Bioidentical Hormone Replacement Therapy Under Attack

By Jeff Morris

Americans face yet another imminent threat to their right to healthcare choice. On October 6, 2005 , pharmaceutical giant Wyeth ( Madison , NJ ) filed a “citizen petition” with the FDA, seeking “actions to counter flagrant violations of the law by pharmacies compounding Bio-Identical Hormone Replacement [BHRT] therapy drugs that endanger public health.” If successful, this will have significant implications for the treatments doctors can prescribe, the substances pharmacists can compound, and the treatments patients can receive.

The petition states, at the outset, that it requests the Commissioner of Food and Drugs “take the actions specified below to address issues related to the growing, unlawful manufacture and marketing of so-called ‘bio-identical hormone replacement therapies’ (‘BHRT’), which are available from numerous compounding pharmacies throughout the United States . It is important to note that this petition is not directed in any way at those pharmacies which satisfy legitimate patient needs by compounding individual products for individual needs that cannot be met by an FDA-approved product.” The petition goes on to state that “Wyeth is a leading manufacturer of FDA-approved estrogen-containing hormone therapy (‘HT’) drug products and is a leader in women’s health.”

“Wyeth is the the largest manufacturer of animal derived hormone,” says Steven Russell, R.Ph., President and CEO of Medaus Pharmacy, Inc. of Birmingham , AL , one of the leading compounding pharmacies in the country. “What is occurring now, is that Wyeth’s sales have plummeted over the years because there has been more of an outcry from the public since the Women’s Health Initiative, and many physicians have investigated the use of bioidentical hormone therapy.” In late May 2002, the Women’s Health Initiative (WHI), the largest study ever conducted on hormone replacement therapy (a 16,600-patient study which lasted over five years but was supposed to continue until 2005) was abruptly halted after researchers said the newly identified risks of taking Prempro outweighed its benefits. Prempro, Wyeth’s hugely popular hormone replacement drug, was taken by millions of women to replace two hormones lost at menopause, thereby reducing the incidence of post-menopausal symptoms such as hot flashes, night sweats and vaginal dryness. But women using Prempro had a 26% higher risk of breast cancer than those taking a placebo, and though it was shown to lower the risk of colon cancer and hip fracture, Prempro raised the number of strokes by 41% and the number of heart attacks by 29%. Study directors advised participants to stop taking the Wyeth medicine and questioned whether other women should continue filling their prescriptions.

Bioidentical hormones are substances with the exact same molecular structure as those made in the human body, and produce the same physiologic responses as the body’s natural hormones. The FDA considers bioidentical hormones to be natural regardless of their source, and as a result, they cannot be patented. Bioidentical hormones that are plant derived have been available for over 20 years. It is these substances that Wyeth’s petition seeks to drive from the marketplace.

“The differences are several-fold,” notes Russell. “First off, Premarin is a patented, brand name product derived from pregnant horse urine (thus the name, ‘pre-mare urine’). Bioidentical hormones are identical to what the human body produces; there is no difference whatsoever. Premarin is not identical, and has numerous side effects. So a physician has the option of prescribing a product that has not been proven to cause adverse reactions like stroke. They are non-patented, and can be compounded by a licensed pharmacist. Bioidentical hormones are derived from plant sources, as are 60 to 70 percent of most medicinals. The end product is 100 percent identical to what the ovaries produce.”

Russell adds that in the Wyeth petition, “they do not even mention that it is the physician’s choice to prescribe this; they contend it is the pharmacist trying to push it down the consumer’s throat. So the only way they can attack is to have a ‘citizen’s group’ petition the FDA to take this off the market. In this petition they flat out requested an injunction against the ability to market this alternative.” Russell says that any prescription written has to meet the guidelines of state boards of pharmacy, as well as federal guidelines. And, he explains, each of the ingredients of bioidentical hormone replacement therapy is approved: “They are recognized by insurance companies, there are no restrictions on them, so to state it is ‘untested and unfounded’ is ludicrous, because there are drug companies that have been producing these components for years. In a nutshell, if this comes to pass, no physician or pharmacist will be able to prescribe or compound bioidentical hormone therapy. The overall danger is no freedom of choice; it would close the door for females to have any options whatsoever.”

Eldred Taylor, M.D., Assistant Clinical Professor of OB/GYN, Emory University , and Director of the Women’s Wellness Group, says that he and others are attempting to counter the Wyeth action. “We’re trying to organize a little grassroots effort to petition the FDA,” he says. “Wyeth has all these organizations backing them that are financially supported by them. It looks impressive, but most of the members are financially tied to these people—so the only motive they have is maintaining that financial source. It damages the credibility of some of these so-called ‘experts’ to support this, when the WHI has shown that there’s a problem.”

Another thing, Dr. Taylor points out, is that in fact, “the way I recommend using bioidentical hormones is, you test for deficiencies in hormones and you correct those deficiencies. I’m using the body’s natural tendencies as a guide, just like you would for potassium and insulin—you test for the low range and give supplementation to bring it back to the normal range. If I’m testing for hormones and see there’s a deficiency, and use these to bring the patient back to a normal level, I don’t see that I need permission; I don’t need a double-blind study to simply bring hormones back to their normal levels. These are not drugs; we know what progesterone does to the body. We don’t have to prove what a bioidentical hormone does, because it is not foreign to the body—yet they want the FDA to approve something that the body makes!” Unlike bioidentical hormones, products manufactured by Wyeth and others, says Dr. Taylor, are “artificial and foreign to the system. In 1973 they did a study to see if they gave Premarin to men if it would increase their heart attack risk; we had known for years that estrogen causes more clotting. We totally forget what physiology has told us, and then we say we’re surprised. But physiology doesn’t change; progesterone will always do what it always does. The problem for Wyeth is there’s been too much of a swing—the WHI hurt them badly.” But Dr. Taylor notes that the Wyeth petition is a threat, because in the past, “the FDA has been very tightly tied to our pharmaceutical industry.” Doctors who support Wyeth “are trying to change their beliefs to make the drugs sound better,” says Dr. Taylor. “They’re trying to come up with new physiology to restore their market, and killing off the competition is one of the methods.” But, he points out, “If you look at the compliance studies of Premarin, usually after two years patients drop it—it’s not terribly well tolerated.”

“This shouldn’t even be Wyeth’s fight,” contends Russell, pointing to its product safety record. “Why is Premarin still out there? Through lobbying and influence–peddling; that product should have been pulled off the market years ago.” Wyeth’s pharmaceutical product line currently includes Premarin® (conjugated estrogens tablets, USP), Premphase® (conjugated estrogens/medroxyprogesterone acetate tablets), and Prempro™ (conjugated estrogens/medroxyprogesterone acetate tablets). Wyeth markets Premarin and Prempro for use after menopause to reduce moderate to severe hot flashes; to treat moderate to severe dryness, itching, and burning, in and around the vagina; and to help reduce chances of osteoporosis; Prempro is for women with a uterus. Premarin is also marketed in a Vaginal Cream specifically to treat dryness, itching, and burning, in and around the vagina due to menopause. All of these products carry a “Black Box Warning”:

Important Safety Information

What is the most important information you should know about PREMARIN (estrogens), PREMPRO (a combination of estrogens and a progestin), or PREMARIN Vaginal Cream (a cream of estrogens)?

• Estrogens increase the chances of getting cancer of the uterus.

Report any unusual vaginal bleeding right away while you are using these products. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your health care provider should check any unusual vaginal bleeding to find out the cause.

• Do not use estrogens with or without progestins to prevent heart disease, heart attacks, strokes, or dementia.

Using estrogens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer, and blood clots. Using estrogens, with or without progestins, may increase your risk of dementia, based on a study of women age 65 years or older. You and your health care provider should talk regularly about whether you still need treatment with estrogens.

By the time of the WHI announcement in 2002, the consumer watchdog group Public Citizen had warned for years that women should take female hormone replacement drugs only for short-term use because of their dangerous potential side effects, including blood clots that can cause heart attacks. “Hopefully we will start to see a very rapid decrease in the number of women who are routinely prescribed hormone replacement therapy long term, at least the women who were defined by this study,” a spokesman for the group said at the time. On the Web site www.truthaboutpremarin.com, site editor Sonja Eick notes:

Premarin contains the following equine estrogens - estrone sulfate (53-61%), equilin sulfate (23-30%) equilenin, 17 a-dihydroequilin, 17 a-estradiol, 17 a-dihydroequilenin and numerous other horse estrogens. Not one of these ingredients are ever found in a woman. Premarin also contains numerous unidentified substances which also have unknown side-effects. Premarin has more of an effect on the liver than non-horse estrogens do. Equine estrogens are many times more potent than a woman's estrogen and may be the cause of many unpleasant and sometimes life-threatening side effects some women have experienced such as: blood clots, breast and uterine cancer, and growth of uterine tumors.

Besides the consequences for women, disturbing allegations of the mistreatment of pregnant mares used to produce the drug abound, as do charges that some 40,000 foals are slaughtered annually as a direct result of Premarin production.

The techniques now being used in an attempt to curtail bioidentical hormone use are nothing new. Russell notes that Wyeth in particular has a history of attacking any company that threatens its market share. “They usually do this through ‘citizen’s petitions’ by raising issues with numerous different organizations for lobbying the FDA.” Wyeth attorneys have long fought to preserve the company’s marketing monopoly by keeping generic equivalents of Premarin off the market, using the same tactics. On November 30, 1994 , Wyeth-Ayerst submitted a citizen petition requesting, among other things, that FDA not approve any generic conjugated estrogens products that do not contain the compound sodium D8,9-dehydroestrone sulfate (DHES). Wyeth-Ayerst also submitted a petition for a stay of action requesting that FDA stay any decision to “receive” an ANDA for a conjugated estrogens product that does not contain DHES and stay any approval of such an application until FDA responds to the petition. Hard as it may be to believe, though Premarin has been on the market since 1942, a generic equivalent still cannot be approved because the FDA cannot agree on what the product’s active ingredients are! In a May 5, 1997 memorandum (updated July 7, 2005) from Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research of the FDA, to Douglas L. Sporn, Director, Office of Generic Drugs, regarding “Approvability of a Synthetic Generic Version of Premarin,” it was concluded:

The reference listed drug Premarin is not adequately characterized at this time. In particular, the estrogenic potency of the product is not clearly defined relative to the estrogenic potency of its constituents. In addition, the contribution of the two most abundant estrogens, sodium equilin sulfate and sodium estrone sulfate, to the overall estrogenic potency is not well understood. Furthermore, the quantitative composition of Premarin with respect to potentially pharmacologically active components has not been defined. Without this information it is not possible to define the active ingredients of Premarin. … the Center concludes that because the reference listed drug Premarin is not adequately characterized at this time, the active ingredients of Premarin cannot now be defined. Until the active ingredients are defined, a synthetic generic version of Premarin cannot be approved.

Thus, a company that has marketed a drug since 1942 without a clear understanding of its active ingredients, but one which has been shown to have serious and potentially lethal side effects, is petitioning the regulatory agency that has allowed this, to prevent the use of alternative therapies that replace hormones with substances identical to those naturally produced by the body. So what can be done? “Most of the patients who are benefiting from this therapy are pretty passionate about it,” notes Dr. Taylor. “A simple response to the FDA from physicians and patients alike, stating the issues involving bioidentical therapies” would be most effective, says Russell. “Awareness of this issue should be brought to the forefront without question.” Resources for this purpose, specifically tailored to physicians, patients, and pharmacists, are available on the Web site of the International Association of Compounding Pharmacists, http://www.iacprx.org/saveBHRT.html. The organization may also be reached at (281) 933-8400.

Orginal article appeared in the e-Journal of Age Management Medicine, Greg Fillmore & Rick Merner, Co-Publishers. This e-Journal is the Official Publication of the Age Management Medicine Group (AMMG).