What are bioidentical hormones

The term “bioidentical hormone therapy” began as a marketing term for custom-compounded hormones. But it is taken to mean hormones that have the same chemical and molecular structure as hormones that are produced in your body. Bioidentical hormones are sometimes called “natural” hormones—even though they are made in a laboratory—because they come from plant sources (usually soybeans or wild yams) before being altered to be like human hormones. After the plant-based hormone is processed, its structure is said to be identical to the estrogen, progesterone, or androgen hormone your body makes. Well-designed studies have yet to prove this theory ¹. Not all hormones made from natural sources are bioidentical.

Bioidentical hormones include commercially available products approved by the U.S. Food and Drug Administration (FDA), such as micronized progesterone and estradiol, as well as compounded preparations that are not regulated by the FDA. Many compounding pharmacies use the term bioidentical hormone to imply that these preparations are natural or the same as endogenous substances and, thus, are safe. The phrase bioidentical hormone therapy has been recognized by the FDA and the Endocrine Society as a marketing term and not one based on scientific evidence ².

Bioidentical hormones do not have to be custom-compounded (meaning custom mixed). There are many well-tested, FDA-approved hormone therapy products that meet this definition and are commercially available from retail pharmacies in a variety of doses that will allow you and your doctor to customize your therapy to meet your needs. Custom-compounded hormones are not safer or more effective than approved bioidentical hormones. They are not tested for safety and effectiveness or to prove that the active ingredients are absorbed appropriately or provide predictable levels in blood and tissue. In fact, they may not even contain the prescribed amounts of hormones, and that can be dangerous. For example, when the progesterone level is too low, you are not protected against endometrial (uterine) cancer. When estrogen levels are too high, there can be overstimulation of the endometrium and breast tissue, putting you at risk of endometrial cancer and possibly breast cancer. A recent investigative report from More magazine showed that many custom-compounded hormone therapy preparations have too little progesterone and too much estrogen.

A compounding pharmacist can offer you a custom-made formulation in one of many forms. You might get a capsule, a skin cream or gel, a tablet to dissolve under your tongue, a suppository, or a nose spray. Some commonly prescribed estrogens and progesterones are bioidenticals, such as Estrace (estradiol). There’s a major difference between custom-made formulations and commercial products. Commercial products are regulated and tested for purity and potency, but compounding pharmacies are not.

Just like synthetic hormone therapy, bioidentical hormones are prescribed to increase or stabilize a woman’s hormone levels. This is most often done during perimenopause, when hormone levels change unpredictably. It’s also done after menopause, when the hormones drop to low levels.

The most important fact to remember about taking bioidentical hormones is that the risks are not yet well understood. They may have the same breast cancer, stroke, blood clot, heart disease, and dementia risks that synthetic hormone therapy has ¹.

There are two types of bioidentical hormone products:

1. Pharmaceutical products. These products have been approved by the U.S. Food and Drug Administration (FDA). Their quality and safety is regulated so it is the same high-quality product every time.
2. Custom-made products. When many people think of bioidentical hormones, they think of custom-made products. These are made in a compounding pharmacy (a pharmacy that mixes medications according to a doctor’s instructions). Drug compounding is often regarded as the process of combining, mixing, or altering ingredients to create a medication tailored to the needs of an individual patient. Compounding includes the combining of two or more drugs. Compounded drugs are not FDA-approved. These products may contain varying amounts of two or three types of estrogen, often mixed with other hormones. Although the individual ingredients are approved by the FDA (except for estriol), the compounds themselves (the final product after the ingredients are combined) are not ³. Because these compounds are not regulated by the FDA, they can be of low quality. The amount of hormone can change with each batch.
   • Examples of compounded hormones include Biest (biestrogen) and Triest (triestrogen) preparations. The name Biest commonly refers to an estrogen preparation based on a ratio of 20% estradiol and 80% estriol on a milligram-per-milligram basis. A similar preparation, Triest, usually contains a ratio of 10% estradiol, 10% estrone, and 80% estriol. These ratios are not based on each agent’s estrogenic potency but on the milligram quantity of the different agents added together ⁴. Other commonly compounded hormones include dehydroepiandrosterone, pregnenolone, testosterone, and progesterone ⁵.

Celebrity endorsements and online marketing have given increased attention to compounded bioidentical hormone formulations. Bioidentical hormones, such as estrone, 17-beta estradiol, and estriol, are identical to human hormones ⁶. Data are limited about the safety and effectiveness of compounded bioidentical formulations. There is concern that these unregulated formulations may have similar adverse effects as estrogen medications, such as endometrial hyperplasia. If a patient prefers a bioidentical hormone, U.S. Food and Drug Administration (FDA)-approved medications containing the bioidentical hormone estradiol can be considered; for women with a uterus, micronized progestogen (100 mg or 200 mg per day) should be added. Some FDA-approved products — such as Estrace, Climara and Vivelle-Dot, which contain estrogens, and Prometrium, a natural progesterone — also are derived from plants.

Most menopause specialists start with FDA-approved products, because they’ve been proven to be safe and effective. For women who cannot take these products due to allergies, or who need a special prescription, custom-made products are an option. Because the quality of custom-made products can vary, however, it is safer to use pharmaceutical products. This way, you’ll know exactly what you’re getting and how much.

If your doctor prescribes hormone therapy, the FDA recommends using the lowest possible dose for the shortest time needed to relieve symptoms. The idea is to avoid taking too much medication for too long to reduce potential risks linked to hormone therapy. You might also want to consider the wide range of non-hormonal options available to treat menopausal symptoms.

Finding the type of treatment that works best for you may take some time. Whatever you choose, your doctor will monitor your therapy regularly.

The American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice and the Practice Committee of the American Society for Reproductive Medicine make the following conclusions and recommendations ⁷:

• Evidence is lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal hormone therapy.
• Customized compounded hormones pose additional risks. These preparations have variable purity and potency and lack efficacy and safety data.
• Because of variable bioavailability and bioactivity, both underdosage and overdosage are possible.
• Conventional hormone therapy is preferred over compounded hormone therapy given the available data.
• Despite claims to the contrary, evidence is inadequate to support increased efficacy or safety for individualized hormone therapy regimens based on salivary, serum, or urinary testing.

FDA approved bioidentical hormones

The following preparations are naturally occurring hormones that are ingredients in FDA-approved products:

Estrogens

• Estradiol-17β (transdermal or oral, micronized):
  • Patch/Film
    • Alora
    • Climara
    • Estraderm
    • Estradot
    • Minivelle
    • Oesclim
    • Vivelle-Dot
  • Transdermal gel
    • Divigel
    • EstroGel
    • Elestrin
• • Transdermal spray
    • Evamist
  • Vaginal cream
    • Estrace Vaginal Cream
  • Vaginal ring
    • Estring
• Estradiol acetate
  • Vaginal ring
    • Femring
• Estradiol hemihydrate
  • Vaginal tablet
    • Vagifem
• Estrone (sodium estrone sulfate)––active ingredient in naturally occurring conjugated equine estrogen preparations and in synthetic conjugated estrogen preparations
  • Vaginal cream
    • Estragyn Vaginal Cream

Progesterone

• Progesterone (oral, micronized or vaginal gel or insert)
  • Micronized progesterone
    • Prometrium

Regardless of the type of preparation, the varying formulations available, pharmacodynamics, and individual patient factors must be taken into consideration when using menopausal hormone therapy.

Are bioidentical hormones safe?

To date, there is no scientific proof that bioidentical hormones, whether prepared by a compounding pharmacy or pharmaceutical company, are safer to use than other forms of hormone therapy. All forms of hormone therapy may have potential risks, whether compounded or pharmaceutical, bioidentical or not.

The unfortunate publicity concerning compounded hormones mislabeled as ‘bioidentical” has suggested that custom made preparations based on saliva or blood levels were safer or better tolerated has lead to a cottage industry which has no scientific basis ⁸. These preparations offer no advantage over regulated and tested preparations approved by the U.S. Food and Drug Administration (FDA), and their risk is equivalent to commercial compounds. Claims that they are safer are misleading particularly since they have not been studied and one of the estrogens used, estriol, has no safety or efficacy data ⁸. Prescribers who claim they are more “natural “ do not inform patients that they are synthesized from plant chemicals extracted from yams or soy similar to some commercial preparations.

According to the U.S. Food and Drug Administration (FDA) and several medical specialty groups, the hormones marketed as “bioidentical” and “natural” aren’t safer than hormones used in traditional hormone therapy, and there’s no evidence they’re any more effective.

The term “bioidentical” means the hormones in the product are chemically identical to those your body produces. In fact, the hormones in bioidentical medications may not be any different from those in traditional hormone therapy. Several hormone therapy products approved by the FDA and prescribed by health care providers contain bioidentical hormones.

“Natural” means the hormones in the product come from plant or animal sources; they’re not synthesized in a lab. However, many of these products still need to be commercially processed to become bioidentical. Traditional hormone therapies don’t necessarily exclude natural hormones. Some FDA-approved products — such as Estrace, Climara and Vivelle-Dot, which contain estrogens, and Prometrium, a natural progesterone — also are derived from plants.

Marketers of compounded bioidentical hormones say their products have certain advantages over traditional hormone therapy:

• They’re produced in doses and forms that differ from those in FDA-approved products. For many nonstandard combinations, you need to go through a compounding pharmacy — one that specializes in making medications customized for your individual needs. However, products from compounding pharmacies haven’t been subject to the same rigorous quality assurance standards that standard commercially available hormonal preparations have to meet.
• They’re custom-made for you, based on a test of your saliva to assess your unique hormonal needs. Unfortunately, however, the hormone levels in your saliva don’t reflect the levels in your blood or correspond to menopause symptoms.

Some women may benefit from nonstandard doses and forms of hormones in compounded bioidentical hormone preparations, but there’s currently no scientific support for an advantage of these compounds over common commercially produced preparations.

Bioidentical hormones side effects

Bioidentical hormones has not been tested in good clinical trials. There are very little safety data. There is no clinical or patient package insert documenting safety or efficacy, no black box warning, no uniform manufacturing standards, and there is no formal review of the accuracy of any of the advertised claims.

Because of a lack of FDA oversight, most compounded preparations have not undergone any rigorous clinical testing for either safety or efficacy, the purity, potency, and quality of compounded preparations are a concern. Over a 6-month period, the FDA performed repeat analytic testing of 29 Internet-ordered samples—including estradiol and progesterone—from 12 compounding pharmacies ⁹. Although none of the preparations failed identity testing, 10 of the 29 preparations (34%) failed one or more standard quality tests performed, including potency testing. In contrast, the analytical testing failure rate for drug therapies approved by the FDA is less than 2%.

Because of variable bioavailability and bioactivity, underdosage and overdosage are both possible. Certain progestin preparations, such as that found in the Mexican wild yam, are not bioavailable to humans and, therefore, patients can believe that they are receiving endometrial protection against hyperplasia when they are not ¹⁰. Similarly, underdosing of estrogen can lead a woman to believe that she is protected against osteoporosis when, in fact, bone resorption is progressing. Estriol is substantially less bioactive than estradiol, and large quantities must be used to achieve any biological effect. The potential for overdosage also exists, which can lead to increased risks of endometrial hyperplasia, endometrial cancer, and venous thromboembolism.

How to stop taking bioidentical hormones

Because of the potential increased risk of breast cancer in women taking combined estrogen/progestogen therapy, some clinicians advise that patients discontinue therapy after three to five years ⁶. An analysis of women in the Women’s Health Initiative (WHI) combined hormone trial who had hot flashes when starting therapy showed that after discontinuation, 56% had moderate to severe hot flashes compared with 21% of women who took placebo ¹¹.

Clinicians should inform patients that some women will have a difficult time stopping hormone therapy ¹¹. There are limited data to inform patients and clinicians about the best way to discontinue hormone therapy. Some patients will be successful with abrupt discontinuation, whereas others may benefit from weaning. The American College of Obstetricians and Gynecologists recommends against routine discontinuation based on age or treatment duration, and advises that the decision to continue or stop hormone therapy should be individualized based on the patient’s symptoms and medical history ¹².

1. North American Menopause Society (2012). The 2012 hormone therapy position statement of the North American Menopause Society. Menopause, 19(3): 257–271. DOI: 10.1097/gme.0b013e31824b970a. Accessed April 18, 2016.[↩][↩]
2. Rosenthal MS. The Wiley Protocol: an analysis of ethical issues. Menopause 2008;15:1014–22[↩]
3. Compounding and the FDA: Questions and Answers. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm339764.htm[↩]
4. Boothby LA, Doering PL, Kipersztok S. Bioidentical hormone therapy: a review. Menopause 2004;11:356–67[↩]
5. Drisko JA. “Natural” isomolecular hormone replacement: an evidence-based medicine approach. Int J Pharmaceut Compounding 2000;4:414–20[↩]
6. Hormone Therapy and Other Treatments for Symptoms of Menopause. Am Fam Physician. 2016 Dec 1;94(11):884-889. https://www.aafp.org/afp/2016/1201/p884.html[↩][↩]
7. Compounded Bioidentical Menopausal Hormone Therapy. Committee on Gynecologic Practice and the American Society for Reproductive Medicine Practice Committee. https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/Compounded-Bioidentical-Menopausal-Hormone-Therapy[↩]
8. Warren MP, Shu AR, Dominguez JE. Menopause and Hormone Replacement. [Updated 2015 Feb 25]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279050[↩][↩]
9. Report: Limited FDA Survey of Compounded Drug Products. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm155725.htm[↩]
10. American College of Obstetricians and Gynecologists. Use of botanicals for management of menopausal symptoms. ACOG Practice Bulletin 28. Washington, DC: ACOG; 2001[↩]
11. Ockene JK, Barad DH, Cochrane BB, et al. Symptom experience after discontinuing use of estrogen plus progestin. JAMA. 2005;294(2):183–193[↩][↩]
12. ACOG practice bulletin no. 141. Management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202–216[↩]