Custom-compounded BHT is a practice almost wholly restricted to the United States. Compounded BHT is a form of alternative medicine. It has been promoted as a panacea for many diseases and for relieving the symptoms of menopause, beyond the medical objective of reducing the risk of osteoporosis. There is little evidence to support these incremental claims; the hormones are expected to have the same risks and benefits of comparable approved drugs for which there is evidence based on extensive research and regulation. The exception is progesterone, which may have an improved safety profile than artificial progestogens, though direct comparisons with progestins have not been made. Risks associated with the less-controlled process of compounding bioidentical hormones are not clearly understood. 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 are similar; and that compounded hormone products may have additional risks related to compounding. A major safety concern in compounded BHT 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 any hormone-related problems and dangers are exclusively related to non-bioidentical hormones, and that compounded BHT is therefore safe and has no side effects. In reality, the risks of bioidentical hormones have not been studied to the extent of non-bioidentical hormones, so the risks are not well-understood. Regulatory bodies require pharmacies to include important safety information with conventional hormone replacement therapy (CHRT) via package inserts. Bioidentical hormones were first used for menopausal symptom relief in the 1930s, after Canadian researcher James Collip developed a method to extract an orally active estrogen from the urine of pregnant women and marketed it as the active agent in a product called Emmenin. It was supplanted on the market when its manufacturer, Ayerst (later Wyeth Pharmaceuticals), began producing the more easily manufactured conjugated equine estrogens in 1941 under the brand name Premarin; by 1992, Premarin was the most widely prescribed drug in the United States. In the 1970s, research and reports indicating risks from synthetic conjugated estrogens began to appear. Investigation determined that the addition of a progestogen to estrogen treatment reduced the risks. As early as 1980, the British Medical Journal (now BMJ) recommended oral bioidentical progesterone as an option when side effects from synthetic progestogens otherwise mandated discontinuing treatment. 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 BHT. Lee authored several popular books on 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; 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 BHT; he promoted a triple-estrogen formula he called 'Triest', which combined the most common 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 most of them to estrone. No followup 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 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 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 actress Suzanne Somers in 2006, the term 'bioidentical' gained more prominence in popular consciousness as a 'poorly understood new adjective' regarding hormone replacement therapy. There is no single definition for the term 'bioidentical hormone replacement therapy' (BHT); 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 not all allegedly bioidentical hormones sold by custom-compounding pharmacies are necessarily molecularly identical to endogenous humans). 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. 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. 'BHT' 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 an emphasis on countering the effects of aging rather than relieving the symptoms of menopause. This compounded BHT 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 BHT has been marketed on the internet by pharmacies which 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: