The Alternative that Isn’t: Bioidentical Hormones
The interest in bioidentical hormone therapy (BHT) has seemingly exploded of late, due in part to celebrity books and daytime television discussion. Suzanne Somers, author of multiple books on BHT, recently made her case for BHT on Oprah. According to Somers, BHT is a veritable “juice of life“; appropriate for women from their twenties right up to menopause and beyond. This article will look at the safety and effectiveness of BHT, and the responsibility of pharmacists and the pharmacy profession in its provision.
Bioidentical and natural is good, synthetic and conventional is bad right?
The term “bioidentical” refers to hormones that are not produced in the body, are but biochemically similar to hormones the body produces. Bioidentical hormones include estrone, estradiol, estriol, progesterone, dehydroepiandrosterone (DHEA), and cortisol. The FDA and Health Canada have approved several prescription products that contain bioidentical hormones. 
But this isn’t what celebrities like Somers are promoting. In the popular media, bioidentical hormone therapy refers to products that are custom manufactured in a pharmacy. Bioidentical is often used synonymously with the term “natural”, inferring that bioidentical, compounded hormones are natural, effective, and therefore good, while pharmaceutical-company manufactured hormones (bioidentical or not) are unnatural, ineffective and dangerous.
“Natural” is a meaningless term with respect to BHT. All bioidentical hormones are manufactured using wild yams or soy as the starting ingredient, and all undergo chemical conversion in a laboratory to be synthesized to the final ingredient.   There are no bioidentical hormones that do not undergo some sort of laboratory manipulation. Consequently there are no truly “natural” bioidentical hormones.
For the remainder of this article, we will refer to BHT to mean pharmacy-compounded hormones, and focus on estrogen and progesterone replacement approaches.
“Compounded”: What do you mean?
At one time, almost all prescriptions were custom manufactured, or compounded. The pharmacist combined raw chemicals into dosage forms like capsules, tablets, liquids and creams. Compounding allows complete customization of a prescription – from a new strength of a capsule, to a liquid form of a tablet, to creams with combinations of ingredients that can be completely individualized. Hormones are usually compounded into creams or gels, but also into troches (lozenges), and sometimes capsules.
These days, commercial manufacturers supply most drug products, and the need for in-pharmacy compounding has dwindled. At the same time, regulatory oversight, by agencies like Health Canada and the FDA, ensure product uniformity, purity, potency, efficacy, and safety standards for consumers. Most importantly, these regulators require manufacturers to demonstrate that a drug studied in clinical trials is equivalent to the one available in the pharmacy. This allows us to accept that the results of research studies are relevant to patients that will receive the drug. We cannot automatically assume this when a product is compounded in a pharmacy, due to the lack of quality control standards, and batch-to-batch variation from different techniques, recipes, and practices.
Any pharmacy is capable of providing compounded prescriptions, but some specialize, calling themselves “compounding pharmacies” and aggressively promote the service. Professional Compounding Centers of America, provides training, formulations (recipes), and raw ingredients to compounding pharmacies. Other companies exist to supply pharmacies with articles, brochures and handouts to promote BHT and other types of compounded prescriptions. To pharmacies and pharmacists, compounding is a business opportunity, and an ideal way for independent pharmacies to compete against large chain stores, which typically do not offer extensive compounding services.
So what’s the problem with regular hormone therapy?
Hormone replacement therapy (HRT) was routinely used in women for decades. Not only was it effective at reducing menopausal symptoms like hot flashes and sleeplessness, it was believed to reduce the risk of osteoporosis, and possibly even heart disease. There was data to suggest some risks existed, but the balance of risks and benefit was believed to favour the use of HRT.
The Women’s Health Initiative (WHI) study was designed to provide conclusive answers about the risks and benefits of HRT. One part of the WHI was a huge study of over 16,000 post-menopausal women (with an intact uterus). It compared women taking conjugated estrogens (Premarin) plus medroxyprogesterone (Provera), packaged as Prempro, to women taking a placebo. The trial was stopped early when it was observed that the HRT group had more breast cancer cases compared to the group taking the placebo. Overall, the risk and benefit was as follows: If 10,000 post-menopausal women take HRT for one year, compared to a similar group taking a placebo, there will be 8 more cases of breast cancer, 7 more heart attacks, 8 more strokes, and 18 more blood clots. However, there will be 5 less osteoporosis fracture, and 6 fewer cases of colorectal cancer. Overall there will be no difference in death rates. (A superb summary of the WHI is available here (PDF)).
BHT advocates cite the results of the WHI as proof of the harmfulness of HRT. However, the results of the trial actually tell otherwise. Some illnesses increased, some decreased. While overall the benefits do outweigh the risks for many women, especially if taken for long periods, the WHI results continue to be studied, and we’re now seeing physicians using HRT in an evidence-based way. For example, there is a renewed interest in using HRT right around the time of menopause. No other therapy has been shown to be as effective for menopausal symptoms, and the overall risks when used for short periods (i.e., less than five years), are low. In fact, the risks of breast cancer from HRT, while increased, are similar to that of other lifestyle risks, including alcohol consumption, obesity, and physical inactivity. ( See this statement from the Society of Obstetricians and Gynecologists of Canada.)
One unfortunate consequence from the WHI was the sense of betrayal women taking HRT felt from health professionals, regulators, and pharmaceutical companies. Those struggling with menopausal symptoms went looking for alternatives. Enter BHT, celebrity endorsements, and compounding pharmacies.
What are the purported benefits of BHT?
A quick search of the internet reveals all kinds of claims for BHT. If you believe what you hear on Oprah, BHT offers a “fountain of youth” for women, with none of the side effects but all of the benefits of conventional HRT. Advocates boldly state that BHT can prevent or cure heart disease, Alzheimer’s disease, and even breast cancer. 
BHT advocates argue that the WHI results were due to the choice of hormones studied, Premarin and Provera, (called PremPro in the US and PremPlus in Canada). Premarin is a mix of bioidentical and other estrogens derived from pregnant horses (PRegnant MARes urINe, hence the name). Provera is medroxyprogesterone, a version of progesterone that is commonly used because bioidentical progesterone is poorly absorbed. BHT advocates describe Premarin and Provera as “unnatural” and the reason for the problems with HRT. For example, Montreal Pharmacy’s website is typical, describing Premarin as “natural for horses but not for women”, and describes BHT estrogens as “anti-carcinogenic.”
Few physician advocates of BHT have any research or significant expertise in hormone replacement, women’s health, or endocrinology. ABC News noted that most of the sixteen physicians quoted in Suzanne Somer’s book,”Ageless – The Naked Truth about Bioidentical Hormones,” have not published a single paper on hormone replacement therapy. Additionally, three of these “cutting edge” physicians have had disciplinary action taken against them.
There are a significant number of supportive articles on BHT in pharmacy compounding journals, with a few appearing in more mainstream medical journals.    A close analysis reveals that the evidentiary base relied upon is weak. A consistent theme is the cherry-picking of supportive studies, and the extrapolation of weak data into broad elaborations of the safety and effectiveness of BHT.
What does the science say?
There are no large well-controlled clinical trials that have evaluated BHT to the extent that HRT has been evaluated. Consequently, there is no conclusive evidence to demonstrate that BHT is either safer, has fewer side effects, or is more effective than HRT.   
BHT often contains combination of estrogens such as triest (estriol, estrone, and estradiol) and biest (estradiol and estriol). Both are arbitrary combinations of estrogens based on bad science.    There is no clinical evidence to show these combinations are appropriate.  While BHT proponents argue that estriol decreases the risk of breast cancer, there is no conclusive evidence to support this claim.  In fact, estriol has been shown to stimulate breast cancer growth to a greater extent than other estrogens.  Products containing estriol have not been approved in Canada or the United States, and given this data, its unlikely they would ever be approved. In fact, the FDA forbids compounding pharmacies from preparing products with estriol. 
A significant concern with BHT is the effectiveness of pharmacy-compounded progesterone. In women who have not had a hysterectomy, some version of progesterone must be given with estrogen to reduce the risk of endometrial cancer. Published reports have identified cases of endometrial cancer in women using BHT, possibly due to poor absorption from pharmacy-compounded progesterone products.  If this is the case, BHT carries significantly greater risks that HRT. Until there is evidence to show otherwise, compounded progesterone should be considered an unreliable source of progesterone. 
Overall, BHT has not been shown to prevent or cure any diseases. Statements of effectiveness for any medical condition, other than menopausal symptoms, are not supported by convincing evidence.
What about saliva tests?
So how do you know that your BHT is giving the desired effect? Some prescribers may order saliva tests to monitor a patient’s response to BHT. However, saliva tests are unreliable and considered by experts to be pseudoscience.     There is no persuasive scientific evidence that saliva tests are useful to monitor response to BHT or HRT.  The single best way to monitor hormone replacement is simply to see if menopause symptoms (e.g., hot flushes) are alleviated.   BHT advocates argue that compounding and saliva allows patients to “balance” their hormones. But the science shows this is implausible. Estrogen and progesterone levels vary day-to-day and hour-to-hour. There are no published studies to demonstrate that single or multiple saliva tests reflect hormone need, or can be used to adjust doses accurately.
What about Big Pharma? Isn’t this just Wyeth reacting?
Wyeth, the manufacturer of Premarin, suffered a huge decrease in sales due to the WHI results. And Wyeth did petition the FDA in 2005, requesting the regulation of BHT compounding by pharmacies. The FDA studied the issue and subsequently took action against compounding pharmacies. While this action has been opposed by several pharmacist and pharmacy compounding organizations, many large medical and public organizations, with no vested interest in HRT or in Wyeth, have spoken out against BHT and strongly support the FDA’s action:
The American Medical Association – representing 135,000 physicians
The American College of Obstetricians and Gynecologists – 52,000 members
Public Citizen an outspoken critic of both FDA and no friend of the pharmaceutical industry, is one of the strongest critics of BHT, labeling it “DO NOT USE” on their worstpills.org website. They went on to say the following:
“Compounding pharmacies have their own financially driven interest in selling untested BHRT drugs. The pharmacies do, in fact, make unsubstantiated claims about the safety and effectiveness of their BHRT products. The overhead is probably quite low for producing, promoting and selling drugs that are not FDA-approved and are made from bulk drug substances (powdered drug) of unknown quality from sometimes questionable sources.”
“Proponents of BHRT, those benefiting economically from their sale, maintain that the right of women and their doctors to choose must be protected. This is a perversion of consumerism often put forward by producers of shoddy products. There is a more fundamental right that is being violated by compounding pharmacies: the right to a marketplace free of potentially dangerous untested products promoted for unsubstantiated uses.” [Source]
So what’s the bottom line?
BHT is the alternative that isn’t. It isn’t safer, it isn’t more effective, and it isn’t based on sound or convincing science. Celebrity advocates and anecdotal evidence are easy to find, but the scientific data to support the broad claims of BHT advocates is absent. Without reassurance about risk or benefit, BHT is not an appropriate or safe option for the overwhelming majority of women.
I’m a patient. What should I know?
BHT therapy means more unknowns than HRT. These risks could have serious long-term health consequences. Despite what you may read on the internet or what you are told by your physician or pharmacist, you must assume the risks of BHT are at least equivalent to that of HRT.
Remember that some Health Canada/FDA-approved types of HRT contain bioidentical hormones. By taking commercially-manufactured HRT, (bioidentical or not) you and your physician will have better information about expected benefits and risks of treatment. You can then make an informed decision based on actual scientific data. With HRT, you will have access to products that follow highly rigorous and regulated manufacturing standards. Compounded products, on the other hand, mean a decision based on less scientific evidence and risks that equal or possibly exceed that of HRT. Essentially you’re in a clinical trial of one person: you. Regardless of your decision, any HRT, bioidentical or not, should be prescribed at the lowest possible dose and for the shortest duration possible.
In exceptional situations where commercially-manufactured products are intolerable, or for some reason, inappropriate for managing your menopausal symptoms, compounded BHT may be an acceptable option. If this is the case, choose your pharmacy carefully. Ask about the pharmacist’s experience with compounding BHT. Preparing BHT involves the measurement of very, very small amounts of raw materials, approaching the error limits of most pharmacy scales. Consequently unless the pharmacy consistently prepares large volumes of BHT creams, you are more likely to receive a product that varies from batch to batch. Remember that pharmacies are not required to disclose warnings with BHT. However the FDA has made it clear that these risks are real, and should be considered equivalent to that of HRT. Review the data on the WHI study.
The term “Hormone Consultant” is a undefined title that provides no assurance that someone is a qualified health professional, or is capable of providing evidence-based and science-based information on hormone replacement. 
Pharmacists or physicians that recommend saliva tests as part of your evaluation are not providing advice that is supported by science.
Most insurance plans refuse to pay for BHT. You may be required to pay cash for your prescription. The costs can be expensive.
Advice for pharmacists?
It is inappropriate to assume that a lack of data with BHT is evidence of safety. Claims cannot be made that BHT is superior with respect to efficacy or safety until these claims have been demonstrated in randomized controlled trials. Further, claims of reduced breast cancer risk, improved cardiovascular protection, improved adherence to therapy, and fewer adverse effects have not been substantiated and are misleading.
Following the release of the WHI, the FDA required all HRT manufacturers to include the same information about risk and benefit of HRT, unless evidence could be provided to demonstrate a different risk profile. Given the size of the WHI it is reasonable to conclude that this data will not emerge for BHT. There is no comparable evidence to demonstrate either improved efficacy or reduced risk with BHT compared with HRT. Consequently it is appropriate to provide the same risk/benefit information to patients taking BHT.
It is the responsibility of pharmacists to offer evidence-based information to patients who are seeking health information. It is also the pharmacist’s responsibility to protect patients from unnecessary risk. It has been argued that the line of professional ethics is crossed when a practitioner promotes his or her own therapy as a “product” which is not considered the standard of care.  Menopausal women are vulnerable to anecdote and misinformation as they seek treatment for what can be very debilitating symptoms.  This puts an additional onus on pharmacists to provide ethical, science-based care.
All forms of hormone replacement must be held to the same standard and level of evidence. Given the limitations of data on BHT, and the potential risks, it is doubtful that BHT will ever be considered an accepted, appropriate therapy, or the standard of care, until important questions of safety and efficacy are addressed. Consequently, the onus is on pharmacists and pharmacies that profit from BHT, and the colleges that regulate them, to ensure that patients receive accurate, evidence-based information about this controversial therapy.
Fears and mistrust of HRT are largely unfounded, and propagated in part by advocates for BHT who may not be providing evidence-based information on the facts of HRT and the additional risks of compounded therapies.
The proliferation of compounding pharmacies specializing in BHT has become a largely unmonitored supply chain of untested products, responding to, but also driving demand for, products that are not the standard of care. It is time for the pharmacy profession to reflect on its obligations to patient care and reevaluate the provision of bioidentical hormones.
For More Information
Sasketchewan’s Academic Detailing Program, RxFiles, prepared a summary of clinical data following the WHI events of 2002. While somewhat dated, it provides a good overview of alternatives from a Canadian perspective. Sasketchewan’s drug information service published a good overview of the BHT issues in 2003.
British Columbia”s Therapeutics Initiative prepared a nice summary of the WHI following the publication of the key clinical data.
FDA’s Q&A on compounding provides their perspective on the practice.
Pharmwatch’s take on Bioidentical Hormone Therapy.
. Pinkerton JV. Bioidentical Hormones. What you (and your patient) need to know. OBG Management 2009;21(1):43-52.
 Health Canada. Drug Product Database (Database on the Internet). Available at: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php . Accessed March 10, 2009.
 Food and Drug Administration. “Bio-Identicals: Sorting Myths from Facts” Available at http://www.fda.gov/consumer/updates/bioidenticals040808.html. Accessed March 10, 2009.
 Schwartz ET, Holtorf K. Hormones in wellness and disease prevention: Common practices, current state of the evidence, and questions for the future. Prim Care Clin Office Pract 2008;35:669-705.
 Hortorf K. The bioidentical hormone debate. Are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy? Postgrad Med 2009;121(1):1-13.
 Paoletti J. Correcting misconceptions about compounding bioidentical hormones: A review of the literature. Int J Pharmaceutical Compounding 2007;11(4):269-72.
 Wepfer S. The science behind bioidentical hormone replacement. Int J Pharmaceutical Compounding 2001;5(6):462-4.
 Boothby LA, Doering LA. Bioidentical hormone therapy. a panacea that lacks supportive evidence. Curr Opin Obstet Gynecol 2008;20:400-7.
 Cirigliano M. Bioidentical hormone therapy: A review of the evidence. J Women’s Health 2007;16(5):600-31.
 Boothby LA, Doering PL, Kipersztok S. Bioidentical hormone therapy: a review. Menopause 2004;11(3):356-67.
 Eden JA, Hacker NF, Fortune M. Three cases of endometrial cancer associated with”bioidentical” hormone therapy. Med J Aust 2007;187(4):244-5.
 MacLennan AH, Sturdee DW. The ‘bioidentical/bioequivalent’ hormone scam. Climacteric 2006;9:1-3.
 Rosenthal MS. Ethical problems with bioidentical hormone therapy. Int J Impot Res 2008;20:45-52.
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