Why compound bio-identical hormones? Are there no similar commercial products? What is unique about the options compounding pharmacists offer compared with what is out in the marketplace?
As the use of compounded hormone replacement therapy has grown and become well-established, questions like these are being asked in various places, and discussed in such forums as the online journal for the American Medical Association and publications from the North American Menopause Society (NAMS). What we do in compounding now — offering topical estrogen therapy, for example — has become commonplace. Patients may need a compounded topical cream or gel if they are having a skin reaction to a commercial patch. Or they may need a preparation in a different strength, combination or base than is commercially available. However, many physicians are influenced by what they read and hear from their professional organizations, and see no unique value in compounded HRT.
In this article, I will offer information that I believe will provide more of a scientific basis for compounding hormone replacement therapy and give pharmacists clinical citations that have been, and continue to be, published at a surprising rate.
First, though, let us acknowledge a common criticism: Compounds are not FDA-approved. This is true, but try to imagine a process where every one of your formulas had to go through that process. Hundreds of individual formulas would have to be evaluated. And then there is the prevalence of off-label use: A lot of FDA approved products are prescribed to treat ailments for which they haven’t been evaluated by the FDA, either.
Compounded HRT therapy is personalized, with multiple doses and ingredients involved. We fill a need, just as we do with many other types of therapies used in medicine that do not involve the FDA process.
As we make the case for compounding HRT, let us briefly review some compounding history. Early education on this topic revolved around using hormones identical to those we produce in our bodies, unlike synthetic hormones or those found in horses. That argument is no longer as useful given the number of estradiol products available in topical forms, products that use the very same estradiol chemical that we compounders use. However, the differences between those and what we offer are unique and significant.
THE ESTROGEN RECEPTOR(S)
In 1996, a team of researchers in Sweden made a quiet discovery, an event that was largely overlooked at the time, but its significance continues to unfold. Up until then, and even today in many circles, talk was of the estrogen receptor, and all of the actions of the estrogen receptor. In 1996, though, Dr. Jan-Åke Gustafsson (now in research at the University of Houston) and his team announced the discovery of estrogen receptor beta, with the original receptor now called estrogen receptor alpha (in discussion, usually referred to as ERα and ERβ). So now let us discuss some of the significance of that second receptor, ERβ.
The two receptors, ERα and ERβ, are structurally similar, but the slight differences between them change the binding affinities of the various estrogens to them. Estradiol, the dominant estrogen in premenopausal women, binds both to ERα and ERβ with approximately equal affinities. Estriol, “the pregnancy estrogen,” binds almost exclusively to ERβ. (While there is much interesting and useful information on estrone, we will save that for another discussion, especially since most compounders do not include it in their formulas.) This is a very significant difference, and there is a great deal of research currently going on concerning ERβ.
Researchers have studied the link between ERβ and breast cancer, often suggesting that ERβ has a protective mechanism. For example, approximately 80% of normal breast epithelial cells have shown ERβ expression, while ERα is only expressed in 10% or less in normal breast epithelium. One study showed that when ERβ expression is lost, clinical prognosis becomes poor and resistance to endocrine therapy increases. Re-expression of ERβ in breast cancer cell lines inhibited cell proliferation, promoted apoptosis and enhanced the efficacy of chemotherapeutic agents. ERβ expression in breast cancer is also associated with a favorable outcome in women treated with adjuvant tamoxifen, even in tumors negative for ERα. It is quite clear that further research into the protective effects of ERβ activity is warranted, and, in light of all of the published research so far, expected.
As mentioned, estriol preferentially binds to ERβ, and thus has a different realm of activity. It is a fascinating hormone, generally considered much weaker than estradiol. Estriol is considered to have both agonistic and antagonistic actions, especially in relation to estradiol. When given alone, it seems to have an estrogenic effect, the magnitude of which depends on the dosage. But, when given with estradiol, it may exert antagonistic effects. While estradiol has shown increased breast density in some studies, no such increase was found with estriol. In rat studies, intermittent implantation of estriol subcutaneously reduced the development of chemically-induced breast cancer by 80-90%. From all that is now being studied, it is clear that estriol has been an intense subject of research.
Moving from the earlier explanations of why we use estriol with estradiol, it is now becoming clear that these estrogens are significantly different, and the combination appears to convey safety benefits that the sole use of estradiol does not. We must keep in mind, though, that while the research is providing very positive information, we do not have clinical studies showing that the safety benefits have been proven in humans. Clearly, though, there is sound reasoning for continuing the research into ERβ and the use of estriol.
Much has changed since the early HRT seminars, before the discovery of ERβ and some of the nuances of estriol. This is where we can make a good case for the therapeutic application of our compounds: We are not just making copies of the commercial topical estradiol products, but rather, we are using USP-grade chemicals, quality bases and accurate dosing devices to prepare products that have an increasingly sound scientific basis.
ADDITIONAL COMPOUNDING ADVANTAGES
There are other significant points we make about the unique HRT compounds we prepare, including our ability to make different dosage forms, such as sublingual, buccal, oral and especially topical.
Also, we are confident in our ability to combine products in these various dosage forms, which is not done commercially except in occasional instances, such as synthetic hormone patch therapy, or non-bioidentical oral therapy. We can combine estriol and estradiol in various strengths, for instance (see PCCA Document #98743). We have long made the case for using progesterone in our products, and have literature supporting that case. (PCCA Document #99339 is very useful in providing succinct information on progesterone.)
We can also include DHEA and/or testosterone in the compounds, and, it must be noted, there is no commercial product for women with testosterone. Clinical articles are available discussing the benefits of testosterone in women; we have access to testing level information, and have the ability to ensure that women get the proper, accurate dosing they require. (I once saw a woman who was given a male commercial product without information on how she was supposed to dose it accurately.) In short, we offer personalized, novel compounding not available through commercial products, and have the literature to back up what we offer.
The history of HRT shows that our knowledge continues to unfold, and our basis for use of our products continues to expand. There is an extensive bibliography here, which can be of great value to you in your desire and need to expand your knowledge and expertise. In continuing to grow in your professional health-care provider role, access to information such as this is vital.
If you have any questions about compounding for HRT, please call AXIS Pharmacy Northwest to speak to a Pharmacist: 425-356-3276.