Cover Story

Compounded hormone therapies: unproven, untested — and popular

Compounded ‘bioidentical hormones’ trade on promise of tailored hormone therapy.

As a growing population of women reaches menopause, physicians may be fielding more questions about compounded hormone therapies — or, more commonly, “bioidentical hormones.”

However, the use of hormone therapies produced by compounding pharmacies is controversial. The controversy centers around the idea that compounded hormone therapies have not been tested and are, therefore, questionable for use. However, the concept of individualized or customized hormone therapy appeals to menopausal or postmenopausal women, and these therapies have caught traction among the public.

JoAnn V. Pinkerton, MD
JoAnn V. Pinkerton

Even the term “bioidentical hormones” has taken on a different meaning. The FDA has approved hormones that are bioidentical, or having the exact structure as those produced in the body. However, marketing of compounded hormone therapies as “bioidentical hormones” may lead to confusion over what the term refers to.

Alan Garber, MD, PhD, chief medical editor of Endocrine Today, said that “bioidentical hormone replacement is a clever marketing concept devoid of scientific underpinnings, and preys upon the patient’s desire for better hormonal replacement therapies that are both safe and effective, properties totally unproven by the proponents of such agents.”

Often, the woman who enters a doctor’s office requesting bioidentical hormones does not truly know what she is asking for.

“What women want is individualized care. What bioidentical hormones promise is tailored hormone therapy,” said JoAnn V. Pinkerton, MD, medical director, Midlife Health Center, and professor of obstetrics and gynecology at the University of Virginia. Women see words like “natural” and “unique.” But, what they see is not always what they get, she said.

An appealing alternative

The popularity surrounding compounded bioidentical hormones is the result of “hyperbolic advertising,” according to Michael Cirigliano, MD, associate professor of medicine at University of Pennsylvania.

Bioidentical hormone therapy typically contains various forms of estriol, estradiol, estrone, micronized progesterone and, sometimes, testosterone and dehydroepiandrosterone. These hormones are compounded for various routes of administration – oral, topical, transdermal or suppository.

Advocates of bioidentical hormones tout them as tailor-made mixtures that replicate the normal estrogen and progesterone profile of a women’s body lost to menopause, without the risks posed by synthetic HT. Proponents emphasize the natural aspect — many bioidenticals are plant-derived, from high-yield soy and Mexican yams, in contrast with animal-derived conjugated estrogens. The Wiley Protocol pointed out that Premarin (Wyeth) stands for “pregnant mares’ urine.”

Michael Cirigliano, MD
Michael Cirigliano, MD, is an associate professor of medicine at the University of Pennsylvania.

Photo by John Flack

“In reality, it is not technically possible to tailor [hormones] to that degree,” Pinkerton said.

“The problem is every one of those compounds has been manipulated ... to attain the end product,” Cirigliano added. The only true source of bioidentical hormone is a pregnant woman’s urine, he said. Yams, horse urine and others are manipulated in a lab.

Still, experts do understand why women view bioidentical hormones as an appealing alternative to conventional HT.

The highly publicized findings from the Women’s Health Initiative, stopped early in July 2002 due to increased risk for stroke, breast cancer and cardiovascular disease, concluded that the risks of HT after menopause outweighed the benefits. The release of these data resulted in a lack of trust and concern among women and a dramatic change in attitude toward hormone therapy.

“Women in droves, 56%, went cold turkey and came off their hormones because they were convinced that they had a 26% increased risk of breast cancer,” Wulf Utian, MD, PhD, told Endocrine Today. “But they didn’t understand that was relative risk.”

Following the WHI report, claims that individualized bioidentical hormones could reduce menopausal symptoms without the risks of HT arose. Even today, more than five years later, a simple Internet search for bioidentical hormones reveals a mix of physician attitudes and websites filled with misinformation.

“Suddenly, there was a light at the end of the tunnel when women saw this attractive advertising surrounding bioidentical hormones,” said Utian, executive director of the North American Menopause Society. “The word ‘bioidentical’ has superseded the word ‘natural,’ and has become part of a selling language.”

The popular media jumped on the highly publicized book by Suzanne Somers, Ageless: The Naked Truth About Bioidentical Hormones. In the introduction, Somers writes: “A better life, a healthier life, a life of youthful energy comes from embracing antiaging medicine, and bioidentical hormone replacement is a big component. This new approach to health gives you back your lean body, shining hair and thick skin … allows your brain to work perfectly and offers the greatest defense against cancer, heart attack and Alzheimer’s disease. Don’t you want that?”

Nonscientific people have become gurus, so to speak, for the menopausal woman, Utian said.

‘Show me the data’

“My motto is, ‘In God we trust. In everyone else, show me the data,’” Cirigliano said.

However, data as to whether bioidentical hormones are superior, safer or more efficacious than conventional HT are scarce. There are no large-scale clinical trials or bioidentical hormones.

Robert W. Rebar, MD
Robert W. Rebar

Robert W. Rebar, MD, said it is difficult to understand why women continue to request bioidentical hormones despite a lack of data. “Why would anyone put something into her body that no one has ever tested?” asked Rebar, Executive Director of the American Society for Reproductive Medicine.

There are a whole series of approved hormone therapies, he said, including well-tested, FDA-approved, brand-name, standard-dosage bioidentical products sold in pharmacies (estradiol: Estrace, Bristol Myers Squibb; Estraderm, Novartis; Femring, Galen; progesterone: Prometrim, Unimed Pharms).

“I say to my patients, ‘Would you rather take a drug that has been well tested and is consistent from batch to batch, or would you rather take a drug that has no testing at all, no documented study to show what the risks are, which probably have the same class risks associated with estrogen?” said Rebar, who is also an Endocrine Today Editorial Board member.

Several medical organizations have spoken out concerning custom-compounded hormones, including The Endocrine Society (see sidebar). According to the North American Menopause Society website, “[Bioidentical hormones] may provide certain benefits, such as individualized doses and mixtures ... not available commercially. However, there may be risks to the consumer ... individually mixed recipes have not been tested to prove that they are absorbed appropriately or provide predictable levels in blood and tissue.”

Utian added, “There is a real potential health downside for women, in that they think they are being protected against certain things and, in fact, may also be put at risk for certain things. It’s just bad science and big business.”

Compounded Bioidentical Hormones vs. Commercially Available Hormones and Their Effects on Menopause Symptoms

Claiming safety

According to The International Hormone Society website, “there currently is sufficient evidence confirming the greater safety of bioidentical sex hormones compared to the nonbioidentical ones, in particular when the transdermal, nasal or intramuscular routes are used instead of the oral route.”

Several small surveys have compared bioidentical hormones and conventional HT (see chart). Boothby et al. conducted a Medline search and concluded that the few studies they could find on these hormones were too small, lacked adequate study design and were unable to prove any advantage over conventional HT.

Utian remained pessimistic about a conclusive clinical trial. “These studies are too expensive and these people really have a market, so why would they want to go and mess it up?”

Researchers from the University of Kansas are currently recruiting women for a small clinical pilot trial designed to compare estradiol, estriol and progesterone with low-dose conjugated estrogen (PremPro, Wyeth). “Estimates from sales of bulk products for compounded products suggest there may be 1 million women, if not more, taking bioidentical hormones. We need to find out if it is safe and a viable alternative to pharmaceutical-prepared synthetic molecules,” principal investigator, Jeanne Drisko, MD, said in an interview.

Comparison of Therapy

FDA regulation

The FDA has regulatory authority over custom-compounded hormones, according to Cirigliano. Available by prescription, these hormones lack a package insert that specifies safety and efficacy data. The FDA requires all FDA-approved HT, however, to contain black-box warnings that state the WHI findings.

“What is in the bottle is not necessarily what is on the label. Sometimes there is more or less, sometimes there are additional substances that should not be there, some of which may be potentially toxic,” Utian said.

In 2001, the FDA analyzed 29 products from 12 United States compounding pharmacies. More than one-third failed one or more standard quality tests, according to the analysis. In addition, nine out of 10 failed assay or potency tests; all contained less of the active ingredient than expected.

In January, the FDA took action against compounded bioidentical hormones and sent letters to seven compounding pharmacies warning them that the claims they make about safety and effectiveness of their bioidentical hormones are unsupported by medical evidence and are considered false and misleading (see sidebar).

“We want to assure that Americans receive accurate information about the risks and benefits of drug therapies,” said Janet Woodcock, MD, chief medical officer and acting director of the Center for Drug Evaluation and Research, said in a press release.

Saliva testing

Saliva testing to determine the amount of hormones in a woman’s body has not been proven accurate or reliable. Even blood tests are inaccurate, as hormone levels vary throughout the day and from day to day, according to the North American Menopause Society.

Some studies indicate that as many as five tests are necessary to get reasonable accuracy, according to Cirigliano. In one such study, Boothby et al concluded that total serum concentrations are appropriate when and if hormone levels are required, but saliva concentrations are not. These researchers said salivary testing provides poor reproducibility and is subject to large interassay variability.

Salivary hormone testing creates a dubious basis for making any such hormonal determination, Cirigliano said. “What [bioidentical hormone advocates] are doing is selling an expensive test and repeat prescriptions that are very expensive,” Utian said. “They are actually selling a fallacy there.”

Common bioidentical hormones made in the compounding pharmacy

Advice for physicians

This issue has made life difficult for physicians, according to Rebar. But the overall goal is to educate patients.

“When a woman comes into the office and requests bioidentical HT and salivary testing, to me it is an opportunity to teach,” Pinkerton said. Education includes making sure the patient understands she is running the same potential risks and benefits as with other therapies. There are times she may prescribe a compounded bioidentical hormone, she said, but not without first evaluating appropriate doses, ranges, costs and risks.

Cirigliano said he will validate the patient by listening in a non-opinionated, non-judgmental fashion. “We do not want to discourage patients from discussing these things with us,” he said. “It can drive people away and then they will just do it without telling us.”

Sometimes, a patient who is already taking compounded bioidentical hormones will enter the office. In that case, Cirigliano said he will monitor the patient and her symptoms. “The bottom line is the placebo effect actually has a fair amount of weight. So if someone feels she is deriving the benefits from some less-than-studied identity, I will work with her as long as she knows the risks and benefits,” he added.

But for most experts the first choice is an FDA-approved hormone therapy with available safety and efficacy data.

As a physician, “I am always in search of the safest, least-invasive way to deal with a patient’s issue. We all are. The problem is we have to hang our hate in some way in what the data suggest. If someone was able to prove to me in some scientific basis, like a well-done randomized trial, that bioidentical hormones are safe, I will be the first in line,” Cirigliano said. – by Katie Kalvaitis

Point/Counter

Was the action by the FDA warranted — and is it enough?

For more information:
  • Boothby LA, Doering PL and Kipersztok S. Bioidentical hormone therapy: A review. Menopause. 2004;11:356-367.
  • Cirigliano M. Bioidentical hormone therapy: A review of the evidence. J Womens Health. 2007;16:600-631.
  • FDA Center for Drug Evaluation and Research. Report: Limited FDA survey of compounded drug products. 2003. Available at: www.fda.gov/cder/pharmcomp/survey.htm. Accessed: Dec. 14, 2007.
  • Somers S. Ageless: The naked truth about bioidentical hormones. New York; Crown Publishing Group:2006.
  • Writing Group for the Women’s Health Initiative Randomized Control Trial. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the WHI randomized controlled trial. JAMA. 2002;288:321.

As a growing population of women reaches menopause, physicians may be fielding more questions about compounded hormone therapies — or, more commonly, “bioidentical hormones.”

However, the use of hormone therapies produced by compounding pharmacies is controversial. The controversy centers around the idea that compounded hormone therapies have not been tested and are, therefore, questionable for use. However, the concept of individualized or customized hormone therapy appeals to menopausal or postmenopausal women, and these therapies have caught traction among the public.

JoAnn V. Pinkerton, MD
JoAnn V. Pinkerton

Even the term “bioidentical hormones” has taken on a different meaning. The FDA has approved hormones that are bioidentical, or having the exact structure as those produced in the body. However, marketing of compounded hormone therapies as “bioidentical hormones” may lead to confusion over what the term refers to.

Alan Garber, MD, PhD, chief medical editor of Endocrine Today, said that “bioidentical hormone replacement is a clever marketing concept devoid of scientific underpinnings, and preys upon the patient’s desire for better hormonal replacement therapies that are both safe and effective, properties totally unproven by the proponents of such agents.”

Often, the woman who enters a doctor’s office requesting bioidentical hormones does not truly know what she is asking for.

“What women want is individualized care. What bioidentical hormones promise is tailored hormone therapy,” said JoAnn V. Pinkerton, MD, medical director, Midlife Health Center, and professor of obstetrics and gynecology at the University of Virginia. Women see words like “natural” and “unique.” But, what they see is not always what they get, she said.

An appealing alternative

The popularity surrounding compounded bioidentical hormones is the result of “hyperbolic advertising,” according to Michael Cirigliano, MD, associate professor of medicine at University of Pennsylvania.

Bioidentical hormone therapy typically contains various forms of estriol, estradiol, estrone, micronized progesterone and, sometimes, testosterone and dehydroepiandrosterone. These hormones are compounded for various routes of administration – oral, topical, transdermal or suppository.

Advocates of bioidentical hormones tout them as tailor-made mixtures that replicate the normal estrogen and progesterone profile of a women’s body lost to menopause, without the risks posed by synthetic HT. Proponents emphasize the natural aspect — many bioidenticals are plant-derived, from high-yield soy and Mexican yams, in contrast with animal-derived conjugated estrogens. The Wiley Protocol pointed out that Premarin (Wyeth) stands for “pregnant mares’ urine.”

Michael Cirigliano, MD
Michael Cirigliano, MD, is an associate professor of medicine at the University of Pennsylvania.

Photo by John Flack

“In reality, it is not technically possible to tailor [hormones] to that degree,” Pinkerton said.

“The problem is every one of those compounds has been manipulated ... to attain the end product,” Cirigliano added. The only true source of bioidentical hormone is a pregnant woman’s urine, he said. Yams, horse urine and others are manipulated in a lab.

Still, experts do understand why women view bioidentical hormones as an appealing alternative to conventional HT.

The highly publicized findings from the Women’s Health Initiative, stopped early in July 2002 due to increased risk for stroke, breast cancer and cardiovascular disease, concluded that the risks of HT after menopause outweighed the benefits. The release of these data resulted in a lack of trust and concern among women and a dramatic change in attitude toward hormone therapy.

“Women in droves, 56%, went cold turkey and came off their hormones because they were convinced that they had a 26% increased risk of breast cancer,” Wulf Utian, MD, PhD, told Endocrine Today. “But they didn’t understand that was relative risk.”

Following the WHI report, claims that individualized bioidentical hormones could reduce menopausal symptoms without the risks of HT arose. Even today, more than five years later, a simple Internet search for bioidentical hormones reveals a mix of physician attitudes and websites filled with misinformation.

“Suddenly, there was a light at the end of the tunnel when women saw this attractive advertising surrounding bioidentical hormones,” said Utian, executive director of the North American Menopause Society. “The word ‘bioidentical’ has superseded the word ‘natural,’ and has become part of a selling language.”

The popular media jumped on the highly publicized book by Suzanne Somers, Ageless: The Naked Truth About Bioidentical Hormones. In the introduction, Somers writes: “A better life, a healthier life, a life of youthful energy comes from embracing antiaging medicine, and bioidentical hormone replacement is a big component. This new approach to health gives you back your lean body, shining hair and thick skin … allows your brain to work perfectly and offers the greatest defense against cancer, heart attack and Alzheimer’s disease. Don’t you want that?”

Nonscientific people have become gurus, so to speak, for the menopausal woman, Utian said.

‘Show me the data’

“My motto is, ‘In God we trust. In everyone else, show me the data,’” Cirigliano said.

However, data as to whether bioidentical hormones are superior, safer or more efficacious than conventional HT are scarce. There are no large-scale clinical trials or bioidentical hormones.

Robert W. Rebar, MD
Robert W. Rebar

Robert W. Rebar, MD, said it is difficult to understand why women continue to request bioidentical hormones despite a lack of data. “Why would anyone put something into her body that no one has ever tested?” asked Rebar, Executive Director of the American Society for Reproductive Medicine.

There are a whole series of approved hormone therapies, he said, including well-tested, FDA-approved, brand-name, standard-dosage bioidentical products sold in pharmacies (estradiol: Estrace, Bristol Myers Squibb; Estraderm, Novartis; Femring, Galen; progesterone: Prometrim, Unimed Pharms).

“I say to my patients, ‘Would you rather take a drug that has been well tested and is consistent from batch to batch, or would you rather take a drug that has no testing at all, no documented study to show what the risks are, which probably have the same class risks associated with estrogen?” said Rebar, who is also an Endocrine Today Editorial Board member.

Several medical organizations have spoken out concerning custom-compounded hormones, including The Endocrine Society (see sidebar). According to the North American Menopause Society website, “[Bioidentical hormones] may provide certain benefits, such as individualized doses and mixtures ... not available commercially. However, there may be risks to the consumer ... individually mixed recipes have not been tested to prove that they are absorbed appropriately or provide predictable levels in blood and tissue.”

Utian added, “There is a real potential health downside for women, in that they think they are being protected against certain things and, in fact, may also be put at risk for certain things. It’s just bad science and big business.”

Compounded Bioidentical Hormones vs. Commercially Available Hormones and Their Effects on Menopause Symptoms

Claiming safety

According to The International Hormone Society website, “there currently is sufficient evidence confirming the greater safety of bioidentical sex hormones compared to the nonbioidentical ones, in particular when the transdermal, nasal or intramuscular routes are used instead of the oral route.”

Several small surveys have compared bioidentical hormones and conventional HT (see chart). Boothby et al. conducted a Medline search and concluded that the few studies they could find on these hormones were too small, lacked adequate study design and were unable to prove any advantage over conventional HT.

Utian remained pessimistic about a conclusive clinical trial. “These studies are too expensive and these people really have a market, so why would they want to go and mess it up?”

Researchers from the University of Kansas are currently recruiting women for a small clinical pilot trial designed to compare estradiol, estriol and progesterone with low-dose conjugated estrogen (PremPro, Wyeth). “Estimates from sales of bulk products for compounded products suggest there may be 1 million women, if not more, taking bioidentical hormones. We need to find out if it is safe and a viable alternative to pharmaceutical-prepared synthetic molecules,” principal investigator, Jeanne Drisko, MD, said in an interview.

Comparison of Therapy

FDA regulation

The FDA has regulatory authority over custom-compounded hormones, according to Cirigliano. Available by prescription, these hormones lack a package insert that specifies safety and efficacy data. The FDA requires all FDA-approved HT, however, to contain black-box warnings that state the WHI findings.

“What is in the bottle is not necessarily what is on the label. Sometimes there is more or less, sometimes there are additional substances that should not be there, some of which may be potentially toxic,” Utian said.

In 2001, the FDA analyzed 29 products from 12 United States compounding pharmacies. More than one-third failed one or more standard quality tests, according to the analysis. In addition, nine out of 10 failed assay or potency tests; all contained less of the active ingredient than expected.

In January, the FDA took action against compounded bioidentical hormones and sent letters to seven compounding pharmacies warning them that the claims they make about safety and effectiveness of their bioidentical hormones are unsupported by medical evidence and are considered false and misleading (see sidebar).

“We want to assure that Americans receive accurate information about the risks and benefits of drug therapies,” said Janet Woodcock, MD, chief medical officer and acting director of the Center for Drug Evaluation and Research, said in a press release.

Saliva testing

Saliva testing to determine the amount of hormones in a woman’s body has not been proven accurate or reliable. Even blood tests are inaccurate, as hormone levels vary throughout the day and from day to day, according to the North American Menopause Society.

Some studies indicate that as many as five tests are necessary to get reasonable accuracy, according to Cirigliano. In one such study, Boothby et al concluded that total serum concentrations are appropriate when and if hormone levels are required, but saliva concentrations are not. These researchers said salivary testing provides poor reproducibility and is subject to large interassay variability.

Salivary hormone testing creates a dubious basis for making any such hormonal determination, Cirigliano said. “What [bioidentical hormone advocates] are doing is selling an expensive test and repeat prescriptions that are very expensive,” Utian said. “They are actually selling a fallacy there.”

Common bioidentical hormones made in the compounding pharmacy

Advice for physicians

This issue has made life difficult for physicians, according to Rebar. But the overall goal is to educate patients.

“When a woman comes into the office and requests bioidentical HT and salivary testing, to me it is an opportunity to teach,” Pinkerton said. Education includes making sure the patient understands she is running the same potential risks and benefits as with other therapies. There are times she may prescribe a compounded bioidentical hormone, she said, but not without first evaluating appropriate doses, ranges, costs and risks.

Cirigliano said he will validate the patient by listening in a non-opinionated, non-judgmental fashion. “We do not want to discourage patients from discussing these things with us,” he said. “It can drive people away and then they will just do it without telling us.”

Sometimes, a patient who is already taking compounded bioidentical hormones will enter the office. In that case, Cirigliano said he will monitor the patient and her symptoms. “The bottom line is the placebo effect actually has a fair amount of weight. So if someone feels she is deriving the benefits from some less-than-studied identity, I will work with her as long as she knows the risks and benefits,” he added.

But for most experts the first choice is an FDA-approved hormone therapy with available safety and efficacy data.

As a physician, “I am always in search of the safest, least-invasive way to deal with a patient’s issue. We all are. The problem is we have to hang our hate in some way in what the data suggest. If someone was able to prove to me in some scientific basis, like a well-done randomized trial, that bioidentical hormones are safe, I will be the first in line,” Cirigliano said. – by Katie Kalvaitis

Point/Counter

Was the action by the FDA warranted — and is it enough?

For more information:
  • Boothby LA, Doering PL and Kipersztok S. Bioidentical hormone therapy: A review. Menopause. 2004;11:356-367.
  • Cirigliano M. Bioidentical hormone therapy: A review of the evidence. J Womens Health. 2007;16:600-631.
  • FDA Center for Drug Evaluation and Research. Report: Limited FDA survey of compounded drug products. 2003. Available at: www.fda.gov/cder/pharmcomp/survey.htm. Accessed: Dec. 14, 2007.
  • Somers S. Ageless: The naked truth about bioidentical hormones. New York; Crown Publishing Group:2006.
  • Writing Group for the Women’s Health Initiative Randomized Control Trial. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the WHI randomized controlled trial. JAMA. 2002;288:321.