Bioidentical hormone replacement therapy

Bioidentical hormones were first used for menopausal symptom relief in the 1930s, It was supplanted on the market when its manufacturer, Ayerst (later Wyeth Pharmaceuticals), began producing the more-easily manufactured 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. Investigations determined that the addition of a progestogen to estrogen treatment reduced the risks. As early as 1980, the British Medical Journal (now The BMJ) recommended oral bioidentical progesterone as an option when side effects from synthetic progestogens otherwise mandated discontinuing treatment. 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 field of BHT. and promoted custom-compounded BHT, 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, basing his claims on anecdotal data rather than peer-reviewed research, which has not been supported by any clinical trials. Wright also authored a popular book on BHT. Compared to previous bioidentical formulas that only used estradiol, he promoted a triple-estrogen formula called Triest, which combined three estrogens found in human females: estriol, estradiol and estrone. It was based on an unpublished study whose conclusions did account for how estrogens are processed and excreted in the body—particularly how the liver processes oral estrogens, converting most of them to estrone. No follow-up was performed by Wright to replicate these observations. Wright may have been the first proponent of BHT 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 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 BHT 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 Suzanne Somers 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; 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.). The FDA considers BHT as currently used by BHT advocates to be a marketing term, not a scientific term, and does not recognize its use. and it may also mean that the hormones are "natural"; throughout the 1990s plant-derived, compounded hormones were referred to as "natural hormone therapy". BHT is often used to refer to a set of diagnostic, prescribing, preparation and marketing practices including compounding, saliva testing, and an emphasis on countering the effects of aging rather than relieving the symptoms of menopause. This compounded BHT package has been promoted by Somers, Oprah Winfrey, and other proponents as safer and more effective than CHRT, though there is no evidence to support these claims. Compounded BHT has been marketed on the internet by pharmacies that make unfounded claims for its safety and its effectiveness for a variety of conditions. 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 in two ways: to refer to the process used to manufacture all estrogens, including bioidentical estrogens, and to compounds that interact with estrogen receptors similarly to estrogen molecules but are not found in nature. Examples of the latter two include diethylstilbestrol and ethinylestradiol. ==Uses==

BHT is used to reduce the symptoms of menopause. It is also promoted by some practitioners for anti-aging purposes providing benefits beyond menopausal symptom relief, such as improving quality of life, though there is little evidence to support these claims. ==Components and compounding==

Compounded preparations of bioidentical hormones usually include estriol, estrone, estradiol, testosterone, progesterone, and sometimes dehydroepiandrosterone (DHEA), either individually or combined. 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. Estriol is not found in any FDA-approved drug, and its safety and effectiveness as a hormone supplement is unknown. 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 BHT but has not been clinically proven to prevent endometrial hyperplasia, as oral progesterone has. A 2012 practice advisory published by Canadian Family Physician concluded "there is no convincing evidence that bioidentical hormones are safer or more effective than synthetic HRT". Other hormones Testosterone supplementation can improve libido in postmenopausal women, but can also reduce levels of high-density lipoproteins. A testosterone patch has been approved for use in the United Kingdom and European Union, but in Canada and the United States there is no long-term safety data on it. 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 into testosterone then estrogen; there are no consistent scientific findings or safety information supporting its use. High levels of DHEA have been linked to breast cancer. Compounding Compounding pharmacies use commercially available bulk drugs to create new formulations which differ in form or dosage from those manufactured on a large scale by pharmaceutical companies. Custom-compounded BHT 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 BHT beyond what can be proven by evidence-based medicine, and many of their claims exceed those made by other BHT practitioners. ==Adverse effects==

BHT benefits and adverse effects are expected to be the same for bioidentical and synthetic hormones. Dosages used in BHT 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. There are potentially serious adverse effects and important safety information that is required to be given with FDA approved HRT as package inserts; however, they are typically not given (or required) with compounded bioidentical preparations, which has caused consumers to falsely assume that bioidenticals are safer than FDA-approved hormones or lack any adverse effects—one of the concerns expressed about the hormones. BHT has also been associated with endometrial cancer. A review of clinical trials studying bioidentical progesterone use found that it was ineffective in managing vasomotor symptoms of menopause, but had mild and self-limiting side effects. ==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. Although all preparations of a given type of estrogen may be molecularly identical before their introduction into the human body, estrogens administered orally are modified by the liver before entering the bloodstream and most of it is converted to estrone; estrogen bypassing the digestive tract and liver via 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. ==Criticisms==

Advocates for BHT have claimed that commonly compounded BHT preparations are not commercially available, but 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 was completed; these preparations are not approved by the FDA or Health Canada. Some advocates of compounding have also claimed that customized compounding provides customized results, but the claim is weak since compounding is aimed at producing a single hormone profile with absolute blood or saliva levels—which has not been demonstrated to be better than CHRT—and does not consider the rate at which individuals will differ in the activity, metabolism and excretion of the hormones. There have been no clinical trials directly comparing the effectiveness or efficacy of bioidentical versus non-bioidentical compounds. BHT skeptics have also pointed out that there is no certainty regarding hormone levels in the body. The warnings are supported by the Society of Obstetricians and Gynaecologists of Canada. Although promoted as a way of customizing treatment, hormone therapy does not require customization; Literature reviews by private practitioners who sell bioidentical preparations suggest benefits and advantages of BHT over its conventional counterpart, but there is skepticism over claims made about BHT; 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 chief medical editor of Endocrine Today called compounded BHT a "marketing concept" with no scientific backing, The following specific claims have been made for the efficacy of bioidentical hormones and compounded BHT, with varying evidence to support or contradict them: Somers' book may have increased awareness of the existence of BHT for a growing number of menopausal women, but also may have caused confusion by making unsubstantiated claims for BHT and referring to bioidentical hormones as non-drug products with fewer risks. Michael Cirigliano and Judi Chervenak have stated in reviews of the literature on BHT that large-scale, peer-reviewed studies should be used to establish the safety, efficacy and beliefs about the use of bioidentical hormones. • Endogeny: this meaning of natural implies that the hormones are molecularly identical to those found within the body. However, BHT is unnatural as it opposes the biologically determined declining levels of fertility hormones in aging women and medicalizes a stage of human life that is probably normal. • Plant-derived: Women who purchase compounded BHT are more likely to associate natural with the idea that the hormones are derived from plant sources. However, both bioidentical and non-bioidentical hormones are sourced from the same plants, generally soy beans or yams. ==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. Its early termination and the subsequent publicity about these previously unappreciated risks led to a decline in prescriptions for CHRT. The results from the study were used by BHT prescribers to promote bioidentical hormones as safer than the FDA-regulated preparations despite a lack of evidence; 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 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, Deborah Moskowitz published an article suggesting that some forms of bioidentical hormones may be safer than non-bioidentical hormones in safety and effectiveness, though this review was criticized for "[attempting] to demonstrate that BHT has a good safety profile, but the data presented only serve to demonstrate similar risks to conventional HRT." 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 including the non-FDA-approved hormone estriol. Stephen Barrett, the site's owner, concludes his review with: "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 BHT is used almost exclusively in the United States, and pharmacists are permitted to adjust dose and delivery method according to the prescription. However, the FDA does have authority over the compounded product. 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 began 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 FDA to survey compounded BHT 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 the 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 BHT endorsed by T. S. Wiley. Its goal is to produce serum levels of estradiol and progesterone that are identical to those of a young woman with a normal menstrual cycle. It has been criticized for a variety of reasons. Wiley has no academic credentials. ==See also==