19 September 2019

Progesterone: a compounding problem?

Clinical Endocrinology Women

If your patient is given the choice between a medicine that has been heavily researched, has proven safety data, is strictly regulated for quality and consistency, and a medicine that claims to have its origin in wild yam or soy and has no evidence for either efficacy or safety, which one are they likely to choose do you think?

No doubt, there will be some patients who that may still stubbornly opt for the more “natural-sounding” treatment, despite the lack of evidence and quality control. But surely they should be few and far between.

In an Australian study published in 2016, among more than 2000 women in Australia who were going through menopause, 11% of women were taking MHT for symptom control. And of these, 10% were being prescribed “bio-identical” progesterone, compounded by a pharmacist. (1)

Compounded bio-identical hormones have been marketed as identical to hormones produced by the body – more or less as “natural”.

And in the vacuum of fear and confusion that followed the infamous 2002 WHI study published in JAMA  [2] that suggested MHT was far more likely to cause breast cancer than previously thought, some women who were desperate for relief from severe menopausal symptoms turned to what they perceived was a natural and safer solution to the problem.

The public demand for these bio-identical hormones (known to be available in the US) led to a surge in pharmacies providing compounding services.

At around the time of the WHI study, it was estimated that less than 20 pharmacies were available to make up these special formulations. And while neither the Pharmacy Society of Australia nor the Professional Compounding Chemists Australia (PCCA) keep a record of exactly how many compounding pharmacies exist in Australia, there are now believed to be between 500 to 600 such facilities currently operating around the country.

Hormone therapy has been frequently credited as the major driver behind this increase.

But compounded bio-identical progesterone and forms of oestrogen have never really been a natural solution.

They are synthetically made, just like regulated and proven treatments, but without the backing of any evidence on efficacy or safety. [3] Preparations often contain a combination of oestrogen, progesterone, testosterone and other hormones and can be delivered as creams, troches or pessaries.

Issues with bio-identical hormones have included:

  • The process of compounding by pharmacists has been subject to variation. Guidelines to ensure standardisation are not universally followed or enforced.
  • They are marketed as “individually tailored” to patients, but experts say this is “virtually impossible” as such tailoring would require regular blood testing to check hormone levels but this is rarely if ever done.
  • The product is expensive.
  • There is a concern that inadequate dosing, particularly of the progesterone, could lead to inadequate protection of the endometrium from the regular oestrogen. [4]
  • It is not known if bio-identical products protect against osteoporosis. [4]

Regulation of the compounding industry has been a particular bone of contention.

Before being marketed in Australia, therapeutic products have to be assessed by the Therapeutic Goods Administration (TGA) and listed on the Australian Register of Therapeutic Goods (ARTG).

However, compounded products don’t need to go through this regulatory process provided they are prepared for an individual for a specific therapeutic need.

And up until 2015, no Pharmacy Board guidelines on compounding existed. In that year, the first Guidelines on Compounding of Medicines were published, and this was updated a few years later with the inclusion of guidelines on compounding of sterile injectable medicines.

While the introduction of these guidelines has apparently improved standards in the world of compounding, there is an issue with enforcement, which is a state-based responsibility. There exists is a wide variation in vigilance in terms of ensuring these guidelines are followed across the different jurisdictions.

Micronised progesterone, available in Australia since June 2017, is approved and regulated by the TGA, has fewer-side effects than many higher dose progesterone formulations, has data suggesting it is safer in terms risk of breast cancer and does not negate the protective cardiovascular effects of oestrogen, unlike most progestins. [5]

This evidence-based and regulated form of progesterone has been termed ‘body identical’ hormone. And this bio versus body might be a little confusing for patients and GPs.

Susan Davis, Professor of Women’s Health in the School of Public Health and Preventive Medicine at Monash University, tells The Medical Republic that, “since the time that micronised progesterone has become available in Australia, there is now no excuse at all for women to be using compounded progesterone. There is no excuse for any doctor to prescribe it, unless in highly exceptional circumstances.”

The “availability of natural [micronised progesterone] means that Australian women can have access to a safer form of MHT,” says Professor John Eden, Head, Sydney Menopause Centre at Royal Hospital for Women, on the Women’s Health Research Institute of Australia (WHRIA) website.

In a recent video series, Dr Terri Foran, a well-known sexual health physician and women’s health expert, says “there is no good long-term evidence to suggest that bio-identical compounded forms of progesterone are any safer or any better than those used in conventional hormone therapy. The safety data for bio-identicals is not to a standard where any medical professional should be making a recommendation of their use to patients.”

And in a recent Q&A published by the RACGP, GP  Dr Magdalena Simonis, says that the idea “that MHT is ‘synthetic’ or unnatural and bioidentical hormones are ‘natural’ is a “gross misconception amongst the public”.

In fact, you can’t find a leading expert in women’s health in Australia who is not on the same page about compounded hormone preparations.

But pharmacists are still compounding menopausal hormone preparations, including compounded progesterone.

It is difficult to know the current extent of the problem as there are no data on how many compounded hormone products are presently being dispensed.

However, many leading specialists in women’s health have raised concerns that women are continuing to be prescribed and continuing to take these unregistered products.

“We continue to see women who have been prescribed compounded progesterone,” says Professor Davis.

So why are there GPs still prescribing bio-identicals?

It is likely, given the history of compounding, that patient demand remains a key factor, but this is now proving to be insufficient justification for a practice that is deemed not in the best interests of the patient.

The RACGP has just recently published a detailed Q&A on MHT and bio-identicals with three GP experts, all of whom are following the same line of those experts quoted above. [6]

The consensus of opinion is that prescribing compounded MHT is not only unnecessary these days, it may also be unethical as it certainly doesn’t align with best-practice principles.

Similarly there is an issue with pharmacists accepting prescriptions compounded MHT, especially progesterone, rather than letting patients know of the availability of a similar product which has been proven to be effective, safe and is TGA-approved.

In fact, the Pharmacy Board Guidelines are very clear on how a pharmacist should be managing their compounding services. (7) Part 2 of the guidelines on compounding medicines, says:

A compounded medicine should be prepared only in circumstances where:

  • an appropriate commercial product is unavailable”.

Professor Davis believes that given the situation, it is finally time for the government to act, and for a body such as the TGA, or AHPRA, to mandate that when any patient is being prescribed bio-identical compounding for MHT, the healthcare professional must at the same time provide that patient with written information that clearly outlines to the patient that the treatment is not evidence-based nor regulated by the TGA, and what the risks potentially are.

They should also be informed that effective, TGA-approved alternatives are available.

“If you get the oral contraceptive pill there will be a TGA approved patient insert telling you that this is a hormone that you shouldn’t take if you get thrombosis or migraines et cetera,” says Professor Davis. “Why is this situation any different? “I think AHPRA is struggling with this and trying to manage the situation, but unfortunately there is no rule saying that you can’t prescribe something to a patient unless there is clear evidence of harm.

“This issue appears to be falling between government cracks from a regulatory and safety viewpoint.

“It should be mandatory for a patient receiving bio-identical MHT to be provided with written information about the safety, or lack thereof, of what they are being prescribed.”.

Professor Davis says that there is a generation of GPs who have been educated at a time when MHT had been demonised and therefore they weren’t educated much around the issue at all.

So now some obviously continue to “have a misguided belief that compounded products are more appropriate”.

References:

  1. Menopause 2016 Jan;23(1): 11-7
  2. JAMA 2002 Jul 17;288(3):321-33.
  3. https://jeanhailes.org.au/news/the-issue-with-bioidentical-hormones-free-health-article
  4. Semin Reprod Med. 2010 Jan; 28(1): 81–90.
  5. https://www.tga.gov.au/sites/default/files/auspar-progesterone-170601.pdf
  6. What should GPs know about bioidentical hormone therapy? August 12, News GP, https://www1.racgp.org.au/newsgp
  7. https://www.pharmacyboard.gov.au/Codes-Guidelines.aspx
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