disease protection you would expect to get from estrogen. Taking natural progesterone, though, does not blunt this cardiovascular benefit of estrogen. And here's why . . .

The PEPI Trial

This effect was demonstrated most clearly in a large well-controlled National Institutes of Health (NIH)-sponsored trial carried out over three years. Known as the "Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial," its results were published in the Journal of the American Medical Association in early 1995. ⁴⁵

The participants in the PEPI trial, 875 postmenopausal women, were randomly assigned to receive either (1) placebo, (2) estrogen (Premarin), (3) estrogen plus progestin (Provera), or (4) estrogen plus natural (micronized) progesterone (an oral formulation). HDL levels in the placebo group decreased by 0.03 mg/dL, compared with their pretreatment baseline. By contrast, in those women who received "unopposed" estrogen replacement, HDL levels increased substantially over baseline to 0.14 mg/dL. By contrast, in the group that received estrogen plus Provera, the increase in HDL was nearly nullified. However, when natural progesterone was substituted for the synthetic progestin, virtually all of estrogen's HDL protection was restored (about 0.12 mg/dL). Also, both Provera and natural progesterone produced significant improvements in LDL, triglyceride, and total cholesterol levels, compared with placebo. The PEPI investigators were surprised by the superiority of natural progesterone over synthetic progesterone. Noted the prominent cardiology researcher, Elizabeth Barrett-Connor, MD, of the University of California, San Diego, "If I were treating a woman primarily because she was worried about heart disease or because she had dyslipidemia and low HDL cholesterol, I would probably see if she wanted to take micronized progesterone. I was quite impressed with the better effect." Another PEPI investigator, the former NIH head Bernadine P. Healy, MD, who is currently at the Cleveland Clinic Foundation, agreed, stating, "I think the biggest surprise certainly was the HDL effect of micronized progesterone." ⁴⁷

Strength and Vitality

The hormone revolution has just begun. In addition to these hormones, large amounts of evidence are also being collected on the benefits of natural estrogens, growth hormone, testosterone, thyroid hormone, and others. "We are truly blessed," writes Regelson, "in that for the first time in history we will be able to live out our days in strength and vitality, unhampered by sickness and debility. With superhormones we have the know-how and the ability to live out our lives the way we want, on our terms."3

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