As we get older, our steroid hormones (estrogen, progesterone, testosterone, etc.) levels naturally decline. With these declining hormones, we lose muscle mass, have less energy, have decreased exercise capacity and often, develop sexual dysfunction. Many physicians treat these changes by prescribing hormone replacement therapy (HRT), and many patients come knocking on doors, looking for these prescriptions. There is, however, large controversary around this practice and very conflicted data about whether HRT is helpful or harmful to patients (1).
Not what I learned in medical school
During my naturopathic medical training, we discussed hormone replacement therapy. Our teachers shared with us a very famous, very large set of research studies called the Women Health Initiative (WHI). We learned that because of the WHI, we have data that HRT increases several risks for women, including increased risk of strokes, other types of blood clots and breast cancer. Yikes! Not good. We learned that short-term, a small amount of HRT could help tie women over during the absolute hardest years of menopause. But we should use it for the shortest time possible and only for women with very severe menopausal symptoms.
However, once I got out into the “real world”, I started to hear a very different story, both from clinicians and patients. I heard from patients that HRT changed their lives. It gave them their mental clarity back, they actually enjoyed their romantic relationships, hormones “helped her not feel like carrying a shotgun and shooting everyone all the time” (actual quote from a patient!). Many of my patients were not interested in life without their hormones because they felt so terrible otherwise. From clinicians, I learned that in fact, the research is really debatable. There are very large, very high-quality research articles showing some harm and risk. There are also very large, very high-quality research articles showing benefits. The research is very conflicting and to declare any one perspective the absolute truth requires you to ignore a huge amount of research from the other perspective.
A brief glance at the research
To summarize the vast collection of research on hormone replacement therapy is far too extensive for this article. However, I will highlight some key points to emphasize the conflicting data.
Take-Home Message 1: Oral estrogen plus synthetic progestin HRT increases the risk of blood clots, coronary heart disease and breast cancer and decreases the risk of colorectal cancer, hip and other bone fractures, and new-onset diabetes.
The Women’s Health Initiative (WHI): This collection of studies looked at thousands of women over many years and analyzed many different factors of women’s health. When the studies on HRT began to be published in 2002 and 2003, it massively changed HRT around the world. When using oral estrogen and synthetic progestins, the studies showed an increased risk of blood clots (strokes and venous thrombosis), coronary heart disease and breast cancer. The studies showed protective benefits for colorectal cancer, hip and other bone fractures and new-onset diabetes. The studies on synthetic progestins and estrogen HRT were actually stopped early because the researchers deemed it unethical to continue the treatment as the risks began to reveal themselves (2).
Take-Home Message 2: Oral estrogen HRT in women without a uterus had less risk of hip and bone fractures and likely less risk of breast cancer, new onset diabetes and coronary heart disease and an increased risk for blood clots and strokes and likely an increased risk for colorectal cancer.
Additional analysis and publications of the WHI looked at HRT using only estrogen. In these analyses, estrogen only HRT demonstrated benefits on hip and total bone fractures and was trending towards a decreased risk of coronary heart disease, new-onset diabetes and breast cancer. There were increased risks for strokes and venous thrombotic events and some trends towards increased risks for colorectal cancer (3).
Take-Home Message 3: Topical/transdermal estrogen is very likely safer than oral estrogen HRT. Bioidentical progesterone is very likely safer than synthetic progestins.
A 2013 study sought to understand if topical/transdermal applications of estrogen HRT was superior to oral HRT. Physiologically, oral HRT goes to the liver first and in the liver, the hormones can increase the production of blood clotting proteins. Many proponents of HRT have argued that we need better studies looking at the various forms of HRT and the associated risks and benefits. This study looked at 727 menopausal women and compared oral versus topical estrogen HRT. Researchers found a mixture of effects depending on oral or transdermal, but overall, this study gave some clues that transdermal applications may be beneficial in comparison to oral, which is consistent with our physiologic understanding as well (4). In a French systematic review of around 75,000 women, lower dose transdermal estrogen HRT was not associated with an increased risk of strokes, where higher dose transdermal estrogen HRT and oral HRT was associated with increased risk of strokes (5). A 2008 review article evaluated research comparing transdermal and oral HRT, as well as different forms of HRT. Researchers reviewed data that suggests that transdermal, not oral, estradiol may lower blood pressure. They also discussed data that suggests that progesterone, not synthetic progestins, may have a lowering effect on blood pressure. They also discussed data that indicates that oral estradiol increases the blood levels of hsCRP and IL-6 (both are blood markers for cardiovascular disease or inflammation), where transdermal estradiol does not have this effect. The article also reviewed research which confirms that transdermal HRT does seem significantly less likely to increase the risk for blood clots when compared to oral HRT (6).
Take-Home Message 4: Starting HRT within ten years of menopause is likely safer than starting it ten years after menopause.
There are additional studies that suggest that starting HRT earlier is safer and more protective than starting HRT later in life. One notable study looked at nearly 40,000 individuals and showed that HRT started within ten years of menopause significantly decreased the risk of coronary heart disease events in women, such as heart attacks. Coronary heart disease events in older women (starting HRT later than ten years since menopause) had an increased risk of coronary heart disease events within the first year of use but then had a protective effect after that, resulting in a neutral effect on coronary heart disease events (7).
The research continues, but I won’t . . .
This is a tiny dent in the existing research on hormone replacement therapy. I hope that you are beginning to understand that for every huge, high quality study that shows a particular set of risks, there are other huge, high quality studies that show some benefits. Transdermal does seem to be safer than oral HRT. Progesterone does seem to have fewer side effects than synthetic progestins. Starting HRT earlier is generally advisable versus starting HRT much later in life. But, the more that I read, the more I realize that this is yet another area of medicine that is not black and white. Patients deserve to know about the existing research, both the anticipated risks and benefits of HRT. And ultimately, I believe that a well-informed patient deserves the sovereignty to decide what treatments are best for them.
About the author:
Dr. Lauren Gresham is a naturopathic physician and Certified Community Health Education Specialist. She prescribes and manages bioidentical hormone replacement therapy as well as manages many other concerns around healthy sexuality. Please call 206-542-4325 to learn more.
- Pharmd, B. R. W., Soojeung, J., & Pharmd, C. (2017). Hormone Replacement. Primary Care: Clinics in Office Practice, 2017-09-01 Volume 44, Issue 3, Pages 481-498.
- Women’s Health Initiative (2002). Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women, 288(3), 321–333.
- Women’s Health Initiative. (2004). Effects of Conjugated Equine Estrogen, 291(14), 1701–1712.
- Wharton, W., Gleason, C. E., Miller, V. M., & Asthana, S. (2013). Rationale and design of the Kronos Early Estrogen Prevention Study ( KEEPS ) and the KEEPS cognitive and affective sub study ( KEEPS Cog ), 1–13.
- Renoux, C. et. al. (2010). Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ. PMID: 20525678
- Hermite, M. L., Simoncini, T., Fuller, S., & Genazzani, A. R. (2008). Could transdermal estradiol + progesterone be a safer postmenopausal HRT ? A review, Clinical Key 1, 1–54.
- Salpeter, S. R., Walsh, J. M. E., Greyber, E., & Salpeter, E. E. (2005). BRIEF REPORT: Coronary Heart Disease Events Associated with Hormone Therapy in Younger and Older Women, 95128, 363–366. https://doi.org/10.1111/j.1525-1497.2006.00389.x