Bioidentical hormone replacement therapy
Encyclopedia
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 hormone
s 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 progestin
s 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.
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.
"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:
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
.
, 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.
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.
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 progestin
s 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.
; 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.
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.
.
, 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.
(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 breast
s, skin, eyes, cardiovascular
, gastrointestinal
, genitourinary
or central nervous system
s. These risks, however, are very low.
can cause the emergence (or significant worsening) of abdominal pain
, constipation
, yeast infections, breast cancer
, cystitis
, acne
, conjunctivitis
, thrombotic disorders
resulting in pulmonary embolus
, stroke
s 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.
before entering the blood
stream 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.
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 trial
s 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."
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 assay
s. 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.
Boothby, Doering and Kipersztok summarize the issue as being a poor effort to apply principles of pharmacokinetics
to achieve individualized dosing for drugs that do not require it.
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.
that is safer than standard HRT. Literature review
s 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:
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 warning
s 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.
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.
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."
When prescribed by a licensed practitioner, the compounding of bioidentical hormones is controlled by the state pharmacy boards rather than the FDA, and pharmacist
s 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.
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s that are identical, on a molecular
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
level, with endogenous hormones in hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
. The term is also associated with pharmacy compounding
Compounding
Compounding is the mixing of drugs by a compounding pharmacist to fit the unique needs of a patient...
, blood or saliva testing
Saliva testing
Saliva testing is a diagnostic technique that involves laboratory analysis of saliva to identify markers of endocrine, immunologic, inflammatory, infectious, and other types of conditions. Saliva is a useful biological fluid for assaying steroid hormones such as cortisol, genetic material like...
, 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
Estrone
Estrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...
, estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
, progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
(which are available both in FDA-approved
Approved drug
In the United States, the FDA approves drugs. Before a drug can be prescribed, it must undergo an extensive FDA approval process. This process involves first testing the drug on animals or in medical labs. If found to be safe by the FDA and approved for the next phase of study, the drug is then...
manufactured products and as pharmacy-compounded products) testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, dehydroepiandrosterone
Dehydroepiandrosterone
5-Dehydroepiandrosterone is a 19-carbon endogenous steroid hormone. It is the major secretory steroidal product of the adrenal glands and is also produced by the gonads and the brain. DHEA is the most abundant circulating steroid in humans....
(both products have more limited availability and approval in Canada and the United States) and estriol
Estriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
(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
Alternative medicine
Alternative medicine is any healing practice, "that does not fall within the realm of conventional medicine." It is based on historical or cultural traditions, rather than on scientific evidence....
, and has been promoted as a panacea
Panacea (medicine)
The panacea , named after the Greek goddess of healing, Panacea, also known as panchrest, was supposed to be a remedy that would cure all diseases and prolong life indefinitely...
for many diseases rather than a means of relieving the symptoms of menopause
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
and/or reducing the risk of osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
(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
Evidence-based medicine
Evidence-based medicine or evidence-based practice aims to apply the best available evidence gained from the scientific method to clinical decision making. It seeks to assess the strength of evidence of the risks and benefits of treatments and diagnostic tests...
and extensive research and regulation. The exception is progesterone, which may have an improved safety profile, though direct comparisons with progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
s 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
American Congress of Obstetricians and Gynecologists
The American Congress of Obstetricians and Gynecologists , formerly the American College of Obstetricians and Gynecologists, is a professional association of medical doctors specializing in obstetrics and gynecology in the United States. It has a membership of over 55,000 and represents 90 percent...
, Society of Obstetricians and Gynaecologists of Canada
Society of Obstetricians and Gynaecologists of Canada
The Society of Obstetricians and Gynaecologists of Canada is a national medical society in Canada, representing over 3,000 obstetricians/gynecologists, family physicians, nurses, midwives, and allied health professionals in the field of sexual reproductive health...
, The Endocrine Society
The Endocrine Society
The Endocrine Society is a professional, international medical organization in the field of endocrinology and metabolism, founded in 1916 as The Association for the Study of Internal Secretions. The official name of the organization was changed to The Endocrine Society on January 1, 1952. It is a...
, the North American Menopause Society (NAMS)
North American Menopause Society
The North American Menopause Society , founded in 1989, is a nonprofit multidisciplinary organization with the mission of promoting the health and quality of life of women during midlife and beyond through an understanding of menopause and healthy aging. Based in Cleveland, Ohio, NAMS has over...
, United States Food and Drug Administration, American Association of Clinical Endocrinologists, American Medical Association
American Medical Association
The American Medical Association , founded in 1847 and incorporated in 1897, is the largest association of medical doctors and medical students in the United States.-Scope and operations:...
, American Cancer Society
American Cancer Society
The American Cancer Society is the "nationwide community-based voluntary health organization" dedicated, in their own words, "to eliminating cancer as a major health problem by preventing cancer, saving lives, and diminishing suffering from cancer, through research, education, advocacy, and...
and the Mayo Clinic
Mayo Clinic
Mayo Clinic is a not-for-profit medical practice and medical research group specializing in treating difficult patients . Patients are referred to Mayo Clinic from across the U.S. and the world, and it is known for innovative and effective treatments. Mayo Clinic is known for being at the top of...
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.
History
Bioidentical hormones were first used for menopausal symptom relief in the 1930s, after Canadian researcher James CollipJames Collip
James Bertram Collip, Ph.D. was part of the Toronto group which isolated insulin. He served as the Chair of the Department of Biochemistry at McGill University from 1928-1941 and Dean of Medicine at the University of Western Ontario from 1947-1961, where he was a charter member of The Kappa Alpha...
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
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
Pharmaceuticals), began producing the more easily-manufactured conjugated equine estrogens in 1941 under the brand name Premarin
Premarin
Premarin is the commercial name for a compound cream of vaginally administered estrogens, consisting primarily of conjugated estrogens. Isolated from mares' urine , it is manufactured by Wyeth Pharmaceuticals and has been marketed since 1942...
; 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
BMJ
BMJ is a partially open-access peer-reviewed medical journal. Originally called the British Medical Journal, the title was officially shortened to BMJ in 1988. The journal is published by the BMJ Group, a wholly owned subsidiary of the British Medical Association...
) 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
Solvay (company)
Solvay S.A. is a Belgian chemical company with its head office in Ixelles, Brussels, Belgium. It was founded in 1863 by Ernest Solvay to produce sodium carbonate by the solvay process. Since then the company has diversified to two major sectors of activity: chemicals and plastics...
.
Physicians John R. Lee and Jonathan Wright
Jonathan Wright (physician)
Jonathan Wright is the Medical Director of Tahoma Clinic in Renton, Washington, where he also practices medicine. He graduated from Harvard University Jonathan Wright is the Medical Director of Tahoma Clinic in Renton, Washington, where he also practices medicine. He graduated from Harvard...
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
American Congress of Obstetricians and Gynecologists
The American Congress of Obstetricians and Gynecologists , formerly the American College of Obstetricians and Gynecologists, is a professional association of medical doctors specializing in obstetrics and gynecology in the United States. It has a membership of over 55,000 and represents 90 percent...
state that blood and saliva testing is unreliable and biologically meaningless. Lee also believed that progesterone acted as a panacea
Panacea
In Greek mythology, Panacea was a goddess of healing. She was the daughter of Asclepius and Epione. Panacea and her five sisters each performed a facet of Apollo's art: Panacea was the goddess of cures, Iaso was the goddess of recuperation, Hygieia was the goddess of disease prevention, Aceso was...
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
Estriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
, estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
and estrone
Estrone
Estrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...
. 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
Crystallography
Crystallography is the experimental science of the arrangement of atoms in solids. The word "crystallography" derives from the Greek words crystallon = cold drop / frozen drop, with its meaning extending to all solids with some degree of transparency, and grapho = write.Before the development of...
evidence has been used to support the idea that these molecules are actually identical to endogenous human hormones. When the Women's Health Initiative
Women's Health Initiative
The Women's Health Initiative was initiated by the U.S. National Institutes of Health in 1991. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women...
'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
Suzanne Somers
Suzanne Somers is an American actress, author, singer and businesswoman, known for her television roles as Chrissy Snow on Three's Company and as Carol Lambert on Step by Step....
in 2006, the term "bioidentical" gained more prominence in popular consciousness as a "poorly understood new adjective" regarding hormone replacement therapy.
Terminology
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
Compounding
Compounding is the mixing of drugs by a compounding pharmacist to fit the unique needs of a patient...
(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 |
|---|---|---|---|
| Estrogens | |||
| micronized 17 beta-estradiol Estradiol Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect... |
|||
| 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 Estrone Estrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol... |
|
| 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 | |||
| Micronized progesterone USP | Prometrium | Pill | |
| Prochieve 4% | Vaginal gel | ||
| Combined preparations | |||
| 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
Diethylstilbestrol
Diethylstilbestrol is a synthetic nonsteroidal estrogen that was first synthesized in 1938. Human exposure to DES occurred through diverse sources, such as dietary ingestion from supplemented cattle feed and medical treatment for certain conditions, including breast and prostate cancers...
and ethinylestradiol
Ethinylestradiol
Ethynylestradiol , also ethynyl estradiol , is a derivative of estradiol. Ethynyl estradiol is an orally bio-active estrogen used in almost all modern formulations of combined oral contraceptive pills...
.
Uses
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.Components and compounding
Typically, compounded preparations of bioidentical hormones include estriolEstriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
, estrone
Estrone
Estrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...
, estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
, testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
and sometimes dehydroepiandrosterone
Dehydroepiandrosterone
5-Dehydroepiandrosterone is a 19-carbon endogenous steroid hormone. It is the major secretory steroidal product of the adrenal glands and is also produced by the gonads and the brain. DHEA is the most abundant circulating steroid in humans....
(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.
Estrogens
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
Estriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
, produced during pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
, 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
United States Pharmacopeia
The United States Pharmacopeia is the official pharmacopeia of the United States, published dually with the National Formulary as the USP-NF. The United States Pharmacopeial Convention is the nonprofit organization that owns the trademark and copyright to the USP-NF and publishes it every year...
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
Health Canada
Health Canada is the department of the government of Canada with responsibility for national public health.The current Minister of Health is Leona Aglukkaq, a Conservative Member of Parliament appointed to the position by Prime Minister Stephen Harper.-Branches, regions and agencies: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
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
and the European Union
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
. Estradiol is available as brand-name products in both oral and transdermal forms.
Progesterone
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-chiefEditor in chief
An editor-in-chief is a publication's primary editor, having final responsibility for the operations and policies. Additionally, the editor-in-chief is held accountable for delegating tasks to staff members as well as keeping up with the time it takes them to complete their task...
of the scientific journal
Scientific journal
In academic publishing, a scientific journal is a periodical publication intended to further the progress of science, usually by reporting new research. There are thousands of scientific journals in publication, and many more have been published at various points in the past...
Climacteric
Climacteric (journal)
Climacteric is an international peer-reviewed medical journal that covers all aspects of aging in men and women, especially during the menopause and climacteric...
state that the greatest difference in function between bioidentical and synthetic hormones may be found in progesterone's behavior compared with progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
. Laboratory studies have suggested that bioidentical progesterone binds primarily to progesterone receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
, while synthetic progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
s 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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
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
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
epidemiological
Epidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...
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.
Other hormones
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 EstratestEstratest
Estratest is a hormone replacement therapy drug that combines esterified estrogens with methyltestosterone in one pill.-Indications:Estratest is used to treat menopausal women who suffer from hot flashes but do not get relief from estrogen-only therapy...
; 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
Precursor (chemistry)
In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....
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
Over-the-counter drug
Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...
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
CompoundingCompounding
Compounding is the mixing of drugs by a compounding pharmacist to fit the unique needs of a patient...
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.
Adverse effects
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 cancerEndometrial cancer
Endometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
.
Estrogens
Less common (but serious) side effects of all post-menopausal estrogens include increased risk or severity of breastBreast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, ovarian
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
or uterine cancer
Uterine cancer
The term uterine cancer may refer to any of several different types of cancer which occur in the uterus, namely:*Uterine sarcomas: sarcomas of the myometrium, or muscular layer of the uterus, are most commonly leiomyosarcomas.*Endometrial cancer:...
, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, heart attack, blood clots, dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
, gallbladder disease
Gallbladder disease
Gallbladder diseases are diseases involving the gallbladder.Gallstones may develop in the gallbladder as well as elsewhere in the biliary tract...
, high blood pressure, liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
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
Melasma
Melasma is a tan or dark skin discoloration. Although it can affect anyone, melasma is particularly common in women, especially pregnant women and those who are taking oral or patch contraceptives or hormone replacement therapy medications...
), and vaginal yeast infection.
Estradiol
EstradiolEstradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
(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 breast
Breast
The breast is the upper ventral region of the torso of a primate, in left and right sides, which in a female contains the mammary gland that secretes milk used to feed infants.Both men and women develop breasts from the same embryological tissues...
s, skin, eyes, cardiovascular
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
, gastrointestinal
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
, genitourinary
Genitourinary system
In anatomy, the genitourinary system or urogenital system is the organ system of the reproductive organs and the urinary system. These are grouped together because of their proximity to each other, their common embryological origin and the use of common pathways, like the male urethra...
or central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
s. These risks, however, are very low.
Progesterone
ProgesteroneProgesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
can cause the emergence (or significant worsening) of abdominal pain
Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, yeast infections, breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, cystitis
Cystitis
Cystitis is a term that refers to urinary bladder inflammation that results from any one of a number of distinct syndromes. It is most commonly caused by a bacterial infection in which case it is referred to as a urinary tract infection.-Signs and symptoms:...
, acne
Acne
Acne is a general term used for acneiform eruptions. It is usually used as a synonym for acne vulgaris, but may also refer to:*Acne aestivalis*Acne conglobata*Acne cosmetica*Acne fulminans*Acne keloidalis nuchae*Acne mechanica...
, conjunctivitis
Conjunctivitis
Conjunctivitis refers to inflammation of the conjunctiva...
, thrombotic disorders
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
resulting in pulmonary embolus
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
s or heart attacks
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
and—due to increased fluid retention—epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
, asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
and cardiac or renal dysfunction. Psychiatric reactions can include emotional instability, depression, aggression, decreased libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
and drowsiness
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
. Adverse effects can also occur in the urinary, central or peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
or bones and muscles.
Administration
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 liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
before entering the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
stream 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.
Criticisms
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
New drug application
The New Drug Application is the vehicle in the United States through which drug sponsors formally propose that the Food and Drug Administration approve a new pharmaceutical for sale and marketing...
had been completed; these preparations are not approved by either the FDA, or Health Canada
Health Canada
Health Canada is the department of the government of Canada with responsibility for national public health.The current Minister of Health is Leona Aglukkaq, a Conservative Member of Parliament appointed to the position by Prime Minister Stephen Harper.-Branches, regions and agencies: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 trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s directly comparing the effectiveness or efficacy of bioidentical versus nonbioidentical compounds.
A 2010 article published in The Medical Letter on Drugs and Therapeutics
The Medical Letter on Drugs and Therapeutics
The Medical Letter on Drugs and Therapeutics is a scientific journal providing evaluations of drugs...
concluded "There is no acceptable evidence that 'bioidentical' hormones are safe or effective. Patients should be discouraged from taking them."
Salivary testing and compounding
BHRT is frequently associated with testing of saliva to establish a baseline hormone level and compoundingCompounding
Compounding is the mixing of drugs by a compounding pharmacist to fit the unique needs of a patient...
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
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
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 assay
Assay
An assay is a procedure in molecular biology for testing or measuring the activity of a drug or biochemical in an organism or organic sample. A quantitative assay may also measure the amount of a substance in a sample. Bioassays and immunoassays are among the many varieties of specialized...
s. 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
North American Menopause Society
The North American Menopause Society , founded in 1989, is a nonprofit multidisciplinary organization with the mission of promoting the health and quality of life of women during midlife and beyond through an understanding of menopause and healthy aging. Based in Cleveland, Ohio, NAMS has over...
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
Society of Obstetricians and Gynaecologists of Canada
The Society of Obstetricians and Gynaecologists of Canada is a national medical society in Canada, representing over 3,000 obstetricians/gynecologists, family physicians, nurses, midwives, and allied health professionals in the field of sexual reproductive health...
.
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.
Boothby, Doering and Kipersztok summarize the issue as being a poor effort to apply principles of pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
to achieve individualized dosing for drugs that do not require it.
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.
Lack of evidence for claims
Bioidentical hormones have been advertised, marketed and promoted as a risk-free panaceaPanacea
In Greek mythology, Panacea was a goddess of healing. She was the daughter of Asclepius and Epione. Panacea and her five sisters each performed a facet of Apollo's art: Panacea was the goddess of cures, Iaso was the goddess of recuperation, Hygieia was the goddess of disease prevention, Aceso was...
that is safer than standard HRT. Literature review
Literature review
A literature review is a body of text that aims to review the critical points of current knowledge including substantive findings as well as theoretical and methodological contributions to a particular topic...
s 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:
| Claim | Evidence |
|---|---|
| Bioidentical hormones fit precisely into human hormone receptors while conventional hormones fit "cockeyed"; this mismatch causes serious side effects | Synthetic progestin Progestin A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy... s and endogenous progesterone have different binding affinities for different receptors, depending on the model and animal used; these differing pharmacodynamics Pharmacodynamics Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect... have not been associated with specific side effects |
| The body is unable to metabolize synthetic hormones | The biological half-life Biological half-life The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition... for synthetic hormones is between five minutes and two days |
| Lack of progesterone causes irregular or painful, heavy menses Menstrual cycle The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle.... |
Oral progesterone is no more effective than placebo at alleviating symptoms of premenstrual syndrome |
| Progesterone can counteract stress Stress (biology) Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance... , 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 Infertility Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term... 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 Cardiovascular disease Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis... and atherosclerosis Atherosclerosis Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol... , 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 Estriol Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human... can decrease the risk of breast cancer Breast cancer Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas... |
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
Suzanne Somers
Suzanne Somers is an American actress, author, singer and businesswoman, known for her television roles as Chrissy Snow on Three's Company and as Carol Lambert on Step by Step....
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
The Oprah Winfrey Show
The Oprah Winfrey Show is an American syndicated talk show hosted and produced by its namesake Oprah Winfrey. It ran nationally for 25 seasons beginning in 1986, before concluding in 2011. It is the highest-rated talk show in American television history....
, 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
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
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 warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
s for all bioidentical products, and the establishment of a mandatory adverse-events registry.
M. Sarah Rosenthal, Director of the University of Kentucky
University of Kentucky
The University of Kentucky, also known as UK, is a public co-educational university and is one of the state's two land-grant universities, located in Lexington, 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
Conflict of interest
A conflict of interest occurs when an individual or organization is involved in multiple interests, one of which could possibly corrupt the motivation for an act in the other....
. 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.
"Natural" claims
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.- Endogeny - this meaning of "natural" implies that the hormones are molecularly identical to those found within the body. However, BHRT (like all types of HRT used in naturally menopausal women) is unnatural in that it opposes the biologically-determined declining levels of fertility hormones in aging women and medicalizes a stage of human life that is probably normal. In addition, most of the conjugated equine estrogens (CEE) extracted from pregnant horse urine (such as PremarinPremarinPremarin is the commercial name for a compound cream of vaginally administered estrogens, consisting primarily of conjugated estrogens. Isolated from mares' urine , it is manufactured by Wyeth Pharmaceuticals and has been marketed since 1942...
) are converted to human estrogens once they enter the body. However, not all are converted, and BHRT advocates allege that the small amount that is not converted may have some harmful effects. This is still being studied.
- Plant-derived - Women who purchase compounded BHRT are more likely to associate the term "natural" with the idea that the hormones are derived from plant sources. However, both bioidentical and nonbioidentical hormones are sourced from the same plants, generally soy beans or yamYam (vegetable)Yam is the common name for some species in the genus Dioscorea . These are perennial herbaceous vines cultivated for the consumption of their starchy tubers in Africa, Asia, Latin America and Oceania...
s.
- Manufacturing - both bioidentical and nonbioidentical hormones are synthesized using the same chemical precursors; diosgeninDiosgeninDiosgenin, a steroid sapogenin, is the product of hydrolysis by acids, strong bases, or enzymes of saponins, extracted from the tubers of Dioscorea wild yam, such as the Kokoro...
is extracted from soy or yam plants, converted into progesteroneProgesteroneProgesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
and used as a hormone chemical precursorPrecursor (chemistry)In chemistry, a precursor is a compound that participates in the chemical reaction that produces another compound. In biochemistry, the term "precursor" is used more specifically to refer to a chemical compound preceding another in a metabolic pathway....
to create the final product. "Natural" is also used to promote the idea of being unmodified, and containing the "goodness" of a pure substance. However, this argument simultaneously draws upon a scientific discourse and methodology; even hormones called "bioidentical" have been heavily processed and converted in a pharmaceutical lab. Premarin (conjugated estrogens extracted from the urine of pregnant horses) contains the only truly "natural" hormones—natural in the sense of being completely unmodified beyond blending the estrogens to achieve a specific ratio.
The monthly newsletter Harvard Women's Health Watch, published by Harvard Medical School
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
, 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
Premarin
Premarin is the commercial name for a compound cream of vaginally administered estrogens, consisting primarily of conjugated estrogens. Isolated from mares' urine , it is manufactured by Wyeth Pharmaceuticals and has been marketed since 1942...
), as well as the molecules extracted from soybean and yam sources used in many bioidentical and nonbioidentical commercial preparations.
Cost
Compounded BHRT is more expensive than conventional, FDA-approved HRT, and is often not covered by health insurance.Safety
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
Women's Health Initiative
The Women's Health Initiative was initiated by the U.S. National Institutes of Health in 1991. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women...
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
The Endocrine Society
The Endocrine Society is a professional, international medical organization in the field of endocrinology and metabolism, founded in 1916 as The Association for the Study of Internal Secretions. The official name of the organization was changed to The Endocrine Society on January 1, 1952. It is a...
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
American Congress of Obstetricians and Gynecologists
The American Congress of Obstetricians and Gynecologists , formerly the American College of Obstetricians and Gynecologists, is a professional association of medical doctors specializing in obstetrics and gynecology in the United States. It has a membership of over 55,000 and represents 90 percent...
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
Mayo Clinic
Mayo Clinic is a not-for-profit medical practice and medical research group specializing in treating difficult patients . Patients are referred to Mayo Clinic from across the U.S. and the world, and it is known for innovative and effective treatments. Mayo Clinic is known for being at the top of...
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
American Cancer Society
The American Cancer Society is the "nationwide community-based voluntary health organization" dedicated, in their own words, "to eliminating cancer as a major health problem by preventing cancer, saving lives, and diminishing suffering from cancer, through research, education, advocacy, and...
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
North American Menopause Society
The North American Menopause Society , founded in 1989, is a nonprofit multidisciplinary organization with the mission of promoting the health and quality of life of women during midlife and beyond through an understanding of menopause and healthy aging. Based in Cleveland, Ohio, NAMS has over...
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
Throat lozenge
A throat lozenge, cough drop, troche, or cough sweet is a small, medicated tablet intended to be dissolved slowly in the mouth to temporarily stop coughs and lubricate and soothe irritated tissues of the throat , possibly from the common cold or influenza...
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
American Medical Association
The American Medical Association , founded in 1847 and incorporated in 1897, is the largest association of medical doctors and medical students in the United States.-Scope and operations:...
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
Erika Schwartz
Erika Schwartz, MD, is a physician who has made numerous television appearances promoting the use of bioidentical hormone replacement therapy to treat the symptoms of menopause, and has written books on hormones and teen weight loss....
, 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
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
levels. Deborah Moskowitz, a Doctor of Naturopathic Medicine
Doctor of Naturopathic Medicine
Doctor of Naturopathic Medicine , in 16 U.S. states and six Canadian provinces refers exclusively to a medical degree granted by an accredited naturopathic medical school...
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
Consumer protection
Consumer protection laws designed to ensure fair trade competition and the free flow of truthful information in the marketplace. The laws are designed to prevent businesses that engage in fraud or specified unfair practices from gaining an advantage over competitors and may provide additional...
site Quackwatch
Quackwatch
Quackwatch is an American non-profit organization founded by Stephen Barrett with the stated aim being to "combat health-related frauds, myths, fads, fallacies, and misconduct" and with a primary focus on providing "quackery-related information that is difficult or impossible to get elsewhere."...
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
Estriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
. Stephen Barrett
Stephen Barrett
Stephen Joel Barrett is a retired American psychiatrist, author, co-founder of the National Council Against Health Fraud , and the webmaster of Quackwatch. He runs a number of websites dealing with quackery and health fraud. He focuses on consumer protection, medical ethics, and scientific...
, 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."
Regulatory status in the United States
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 pharmacist
Pharmacist
Pharmacists are allied health professionals who practice in pharmacy, the field of health sciences focusing on safe and effective medication use...
s 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
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...
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
American Medical Association
The American Medical Association , founded in 1847 and incorporated in 1897, is the largest association of medical doctors and medical students in the United States.-Scope and operations:...
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.
Wiley Protocol
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.See also
- EMASEuropean Menopause and Andropause SocietyThe European Menopause and Andropause Society is a medical association focused on the study and treatment of the climacteric in men and women...
, The European Menopause and Andropause Society - The Endocrine SocietyThe Endocrine SocietyThe Endocrine Society is a professional, international medical organization in the field of endocrinology and metabolism, founded in 1916 as The Association for the Study of Internal Secretions. The official name of the organization was changed to The Endocrine Society on January 1, 1952. It is a...
- International Osteoporosis FoundationInternational Osteoporosis FoundationThe International Osteoporosis Foundation , headquartered in Nyon, Switzerland, is a non-governmental organization founded in 1998. It was formed from the merger of the European Foundation for Osteoporosis, founded in 1987, and the International Federation of Societies on Skeletal Diseases...
- American College of Obstetricians and GynecologistsAmerican Congress of Obstetricians and GynecologistsThe American Congress of Obstetricians and Gynecologists , formerly the American College of Obstetricians and Gynecologists, is a professional association of medical doctors specializing in obstetrics and gynecology in the United States. It has a membership of over 55,000 and represents 90 percent...
- American College of PhysiciansAmerican College of PhysiciansThe American College of Physicians is a national organization of doctors of internal medicine —physicians who specialize in the prevention, detection, and treatment of illnesses in adults. With 130,000 members, ACP is the largest medical-specialty organization and second-largest physician group in...
- Women's healthWomen's healthWomen's health refers to health issues specific to human female anatomy. These often relate to structures such as female genitalia and breasts or to conditions caused by hormones specific to, or most notable in, females. Women's health issues include menstruation, contraception, maternal health,...
- MenopauseMenopauseMenopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
- Hot flash
- North American Menopause SocietyNorth American Menopause SocietyThe North American Menopause Society , founded in 1989, is a nonprofit multidisciplinary organization with the mission of promoting the health and quality of life of women during midlife and beyond through an understanding of menopause and healthy aging. Based in Cleveland, Ohio, NAMS has over...
, also known as NAMS
External links
- Senate Hearings on Bioidentical Hormones: Sound Science or Bad Medicine? by the United States Senate Special Committee on Aging
- Interview regarding bioidentical hormones with Arlene Weintraub on the Canadian Broadcasting CorporationCanadian Broadcasting CorporationThe Canadian Broadcasting Corporation, commonly known as CBC and officially as CBC/Radio-Canada, is a Canadian crown corporation that serves as the national public radio and television broadcaster...
radio program The CurrentThe Current (radio program)The Current is a Canadian current affairs radio program, hosted by investigative reporter Anna Maria Tremonti on CBC Radio One. It airs weekdays starting at 8:37 a.m. local time and runs until 10 a.m. for most of the year, although during the summer the program airs until 9:30 a.m...
, November 8, 2010