Here is the most common question I have heard about hormone replacement therapy (HRT): Is it safe? 

Unfortunately, there is no short, simple answer to this question.  The safety of HRT is dependent on a myriad of factors including pre-existing conditions, age, and genetic markers, making it a highly individualized decision.  So, yes, that adds some complexity. But, unfortunately, there is so much additional confusion and misinformation regarding the safety and use of HRT for ALL women.  On one hand, we know the decision to utilize HRT is based on individual factors, but on the other hand we are still faced with an old narrative that states that HRT is dangerous for all women.  Let’s dive into the reasons for this.  Bear with me, I’m putting on my science-hat today and climbing on top of my soapbox.

Up until 2002, most women were prescribed HRT in the form of Premarin, which is an oral form of conjugated estrogens (i.e., a mixture of various forms of estrogen hormones). Then, in 2002 the National Institute of Health released the results of a series of studies called the Women’s Health Initiative (WHI) that purported the idea that hormone replacement increased the risk of cancer, stroke, and heart attack.  In fact, the WHI released their findings to the press before the data had been fully analyzed.  Ultimately, once the data analysis was complete, the evidence showed that the findings were much more nuanced and related to subjects’ personal health histories than what had been reported to the press.

But the damage was done.  It was the single biggest medical news story of 2002. Women panicked.  Physicians REALLY panicked.  Immediately, women stopped renewing their prescriptions for Premarin and physicians stopped prescribing HRT.  Women were told to: “Suck it up. It’s just a phase all women go through, you’ll get through it”.

In fact, the 2002 WHI study that prompted this narrative has been found to be wrought with flaws.  There have been hundreds of studies released along with medical papers, journal articles, and multiple books written about flawed practices utilized in the study that led to misleading results. 

My Illustrative Case Study

To illustrate the points, and help you understand the reason for so much confusion, I’m going to break down two examples (of the multitude of problematic issues) with the study.

• The first problematic issue with the WHI’s findings is that the Age Range of the subjects was 50-79 years. In fact, the average age of the women enrolled was 63 and most were 12-15 years beyond their last menstrual cycle. Only 3.5% of the women studied were between the age of 50-54 (the average age that women typically begin hormone replacement therapy). (Cagnacci & Venier, 2019)
• The second problematic issue is that the WHI study utilized a “one size fits all” method of prescribing HRT.  When any drug is administered or prescribed, there are 3 things to consider:
  • the Type of drug
• • the Route in which it’s administered (oral, IV, injection, transdermal patch, topical cream . . . the list of routes goes on and on )
  • the Dosage (how many mg, micrograms, etc.)
• The WHI study utilized – for ALL of the patients:
  • A single type, route, and dose of estrogen (oral, conjugated equine estrogen) in the form of Premarin.
  • A single type, route and dose of synthetic progesterone was used in the form of Medroxyprogesterone.
• This “one size fits all” approach is not in keeping with best practices for safe prescribing of hormone replacement. 
• So now, let’s breakdown a few physiological facts that highlight the problems with these methods I just reviewed:
  • Estrogen keeps our blood vessels flexible and dilated.  If it has been 10 years since your last menstrual period, and you have not been replacing your body’s natural estrogen, your blood vessels will have significantly contracted and stiffened. (Woods & Warner, 2014)
  • Oral estrogen (like many oral medications) is metabolized in the liver.  One of the effects of the metabolization process of oral estrogen is that it increases the production of several clotting factors in the blood.(Woods & Warner, 2014)
• So, now:
  • Take what we know about the age and 12-15 year post-menopausal status of the subjects likely resulting in contracted/stiffened blood vessels.
  • Combine that with the fact that oral estrogen increases the production of clotting factors . . .
  • The result? Now we can see the reason for the results of the WHI study indicating an increased risk of stroke and cardiovascular incidents.

Relative Risk vs Absolute Risk

Another “finding” of the WHI study, and the one that garnered the most media attention was the purported significant increase in the risk of breast cancer in the subjects studied.  There are a myriad of nuanced factors to counter these findings, but one that has been universally accepted is the media’s misuse of the type of “risk”.  

When I took my medical statistics class, I learned the difference between “relative risk” and “absolute risk”.

• Absolute Risk is the actual probability of an outcome occurring.
• Relative risk is a bit more complex to break down, but it examines the risk between the experimental group and the control group, without factoring in any other influences (like the the fact that 1 in 8 women will develop breast cancer).  Therefore, in this case, the relative risk results in a much higher appearing percentage because it does not factor in genetic and environmental factors that exist for everyone.

So how does this apply to the study and how the media reported it? The media latched onto the Relative Risk of 25% risk of breast cancer.  (But remember, this does not take into account any additional factors. ) What should have been reported was the Absolute Risk (the actual probability)  of breast cancer from HRT was found to be 0.08%. (Haver, 2024) I don’t think any of us are surprised by the media wanting to use a more tantalizing statistic, even if it was drastically misleading.

But the damage was done.  It was the single biggest medical news story of 2002. Women panicked.  Physicians REALLY panicked.  Immediately, women stopped renewing their prescriptions for Premarin and physicians stopped prescribing HRT. 

Enormous strides have been made in HRT research since the 2002 WHI study.  We now have a wonderful variety of Types, Routes, and Dosages to customize medications for individual needs.  Instead of the old “one size fits all” approach, today’s approach to HRT is the “goldilocks method”.  Not too much, not too little, but “just right” for each specific patient.

Translational Medicine

So, if we have all of this information now, why are there still so many healthcare providers who are reluctant/avoidant to prescribe HRT? To answer this question, we need to examine the process of Translational Medicine. 

Also referred to as “Bench to Bedside Medicine”, Translational Medicine is the process of taking what was learned on the “lab bench” in a research study and translating it to the medical practice, or “bedside” of healthcare providers. (Pennmedicine.org)

Here’s the alarming truth about Translational Medicine in real-world practice:  The average time that it takes for the evidence of clinical research to impact and influence a physician’s practice of medicine is 17 years. (Morris et al., 2011).  Yes, you read that correctly. 

It takes an average of 17 years for the benefits of new research to affect the way your doctor treats you. 

Now, there are exceptions to this statistic.  Continuing Education is a requirement of everyone with a Medical or Nursing License, and it is one of the primary means for expanding practice methods through new research findings.  But here’s the thing to remember, by and large, we can select which continuing education courses or seminars we want to attend. So, like my article, “Is it Time to Break Up with Your OBGYN” (here’s a link) states, your healthcare provider has to actively seek out the most recent data and information and then choose to apply it to their practice.

How Do We Apply This?

Thank you for hanging in there with me as my inner science geek took the wheel today.   I’m a huge believer in the power of knowledge, so hopefully, in breaking down some of the reasons for the confusion and misinformation that exists regarding HRT, we are empowering ourselves. We are, after all, intelligent, educated women.

So, what do we do with this knowledge?  We advocate for ourselves, we ask questions, do our research, and apply our knowledge to partner with our healthcare providers to open the pathways to the safe and available care and treatment that we deserve. Cheers to Knowledge, Friends!!

Resources used for this article:

Cagnacci, A., & Venier, M. (2019, September 18). The controversial history of Hormone Replacement therapy. Medicina (Kaunas, Lithuania). https://pmc.ncbi.nlm.nih.gov/articles/PMC6780820/ 

Haver, M. C. (2024). Chapter 2 / A Seismic Shift Occurs. In The New Menopause Navigating your Path Through Hormonal Change with Purpose, Power and Facts. essay, Rodale. 

Morris, Z. S., Wooding, S., & Grant, J. (2011, December). The answer is 17 years, what is the question: Understanding time lags in translational research. Journal of the Royal Society of Medicine. https://pmc.ncbi.nlm.nih.gov/articles/PMC3241518/#:~:text=It%20is%20frequently%20stated%20that,evidence%20to%20reach%20clinical%20practice.&text=Balas%20and%20Bohen%2C16%20Grant,different%20points%20of%20the%20process. 

Pennmedicine.org. (n.d.). https://www.pennmedicine.org/research-at-penn/translational-research#:~:text=What%20is%20Translational%20Research?,for%20Translational%20Medicine%20and%20Therapeutics. 

Woods, J., & Warner, E. (2014, December 4). Was the Women’s Health initiative good or bad for Women’s Health?University of Rochester Medical Center. https://www.urmc.rochester.edu/ob-gyn/ur-medicine-menopause-and-womens-health/menopause-blog/december-2014/was-the-women-s-health-initiative-good-or-bad.aspx