Women’s Health

HRT Has an Uncertainty Problem. Does Compounding Make It Worse?

The pendulum has swung back and forth on hormone replacement therapy. Bespoke and supposed more ‘natural’ hormone combinations put together by compounding pharmacists have become popular. Mainstream endocrinologists see compounding as risky, partly because the practitioners who prescribe it may not see the dangers.

Jan Greene
Contributing Editor

JoAnn Pinkerton, MD, a gynecologist whose medical practice focuses on women’s midlife issues, worries about the millions of women who have sought out hormone therapy for their menopause symptoms from alternative practitioners because of fear of, disdain for, or distrust of Big Pharma and traditional hormone replacement therapy. Pinkerton tells of a 65-year-old patient whose naturopath put her on an estrogen product and an alternative anti-aging protocol for years. What the naturopath apparently didn’t factor in was the patient’s breast cancer history, which had been a large, node-positive, estrogen-positive cancer. Pinkerton checked the woman’s blood and found very high levels of estrogen. “If she had any cells that escaped [her breast cancer treatment] she could be feeding them,” Pinkerton says.

Menopausal women struggling with symptoms from the ebbing of estrogen have seen the medical establishment’s advice on what to do swing wildly back and forth. Starting in the 1960s, they could get estrogen HRT and later, estrogen with progesterone, added to protect against uterine cancer. When, in 2002, the results of the NIH-sponsored Women’s Health Initiative study on postmenopausal health suggested that HRT could raise cardiovascular and breast cancer risks, many women either gave up on HRT altogether or turned to alternative options.

In the intervening years, new interpretations of the WHI data and follow-up research have produced a more nuanced picture of the risks and benefits. As a result, the advice is complex, evolving, and still percolating down to providers. Clinicians who see women at midlife may offer widely varying advice about HRT.

The uncertainty has created an opening for alternative practitioners (and their celebrity promoters) for so-called bioidentical hormones—versions of estrogen and progesterone derived from Mexican yam and soy that are closer to those a woman’s body produces than the conjugated estrogen derived from mares’ urine (Premarin). Bioidentical versions of estrogen and progesterone are produced by both pharmaceutical companies and compounding pharmacists working with alternative providers.

The difference is that compounding pharmacists are free to include varying dosages of estrogen and progesterone. Their recipes may also include testosterone and DHEA (a hormone produced by the adrenal glands). Some use blood tests to track the amount of resulting estrogen and labs that they say can track subtle changes in hormone levels through saliva tests. All of this makes many doctors nervous.

Systemic bioidentical hormone therapy
BHT approved by the FDA Compounded BHT
Estrogena
Estradiol oral tablets (0.5, 1.0, or 2.0 mg) Estradiol
Estradiol transdermal patches (14, 25, 37.5, 50, 75, 100 μg) Estriolb
Estradiol transdermal gels, emulsions, spray (doses range) Biestrogen (20% estradiol, 80% estriol)
Estradiol vaginal ring (provides 90-day systemic levels) Triestrogen (10% estrone, 10% estradiol, 80% estriol)
Micronized progesterone oral capsules (100, 200 mg) Progesteronea
Combination therapiesc
Estradiol with progesterone
Estriol with progesterone
Biestrogen with progesterone
Triestrogen with progesterone
Testosteronea,d
BHT=bioidentical hormone therapy, FDA=U.S. Food and Drug Administration, HRT=hormone-replacement therapy.
aCompounded products (estradiol, estriol, biestrogen, triestrogen, progesterone, testosterone) are available as oral capsules, creams, or gels.
bEstriol is an endogenous estrogen that is prominent during pregnancy. There is no FDA-approved preparation of estriol. Compounding of this product has been permitted because estriol has a United States Pharmacopeia monograph. The FDA has urged compounders to file an investigational New Drug Application for this product.
cCombination therapies are available as capsules or creams; no FDA-approved estradiol and progesterone combination therapy is currently available.
dTestosterone is not available in FDA-approved formulations specifically dosed for women.
Source: Adapted from Stuenkel CA and Manson JE, JAMA Internal Medicine, December 2017

But that hasn’t stopped millions of women from seeking out compounded hormones; a 2015 survey estimated 26 million to 33 million such prescriptions are filled each year, with sales over $1 billion. There are plenty of conventional providers willing to take their patients on this alternative path; a survey of Kansas physicians published in 2018 found 66% had prescribed compounded bioidentical HRT. More than half of the primary care doctors in that survey disagreed with the statement that conventional HRT is more appropriate than compounded preparations.

This is all despite a clear message from mainstream endocrinologists that getting your hormones from a compounding pharmacy is unsafe. Their main arguments include the absence of FDA approval and uncertainty about whether they are delivering the promised level of hormone. Moreover, as in the case of Pinkerton’s patient, some of the practitioners who prescribe bespoke HRT may have a blind spot about the possible risks because tailored and natural may seem safe.

In mid-2018, the California Medical Board came down hard on so-called “doctor to the stars” Prudence Hall, MD; her “mindful” medical approach was featured on Oprah’s television network and drew testimonials from Suzanne Somers and Cindy Crawford. When one of her patients developed an aggressive ovarian cancer after being given compounded hormones and other supplements, the board placed Hall on probation for four years and faulted her for being unaware of the health risks of plant-based hormones.

False dichotomy

While some doctors still hew to the anti-HRT line resulting from the WHI study and recommend their patients steer clear altogether, others are following the latest practice guidelines that say hormone replacement is just fine if it is initiated within a few years after a woman’s periods end and doesn’t continue for more than 10 years.

Women also need an individualized risk assessment; someone with breast cancer risk, for instance, would not be a candidate for any form of HRT.

JoAnn Pinkerton, MD

The problem is that many providers (and insurers) haven’t kept up with choosing the right product for a woman’s specific problem, says JoAnn Pinkerton, MD.

Pinkerton, executive director of the North American Menopause Society and a professor of obstetrics and gynecology at the University of Virginia Health System, likes to bust one myth right up front: Women aren’t facing a binary choice between old-fashioned, mainstream Big Pharma HRT and a “natural” approach offered by an alternative provider. She points out that there are plenty of FDA-approved, mainstream products made from bioidentical hormones, and they come in a wide variety of forms (pills, patches, gels, sprays, creams, rings) to suit a woman’s specific needs. For instance, if a woman’s main problem is vaginal dryness, she can be prescribed a bioidentical hormone cream that treats the local area and has minimal systemic effects.

The problem is that many providers (and insurers) haven’t kept up with choosing the right product for a woman’s specific problem or risk factors, Pinkerton says. “In the past five years we’ve made tremendous strides in understanding who are the best candidates for hormone therapy and all the different options available.”

For many symptomatic menopausal women under age 60 or within 10 years of menopause, the benefits of hormone therapy will outweigh the risks, says Pinkerton (and that is what the North American Menopause Society guidelines say). “But for women who use hormones later, we need to minimize risks, often with lower dose, transdermal products,” she says.

Many providers and insurers don’t know what products to choose for a specific problem, says JoAnn Pinkerton, MD, of the North American Menopause Society.

Pinkerton is frustrated by the narrow set of options most insurers will cover, mostly focused on pills or a weekly patch. “Insurance companies don’t really understand the differences between systemic and vaginal therapies and the different risks women have, particulary as they age, while on oral therapies,” she says. Her older patients do better on newer low-dose transdermal hormone therapy options but may have trouble getting them covered. “I wish managed care could understand that in 16 years we’ve come a long way in understanding for whom hormone therapy is safe and that we need to use our knowledge to pick the safest therapy for women as they age.”

The HRT landscape is constantly shifting and will again in spring 2019 when the newly FDA approved Bijuva, the first oral combination of bioidentical estrogen and progesterone, comes on the market. One analyst said that Bijuva, made by TherapeuticsMD, a company in Boca Raton, Fla., that specializes in products for women, could be a blockbuster. Pinkerton says the new medication may be attractive to many women who want to take oral combined bioidentical hormones but are more comfortable with an FDA-approved version. However, she worries about how long it may take to get on to insurers’ formularies.

There are a growing number of FDA-approved bioidentifical hormones. However, as Pinkerton points out, they are estrogen alone. For women with a uterus, bioidentical progesterone has needed to be given separately.

Overall, women and their physicians have an increasing number of HRT products to choose from, although for women with insurance, formulary tiers and cost may hem in the range of affordable picks. Pinkerton points to the increasing number of low-dose synthetic combinations on the market and the range of options for women with vaginal atrophy or who suffer from painful intercourse, which include both bioidentical vaginal estradiol creams and rings, low-dose suppositories, and Osphena (ospemifene), a selective estrogen receptor modulator.

What does natural and bioidentical really mean?

Bioidentical refers to a version of hormones that is chemically identical to the form the body produces. While “bioidentical” and “natural” suggest something better or safer than what is produced by pharmaceutical companies (and the demonized “pregnant horse pee” contained in Premarin), reality is less black and white.

The terms bioidentical or natural are used for progesterone that is extracted from soy or the wild Mexican yam through a laboratory process that converts the plant’s diosgenin into hormones usable by the body. Pharmaceutical companies produce an FDA-approved version of progesterone through this process for products such as Crinone (made by Allergan) and Prometrium (made by Abbott).

Soy products are also used to synthesize bioidentical estrogen such as the bioidentical estradiol in Novartis’s Vivelle-Dot patch.

Over-the-counter progesterone creams may use unprocessed wild Mexican yam as a source, but the body cannot metabolize the substance produced by the plant—diosgenin—until it is processed in a lab, so these products are not actually providing progesterone unless USP progestrone has been added.

Using terms such as “natural” and “synthetic” may be misleading. After all, Premarin might be deemed natural because it comes from a biological source (pregnant mares). But it isn’t bioidentical because it is chemically different from what is produced by the human body. At the same time, bioidentical estrogen from plant sources may be bioidentical but could also be considered synthetic because it’s processed in a lab.

Compounding pharmacists source their estrogen and progesterone from FDA-approved, USP sources, and will generally use bioidentical versions and put them in a cream form to avoid concerns about oral use and possible liver damage. Their patients are generally looking for a product that is bioidentical and in a dosage individualized for them.

The FDA has approved an oral combination pill of bioidentical versions of estrogen and progesterone that will be available on the market as Bijuva in spring 2019. The product may be appealing to women who want a product as close as possible to what the body produces; others may be turned off by the fact that it is being sold by a publicly traded company.

Current HRT guidelines: Risk–benefit ratio changes with age

The current advice for HRT for menopause symptoms from the North American Menopause Society (updated in 2017) is that hormone therapy remains the most effective treatment for vasomotor symptoms and genitourinary syndrome of menopause. The guidelines recommend individualizing therapy. The panel concluded that’s there a positive benefit-to-risk ratio for HRT for women who are younger than 60 or within 10 years of menopause and having no contraindications. The ratio is less favorable for women who are 10 years away from the onset of menopause or who are older than 60. HRT is not recommended for them.

HRT had been recommended as a way to reduce the risk of osteoporosis. Last year the U.S. Preventive Services Task Force said that HRT combined estrogen and progestin and should not be prescribed to prevent chronic conditions like osteoporosis. However, the recommendation was limited to chronic illness prevention and didn’t address treatment of menopausal symptoms.

The FDA tiptoes in

Despite the many millions of American women navigating this confusing area of health care with little guidance, the FDA has largely stayed out of compounded hormones citing lack of jurisdiction. But the agency does have a regulatory project under way to address compounding in general. It has been working since 2013 on a list of substances that should not be compounded. Estrogen has appeared on a draft of that list, prompting protests from alternative medicine practitioners that they will lose the ability to provide a compounded version of HRT.

The FDA recently asked the National Academies of Science, Engineering, and Medicine to carry out a study on compounded hormones even though FDA regulates them only tangentially. “We anticipate this study will help inform regulatory decisions related to compounded drugs, such as development of a list of bulk drug substances that may be used in compounding by outsourcing facilities, and will also be of use to health care providers and patients,” an FDA spokesperson said in response to questions. The study is just getting under way in early 2019, and a report is expected in 2020.

These pharmacists compound, but they’re not the problem, they say

Cheri Garvin

Like many of her colleagues, compounding pharmacist Cheri Garvin, who practices in Leesburg, Va., is straddling the mainstream and alternative medical worlds. Her pharmacy produces bespoke versions of medications for children or people who can’t swallow well, as well as serving alternative medicine providers who offer patients alternative HRT. She works with a laboratory that offers hormone consultations along with saliva test monitoring. Patients sometimes come directly to her pharmacy with their complaints and she works with their physician on a compounded solution.

Garvin’s philosophy on hormones is to use the lowest dose possible that gives relief. “We’ve gone from the WHI study to Suzanne Somers saying everyone should be on hormones,” Garvin notes. “We’ve come to realize there is a need there. There are some positives to it but obviously some health concerns we need to keep in mind.”

Michael Sun

Michael Sun is finishing pharmacy school in California and doing a residency at a compounding pharmacy in Arizona. Fully two thirds of the patients he sees there are women seeking relief from menopause symptoms.

Recognizing a lack of clear standards on compounded hormones, Sun is carrying out a small research study in which he is recruiting patients, having them fill out a standardized symptom survey, providing a compounded hormone cream, and carrying out follow-up blood tests and surveys at six-week intervals.

He hopes to quantify the positive role a compounding pharmacist can have, in conjunction with a prescribing physician. He notes that many physicians will send an open-ended prescription to a compounding pharmacy, leaning on the pharmacist to figure out dosing.