Jeff's Lunchbreak

First of all, there's an article from Skeptic magazine, The double-blind gaze: how the double-blind experimental protocol changed science, which I highly recommend for background on understanding the importance of evidence based medicine. Here's part of the introduction of that article.

Why Double-Blind Studies?

The experience of the last forty years has shown that, for most types of medical treatments, only a randomized double-blind, placebo-controlled study can properly answer the deceptively simple question: "Does Treatment A benefit Condition B?"

Commonsense says that it's easy to tell if a treatment works--simply try it. However, in this case, common sense is wrong. Unblinded observation allows one to draw valid conclusions only in the case of "high effect size treatments." A high effect-size treatment is one that, in nearly all subjects, causes effects that lie entirely outside the range of normal variation of that subject. To test the hypothesis "will a quart of hard liquor cause drunkenness?" one would not need a double-blind study. The behavior and physiology of a person who has consumed that much alcohol are sufficiently different from the behavior and physiology of a person who has not consumed alcohol, that simple observation would be sufficient to verify the hypothesis.

A number of medical treatments fall into the high effect-size category: for example, appendectomy for appendicitis, penicillin for streptococcal pneumonia, vitamin C for scurvy, anesthetics to produce unconsciousness, and defibrillation for restoring heart function. However, for many medical treatments, the subjective and objective signs of untreated individuals overlap considerably with those of treated individuals. People who have an ankle sprain may experience a reduction of symptoms when they take ibuprofen, for example, but not the elimination of symptoms; furthermore, ankle sprain symptoms change from moment to moment and are affected by state of mind. This type of fluid, inconsistent data turns out to be very difficult to appraise accurately. Only double-blind studies are up to the job.

Confounding Factors

Subtle influences called "confounding factors" can easily create the illusion of efficacy when an ineffective treatment is used. Consider the practice of "letting blood," a technique that endured for many centuries, and reached its heyday in the 17th and 18th centuries. The medical literature of Enlightenment-era Europe is full of testimonials to the marvelous effect of slitting a vein. Today, it's clear that bleeding is not helpful, and no doubt was responsible for killing a great many people.

Why did bloodletting survive so long? Not because the people who used it were stupid, dishonest, or unobservant--the greatest minds of the time were certain that letting blood was a medical necessity. The practice endured because they saw benefits from it. If one begins with the assumption that a treatment is helpful, one is highly likely to observe benefits by using it. Such misleading observations are ensured by the following confounding factors (among others):

• The Placebo Effect
• The Re-interpretation Effect
• Observer Bias
• Natural Course of the Illness
• Regression to the Mean
• The Study Effect (Hawthorne Effect)

That article has quite a bit more information, and I'd highly recommend reading the whole thing.

Considering these confounding factors, it's very difficult to tell whether treatments are effective without doing an actual clinical trial with a control group to compare to. Given the lack of clinical studies I've seen for BHRT, I'm very skeptical of any claimed benefits relative to convention HRT.

Moving on to what people have written specifically about BHRT...

Here's a good article from the FDA. I don't normally do this, but I simply quoted their whole article since it was so good:

Bio-Identicals: Sorting Myths from Facts

"A natural, safer alternative to dangerous prescription drugs"

"Can slim you down by reducing hormonal imbalances"

"Prevents Alzheimer's disease and senility"

All of these claims have been made by marketers of compounded "bio-identical" hormones, also known as "bio-identical hormone replacement therapy" (BHRT). But these claims are unproven. FDA is concerned that claims like these mislead women and health care professionals, giving them a false sense of assurance about using potentially dangerous hormone products.

FDA is providing the facts about "BHRT" drugs and the uncertainties surrounding their safety and effectiveness so that women and their doctors can make informed decisions about their use.

"BHRT" is a marketing term not recognized by FDA. Sellers of compounded "bio-identical" hormones often claim that their products are identical to hormones made by the body and that these "all-natural" pills, creams, lotions, and gels are without the risks of drugs approved by FDA for menopausal hormone therapy (MHT). FDA-approved MHT drugs provide effective relief of the symptoms of menopause such as hot flashes and vaginal dryness. They also can prevent thinning of bones. FDA has not approved compounded "BHRT" drugs and cannot assure their safety or effectiveness.

During menopause, a woman's body produces less of the hormone estrogen, which may lead to hot flashes, vaginal dryness, and thin bones. MHT drugs contain estrogen or a combination of estrogen and another hormone, a progestin. FDA-approved MHT drugs are sold by prescription only, and FDA advises women who choose to use hormones to use them at the lowest dose that helps, for the shortest time needed.

Some "BHRT" drugs are compounded in pharmacies. Traditional compounding involves combining, mixing, or altering ingredients by a pharmacist, according to a prescription from a licensed health care professional, to produce a drug that meets an individual's special medical needs. FDA considers traditional compounding to be a valuable service when used appropriately, such as customizing a drug for someone who is allergic to a dye or preservative in an FDA-approved medicine. But some pharmacies that compound "BHRT" drugs make unsupported claims that these drugs are more effective and safer than FDA-approved MHT drugs.

FDA is taking action against pharmacies that make false and misleading claims about "BHRT" drugs and is encouraging consumers to become informed about these products and their risks. Here is some information to help sort the myths from the facts:

Myth: "Bio-identical" hormones are safer and more effective than FDA-approved MHT drugs.

Fact: FDA is not aware of any credible scientific evidence to support claims made regarding the safety and effectiveness of compounded "BHRT" drugs. "They are not safer just because they are 'natural,'" says Kathleen Uhl, M.D., Director of FDA's Office of Women's Health.

Drugs that are approved by FDA must undergo the agency's rigorous evaluation process, which scrutinizes everything about the drug to ensure its safety and effectiveness—from early testing, to the design and results of large clinical trials, to the severity of side effects, to the conditions under which the drug is manufactured. FDA-approved MHT drugs have undergone this process and met all federal standards for approval. No compounded "BHRT" drug has met these standards.

Pharmacies that compound these "BHRT" drugs may not follow good drug manufacturing requirements that apply to commercial drug manufacturers. Compounding pharmacies custom-mix these products according to a health care professional's order. The mix contains not only the active hormone, but other inactive ingredients that help hold a pill together or give a cream, lotion, or gel its form and thickness so that it can be applied to the body. It is unknown whether these mixtures, which are not FDA-approved, are properly absorbed or provide the appropriate levels of hormones needed in the body. It is also unknown whether the amount of drug delivered is consistent from pill to pill or each time a cream or gel is applied.

Myth: "Bio-identical" hormone products can prevent or cure heart disease, Alzheimer's disease, and breast cancer.

Fact: Compounded "BHRT" drugs have not been shown to prevent or cure any of these diseases. In fact, like FDA-approved MHT drugs, they may increase the risk of heart disease, breast cancer, and dementia in some women. (See www.nhlbi.nih.gov/whi/index.html for information on the Women's Health Initiative, a large, long-term study that tested the effects of FDA-approved MHT drugs.) No large, long-term study has been done to determine the adverse effects of "bio-identical" hormones.

Myth: "Bio-identical" hormone products that contain estriol, a weak form of estrogen, are safer than FDA-approved estrogen products.

Fact: FDA has not approved any drug containing estriol. The safety and effectiveness of estriol are unknown. "No data have been submitted to FDA that demonstrate that estriol is safe and effective," according to Daniel Shames, M.D., a senior official in the FDA office that oversees reproductive products.

Myth: If "bio-identical" products were unsafe, there would be a lot of reports of bad side effects.

Fact: "Bio-identical" products are typically compounded in pharmacies. "Unlike commercial drug manufacturers, pharmacies aren't required to report adverse events associated with compounded drugs," says Steve Silverman, Assistant Director of the Office of Compliance in FDA's Center for Drug Evaluation and Research. "Also, while some health risks associated with 'BHRT' drugs may arise after a relatively short period of use, others may not occur for many years. One of the big problems is that we just don't know what risks are associated with these so-called 'bio-identicals.'"

Myth: A pharmacy can make a "BHRT" drug just for you based on hormone levels in a saliva sample.

Fact: "Advertisements that a drug can be created 'just for you' based on saliva testing are appealing," says Uhl, "but unrealistic." Hormone levels in saliva do not accurately reflect the amount of hormones a woman has in her body for the purpose of adjusting hormone therapy dose levels. A woman's hormone levels change throughout the day, and from day to day. FDA-approved tests can tell a woman's hormone level in a specific body fluid, such as saliva, blood, or urine, at that particular point in time. "These tests are useful to tell if a woman is menopausal or not," says Uhl, "but they have not been shown to be useful for adjusting hormone therapy dosages."

Myth: FDA wants all compounded hormone therapies off the market.

Fact: "We are not trying to pull all compounded hormone therapies off the market," says Silverman. "We believe that, like all traditionally compounded drugs, a woman should be able to get a compounded hormone therapy drug when her physician decides that it will best serve her specific medical needs. But we also want women to be informed and careful about choosing products that have not been proven safe and effective. And pharmacies cannot promote compounded drugs with false or misleading claims."

In addition, FDA has not approved any drug containing the hormone estriol. Pharmacies should not compound drugs containing estriol unless the prescriber has a valid investigational new drug (IND) application. INDs provide benefits that include allowing physicians to treat individual patients with drugs that are not FDA-approved, while also providing additional safeguards for patients.

Myth: All women who take FDA-approved MHT drugs are going to get blood clots, heart attacks, strokes, breast cancer, or gall bladder disease.

Fact: Like all medicines, hormone therapy has risks and benefits. For some women, hormone therapy may increase their chances of getting these conditions. However, there are no convincing data that there is less risk of developing a blood clot, heart attack, stroke, breast cancer, or gall bladder disease with a "BHRT" product. Women should talk to their health care professional about taking hormones. If you decide to use MHT drugs for menopause

• use at the lowest dose that helps
• use for the shortest time needed

If you are taking a compounded "BHRT" drug now, talk to your health care professional about treatment options to determine if compounded drugs are the best option for your particular medical needs.

This article appears on FDA's Consumer Updates page, which features the latest on all FDA-regulated products.

Updated: April 8, 2008

Peer-reviewed assessments of the evidence for and against BHRT point to a lack of consensus, stemming from a dearth of randomized controlled trials. A 2006 literature review concluded that BHRT is "well tolerated, provides symptom relief, and can address many of the health needs as well as the individual preferences of menopausal and perimenopausal women" [1]. A subsequent review (2009) assessed 200 studies and concluded that there was evidence to suggest bioidentical hormones were safer and more effective than synthetic hormones.[9] It should be noted, however, that while both reviews appeared in peer-reviewed journals, the authors are prominent advocates of BHRT, with potential conflicts of interest. The author of the first review, Deborah Moskowitz, has been associated with a manufacturer of bioidentical hormone preparations [2], while the author of the second is Dr. Kent Holtorf (bio) a prominent natural/bioidentical hormone advocate.

Another 2008 review concluded that there was little evidence to support the use of compounded hormone products based upon saliva testing, and that individualized compounded hormone products have no proven advantage over conventional hormone therapies.

Here's an excerpt from an article by the Mayo Clinic.

There's a lot of interest in bioidentical — or so-called "natural" — hormone therapy for menopause symptoms. However, there's no evidence that bioidentical hormones are safer or more effective than standard hormone replacement therapy.

Here's a bit more from the same page, just a little further down.

According to the North American Menopause Society (NAMS), custom compounds may provide certain benefits, such as individualized doses and mixtures of products and forms that aren't available commercially. However, they may also pose risks to consumers. These compounds haven't been approved by the Food and Drug Administration (FDA) and as a result haven't been tested for purity, potency, efficacy or safety. These products may even contain unknown contaminants. For this reason, NAMS does not recommend these custom-mixed products over well-tested, government-approved commercial products for the majority of women.

Here are a few paragraphs from an article from a Harvard Women's Health Watch newsletter.

Many women assume that “natural” hormones would be better or safer — but the term “natural” is open to interpretation.

Any product whose principal ingredient has an animal, plant, or mineral source is technically natural. It doesn’t matter whether the substance is ground, put into capsules, and sold over the counter — or extracted in a laboratory, manufactured by a pharmaceutical company, and made available only by prescription. For example, the soy plant is the source of supplements that some women take to ease menopausal symptoms; it’s also used, along with yams, to make the estrogen in the FDA-approved hormone drug Estrace.

But unlike Estrace, soy supplements aren’t regulated and haven’t been rigorously tested in humans, so we don’t know whether they’re safe or effective. There’s some evidence that certain soy components may actually stimulate breast tumor growth. So “natural” doesn’t necessarily equal “safe” — and may simply be a euphemism for “unregulated.”

Here's more from the same page.

Are bioidenticals safer? No one knows. Studies have shown they can help relieve hot flashes and vaginal dryness, but as yet, few large studies have investigated the differences among the various hormones and methods of administration. More research is needed to further understand these differences and compare the risks and benefits.

Women taking bioidentical estrogen who have a uterus must still take an FDA-approved progestin or micronized progesterone to prevent endometrial cancer. So-called natural, plant-derived progesterone creams sold over the counter contain too little of the hormone to be effective. And yam extract creams don’t help because your body cannot convert them into progesterone.

Here's even more from the same page.

Much of the confusion about bioidentical hormones comes from the mistaken notion that they must be custom-mixed at a compounding pharmacy. But custom compounding is necessary only when a clinician wants to prescribe hormones in combinations, doses, or preparations (such as lozenges or suppositories) not routinely available — or to order hormones not approved for women, such as testosterone and DHEA. Compounding pharmacies use some of the same ingredients that are made into FDA-approved products, but their products are not FDA-approved or regulated.

One size doesn’t fit all in women’s health. Compounded hormones can certainly help to individualize treatment, but if you’re considering them, be aware of the following:

• Compounded drugs are mixed to order, so there are no tests of their safety, effectiveness, or dosing consistency.
• There is no proof that compounded hormones have fewer side effects or are more effective than FDA-approved hormone preparations.
• Some clinicians who prescribe compounded hormones order saliva tests to monitor hormone levels. Most experts say these tests are of little use because there’s no evidence that hormone levels in saliva correlate with response to treatment in postmenopausal women.
• There is no scientific evidence that the compounded preparations Biest and Triest, which are largely estriol, are safer or more effective than other bioidentical and FDA-approved formulations. Some proponents claim that estriol decreases breast cancer risk and doesn’t increase endometrial cancer risk. Both claims are unproven.
• Heath insurers don’t always cover compounded drugs.

This doesn’t mean that you shouldn’t consider compounded hormones. Just realize that, in a real sense, you’re going to be an experiment of one. Unless your clinician has considerable experience with bioidentical hormones and a particular compounding pharmacy, you’re better off with a prescription for commercially available hormones, many of which are bioidentical.

And finally, here's the conclusion from that page.

The risk of any hormonal product depends on more than how the hormone is made. That’s why it’s important to work closely with a clinician to decide what’s right for you. If your symptoms are bothersome, discuss your options with a physician or other specialist in menopausal health. To learn more about menopause and bioidentical hormones, visit the Web sites of the Association of Women for the Advancement of Research and Education Project (Project Aware), www.project-aware.org, and the National Women’s Health Information Center, www.4woman.org/menopause.

One of the odd claims I found repeated numerous times in sources promoting BHRT is that bioidentical hormones aren't profitable for drug companies because they're not patentable. Here's an example of such a claim.

This occurs primarily because studies are usually funded by pharmaceutical manufacturers, who profit by selling patented synthetic hormones. Bio-identical hormones, which are chemically identical to hormones produced naturally in the human body, are not patentable.

This claim is easily put to rest by examining just how many commercially available hormones are bio-identical (see Wikipedia). There's Estrace, Alora, Climara, Esclim, Estraderm, Vivelle, and many others. Obviously, these manufacturers are finding a way to make a profit off of bio-identical hormones. To tell the truth, I'm not sure if bio-identical hormones can't actually be patented. To look at another chemical in our body, genes can certainly be patented. So, there's no barrier to patenting hormones just because they're part of our body. But I guess it depends on which hormones specifically you're talking about, and whether their chemical structures are already in the public domain.

It's a bit silly to claim that manufacturers can only make a profit off of a patentable item. For one thing, manufacturing processes and uses can sometimes be patented even when the item itself isn't patentable. A patent on a manufacturing process could be enough to eliminate competition for a bioidentical hormone if it was the most economical way to produce it. For another, we buy non-patentable products every day, and those manufacturers are certainly profiting by it. Just looking at my desk as I'm typing this, I have a mug, pens, pencils, paper, index cards, binders, bolts, paper clips, etc. Patented items are obviously not the only items that manufacturers sell.

Anyway, like I already said, the data's not there yet to support claims that BHRT is safer than conventional HRT, and in fact it appears to carry similar risks. Whether or not the risk of HRT is worth it is up to the individual patient, but patients definitely shouldn't be buying into the claims of BHRT proponents and assuming that BHRT is safer.