Non-FDA Approved Hormone Therapies on the Rise

Use of potentially risky, non-FDA approved hormone therapies may soon be as common as use of FDA-approved hormone therapies, according to a study by University of Virginia gynecology researcher JoAnn Pinkerton.

Based on an online survey of pharmacists, between 28 and 68 percent of menopausal hormone users take “compounded therapies,” hormone formulations that have been compounded by pharmacists, the study reports. Some of the ingredients, like estradiol and progesterone, are available in FDA-approved therapies, while others, such as estriol, are considered investigational in the US. The compounded products have not gone through rigorous clinical trials, and are not approved or monitored by the FDA.

This rise is believed to have occurred in reaction to the 2002 Women’s Health Initiative (WHI), the massive FDA-approved hormone study that was halted early because of some small but apparently significant health problems.

Since then, many new studies and meta-studies have found that most FDA-approved hormone formulations are not harmful in the way they were interpreted to be post-WHI. Indeed, many are now associated with increased longevity when used properly in healthy menopausal women under 60, starting the therapy shortly after menopause. Still, between 2002 and 2012, sales of FDA-approved hormones dropped 61 percent, as sales of unapproved hormones rose.

One reason: unapproved compounded therapies have been touted as “bioidentical,” without full disclosure of their unmonitored status, by various celebrities.

The irony is that women essentially have available to them FDA-approved bio-identicals. Called “physiologic” hormone formulations, they are more “humanlike” than the synthetic progesterone (Wyeth’s Provera), and to some extent the estrogen (Wyeth’s Premarin), in the WHI. (Please see Bioscience Technology's recent article on physiologic FDA-approved hormones here. FDA-approved physiologic hormones include 17-beta estradiol patches like Climara and Vivelle, and micronized progesterone gels and pills, like Crinone and Prometrium.) But unlike unapproved compounded bioidenticals, the FDA-approved therapies of physiologic hormone preparations are known, catalogued, studied, uniformly packaged, and approved. Furthermore, unlike compounded unapproved bioidenticals, the FDA-approved formulations’ long-term effects are continually being studied. This is possible precisely because their ingredients are so well-known, uniform, and titred, in order to make it through the FDA approval process and ongoing FDA monitoring.

But many patients—and many providers—do not even know that there is an approved version of physiologic therapies, according to the Pinkerton study. Others don’t know their bioidenticals are unapproved by the FDA.

Decrease in prescriptions

“Data over the last decade show a 61 percent decrease in prescriptions for FDA-approved formulations of menopausal hormone therapy (MHT), from 93 million to 36 million,” Pinkerton told Bioscience Technology. “This decline began in relation to the first results released from the WHI. Since then, health care providers have been trying to meet the needs of symptomatic menopausal women in an atmosphere of fear of hormone therapy. At the same time, there have been unsubstantiated claims that compounded hormone therapies are safer than FDA approved products. Almost half of the compounding websites reviewed” in Pinkerton’s study “contained claims that compounded MHT was generally safer than FDA-approved MHT and had fewer side effects.” (See also the Yuksel et al. survey in abstract #S10 at the 2014 NAMI conference.)

Furthermore, Pinkerton told Bioscience Technology, recent consumer and pharmacy data from the above survey “suggest that there has been a sharp increase in the use of compounded menopausal hormone therapies since 2002, and that there is a lack of awareness that these compounded formulations, which require a prescription, are not approved by FDA.”

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Pinkerton noted that “all” the major medical societies (ACOG, the Endocrine Society, NAM, ASRM) “recommend FDA-approved well-studied therapies as first line due to published data on safety, efficacy, and presence of labels and black box warnings when appropriate. However, some providers may believe the hype and myths that compounded therapies are ‘safer than approved therapies’ and, ‘have no risks’ or ‘fewer risks’ despite the absence of well-controlled clinical trial efficacy and safety data on the compounded products themselves."

In other words, Pinkerton said, “Providers may not be aware of unique risks associated with compounding.”

Product risks

There are many dangers here, said Pinkerton. “Unsubstantiated claims lead women to think that these products have no risk, low risk or may even prevent cancer.” For example, she said, a compounded form of an estrogen called estriol “has been touted to prevent breast cancer without any data to back up the claim. Estriol is a weak estrogen but has potential to stimulate breast and uterus if dosed high enough."

The lack of a label or any warning about “risks of the hormone therapy, relative and absolute contraindications, along with a lack of understanding of unique risks associated with compounding, may lead to a false sense of safety or security,” Pinkerton said.

Furthermore, she said, potential risks of compounded hormone therapies “beyond the lack of rigorous testing, thus limiting safety and efficacy data and lack of appropriate labeling, regulation or monitoring, include possible presence of contaminants, lack of sterility, and concerns of overdosing or underdosing, which could increase health risks such as cancer.”

In short, Pinkerton said, FDA-approved menopausal hormone therapies provide “tested and regulated therapy, while compounded therapies provide less tested and less well regulated therapies.”

Agreed Rogerio Lobo, a Columbia University endocrinologist involved in many trials of FDA-approved therapies: “All major Societies (Endocrine, ACOG, ASRM, NAMS) have written strong statements against the proliferation of compounding hormonal preparations.”

Lobo, who was not involved in the Pinkerton study, told Bioscience Technology that “among the concerns are that they are not regulated, have no quality control, and they make false claims that they are safer, when they are not. Also, they usually contain a mixture of hormones and pro-hormones, many of which are not necessary and are not physiologic. Patients have no idea about these issues, and that they are not FDA-approved. However patients gravitate to this because of the claims of ‘natural’ and ‘safe’ and a lot of this is driven by mass media.”

A major problem has been that patients don’t know to ask some simple questions, Lobo said. “If patients were to ask if the product is FDA-approved, they should get the correct answer, but they don't know to ask this question. They ask the provider about recommendations for natural and safe and this is what they get.”

Protection

Patients can protect themselves by checking box labels, said Pinkerton. “Compounded therapies, obtained from compounding pharmacies, lack approved FDA package labeling outlining risks, benefits, and approved indications. In particular, compounded products do not provide the black box warning about estrogen and progestogen that appears with all FDA-approved therapies.”

Patients can also ask their provider or pharmacist if the product they are receiving is compounded. If it is, patients can either request FDA-approved products instead, or ask a series of questions. They should ask why the compounded drug was recommended; what its risks are; and whether the pharmacy is accredited by pcab.org, so a follower of good manufacturing practices.

Cautioned Pinkerton: "With the knowledge that compounded menopausal hormone therapy prescriptions may be approaching the same numbers as FDA-approved menopausal hormone therapy, we need to increase awareness among practitioners and patients of potential safety implications associated with compounded hormone therapy.”

Pinkerton emphasized, like Lobo, that all major medical societies “with menopausal specialists are unanimous that FDA-approved estradiol and progesterone therapies are preferred.”

Both Pinkerton and Lobo prescribe FDA-approved physiologic hormones. As noted above, approved hormones can include 17-beta estradiol patches like Climara and Vivelle; micronized progesterones like the Prometrium pill and Crinone gel. They also prescribe the less physiologic, but still humanlike, Premarin from the WHI study, if they and countless other professionals avoid the WHI’s synthetic, non-physiologic progesterone, called Provera.

Many believe Provera may have caused many of the problems seen in the WHI, although that study and others have found timing of therapy initiation is also key for safe and effective hormone use.