Is Hormone Replacement Therapy Safe?

Dr. Scott Resnick | Chattanooga TN

The question of the safety of hormone replacement therapy is frequently brought to my attention, and for good reason.  In recent years the media has delivered varying reports that have questioned whether the use of hormone replacement in the menopausal years is safe or not.  Does the use of hormonal therapies lend years and improved health to a woman’s life, or is it associated with an increased health risk?  

Sadly I feel that the accuracy of the response has depended on the perspectives, and the political and/or financial objectives of the party making the claim.  Let’s take a moment to look at that last statement.  

I recall sitting in my medical office in the Summer of 2002, and having my office manager appear at my door with a look of dread.  “We are going to be inundated with patient calls,” she said, “I just heard on the news that a large trial showed that hormone replacement in menopause increases the risk of breast cancer.”  The claim to which she was referring came from a newscaster on the morning news, who briefly and with a sensationalist air described the results of the Women’s Health Initiative, a large trial that looked at the use of hormonal therapies.  On May 31st, 2002, after a mean of 5.2 years of follow-up, the study revealed: “estrogen plus progestin vs. placebo (The first gross inaccuracy, more later) “was stopped because the test statistic for invasive breast cancer exceeds the stopping boundary for this adverse affect and the global index statistic (whatever this means) supported risks exceeding benefit”. 

Bottom line: Hormone replacement increases the risk for breast cancer.

When painted with broad strokes, the data suggested that the women receiving estrogens and progestins had an increase of invasive breast cancer and stroke, while at the same time a decrease in their risk of colon cancer, osteoporosis, and total mortality.  This is what was reported in the news and doctor’s offices around the country, and hundreds of thousand of women, if not millions, went cold turkey off of their hormonal regimens.              

But with so many sensationally reported studies, I find that it is somewhat helpful to let the dust settle, and to take a step back and reexamine the data, if not simply read the paper.  I chose to do the latter, and to look at the raw data.  This is what I found.            

To begin with, I believe that simply the title of the paper is misleading.  The JAMA paper (http://jama.jamanetwork.com/article.aspx?articleid=195120) is titled, “Risks and Benefits of Estrogen plus Progestin in Healthy Postmenopausal  Women.”   I can assure all readers that the description of what the trial set out to evaluate is at least a half truth.  Yes, the study used a Progestin.  This is a progesterone-like compound, that has effects on the progesterone receptor in the human body.  The medicine is known as medroxyprogesterone.  It is not biologically identical to the human molecule progesterone, but at least the nomenclature in the title was correct.

But what about the use of the word estrogen?  Estrogen is a steroidal molecule found in the human body that binds and activates the cellular estrogen receptor.  This study however, referenced throughout the text but not in the title, utilized a drug (premarin) known to contain conjugated equine estrogens.  These are estrogen-like molecules, with ‘horsey’ names like equilin and equilenen that are harvested from the urine of pregnant horses.  These molecules are not naturally found in the human body, and don’t have the same chemical composition of estrogen.  But they do have a biological effect on the human receptors.  So why not call a “spade a spade” and utilize the correct terminology?  It may just be that Pfizer, who makes the drug Premarin (prenant mare urine), has found in surveys that women want to think that they are taking estrogen, not the distilled urine from horses.  Sadly, the lead investigators in this study were similarly bamboozled, and chose not to use correct medical terminology in the title of the paper.  This should have been a big red flag from the start.

Additionally, the study enrolled a group of women who were quite a bit older than the average woman who would be seeing her gynecologist with complaints of menopausal symptoms.   The average age at the onset of the trial in the intervention and placebo groups was 63 years old.  Recall that the average age of menopause is something like 50.7 years old, so these patients were not enrolled onto a treatment trial until a full decade after their natural menopause.  It is well known that a woman’s risk of breast cancer increases with age, and I have no doubt that within a group of 63 year-olds, a certain number will have existing, but non-diagnosed cancerous cells.  When the number of cell doublings for a cell are calculated, 8 years, or 20-30 doublings of the cells, is required before the cancer can be detected with a mammogram.  So with an enrolled group of older women, in whom it is likely that an undetectable cancer already exists, it is not surprising when a hormone appears to stimulate cancer growth.

Lastly, it should be known that in one of the several post-publication analyses of the vast amount of data collected in this trial, that it appears that when the estrogen alone group was analyzed, that there was not an increase of breast  cancer.  It is felt that the increases of breast cancer in the study were attributable to the use of the similarly non-biologic progestin, medroxyprogesterone.  This gave the equine estrogens a temporary hormonal hall pass.  But what is really best for our menopausal patients?

At this point I would like to direct our discussion to another paper that was published in a 2008 paper by Agnes Fournier in the journal Breast Cancer Research and Treatment.  ww.ncbi.nlm.nih.gov/pmc/articles/PMC2211383/ 

This study, which was conducted in Europe where women and doctors generally eschew the use of horsey hormones, and utilize the human, bio-identical hormones estradiol and progesterone, looked at the question of whether hormone replacement increased the risk of breast cancer.  The massive study, with 80,377 women, showed that when women took “unopposed” estrogen alone, the risk of breast cancer increased by about 29%; a relative risk of 1.29.  When paired with the balancing, natural hormone progesterone, the relative risk, or the risk relative to a non-treated woman was 1.0.  This means that there was no increased risk of breast cancer in the hormone users versus never users.

So what, then is the best recommendation that I can make to a menopausal woman who wishes to consider hormone replacement therapy?  Understand that this is an individual decision, and one that should ideally be made with a health care provider who is not strongly influenced by the sirens of the big pharmacological companies, who by law are unable to patent and profit from a bio-identical hormone.  I personally feel that the best way to approach this question is with a review of the research, part of which I have outlined above.  I also think that a careful review of family history, medications and a physical exam is required as well.

But the concept I feel I must stress is that biological systems, in this case systems involving hormone replacement, don’t occur in a vacuum.  It is essential to take a functional approach to clinical conditions such as these.  Ideally one should consider body shape and morphology, energetics, detoxification and bowel function in your decision to use hormonal therapies.  For women with a strong family history of breast cancer I am going to consider the use of genetic screening as an adjunct to the use of hormones as we proceed.  In this way we can get an idea of the metabolic pathways that determine how and where the estrogen molecules will be utilized.

And finally, I solemnly swear that I will never prescribe to my patients a hormone that came out of a horse.   So hoof it over to an educated provider, and get saddled up with a safe, balanced hormonal regimen.   Take the reins of your health care, and ride off into the sunset with a balanced, functional program.  Hi-yo Silver, away!