Consider the woman who reads that bio-identical hormones may be useful for her menopausal symptoms.  She goes to see her doctor, who states he has seen nothing in the medical press to support it, and that the medical literature considers natural hormones to be dangerous.

What if the medical literature has been manipulated?  What if her doctor, in good faith, did not find a diversity of opinion because publications placed by professional ghostwriting firms had “crowded out” authentic scientific debate.

Attached to this blog are the hearings Sen. Charles Grassley’s committee on medical ethics.  They document unregulated medical ghostwriting.  While many journals and medical schools now have regulations for disclosure, loopholes remain.

The ghostwriting process was simple: drug companies identified medical authorities who were predisposed to their point of view.  A medical ghostwriting company was hired to produce a review of the literature favoring pharmaceutical firms’ points of view.   If the ghostwriting firm could not place the article in one journal, it rewrote it and submitted it to another. There was no disclosure of the real authorship or origin of the article.

So when the family physician, made curious by his patient’s request, surveyed the medical literature, he cannot find anything except negative reviews.

The effects of crowding out are not benign.  The first documented episode of crowding out had to do with the safety of Vioxx.  While there were rumors about heart attacks, references were hard to find. When the FDA reviewed a special Vioxx study (VIGOR) it resulted in a warning to Merck “Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions. Because of the crowding out, a similar arthritis drug –Celebrex – which had no major cardiac risk, was perceived by the public to also be dangerous.  A risky drug remained on the market longer than it should, and a safer medication was underutilized for years after.

Before one concludes that only big pharmaceutical firms are at fault, the Federal Trade Commission has taken up regulation of fraudulent claims in the nutraceutical and supplement industry.  This has already led to such food giants Nestlé and Dannon scaling back claims for benefits for probiotic yogurts.    Since supplement companies can command massive advertising budgets, yet another form of crowding out may be taking place.

However, on Sept. 28, 2010, The Federal Trade Commission charged Los Angeles-based POM Wonderful with over-hyping its products by making false and unscientific claims that they can prevent or be used to treat disorders ranging from erectile dysfunction, to prostate cancer, and heart disease.

The FTC issued an administrative complaint charging the makers of POM (pomegranate) supplements with making misleading claims about its products, thus violating federal law.

The statements by large pharmaceutical and supplement companies that flood the media and internet must be viewed with a degree of healthy skepticism.  A large component of our practice is researching pharmaceutical and supplement claims.

Senate Hearing Link:

http://finance.senate.gov/newsroom/chairman/release/?id=af4af834-3fab-4293-be6d-ca7f1246484f.

There has been a major shift in federal policy on nutritional supplements.  The Federal Trade Commission, which regulates truth in advertising, is requiring scientific proof of advertised claims. Normally the Food and Drug Administration evaluates scientific evidence, and the Federal Trade Commission regulates blatant fraud, such as snake oil, counterfeit products, and credit card scams (beware the “first month free” offer).

The FTC has teeth, including the power to freeze assets, websites, and call in the Justice department. This has led to companies as large as Nestlé and Dannon to change their claims for probiotic yogurt and other foodstuffs.

The Pomegranate Seed is Full of Red Juice

The P O M pomegranate brand has come under special scrutiny for disregarding scientific literature in making its claims (in articles in Forbes, and L A Time) .  In 2009, an article was published in the Journal of cardiology documenting 190 research subjects did not experience any benefit from 18 months of pomegranate juice ingestion.  That was the bottom line. In an effort to rescue the project, the research team identified a group of patients at higher cardiac risk to have less atherosclerotic progression.

However, there is no statistical validation for cherry picking a patient group.  Example: we treated a million people and then went back and found ten who got better – how do you know they would not have gotten better without treatment?  The research was funded by the Corporation, which continue to advertise significant benefits, even though it should have known better. Look for fewer boisterous claims from other manufacturers and a lot more fine print on those that are made.

Bio-identical hormone replacement is one of the most complex areas of medicine.  If one reads Suzanne Summers book Ageless, one might assume that one could use hormone creams and have fabulous predictable results. John Lee, M.D., and Jonathan Wright, M.D. pioneered the concept of hormone replacement. Lee treated progesterone as a cure-all – it isn’t.  Wainwright chose to use a combination of three hormones – Triest – one of which, estrone, is actually toxic.

Estrogen is both good and bad for postmenopausal women.  It reduces osteoporosis and menopausal symptoms. But many scientific questions are hardly settled. One study of retired nurses showed that those women who had the naturally highest level of estrogen (ie without any replacement) had the highest number of estrogen positive breast tumors.  In contrast, women with previous hysterectomies in the Women’s Health Initiative who were treated with estrogen for an average of seven years,  were 18% less likely to develop breast cancer.  So do we conclude that high estrogen is hazardous, or that seven years of estrogen, while beneficial, may not be a long enough to show harm?

Are we asking the right question about hormonal risk and benefit for menopausal women? Most of the cancer risk is related to estradiol. Conventional bio-identical hormone replacement uses estradiol  (and adds progesterone to nuetralize estrogens bad effects). But recent science shows that estrogen does good or ill through two receptors.  Stimulation of the alpha receptor is carcinogenic.  Stimulation of the beta receptor protects against breast cancer.  So a by keeping beta stimulated and alpha unstimulated, the risk of cancer is reduced. Newer replacement regimens keep beta stimulated with soy protein, vitamin B, broccoli, and testosterone. In some cases, no estrogen is necessary.

Rather than focusing on limiting the symptoms of menopause versus the risk of breast cancer, would the focus on limiting menopausal symptoms versus the risk of heart disease be better? The risk of a 50-year-old woman dying of heart disease is 1000% higher than dying of breast cancer, and exercise reduces the risk of both.   Using hormone replacement as a component of an exercise and diet program aimed at reducing the risk of heart disease will make comparative rise in the risk of breast cancer less consequential in comparison to risk of dying of heart disease.

Hormonal replacement concepts are evolving, and receptor behavior is a crucial addition because decisions involving long term metabolic programs can never be black and white. But each shift in the odds allows clearer discussion of quality of life along with quantity of life. Medically responsible interventions must be tailored to the individual’s unique health needs and understanding of risk versus benefits. I will revisit this topic several times in the next few weeks. For the moment, the addition of receptor activity modulation to bio-identical hormone replacement changes the equation to give patients more options.

There was a remarkable study published in 2009 on cancer and mushrooms. One might think medieval alchemists had converted dross into gold. More than 50% decrease was claimed for some groups.

Portobello Mushroom

However, further investigation into the mushrooms, one being the button mushroom – Agaricus bisporus – also called portobello – by  the City of Hope – for activity against recurrent breast cancer in postmenopausal women showed minimal results.  In what should have been a home run,  the trial showed no significant change in the cancer causing hormone that was the target. The epidemeologists and biochemists were in profound disagreement.

Shitake Mushroom

The other mushroom of note, the “fragrant” shiitake mushroom was evaluated to fight small cell lung cancers. It provokes an immune response against cancer.  The study tested increasingly higher doses of the shiitake extract against the inflammatory protein interleukin – 12.  While interleukin-12 decreased, the authors admitted that their strongest concentration of shiitake was not even in the ball park to have  a clinical effect.

Was the problem in the original epidemiological study? Careful analysis shows it was biased in many ways.  Chinese women only have 20% of the American rate of breast cancer  – so an error counting even a few cases can produce large errors in conclusions. The statistic chosen by the researchers – the “odds ratio” – amplifies the results of that type data.   The breast cancer group was interviewed in the hospital after their surgery. Being told you have cancer may affect your memory of the “preventive” foods that didn’t work.  Better if the researchers had surveyed the homes for supplies of mushrooms – beats memory every time. The women who consumed fewer mushrooms also were exposed to more cigarette smoke and had lower levels of education, known risks for cancer. Lastly, the researchers set up arbitrary levels of consumption (one group consumed 11 times the amount of mushrooms) rather than a progressive scale, such that they generated great statistics but ignored the principle of dose-response.

So what does this say about mushrooms and cancer?  They still might be very useful, but we just don’t know. Bad design leads to ambiguity, though sometimes great headlines. Many illnesses are a multi-step process. Vascular inflammation (heart attacks, strokes) has a wealth of data identifying  steps where intervention can work. In our practice, we use medications, supplements,  diet, and exercise to reduce its inflammation in a stepwise fashion. Headlines, whether negative (such as about niacin recently) or positive (mushrooms) rarely communicate the complexity of the process, and fail to provide guidance to individual patients.

The M.  D.  Anderson Hospital reported that administration of Celebrex, an arthritis medication, reduced the amount of precancerous markers in smokers.  This finding was reiterated by Sloan-Kettering this year. The original study was not structured to go on long enough to see if the Celebrex group got fewer lung tumors.  However, there is experience with lung tumor markers in those who have stopped smoking to indicate that when the marker goes down, the tumors decrease.  This will lead us to a discussion of the inflammation theory of aging, but first we have to clear up some old Celebrex issues.

Celebrex and Vioxx were released in 1999.  Reports of excessive heart attacks resulted in Vioxx being removed from the market in 2004.  Because Vioxx and Celebrex have a similar chemical action, the M.D. Anderson study was suspended for three years to investigate the safety of Celebrex.  Analysis of the data showed that Vioxx produced three times the number heart attacks than Celebrex – that the group of patients taking Celebrex actually had fewer heart attacks than the group of patients taking no medicines.

The inflammation theory of disease postulates that all our major chronic diseases – arthritis, cancer, heart disease, and dementia – start with small amounts of inflammation that go unchecked.  Further, if one could apply small amounts of anti-inflammatory foods or medications in the right amount at the right time, such chronic diseases could be prevented.  So Celebrex, designed for joint inflammation, may reduce lungs tumors. Statin drugs, which reduce vascular inflammation, also reduce colon cancer. These crossover effects are promising but still speculative. Stay tuned for my next blog on mushrooms reducing breast cancer, where the links in the chain are more evident.

All Sneakers are Not Alike

There is a new type of sneaker on the market – Shape Ups, MBT’s, and Easy Tones.  They are easily recognized because the sole is extra thick, rounded, and the heel is missing.  This forces the wearer to adopt a rolling motion when walking.  This would, in theory, make the wearer expend more calories per stride.  However, the overall effect is the same as if one had unstable ankles.  I doubt anyone could sell a shoe if they said it was the Unstable Ankle Shoe.  But the lure of stronger back, firmer legs and tighter abdomen, not to mention the internet buzz about shapely calves and a tighter butt, is enticing. However, since low intensity exercise can suppress appetite I felt obligated to research Toning Shoes as a low intensity alternative.  Also, at anywhere from $100-$245, one could purchase several pairs of high quality sneakers for the same price for regular exercise.

The Exercise and Health Program at the University of Wisconsin in La Crosse, Wisconsin did extensive testing on the shoes.  The manufacturers are correct in that walking on unstable ankles forces one to shorten stride and walk more upright.  However, the amount of extra calories consumed is miniscule.  When oxygen consumption was measured by the Wisconsin team using VO2 equipment similar to what we use at Age Management Boston, there was no meaningful difference.  Similarly, the contention that something you wear on your foot will change the muscle tone of your rear was also refuted.  The Wisconsin team measured electrical discharge from leg muscles up to the lower back during exercise with both normal sneakers and toning sneakers.  There was no difference.  In practice, the best way to develop the gluteus maximus (the butt) is with sprinting motions, such as bicycle sprints, or running uphill.  Deep squats also develop the same muscles, but create excessive strain on the back, hips, and knees, and are not recommended. Lastly, since the toning sneakers create ankle instability, they should be avoided by anyone with ankle, knee, or hip arthritis. My conclusion is they tone the wallet more than the body.

The Harvard School of Public Health has completed a study that demonstrates that the selection of foods, rather than total calories, drives long term weight gain in adults.  Among those who gained weight, the most offending substances, in order, were potato chips, potatoes, sugar sweetened beverages, and red meats.  The average weight gain was 3 1/3 pounds per four years. Conversely, among those who maintained a stable adult weight, the most beneficial foods were, in order, yogurt, nuts, fruits, whole grains, and vegetables.

Before you reach for the bag of trail mix – a concoction of yogurt covered nuts and fruit (and a little chocolate), as a means of preventing adult weight gain, there are a few cautions.  Exercise had twice the benefit of any of the beneficial foods. So hold the pure trail mix diet. Neither the eating pattern nor the exercise patterns in patients with stable weight gain are detailed in the prerelease publicity for the study. One of the authors commented that the beneficial food group was significantly higher in fiber and that may have a lot to do with the conclusions.

On the other hand, Oprah Winfrey once characterized potato chips as her drug of choice.  Please look forward to the June 23 issue of the New England Journal of Medicine (nejm.org)