More Women Choose Custom-Made Hormone Therapy; Influential Docs Worry About Potential Harm

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Ian Fouts, a pharmacy technician at Bird's Hill Compounding Pharmacy, works on a patient's compounded prescription. (Rachel Zimmerman/WBUR)
Ian Fouts, a pharmacy technician at Bird's Hill Compounding Pharmacy, works on a patient's compounded prescription. (Rachel Zimmerman/WBUR)

When Audrey Foster reached menopause, about 15 years ago, her Boston gynecologist prescribed hormones, even though her symptoms — a few mild hot flashes, a dip in libido and energy — weren't too bad.

Foster says that "automatically, without hesitation," the doctor put her on a popular, name-brand hormone replacement drug that was later found to increase the risk of breast cancer, heart disease and blood clots among some women.

But, Foster says, "You're going to the top doctor at the top hospital — you do what he says."

She experienced serious side effects, including bleeding, she says, so she stopped the medication and searched for a new doctor.

She found an obstetrician-gynecologist in nearby Needham who offered a more "holistic" approach and delivered the personalized care Foster craved. That doctor again prescribed hormone therapy, but in a different form: a custom-compounded, so-called "bioidentical" hormone medication that combined a low dose of estradiol (a form of estrogen), progesterone and testosterone in a cream especially made for Foster.

The term "bioidentical hormone" doesn't really have a standard definition. In general, it's taken to mean hormones that have the same chemical and molecular structure as hormones produced in the human body. These days, there are FDA-approved versions of bioidentical hormones, and there are alternative, custom-prepared varieties — like the one Foster uses — made in specialized "compounding" pharmacies.

Studies show that up to a million or more women take the custom-made hormone medications, and the number is increasing. But the trend frustrates and even alarms many doctors because custom-compounded varieties aren't FDA approved, nor do they carry labels detailing the risks and possible side effects of all types of hormone therapy.

"The promotion of the custom-compounded hormones is misleading many women into thinking that they are safer and more effective than the FDA-approved treatments and this isn't the case," says Dr. JoAnn Manson, chief of the division of preventive medicine at Brigham and Women's Hospital in Boston. "In fact it's very likely to be the opposite."

Manson, also a professor at Harvard Medical School, says she's concerned that so many women are taking the custom-compounded medications when FDA-approved options, mostly estradiol or progesterone, are available.

There's scant research on compounded hormone therapy — either their harms or benefits. One problem, according to critics, is the potential for contamination: They cite the more than 60 deaths in 2012 linked to tainted medication produced by a Massachusetts compounding pharmacy that involved drugs injected into the spine. Others note that custom-compounded blends are different: they're generally administered topically in creams and lotions, orally or vaginally.

A Dab On Each Thigh

Foster says applying her hormone cream has become routine.

"It's part of my ablutions," she said in an interview at her Back Bay home. "With brushing my teeth, I put on my hormone the evening it goes on my right thigh...and in the morning on my left."

The dose is based on an analysis of Foster's blood and its particular hormone levels, as well as ongoing conversations with her doctor about her symptoms, medical issues and lifestyle priorities.

"I just feel like it's so personalized and I've really felt well being on them," says Foster, now 64.

But Manson and others worry about possible harms: over-dosing or under-dosing, which can also lead to health problems. They also point out that no package insert comes with the products to inform patients about risks, dosing and side effects.

Calls To Action

Groups including the American College of Obstetricians and Gynecologists, the Endocrine Society and the North American Menopause Society have raised questions about the safety of custom-compounded hormone therapy, except in special cases — for instance, when a patient is allergic to an FDA-approved drug. Now Manson and colleagues are going further, calling for action to alert consumers that there are commercially available, FDA-approved bioidentical hormone replacement options. They come in various doses and forms, like patches and creams, with names like Alora, Vivelle Dot and Prometrium.

Among other strategies, Manson says, she and other "doctors concerned about women's health" are calling on the FDA to require a package insert or labeling on the compounded hormone medications, both to say they are not FDA-approved and to list the potentially serious side effects that come with hormone replacement therapy.

An FDA spokesperson said that federal law limits the agency's ability to require certain labeling on certain custom-made compounded hormones.

"This is not going to happen in the next week or so," acknowledges Manson. "It's a lengthy process."

It's pretty clear why Manson and others are raising the volume on their concerns: Use of custom compounded hormones is on the rise. A 2015 study concluded that from 1 million to 2.5 million women are using these custom-made medications, yet many "are unaware that compounded hormones have not been evaluated or approved by the FDA."

A separate analysis found that the number of prescriptions for custom-compounded hormone medications reached an estimated 26 to 33 million annually. "That approaches the 36 million prescriptions per year for well-regulated and tested FDA-approved hormone therapy," notes the North American Menopause Society, which publishes the journal Menopause, where the analysis appeared. Sales of these compounded hormone medications are estimated at $1.3 to $1.6 billion and growth is expected to continue, according to the study, funded by TherapeuticsMD, a company focused on women's health products.

Dr. Nanette Santoro, a professor of obstetrics and gynecology at the University of Colorado School of Medicine, says "a marketing juggernaut" promoting custom-compounded hormones makes it urgent to call out their potential dangers.

"There's a sense of alarm in the medical community," Santoro says. "We need to do something." In part, she says, mainstream medicine didn't see this coming, adding she's "baffled" by the surge in popularity of compounded hormone therapy.

(Manson says she takes no money for hormone research from drug companies; Santoro says one industry grant she received related to hormone research ended two years ago. Calls to hormone drug makers and the pharmaceutical industry trade group were not returned.)

Rising Popularity

Santoro and Manson say the very doctors and groups now unhappy by the growth in compounded hormone medications have contributed to the steep rise in their popularity.

In 2002, the Women’s Health Initiative, a major clinical trial for which Manson was one of the lead investigators, linked popular FDA-approved menopausal hormone therapy to increased health risks, notably breast cancer, heart problems and blood clots. That study included an estrogen-only pill and estrogen plus progestin, both derived from the urine of pregnant horses (the most common formulations at the time) and thus not "bioidentical" to human hormones.

Further analysis of the initial findings have shown that the risk is highly dependent on a woman's age, medical history and other factors. But the results were so alarming to some that use of hormone replacement therapy plunged from about 17.9 million in 2002 to about 3.7 million in 2013, according to reports.

Many doctors stopped prescribing these medicines altogether, even for newly menopausal women with severe hot flashes and other symptoms, leaving these women in the lurch. "The WHI results were never intended to be extrapolated to women in early menopause who had distressing menopausal symptoms," Manson says.

Some women and doctors felt a sense of "betrayal" after the WHI, Santoro says, a feeling that "we were told that the balance of benefit to risk for hormones was very favorable for menopausal women…and now we find out all these risks?"

With women still experiencing symptoms but not quite sure where to turn, a new industry began to flourish. The popularity of "bioidentical" hormones is fueled, in part, by celebrity backers, such as actress and author Suzanne Somers. TV personality Oprah Winfrey wrote that after only one day on "bioidentical" estrogen, "I felt the veil lift. ... After three days, the sky was bluer, my brain was no longer fuzzy, my memory was sharper. I was literally singing and had a skip in my step."

Santoro says some of the hype suggests these "bioidenticals" are "different from the bad hormones that mainstream medicine is promoting" and that "this is the hipster hormone... it's custom designed for you. We'll dial you up to what you were in your 20s and you'll feel like a filly."

But, Santoro says, "there's no science" to back up these claims.

Santoro doesn't cite any illness or harm directly related to compounded hormone drugs for menopause. "There is no monitoring process for treatments like this," she says, adding there have been a few isolated case reports of problems, for instance, endometrial cancer, which has been linked to hormone use in general. But she says the absence of harm doesn't prove safety, and it's not right that government-approved hormone drugs include warnings on potential risks while the custom-made varieties do not.

Taking compounded hormone medication, she says, "is like trying to make your own penicillin at home by letting an orange peel grow blue fungus in your pantry, and then scraping off about a teaspoon ... as opposed to taking a 500 milligram tablet of penicillin."

Even doctors who prescribe compounded hormone medication say some clinicians aren't properly trained in their use: They can overstate benefits, for instance, or rely on questionable methods to determine hormone levels, such as saliva tests.

In 2008, the FDA sent warning letters  to seven compounding pharmacy operations that claims of safety and effectiveness of their "bioidentical hormones" are "unsupported by medical evidence, and are considered false and misleading."

An FDA spokesperson says the agency remains concerned about potential health risks related to compounded drugs that may be "sub- or super‑potent, contaminated, or otherwise adulterated."

Via email the agency adds: "The adverse events most commonly associated with these products, like those related to conventionally manufactured hormones, which include breast cancer, strokes, blot clots, and heart problems, are likely to occur only after years of use, and the patient may not connect the event with the hormones they have been taking."

Patient Options

Dr. Carolyn Shaak, the Needham ob-gyn who treats Audrey Foster, started prescribing custom compounded hormone medication 20 years ago, even before the controversy over hormone replacement therapy erupted after the WHI trials. At that time, there were no low-dose "bioidentical" hormone alternatives on the market.

Now, Shaak says, she's happy to see more FDA-approved options available, and welcomes the idea of labeling compounded hormone medications to detail risks. But Shaak also says hormone compounding — which filled a market gap for years — is here to stay. The reason, she says, is that alternatives are still needed for women seeking varied doses or for those who want testosterone — which is not available for women as an FDA-approved bioidentical drug.

"We have been looking for that golden formula, that one combination of progesterone, estradiol and testosterone ... that would serve as perfect hormone replacement for all women," Shaak says. "We have not found it ... The variation amongst women and within a woman over the years is too huge."

Shaak adds: "We're not trying to circumvent the FDA, we are trying to do something the FDA can't do."

To that end, she says, she uses blood tests to assess hormone levels like fertility clinics or doctors testing for diabetes or thyroid problems use them: "We believe women should be treated just like anyone with a hormone imbalance."

The cost for the triple hormone combination therapy that Foster gets runs about $100 per month. "I just want women to start hormones with an experienced doctor who has a clue about what daily dose they should be seeking and an experienced, reputable compounding pharmacy," Shaak says.

Next door to her office in Needham is the Bird's Hill Compounding Pharmacy. Step inside and you'll see pharmacists behind glass weighing ingredients, mixing creams and manning capsule machines.

Andrew Stein, a pharmacist and manager at Bird's Hill, doesn't dispute that custom-compounded hormones are not FDA approved. But that's because the doses and key ingredients aren't standardized; they are made for each patient. Still, he says, these medications are subject to internal and external safety checks, and with the correct dosage and under supervision from a physician, the prescription compounded hormone medication he sells can be a good alternative.

The main difference, he says, is that these medicines are made from scratch, to fit each patients' particular needs: "It's like baking a cake every time — you have the recipe and the ingredients and you follow that recipe."

Still, why would consumers choose custom compounded hormones over FDA-approved products?

They're "individually tailored" Stein says, not a "cookie cutter approach."

Stein says the custom-compounded hormones he sells are quite different from the medications distributed by New England Compounding Center — the pharmacy linked to deaths from contaminated drugs. Those drugs, Stein reiterates, were injected into sensitive tissue. Stein's compounded hormone therapy, he says, is different in several ways, and not injected.

Still, insurers are reacting.

Blue Cross Blue Shield of Massachusetts, for instance, last year instituted a stringent new policy on compounded drugs amid concerns over safety, effectiveness and cost, a spokesperson said.

Now, to get compounded hormones covered by the state's largest insurer, doctors must prove that patients took two other FDA-approved drugs that failed; provide two peer-reviewed published studies showing the compounded drugs work; and list all ingredients in the compounded medication.

The new policy is working well, says Dr. Tony Dodek, Blue Cross's associate chief medical officer.

"Not only has the volume of [compounded drug] prescriptions diminished," he says, "but we've been able to control the expense associated with them and in many case we've been able to steer members to FDA-approved medications..."

Hormone 'Epic' Continues

Dr. Marcie Richardson, an ob-gyn and director of the menopause consultation service at Harvard Vanguard, takes a hybrid approach. She prescribes compounded hormone medications in some cases — when a patient already taking them doesn't want to switch, and for women who need testosterone.

But she's "irked" by the promises of youth and restored vigor made by some promoting compounds, and tries to steer patients to FDA-approved options when possible. "The hormone epic is far from over," Richardson wrote in an April editorial in Menopause. "This push for individualized, natural, compounded hormones is thriving," despite the warnings from from professional groups.

Still, Audrey Foster says, she sees no reason to change her regimen — at least not now.

"I feel that these hormones are making me a healthier, more active person — it could be a placebo for all I know, but I feel like it's working," she says. "I might be naive...[but] at least there's a doctor giving me a blood test, time and checking on me regularly. It may be blind faith but I believe in this system. I do."

This segment aired on October 11, 2016.

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Rachel Zimmerman Reporter
Rachel Zimmerman previously reported on health and the intersection of health and business for WBUR. She is working on a memoir about rebuilding her family after her husband’s suicide. 



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