There appears to be a well-orchestrated attempt by the pharmaceutical industry to eliminate bioidentical hormones and as well as the compounding pharmacies that fill the longstanding hormone gap that commercially available products cannot fill for patients, in particular female patients.  Subcutaneous pellet therapies in particular have come under considerable attack and the recent article published in  Tthe Menopause journal, “Safety assessment of compounded non-FDA approved hormonal therapy versus FDA approved hormonal therapy in treating post-menopausal women” by Xuezhi Jiang et al. further attempts to taint the compounding industry with their highly biased unsubstantiated conclusions.

When it comes to clinical “research” it is imperative that one looks at published works with a critical eye and assess what the data is truly telling us to ensure that the information is not being presented is a biased manner. (A basic understanding of medical statistical is also very helpful.)  

It is unfortunate that often subjective opinions by authors can highly influence a studies outcome/message.  They attempt to direct a preconceived notion about a clinical relationship and try to convince the reader that their observation is proving a causative effect when the data set driving this conclusion is highly conflicted or biased.  There are substantial areas of concern related to this publication and the conclusions the authors are attempting to make against non-FDA approved hormonal (pellet) therapy. Even the authors admit in the discussion section, that the study has significant limitations that need to be explored.  There are ones that are not brought to light in this section, and one should explore all the limitations before coming to the conclusions that the authors suggest.  These include the following:

Data collection utilizing the proportional quota sampling method

Since quota sampling is a non-random sampling method, it is impossible to find the sample error. Also, there is always a chance of sampling bias, given the researcher can chose to ignore certain important characteristics for ease of access and cost savings.  How were the pellet therapy patients chosen compared to non- pellet therapy patients?  Did they focus on pellet patient who had AUB or underwent a hysterectomy as part of the first sampling criteria to stack the deck against this criterion in this cohort?

Utilizing chart review of documented patient subjective complaint to conclude side effects/adverse outcomes

There was no standardization or control of data collected (such as validated questionnaires) and relied solely on medical student chart review to retrieve data which is inherently highly unreliable and possibly unobjective.

Comparing specialist to generalist documentation when focusing on subjective documented complaints leading to appearance of more events in specialist group

For example, if a patient sees a cardiologist the progress notes will have significant documentation toward cardiac signs and symptoms. Compare that to a primary care note, where the focus will be more broad and less detailed in regards to cardiac complaints unless the visit is specifically focused on a cardiac issue such as chest pain etc.  If one were to do a retrospective chart review comparing the cardiologist to the PCP, you may come to the conclusion (as they did similarly in this study) that cardiologist have more cardiac side effects when treating patients compared to the primary care physician. The two pellet doctors who composed the non-FDA approved hormonal therapy cohort are typically “menopausal specialist” and would have progress notes highly focused on concerns related to hormones where as a traditional Ob/Gyn progress notes would be less detailed and specific to the hormone issues in general.

Single institution retrospective study

Having only one institution does not allow for regional or other variations as well as opportunity for “group think” in regards to medical opinions.

Inclusion of only two private practices that provided pellet therapy without an understanding of their training and skill set in hormonal pellet therapy

Not all providers are equally qualified or have the level of expertise required to provider pellet treatments to their patients in a standard of care that is consistent with those properly trained in restorative/hormonal medicine. Unclear the amount or type of training of the provider had in the study and how they would compare to the lion share of the physicians providing this sort of care.

Misrepresentation of “supra-physiologic” blood levels (in particular testosterone) and correlation to clinical outcomes with the suggestion that this is clinically harmful to patients

A large area of on-going misunderstanding and lack of proper education is related to the treatment of patient utilizing hormone pellets and the proper assessment of labs and treatment levels.  Many providers do not gain the proper training related to these specific treatments including dosing and lab interpretation. Despite conflicted industry supported medical society guidelines, there is a growing body of evidence-based research related to testosterone dosing, lab interpretation and physiologic versus pharmacologic dosing and serum levels related to efficacious treatment with women.

It is important that to understand that the serum testosterone laboratory ranges utilized in subcutaneous testosterone hormone replacement therapies are based on “endogenous” hormone production. However, the established normal endogenous testosterone ranges have been shown to be inaccurate in women and children and are not utilized during BHRT pellet therapy. While BHRT necessarily relied on endogenous testing, it employs a much higher, therapeutic (pharmacologic treatment) range or normal values than those that would be expected in a non-therapeutic patient.These pharmacologic treatment serum levels average between 4-6-fold higher than the normal reference ranges for endogenous testosterone levels. This is mostly due to the tight binding of testosterone to SHBG and its inability to bind with the androgen complex, therefore unable to elicit a biological/clinical response at lower endogenous levels.

The higher testosterone levels associated with BHRT pellet therapy in women set forth are purposefully titrated in order to alleviate symptoms associated with menopause. These levels are specifically calculated to offer optimal relief of symptoms and are not detrimental to the patients. Similarly, the common subcutaneous testosterone dose utilized to attain these levels, which range from 75mg-225mg have also been shown to be efficacious without causing any significant adverse effects. Indeed, breast cancer patients treated with testosterone routinely received doses as high as 500-1800mg. Even this doses and their resultant testosterone serum levels, are well-documented to cause no serious or non-reversible adverse effects in the patients who receive them.

Serum testosterone levels revealed by blood testing are highly variable and are not reflective of clinical end organ response. Instead, these levels provide only a transient picture of a dynamic equilibrium. For this reason, many BHRT physicians do not even utilize blood testing of serum levels, but instead monitor their patients symptomatically. Move over, physicians who do utilize such testing look to it as one guiding factor, rather than the sole determinative means of monitoring a patient’s response to therapy.

Many of the medical society guidelines and “statements” recommend against treating women with testosterone because serum levels do not correlate with symptoms. Much of the newest research shows that neither symptoms of androgen deficiency nor response to therapy correlate with baseline testosterone levels which is consistent with older studies and the physiology of androgens in women. The decision to initiate testosterone therapy is a clinical decision between the doctor and the patient based on the patient’s symptomology.

This concept is in agreement with the American College of Obstetricians and Gynecologists (ACOG) Committee Opinion, which states that "Individualized testing is only indicated when a narrow therapeutic window exists for a drug or drug class. Steroid hormones do not meet these criteria and do not require individualized testing” and “If treatment is initiated for symptom control, subjective improvement in symptoms is the therapeutic end point, and there is no need to assess hormone levels. Hormone therapy should not be titrated to hormone levels.”

Some guidelines use the terms ‘physiologic dosing’ and ‘physiologic ranges’ when making recommendations for testosterone therapy. Testosterone’s effect is dose dependent, and there is no evidence (i.e., drug-concentration in blood studies), or documented safety concerns, supporting the ‘opinion’ that serum testosterone levels on therapy should remain within endogenous or ‘physiologic’ ranges. In point of fact, concentration/dose-response studies support the opposite.

Doses and therapeutic ranges for exogenous therapy with testosterone pellet implants have been published in the peer-reviewed literature trough levels, measured when symptoms returned, confirm that T levels on exogenous therapy cannot be compared to, monitored by, or dosed based on endogenous testosterone ranges in serum.

Adequate dosing of testosterone is critical for optimal therapeutic effect or clinical benefit. Symptom response and control of disease should guide therapy rather than arbitrary serum testosterone levels. Testosterone therapy is continued or adjusted based on the patient’s response to therapy (benefits) versus side effects, not on a single testosterone level, which is inherently unreliable.

Aside from the major study limitations and flaws in the study, it is also unfortunate that in the discussion section, the authors continue to propagate the biases that were presented in the “Global Consensus Position Statement on the Use of Testosterone Therapy for Women” (Davis et al) published in the International Menopause Society Journal. The “consensus” was formatted to appear as “guidelines,” but there was no peer review process.The paper itself is both biased and flawed, as are the Endocrine Society’s guidelines on androgen therapy in women.They have no evidence to recommend against compounded hormones, and in fact proclaim many of their recommendations are based on “expert opinion,” which in itself is problematic.The panel of so-called “experts” did not routinely treat women using testosterone, so how can they make properly informed recommendations?

In 2019, the publication “Testosterone Insufficiency and Treatment in Women: International Expert Consensus” was released by a group of established experts in the field of compounded bioidentical hormone replacement therapy (cBHRT).  This group of experts (Donovitz, Schwartz, Miller, Barber, Comite, Janson, Leake, Lee, Life, Martinez and Woodford) had over 100,000 patient YEARS’ experience with testosterone supplementation in women.  This real-world experience coupled with the roughly 100 references/studies (versus the one meta-analysis/14 references in the above-mentioned testosterone consensus by the International Menopause Society publication and the paltry “expert opinion” by authors who don’t routinely treat women with testosterone therapy) guided their recommendations which included:

• Testosterone is NOT a male-exclusive hormone. It is the most abundant gonadal hormone throughout a women’s life.
• Serum testosterone levels do not correlate with symptoms of testosterone deficiency in women. Optimal ranges of serum testosterone levels in women have not been established.
• Female testosterone insufficiency is a clinical syndrome that may occur during any decade of adult life.
• Testosterone therapy may be breast protective.
• Testosterone insufficiency in women negatively affects sexuality, general health and quality of life. Supplementation may positively influence sexuality, general health and quality of life.
• Testosterone insufficiency may be associated with an increased risk of cardiovascular disease in women.
• Testosterone optimization may be brain protective and may enhance cognitive function.
• Testosterone optimization may be a key component for improved bone health.
• Testosterone therapy in women has no adverse effects on lipids and/or cardiovascular risk.
• Studies of testosterone supplementation show benefits exceed the risk and that consistent purity and potency can be achieved.

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This report by true expert front line physicians with substantial experience and minimal conflict of interest should be given considerable weight by organizations crafting guidelines or authors of articles addressing female hormone replacement.  At the very least the publications should recognize the counter arguments to provide substantive balance to them.

The incredibly harmful conclusions based on highly conflicted and biases, which were outline in the two-part article in the International Journal of Compounding Pharmacies (Gender Bias in the Treatment of Menopausal Women, I am Hot as Hell and Not Going to Take it Anymore Parts One and Two, Dr. Angela DeRosa International Journal of pharmaceutical Compounding Vol 24 No. 6 Nov/Dec 2020 & Vol 25. N0. 1 Jan/Feb 2021) will continue to further propagate gender bias in the treatment of menopausal women and harm the health of women for decades to come.This is an unacceptable outcome, and we need to continue to ask why.

Lastly, in the Medscape post on June 18th 2021 which discussed the findings of Dr. Jiang’s study, the commentary was provided by physicians that receive considerable funding from the pharmaceutical companies who have a considerable stake and desire to see compounded hormone (their competition) debased.They even go as so far to bring up the negative NASEM study/report on the clinical utility and safety of bio-identical compounded hormone therapy which was funded by the FDA to highlight their safety concerns about compounded BHRT. However, what is not noted, is that this report has been largely debunked by independent investigator based on serious concerns of bias and possible illegal collusion by the FDA with the committee members. Their findings were substantial and include the following:

• The committee and its review team included individuals who may have been biased against compounded hormones.
• Jane Axelrad, former FDA official and outspoken critic of compounded hormones, played multiple key roles in the development of the NASEM report.
• The committee did not include any prescribers or pharmacists with substantive, patient-facing experience with compounded hormones.
• The definition of “clinical utility” developed and relied upon by the committee does not reflect an accurate or complete representation of the term.
• The studies relied upon by the committee do not reflect an accurate or complete representation of compounded hormones.
• The standards for evaluating the safety and efficacy of FDA-approved drugs cannot be reasonably applied to highly individualized compounded medications.
• The committee relied upon the discredited 2002 Women’s Health Initiative study in developing its conclusions.
• The committee ignored the body of evidence demonstrating the safety and efficacy of compounded hormones.

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All this put together, it should the very least give pause to accepting the information presented in the article published by Dr. Jiang as reliable.

As one looks at “research” and subsequent editorials about such research, one should also pay attention to who is driving the research and who has something to benefit from the findings, in particular financial gain. Unfortunately, these publications do not meet this “smell test” and their findings and public conclusions should be questioned.

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