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Bioidentical hormone replacement therapy (BHRT), also known as bioidentical hormone therapy or natural hormone therapy, is a poorly-defined term referring to the use of hormones that are identical, on a molecular level, with endogenous hormones in hormone replacement therapy. The term is also associated with pharmacy compounding, blood or saliva testing, efforts to reach a targeted level of hormones in the body (as established through blood or saliva testing) and unfounded claims of safety and efficacy. Specific hormones used in BHRT include estrone, estradiol, progesterone (which are available both in FDA-approved manufactured products and as pharmacy-compounded products) testosterone, dehydroepiandrosterone (both products have more limited availability and approval in Canada and the United States) and estriol (which is available in Europe but is not approved in Canada and the United States).
Custom-compounded BHRT is a practice almost wholly restricted to the United States. BHRT is a form of alternative medicine, and has been promoted as a panacea for many diseases rather than a means of relieving the symptoms of menopause and/or reducing the risk of osteoporosis (the goals of traditional hormone replacement therapy). There is no evidence to support these claims; the hormones are expected to have the same risks and benefits of comparable approved drugs for which there is an evidence base and extensive research and regulation. The exception is progesterone, which may have an improved safety profile, though direct comparisons with progestins have not been made. Bioidentical hormones may also present extra risks, due to the process of compounding. In addition, the accuracy and efficacy of saliva testing has not been definitively proven, and the long-term effects of using blood testing to reach target levels of hormones have not been researched.
The International Menopause Society, American Congress of Obstetricians and Gynecologists, Society of Obstetricians and Gynaecologists of Canada, The Endocrine Society, the North American Menopause Society (NAMS), United States Food and Drug Administration, American Association of Clinical Endocrinologists, American Medical Association, American Cancer Society and the Mayo Clinic have released statements that there is a lack of evidence that the benefits and risks of bioidentical hormones are different from well-studied nonbioidentical counterparts; until such evidence is produced the risks should be treated as if they were similar; and that compounded hormone products may have additional risks related to compounding. A major safety concern in bioidentical hormone replacement therapy is that there is no requirement to include package inserts, despite the potential for serious adverse effects (including life-threatening adverse effects) associated with HRT. This can lead to consumers' being deceived (and harmed), as they are misled into believing that BHRT is safe and has no side effects. Regulatory bodies require pharmacies to include important safety information with conventional hormone replacement therapy (CHRT) via package inserts.
Bioidentical hormones were first used for menopausal symptom relief in the 1930s, after Canadian researcher James Collip developed a method to extract an orally-active estrogen from the urine of pregnant women and marketed it as the active agent in a product called Emmenin. It was supplanted on the market when its manufacturer, Ayerst (later Wyeth Pharmaceuticals), began producing the more easily-manufactured conjugated equine estrogens in 1941 under the brand name Premarin; by 1992, Premarin was the most widely-prescribed drug in the United States.
In the 1970s, research and reports indicating risks from synthetic conjugated estrogens began to appear. Investigation determined that the addition of a progestogen to estrogen treatment reduced the risks. As early as 1980, the British Medical Journal (now BMJ) recommended oral bioidentical progesterone as an option when side effects from synthetic progestogens otherwise mandated discontinuing treatment. Starting in 1980, side effects caused by synthetic progestin use prompted more research into bioidentical progesterone. In May 1998 the FDA approved Prometrium, an oral bioidentical progesterone product produced by Solvay Pharmaceutical.
Physicians John R. Lee and Jonathan Wright were pioneers in the area of BHRT. Lee authored several popular books on BHRT and promoted custom-compounded BHRT, with the goal of achieving what he called a "natural hormone balance". He based this goal on the clinical testing of saliva to establish where "deficiencies" existed, though agencies such as the FDA and the American Congress of Obstetricians and Gynecologists state that blood and saliva testing is unreliable and biologically meaningless. Lee also believed that progesterone acted as a panacea and general health tonic for many health conditions; he based his claims on anecdotal data rather than peer-reviewed research, and there have been no clinical trials demonstrating this to be true. Wright also authored a popular book on BHRT; he promoted a triple-estrogen formula he called "Triest", which combined the three estrogens (of over 25 types) found in human females: estriol, estradiol and estrone. Previous bioidential formulas had used only estradiol. This triple formula was based on a single unpublished study whose conclusions did not take into account how estrogens are processed and excreted in the body—particularly how the liver processes oral estrogens, converting many of them to estrone. No followup was performed by Wright to replicate these observations. Wright may have been the first proponent of BHRT to use the term "bioidentical"—the word he coined to describe unpatentable, plant-derived molecules he believed were identical to human hormones. However, no structural crystallographic evidence has been used to support the idea that these molecules are actually identical to endogenous human hormones. When the Women's Health Initiative's reports on the unappreciated risks of equine estrogens were released, many prescribers of BHRT used Wright's assertions (and his terminology) to proclaim the superiority of bioidentical molecules despite a lack of scientifically-supported evidence. Following the publication of a popular book written by actress Suzanne Somers in 2006, the term "bioidentical" gained more prominence in popular consciousness as a "poorly understood new adjective" regarding hormone replacement therapy.
There is no single definition for the term "bioidentical hormone replacement therapy" (BHRT); it is generally used to refer to 17β-estradiol, but other uses include plant-based or compounded estrogen products that blend estradiol with estriol and sometimes with estrone. A "bioidentical hormone" is defined as a molecule identical to a hormone produced by the human body. Though the term "bioidentical" has been used in FDA packaging inserts since before 1998, the FDA considers "BHRT" to be a marketing term and does not recognize its use. The meaning of "plant-derived" has also been attached to the term "bioidentical", and it may also mean that the hormones are "natural"; throughout the 1990s plant-derived, compounded hormones were referred to as "natural hormone therapy". However, the term "natural" can be applied to all products where the principal ingredient originates from an animal, plant, or mineral source, and both bioidentical and nonbioidentical hormones can be produced from the same plant sources.
"BHRT" is often used to refer to a set of diagnostic, prescribing, preparation and marketing practices including compounding (the preparation of custom-mixed hormones by a pharmacist, according to a prescription), saliva testing, and efforts to counter the effects of aging rather than relieving the symptoms of menopause. This compounded BHRT package has been promoted by Suzanne Sommers, Oprah Winfrey and other proponents as safer and more effective than CHRT, though there is no evidence to support these claims. Compounded BHRT has been marketed on the internet by pharmacies which make unfounded claims for its safety and its effectiveness for a variety of conditions.
The lack of distinction between FDA-approved bioidentical hormones and compounded bioidentical hormones as part of a package that includes saliva testing and compounding has resulted in considerable confusion regarding exactly what BHRT is.
There are a variety of FDA-approved products made using bioidentical estrogens and micronized progesterone, used to treat the symptoms of menopause:
|Hormone class||Type||Brand names||Preparations||Notes|
|micronized 17 beta-estradiol|
|Estrace and others||Pill and vaginal cream||Vaginal cream for vaginal symptoms only; sourced from plants; estradiol is bioidentical until ingested and converted in the liver to estrone|
|Alora, Climara, Esclim, Estraderm, Vivelle and others||Patch||Sourced from plants|
|Estrogel||Transdermal gel||Sourced from plants|
|Estrasorb||Topical cream||Sourced from plants|
|Estring||Vaginal ring||For vaginal symptoms only; sourced from plants|
|Estradiol acetate||Femring||Vaginal ring|
|Estradiol hemihydrate||Vagifem||Vaginal tablet||For vaginal symptoms only|
|Micronized progesterone USP||Prometrium||Pill|
|Prochieve 4%||Vaginal gel|
|17 beta-estradiol and norethindrone acetate||Combipatch||Patch||Estradiol is bioidentical, but the progestin is not|
|17 beta-estradiol and norgestimate||Prefest||Pill|
|17 beta-estradiol and levonorgestrel||Climara Pro||Patch|
The term "synthetic" is also used incorrectly by lay "experts" in two different ways - to refer to the process used to manufacture all estrogens, including bioidentical estrogens, and to compounds that interact with estrogen receptors similar to estrogen molecules but are not found in nature. Examples of the latter two include diethylstilbestrol and ethinylestradiol.
BHRT is used to reduce the symptoms of menopause. It is also promoted by some practitioners for anti-aging purposes and as providing benefits beyond menopausal symptom relief—improving the quality of life, though there is little evidence to support these claims.
Typically, compounded preparations of bioidentical hormones include estriol, estrone, estradiol, testosterone, progesterone and sometimes dehydroepiandrosterone (DHEA), either individually or in some combination. They are promoted as natural, safer and (in some cases) more efficacious than CHT; however, there are no scientific studies to support claims of superiority of BHs over CHRT. Estimates from sales of bulk hormones for compounding suggest that more than one million women may be using compounded BHRT in the U.S. Bioidentical hormones are expected to have the same risks as conventional hormones made with the same products.
In premenopausal women the majority of estrogen produced by the body is estradiol (produced primarily in the ovaries), while in postmenopausal women estrone (produced in fat cells) is the type of estrogen present in the greatest amount; however, the body is able to convert one type of estrogen into another to a certain extent. Because of the limited research into potency, delivery methods and conversion of the various estrogens, a valid scientific understanding of compounded estrogen products has not been achieved. Synthetic estradiol, taken orally, splits when absorbed in the gastrointestinal tract and delivers bioidentical estradiol to the bloodstream.
The hormone estriol, produced during pregnancy, is frequently compounded into bioidentical preparations in the United States. While some think it to be a weaker estrogen, with a more limited period of effectiveness than estradiol, it has been demonstrated to be a stronger estrogen in certain ways. Though initial research in the 1970s suggested possible use, followup studies have failed to confirm this potential. Estradiol is not found in any FDA-approved drug, and its safety and effectiveness as a hormone supplement is unknown.
Estriol was part of the United States Pharmacopeia before FDA approval was needed for its use. Its approval was grandfathered by the FDA until 2008 when the agency banned its use, stating that manufacturers of estriol would have to create a new application and estriol would be treated as a new drug. Its use is not approved by Health Canada; estriol is not available as a pharmaceutical preparation in Canada or the United States, but is a commonly-prescribed conventional treatment in other countries and is available as a cream or vaginal suppository in the United Kingdom and the European Union. Estradiol is available as brand-name products in both oral and transdermal forms.
Progesterone is used both orally and transdermally. Oral progesterone is micronized (ground) to increase availability, and is approved by the FDA to treat endometrial hyperplasia when used in opposition to estrogen. It has also been approved to relieve menopausal symptoms, either alone or in combination with estrogen. It is more reliable in treating menopausal sleep disorders than synthetic progestins. Transdermal progesterone is often used as a component of compounded BHRT but has not been clinically proven to prevent endometrial hyperplasia, as oral progesterone has. The editors-in-chief of the scientific journal Climacteric state that the greatest difference in function between bioidentical and synthetic hormones may be found in progesterone's behavior compared with progestin. Laboratory studies have suggested that bioidentical progesterone binds primarily to progesterone receptors, while synthetic progestins activate other receptors with a variety of effects. The editors suggested that progesterone may have neutral-to-positive effects on the cardiovascular system, and induce apoptosis in breast epithelial cells. They also called for more research to examine and confirm the effects of progesterone on health, and for continued use of regulated (rather than unregulated) individually-compounded products provided by pharmacies. These compounds have not been directly compared with each other in appropriate scientific tests, though as of 2010 trials had begun. Progesterone is approved for use by both the FDA and Health Canada as a brand-name oral preparation. The French epidemiological study Etude Epidemiologique aupres de femmes de l’Education Nationale suggested micronized progesterone may offer a reduced risk of breast cancer compared to other progestins, though large-scale clinical trials have not yet been conducted.
Testosterone supplementation can improve libido in postmenopausal women, but can also reduce levels of high-density lipoprotein (good cholesterol). Commercial sources for testosterone for women in the U.S. are limited, and include the commercially-prepared estrogen-testosterone mixture Estratest; compounding pharmacies are the main source of testosterone-only preparations for women. There is little published data to indicate dosing, duration and method of administration, although there is increasing popular awareness of testosterone's use for increasing postmenopausal libido. A testosterone patch has been approved for use in the United Kingdom and European Union, but in Canada and the United States it awaits long-term safety data.
DHEA is an androgen precursor that lacks FDA and Health Canada approval for use in women, and is not available in Canada as a pharmaceutical preparation; it is sold as an over-the-counter drug or incorporated into compounded preparations in the United States. In the body, it can be converted to testosterone and then to estrogen; there are no consistent scientific findings or safety information supporting its use. High levels of DHEA have been linked to breast cancer.
Compounding pharmacies use commercially-available bulk drugs to create new formulations which differ (in form or dosage) from those manufactured on a large scale by pharmaceutical companies. Custom-compounded BHRT is almost wholly restricted to the United States, where pharmacy compounding is governed at the state level while the FDA has regulatory authority over the compounded product. Some internet-based compounding pharmacies understate harm and claim benefits of compounded BHRT beyond what can be proven by evidence-based medicine, and many of their claims exceed those made by other, more mainstream, BHT practitioners.
The benefits—as well as adverse effects—are expected to be the same for bioidentical and synthetic hormones. Dosages used in BHRT can be as high as ten times the oral dose provided by comparable HRT regimens; the hormones used are known to adversely impact biological markers of cardiovascular disease, and may produce a substantially-higher risk of heart attack or stroke because of this. There are potentially-serious adverse effects and important safety information which is required to be given with FDA approved HRT in the form of package inserts; however, package inserts are typically not given (or required) with compounded bioidentical preparations. This has led consumers into the erroneous assumption that bioidenticals are safer than FDA-approved hormones or lack any adverse effects—one of the concerns expressed about the hormones. BHRT has also been associated with endometrial cancer.
Less common (but serious) side effects of all post-menopausal estrogens include increased risk or severity of breast, ovarian or uterine cancer, stroke, heart attack, blood clots, dementia, gallbladder disease, high blood pressure, liver problems, high blood sugar, fluid retention, enlargement of benign tumors (fibroids) of the uterus, a spotty darkening of the skin, especially on the face (melasma), and vaginal yeast infection.
Estradiol (a type of estrogen) is—in the case of naturally menopausal women—only recommended for use for the shortest period of time and at the lowest effective dose due to its adverse-effects profile. There is the potential for a range of adverse effects in breasts, skin, eyes, cardiovascular, gastrointestinal, genitourinary or central nervous systems. These risks, however, are very low.
Progesterone can cause the emergence (or significant worsening) of abdominal pain, constipation, yeast infections, breast cancer, cystitis, acne, conjunctivitis, thrombotic disorders resulting in pulmonary embolus, strokes or heart attacks and—due to increased fluid retention—epilepsy, migraine, asthma and cardiac or renal dysfunction. Psychiatric reactions can include emotional instability, depression, aggression, decreased libido and drowsiness. Adverse effects can also occur in the urinary, central or peripheral nervous system or bones and muscles.
Hormones can be administered in a variety of ways, including percutaneous skin and vaginal creams, oral pills, topical gels, vaginal rings and tablets, and transdermal patches. Though all preparations of a given type of estrogen (e.g. estradiol) may be molecularly identical before their introduction into the human body, estrogens administered orally are modified by the liver before entering the bloodstream and in this process, most is converted to estrone. However, estrogen bypassing the digestive tract and liver and entering through the skin is not converted to a new form before entering the bloodstream. Creams and gels applied to the skin also enter the blood directly and without modification but absorption of the gels, creams, and patches can vary from application to application, depending on the temperature and condition of the skin. Pharmaceutical compounding is frequently used to modify the dose, form, and additives of the preparations, based on instructions from a health-care practitioner.
The primary difference between the popular promotions of CHRT and compounded BHRT involves BHRT advocates' use of regular testing of blood or saliva-bound hormone levels, use of individualized compounding rather than standard doses, dosing to attain certain levels in the body rather than for symptom relief, and the use of hormones for purposes other than relief of menopausal symptoms. Proponents of compounded BHRT have been criticized by many mainstream medical sources for making unsubstantiated claims about its effectiveness for a variety of purposes, and for promoting it as more safe and "natural" than CHRT.
Advocates for BHRT have claimed that commonly-compounded BHRT preparations are not commercially available; this is false, as there are many FDA-approved hormone preparations containing bioidentical molecules available both as proprietary or generic brands. The exception is estriol, used in the compounded bioidentical preparations Triest and Biest—in 2008, the FDA banned estriol until a New Drug Application had been completed; these preparations are not approved by either the FDA, or Health Canada. Some advocates of compounding have also falsely claimed that customized compounding provides customized results; this is incorrect since it is aimed at producing a single hormone profile with absolute blood or saliva levels—which has not been demonstrated to be better than CHRT—and does not consider the rate at which individuals will differ in the activity, metabolism and excretion of the hormones. There have been no clinical trials directly comparing the effectiveness or efficacy of bioidentical versus nonbioidentical compounds.
A 2010 article published in The Medical Letter on Drugs and Therapeutics concluded "There is no acceptable evidence that 'bioidentical' hormones are safe or effective. Patients should be discouraged from taking them."
BHRT is frequently associated with testing of saliva to establish a baseline hormone level and compounding of the substances by pharmacists (according to a doctor's advice) to produce preparations (and blood levels) of hormones that are individualized to the patients. There is no research demonstrating any benefit to either of these practices. Though promoters of BHRT claim that saliva testing can be used to "customize" the level of hormones for individuals, and tests are used to determine which hormones are supposed to be deficient and require supplementation, there is no scientific basis to support the use of saliva testing. Estrogens are secreted in pulses within and over days, resulting in varying saliva levels. Certain compounding formulations also attempt to use a single profile for all women, with no evidence that a specific profile is beneficial in all cases and no recognition that women differ in their sensitivity to hormones and metabolic rate. Testing-based customizing also does not account for much of the effects, and synthesis of hormones occurs within tissues rather than in the blood; therefore, blood or saliva levels of hormones may not necessarily reflect actual biological activity. Other concerns include lack of evidence that samples are stable during storage and transportation, poor replication of results and considerable variation among assays. There are also no studies that link symptoms with blood or saliva levels of hormones. The FDA recommends, instead, adjusting hormone therapy to the symptoms of the patient, and there is no reason to adjust the dosing or monitor patients receiving BHRT. Skeptics of BHRT have also pointed out that there is no certainty regarding hormone levels in the body. The North American Menopause Society has supported warnings about the potential harm BHRT could cause, as it unnecessarily compounds drugs that are already FDA-approved in ways that lack an evidence base of safety or harm; this warning is supported by the Society of Obstetricians and Gynaecologists of Canada.
Although promoted as a way of customizing treatment, hormone therapy does not require customization; the use of testing to determine the amount of hormones administered could result in the dose being higher than the minimum recommended level to alleviate symptoms, or the administration of unnecessary hormones to asymptomatic women may result in greater risks to the patient. In addition, analysis of the material used to promote BHRT suggests that rather than basing hormone doses on saliva results, practitioners are actually adjusting the dose based on symptoms. Health practitioners customize the care of their patients on an ongoing basis by choosing the medication, dose and administration route individually, using approved medications that have a demonstrated safety record and are not subject to the errors and inconsistencies of custom-prepared combinations. Different bioidentical preparations result in mixtures with different strengths, and practitioners using compounded formulations may be unaware of the total dose of hormones their patients receive. In a 2001 test of compounded bioidentical hormone products, the FDA found that 10 out of 29 products failed their quality tests; nine out of ten failed potency tests (comparable rates for drug manufacturers were less than 2% and 0.13%, respectively) A 2006 test found potency levels ranging from 67.5% to 268.4% of the potency specified on the label; some samples were mixtures of different hormones with some being above, and others below, the specified potency. The failure of potency testing could be problematic and dangerous for progesterone products, where specific levels of progesterone are required to protect the endometrium against precancerous hyperplasia.
Saliva testing has not been shown to accurately measure blood-bound hormone levels. The FDA recommends the lowest dose of hormones that effectively relieve symptoms and does not recommend custom compounding, blood or saliva testing.
Bioidentical hormones have been advertised, marketed and promoted as a risk-free panacea that is safer than standard HRT. Literature reviews by private practitioners who sell bioidentical preparations suggest benefits and advantages in the use of BHRT over its conventional counterpart, but there is significant skepticism over claims made about BHRT; there is no peer-reviewed evidence that compounded bioidentical hormones are safer or more effective than FDA-approved formulations or that they carry less risk. The hormones are expected to carry the same risks as their conventional counterparts, while the risks of including estriol—a hormone normally produced in large amounts only in pregnant women—have not been studied. The United States Food and Drug Administration (FDA) warned that claims about compounded BHRT products are unsupported by medical evidence—unlike claims about manufactured, FDA-approved products. The chief medical editor of Endocrine Today called compounded BHRT a "marketing concept" with no scientific backing, and the FDA warned that pharmacies use these terms to imply that the drugs are natural and have the same effects as endogenous hormones. Other claims include compounded BHRT's ability to prevent or treat conditions such as heart disease, stroke, Alzheimer’s disease, endometrial and breast cancer; fewer side effects; and custom blending to uniquely address individuals. There is no credible evidence to support these claims. Bioidentical hormones and compounded BHRT are expected to have the same risks and benefits as CHRT; the latter benefits from years of study and regulation, while compounded BHRT has no scientific data to support claims of superior safety or efficacy. The following specific claims have been made for the efficacy of bioidentical hormones and compounded BHRT, with varying evidence to support or contradict them:
|Bioidentical hormones fit precisely into human hormone receptors while conventional hormones fit "cockeyed"; this mismatch causes serious side effects||Synthetic progestins and endogenous progesterone have different binding affinities for different receptors, depending on the model and animal used; these differing pharmacodynamics have not been associated with specific side effects|
|The body is unable to metabolize synthetic hormones||The biological half-life for synthetic hormones is between five minutes and two days|
|Lack of progesterone causes irregular or painful, heavy menses||Oral progesterone is no more effective than placebo at alleviating symptoms of premenstrual syndrome|
|Progesterone can counteract stress, increase metabolism and decrease abdominal fat||There is no evidence to support weight loss due to progesterone|
|"Normal" levels of progesterone protect against breast cancer||The claim is based on a single study of infertile patients during child-bearing years. Some evidence exists supporting a link between hormonal treatment for infertility and a reduced risk of breast cancer, but these benefits may not translate to women seeking relief from the symptoms of menopause|
|Progesterone therapy can prevent cardiovascular disease and atherosclerosis, and raise good cholesterol||The use of micronized progesterone does not affect cardiovascular risk|
|The side effects reported in the Women's Health Initiative study were due to the synthetic nature of the hormones used||"Cardiovascular benefit has not been proven with micronized progesterone in observational or experimental research...a multicenter, case–control study was conducted in postmenopausal women aged 45–70 years to examine potential differences in cardiovascular risk between the subtypes of synthetic progestins and micronized progesterone...Micronized progesterone and pregnane derivatives were not associated with an increased venous thromboembolism risk, whereas norpregnane derivatives...were associated with increased risk of thromboembolism...Thus, certain progestins are associated with increased cardiovascular risk, whereas pregnane derivatives and micronized progesterone neither increase nor decrease cardiovascular risk in the doses studied"|
|Proponents claim that bioidentical hormones, in addition to the demonstrated benefit of improving bone-mineral density, protecting the eyes and skin from drying out, regulating the menstrual cycle, improving mental function, improving blood cholesterol and reducing hot flashes and night sweats associated with menopause||There is no published evidence (derived from controlled research) supporting the claims of superior beneficial effects for bioidentical hormones as compared to conventional hormome therapy. Risk data have been published for conventional hormone therapy, and CHRT is not recommended to manage any chronic diseases, or for the prevention of cardiovascular disease|
|Estriol can decrease the risk of breast cancer||Estriol has been shown to cause breast cancer cell growth|
|Pharmacists use their expertise regarding bioidentical hormones to meet the needs of their clients and improve health outcomes||Compounding is a legitimate practice, but there is no evidence that clearly illustrates the benefits and risks of BHRT|
In 2006, actress Suzanne Somers released the book Ageless: The Naked Truth About Bioidentical Hormones endorsing the use of bioidentical hormones. The book was criticized by a group of doctors who (though generally supportive of BHRT) state that more research is required, and object to protocols mentioned in the book—because of their potential danger and the promters' lack of qualifications. Somers' book may have raised the profile of BHRT for the growing number of menopausal women, but also may have caused confusion by making unsubstantiated claims for BHRT and referring to bioidentical hormones as non-drug products with fewer risks. Bioidentical hormones have also been discussed on The Oprah Winfrey Show, with Somers as a guest.
Bioidentical-hormone proponents Erika Schwartz and Kent Holtorf criticized a 2008 literature review on bioidentical hormones for addressing only compounded bioidentical hormones and not reviewing FDA-approved bioidentical products, which they believed added to the existing confusion. Michael Cirigliano and Judi Chervenak have stated in reviews of literature on BHRT that large-scale, peer-reviewed studies should be used to establish the safety, efficacy and beliefs about the use of bioidentical hormones. Two 2008 studies conducted in France found that estradiol plus micronized progesterone did not increase the incidence of breast cancer, while a comparison of estradiol plus different types of progestins found a reduced risk of invasive breast cancer with micronized progesterone. Christine Derzko stated that the evidence supported the use of bioidentical estrogen plus progesterone, but since the trial was an observational cohort study rather than a randomized controlled trial that compared different types of hormones head-to-head, more data was required before concluding bioidentical hormones were safer and preferred. Derzko concluded that there was weak (but promising) preliminary evidence that bioidentical hormones may present equal (or possibly lower) risks than conventional HRT; however, there was no data supporting the use of compounding. Derzko recommended following evidence-based medicine and cited concerns over BHRT by numerous medical organizations—requirements for oversight over compounding, black box warnings for all bioidentical products, and the establishment of a mandatory adverse-events registry.
M. Sarah Rosenthal, Director of the University of Kentucky Program for Bioethics and Patients’ Rights, has stated that she believes BHRT is an experimental therapy that is often prescribed by practitioners who sell the products, and are thus in an unethical position of conflict of interest. Rosenthal has also described problematic issues with BHRT including patients receiving information from popular books while lacking the scientific literacy to separate rhetoric from evidence about hormone replacement, illegitimate claims of a "big pharam" conspiracy to suppress bioidentical prescribing, the extra and unnecessary cost of the products that are often not covered by insurance plans, and the inaccurate depiction of bioidentical prescribing as "cutting edge science" rather than unproven alternative medicine.
Bioidentical hormones are frequently marketed as being "natural", or more natural than conventional HRT. The term "natural" can be used to suggest or emphasize a variety of different ideas—similarity with endogenous hormones, extraction from a plant-based source, and that the hormones are not manufactured or synthesized.
The monthly newsletter Harvard Women's Health Watch, published by Harvard Medical School, states that "natural" does not automatically mean "safe", and that "natural" can be used to indicate any product with an animal, plant, or mineral source—including hormones that are not bioidentical (such as Premarin), as well as the molecules extracted from soybean and yam sources used in many bioidentical and nonbioidentical commercial preparations.
Bioidentical hormones are expected to carry the same risks and benefits as their non-bioidentical counterparts, but there have been no studies that directly compare compounded bioidentical hormones with their non-bioidentical counterparts. Hormones—as used in CHRT—have been studied for years and their risk, benefit, and effectiveness profiles are known and demonstrated through considerable research.
In 2002, the Women's Health Initiative study (WHI), which was designed to demonstrate additional benefits for conventional hormone therapy (study participants were given Prempro or a placebo), was terminated prematurely after preliminary data indicated small increases in the risks of breast cancer, heart attack and stroke in older women using Prempro. The early termination of the WHI study (which used conjugated equine estrogens) and the subsequent publicity about these previously-unappreciated risks led to a decline in prescriptions for CHRT. The results of the WHI were used by BHRT prescribers to promote bioidentical hormones as safer than the FDA-regulated preparations despite a lack of evidence; according to the FDA, the results found by the study apply to all estrogens. BHRT has since been strongly promoted as a natural alternative with fewer risks than CHRT, though there is no evidence to support this claim. BHRT practitioners recommend compounded products due to their claim that they more closely mimic the composition and ratio of circulating hormones in a woman's body than do commercially-manufactured products.
The Endocrine Society issued a position statement that bioidentical hormones carry essentially the same risks and benefits as non-bioidentical molecules. In February 2009 the American Congress of Obstetricians and Gynecologists re-iterated its position (of November 2005) that there are no proven benefits in regard to the safety or efficacy of compounded bioidentical hormones, nor are there any benefits in salivary testing of hormone levels or customized dosing of hormones. The Mayo Clinic states that there is no evidence that pharmacy-compounded BHRT is safer or more effective than conventional hormone replacement, and that some bioidentical hormones are already available in certain FDA-approved products. The American Cancer Society also stated that "natural" and "bioidentical" hormones present the same risks as synthetic hormone replacement therapy such as heart disease, blood clots, strokes and an increased risk of breast cancer with long-term use.
The U.S. Food and Drug Administration has warned several pharmacies about making unsubstantiated claims about the safety and effectiveness of compounded hormone products. The North American Menopause Society has stated that compounded bioidentical hormones have not been approved by the FDA; there is no guarantee of purity, potency, efficacy or safety, and they may contain unknown contaminants. The Australian Menopause Society has similarly stated that there is no evidence that bioidentical hormones administered using lozenges are any safer than their approved counterparts. The International Menopause Society has stated "There are no medical or scientific reasons to recommend unregistered 'bioidentical hormones'. The measurement of hormone levels in the saliva is not clinically useful. These ‘customized’ hormonal preparations have not been tested in studies and their purity and risks are unknown."
In November 2006, the American Medical Association adopted a policy requesting that the FDA better monitor and regulate bioidentical hormones, releasing an editorial stating that compounded bioidentical molecules were expected to have the same risks as conventional hormones until proven otherwise.
Erika Schwartz, author of The Hormone Solution (Warner 2002), and bioidentical advocate Kent Holtorf published peer-reviewed papers stating that there is evidence to support a superior safety profile for bioidentical hormones when compared with non-bioidentical hormones, as well as improved relief of postmenopausal symptoms and better bone density and serum lipoprotein levels. Deborah Moskowitz, a Doctor of Naturopathic Medicine who works for a manufacturer of a bioidentical product, also published an article stating that bioidentical hormones are superior to non-bioidentical hormones in safety and effectiveness though this review was criticized for "[attempting] to demonstrate that BHRT has a good safety profile, but the data presented only serve to demonstrate similar risks to conventional HRT."
The alternative medicine watchdog site Quackwatch recommends against the use of bioidentical hormones due to lack of quality control over compounding, posing the same risks as conventional hormones, the use of unnecessary saliva testing, and for including the non-FDA-approved hormone estriol. Stephen Barrett, the site's owner, concludes his review with the statement "The bottom line for consumers is very simple: Steer clear of anyone who prescribes "bioidentical" hormones or recommends saliva testing as the basis for evaluating hormone status."
Compounded BHRT is used almost exclusively in the United States, and many FDA-approved fomulations that are wholly or partially made of bioidentical hormones are available. Topical hormone preparations such as progesterone, estrogen and DHEA creams can be purchased in stores or over the internet and are not regulated by the FDA, as they are generally considered cosmetic.
When prescribed by a licensed practitioner, the compounding of bioidentical hormones is controlled by the state pharmacy boards rather than the FDA, and pharmacists are permitted to adjust dose and delivery method according to the prescription. However, the FDA does have authority over the compounded product. In 2001 the FDA surveyed a limited number of compounded preparations, including eight hormone compounds. All three estradiol products passed every test; however, two out of five progesterone products failed at least one test of potency, content or uniformity.
In October 2005 Wyeth Pharmaceuticals, a manufacturer of both FDA-approved bioidentical and nonbioidentical HRT preparations, filed a Citizen Petition with the FDA asking for enforcement action against compounding pharmacies which dispensed BHRT, and to investigate labeling and advertising guidelines. Soon after, the FDA took a number of enforcement actions against several (primarily Internet-based) pharmacies that were producing compounded BHRT and in 2008, banned the use of estriol in the US. The FDA stated that they did not take these regulatory actions against compounded bioidentical hormones in response to Wyeth's request, since that is not the purpose of a citizen petition. They said that they had an ongoing investigation when they received the petition. The FDA has acknowledged that they are unaware of any adverse events connected to the use of estriol, but ordered pharmacies to discontinue its use. The agency's Assistant Director of the Office of Compliance stated that use of estriol would require a permit for research and a new drug application. The FDA also stated that it has not approved any drug containing estriol and that no information had been submitted to the FDA regarding its safety and effectiveness. The FDA's concerns over the marketing and use of bioidentical hormones were supported by the American Association of Clinical Endocrinologists. In response to the FDA's actions, the International Academy of Compounding Pharmacists (IACP) enlisted thousands of women to join a letter-writing campaign to the FDA to reverse this action, citing Wyeth's attempt as a "self-serving, and at times duplicitous, campaign to restrict patients’ access to alternatives to its own products".
In November 2006, the American Medical Association adopted a policy urging the Food and Drug Administration to survey compounded BHRT products for purity and dosage; to maintain a registry and require mandatory adverse event reporting by manufacturers and compounding pharmacies related to bioidentical hormones; to mandate the inclusion of uniform patient information, including warnings and precautions regarding bioidentical products; and to prohibit use of the term "bioidentical hormones" unless the agency has approved the preparation.
On July 18, 2008, a US Appeals Court issued a ruling stating that new drug approval processes should not be applied to compounded drugs that complied with established guidelines, and also that provisions of the regulations relevant to the use of estriol were still in effect, preventing the FDA from taking action against pharmacies using estriol in compounded products.
The Wiley Protocol is a version of compounded BHRT, endorsed by T. S. Wiley, whose goal is to produce serum levels of estradiol and progesterone that are identical to those of a young woman with a normal menstrual cycle. The Wiley Protocol has been criticized for a variety of reasons.