Promoted to treat vague symptoms and conditions like “hormone imbalance,” custom-compounded bioidentical hormones are increasing in popularity — and problems.
By the time the patient came into the care of endocrinologist Margaret Wierman, MD, she had already had her ovaries removed. She had presented to the obstetrics and gynecology department with very high testosterone levels and postmenopausal hirsutism that included extra facial hair and male pattern balding. An ultrasound had led to worries about an ovarian tumor, and hence their removal. When her postoperative androgen levels remained elevated, she was referred to endocrinology.
Only when Wierman did an in-depth history did the woman finally reveal that she and her husband had gone to an anti-aging clinic and been implanted with testosterone pellets. “I watched her for over 12 months, as her testosterone slowly fell,” says Wierman, who is professor in medicine, OBGYN, physiology, and biophysics at the University of Colorado School of Medicine and chief of endocrinology at the Rocky Mountain Regional Veterans Affairs Medical Center. The patient didn’t know to mention the testosterone treatment to earlier providers, perhaps because “she didn’t actually know what she had gotten,” Wierman says.
The patient had received a treatment known as bioidentical hormone replacement therapy (BHRT) that is being promoted on the internet, at anti-aging clinics, and by many practitioners. BHRT pellets are subcutaneous implants generally inserted into the hip area and used to treat everything from low libido to hair loss. Hormones may include various estrogens and prohormones such as DHEA or androstenedione, but the most commonly reported problems seem to stem from women given long-term supraphysiologic doses of testosterone, a treatment for which there is no generally accepted medical indication.
- An alarming number of patients have begun appearing in endocrinologists’ offices with symptoms caused by high testosterone levels from custom-compounded bioidentical hormone implants.
- These products are gaining traction through word-of-mouth, anti-aging clinics, and internet promotion as “more natural” and “individualized” approaches to correcting “hormone imbalance” compared with FDA-approved hormone replacements.
- Some practitioners are providing these products in direct contravention of the recommendations of evidence-based clinical guidelines.
Nanette Santoro, MD, E. Stewart Taylor Endowed Chair in the Department of Obstetrics and Gynecology at the University of Colorado School of Medicine in Denver, traces the appeal of this treatment back to a reaction to misleading interpretations of the results of menopausal hormone therapy from the Women’s Health Initiative. “The message patients got was that mainstream medicine hormones are bad, and that message was distorted into: ‘Those hormones that doctors give you are bad, but this mom-and-pop shop is compounding this all-natural stuff, and they have not been proven to cause any of these problems.’”
The use of BHRT is spreading via the internet, word of mouth, and even physicians and nurse practitioners. Linda Buckley, MD, an endocrinologist in private practice in the Denver area, says these patients used to present a couple of times a year, but now they are beginning to appear weekly: “We really saw it take off it when the GYNs in the community started using it, because patients were going to their providers with nonspecific complaints like poor libido and decreased energy. We have seen women with testosterone levels of 400 or 500 or 600 ng/dL. They have acne and hair growth, and they are irritable.” The normal range is generally less than 50 ng/mL in premenopausal women and less than 20 ng/dL in postmenopausal women.
One of the first of these patients had a history of estrogen-positive breast cancer treated with an ovariectomy and a bilateral mastectomy. Her plastic surgeon recommended BHRT testosterone pellets, apparently unaware that the testosterone can be aromatized into estrogen. “We do everything we can to deplete the patient of estrogen when they have estrogen-positive breast cancers. It was highly alarming to us. We spoke to this plastic surgeon, who made some very erroneous statements,” Buckley says.
Wierman had a patient with an enlarging meningioma who had been given pellets containing testosterone, estrogen, and progesterone: “She had levels in the male range of testosterone, which can be converted into estrogens when given at high doses. There are data about these meningiomas growing in response to estrogen and progestins. So it makes you wonder whether this tumor in her brain grew because of the pellets that she got put inside her.”
Santoro had a patient who had testosterone levels close to the male range: “We are going on six months of waiting for her testosterone to come back down to the upper limit of the normal female range.” Santoro has also seen aromatase inhibitors being given with the testosterone “to supposedly block the estrogen effect on the breast and make the treatment safe for people with cancer. That is going to very dangerous places, as there are no follow-up data on such treatments that would justify widespread use.”
“Pharmacologic levels of testosterone in women as given in pellets or injections tend to cause a worsening cholesterol profile, high LDL cholesterol, male pattern balding, hirsutism, and acne. They obviously are anabolic, so they may increase muscle mass and decrease fat mass, and at high levels, they may activate ‘more energy’—but at what cost?” – Margaret Wierman, MD, professor in medicine, OBGYN, physiology, and biophysics, University of Colorado School of Medicine; chief of endocrinology, Rocky Mountain Regional Veterans Affairs Medical Center, Denver
Testosterone in Women
Buckley says that it can be difficult to discover the cause of some women’s problems because these “patients were told ‘don’t tell your endocrinologist that you are doing this. They don’t agree with this.’ The practitioners make derogatory comments about endocrinologists not being supportive of testosterone replacement in women.”
The reason that endocrinologists do not support testosterone treatment in healthy women can be found in “Androgen Therapy in Women: A Reappraisal: An Endocrine Society Clinical Practice Guideline.” “We continue to recommend against making a diagnosis of androgen deficiency syndrome in healthy women because there is a lack of a well-defined syndrome, and data correlating androgen levels with specific signs or symptoms are unavailable,” the guideline concludes. “We recommend against the general use of T for the following indications: infertility; sexual dysfunction other than hypoactive sexual desire disorder; cognitive, cardiovascular, metabolic, or bone health; or general well-being.”
The “Secret Hormone”
The website of BioBalance Health — one company pushing the treatment — contradicts the guideline by calling testosterone a “secret hormone” that is “not acknowledged by the medical community as important to women.”
BioBalance describes a condition that “has no official name in the medical world. We have named it Testosterone Deficiency Syndrome (TDS) for women. If you have experienced three or more of these symptoms, you may have Testosterone Deficiency Syndrome: loss of libido, can’t sleep, fatigue, hair loss, anxiety, depression, memory loss, weight gain, stubborn belly fat, loss of balance, hot flashes, no motivation, muscle tone loss, arthritis, stamina decrease, [or] sagging skin.” The website promises that BHRT can treat these symptoms.
The Hormone Therapy Centers of America website makes similar promises, saying the benefits of BHRT include “calmer, more stable mood; reduced body fat; increased energy levels; higher sex drive; stronger mental clarity; and improved muscle tone and mass” as well as “protection from age-related conditions such as heart disease, cancer, diabetes, Alzheimer’s, arthritis, [and] osteoporosis.”
The BioTE Medical website promises to correct another problem unknown to most of medical science called “hormone imbalance”: “Many women will experience a hormone imbalance and not even realize it. Symptoms can range from subtle to debilitating and are often masked by medications that are prescribed for anxiety, depression, insomnia, weight gain, and more.” BioTE Medical claims it provides individualized treatment that “studies have shown improvements in menopause, depression, anxiety, low sex drive, osteoporosis, heart disease, PMS, and many other conditions.”
The literature review performed as part of the guideline-writing process did not find these studies. Instead, Wierman, who chaired the guideline committee says the review failed to document the benefit of high physiologic doses of a testosterone patch except for a subset of women with hypoactive sexual desire disorder where the medication increased satisfying sexual events by one per month and improved libido. They suggested a short-term trial for these women with hypoactive desire disorder could be considered, but with careful monitoring. The drug, however, was later denied approval by the FDA because of concerns regarding cardiovascular safety and risk for breast cancer. Thus, there are currently no FDA-approved formulations of testosterone for women.
“Pharmacologic levels of testosterone in women as given in pellets or injections tend to cause a worsening cholesterol profile, high LDL cholesterol, male pattern balding, hirsutism, and acne. They obviously are anabolic, so they may increase muscle mass and decrease fat mass, and at high levels, they may activate ‘more energy’—but at what cost?” Wierman says.
The unreliability of the custom-compounding process for creating the pellets is another area of concern. The Endocrine Society scientific statement on compounded bioidentical hormones says:
- “There is a general lack of standardization and quality control regarding how custom-compounded bioidentical hormones are produced and administered, leading to the possibility of overdosing, underdosing, or contamination.
- “No evidence supports the popularized notion that custom-compounded bioidenticals have fewer risks when compared with Food and Drug Administration (FDA)-approved hormone treatments.
- “The [widely available] FDA-approved bioidentical hormones produced in monitored facilities demonstrate a high quality of safety and efficiency in trials; therefore, there is no rationale for the routine prescribing of unregulated, untested, and potentially harmful custom-compounded bioidentical HTs.”
The companies that market BHRT offer misleading — and obtuse — statements about their relationship with the FDA. The website of a cardiologist in the Charlottesville, Va., area who offers BioTE Medical’s product as part of her “wellness” practice says: “Although Synthetic hormones (HRT) are FDA approved, the FDA cannot approve or patent natural pellet therapy (BHRT) because it’s (sic) consists of natural occurring substances. For example, water cannot be FDA approved or patented.”
BioTE itself says that its “hormones are compounded in one of two pharmacies in the United States that are licensed FDA outsourcing centers and are held to strict standards.”
However, the FDA says that “compounded BHRT products are not FDA-approved, which means these products have not undergone an FDA assessment of quality, safety, effectiveness, and bioavailability.”
High Out-of-Pocket Costs
BHRT treatment is not cheap. The BioBalance Health website warns that insurance is not likely to cover the average annual cost of $1,536, but that patients will “save money on copays for the medications you will no longer need for blood pressure, cholesterol, dry eyes, osteoporosis, and anxiety/depression; save your marriage if health and sex are points of contention; [and] prevent Alzheimer’s disease and dementia—better than the expensive long-term care insurance.”
The websites turn this high cost to their advantage by using it to recruit more physicians to offer the treatment after receiving training from the company. BioBalance Health says physicians can “start a new practice or use your existing one to create an additional revenue stream of over $250,000 the first year for virtually no additional costs.”
“The message patients got was that mainstream medicine hormones are bad, and that message was distorted into: ‘Those hormones that doctors give you are bad, but this mom-and-pop shop is compounding this all-natural stuff, and they have not been proven to cause any of these problems.’” – Nanette Santoro, MD, E. Stewart Taylor Endowed Chair, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Denver
The Hormone Therapy Centers of America site asks: “What other procedures or services have you investigated lately that allow you to realistically add $250,000 a year to your practice for an investment of $2,500?”
The lucrative possibilities may be tempting some practitioners: One Colorado OB/GYN practice reportedly dropped its obstetrics work in order to focus solely on supplying BHRT pellets. A clinician at a different practice began offering pellet treatment to avoid losing patients to competitors who did.
Medical Community Pushes Back
Wierman, Santoro, and Buckley are all pushing back against the use of BRHT by encouraging the Endocrine Society to become more active and approaching their state medical board.
“The medical community is engaging directly with the FDA,” according to Stephanie Kutler, director of policy and advocacy programs at the Endocrine Society. At the behest of the Endocrine Society leadership, Society experts joined several other professional associations on a recent conference call with the FDA organized by the North American Menopause Society to present “evidence to support our position that bioidentical hormones should be more closely regulated by the FDA and only prescribed when clinically necessary,” Kutler says.
The Society welcomes a recent announcement that the FDA has commissioned a study by the National Academies of Science, Engineering, and Medicine to examine the scientific evidence relating to the clinical utility, safety, and effectiveness of BHRT products and plans to have some member experts engage with the study task force.