Hormones
Risks of Hormone Replacement Therapy in Women
Hormone replacement therapy, or HRT, for peri or postmenopausal women is one of the most satisfying treatments that we, as ‘anti-aging’ doctors, are able to prescribe. We all have high numbers of very satisfied women who let us know that since the prescribing of HRT, they ‘got their lives back.’ I can attest to this as I have post-graduate training in HRT, being board-certified and having a Fellowship in HRT therapies with the American Academy of Anti-Aging Medicine (A4M).
However, getting to this place of being able to help women through the hormonal transitions of life using natural and bioidentical options has been a long time coming. Many were turned away from a large early study from the Women’s Health Initiative that warned of the dangers of synthetic hormones, and unfortunately this fear continues to permeate much of the conversation around using HRT.
In this article, I’m going to walk you through the history of HRT, along with the studies that came after that first Women’s Health Initiative trial that clarified many of our questions regarding HRT, so that it can be used safely and effectively to improve the quality of life for so many women.
Keep reading to learn more about HRT – Is it our enemy or our friend?
This article will cover:
When discussing HRT for women in their perimenopausal or post-menopausal years, we are mostly talking about estrogen and progesterone hormone replacement therapy, the two main sex hormones involved in a woman’s sense of well-being.
As estrogen and progesterone levels fluctuate and eventually decline through the perimenopausal years and then reach the very low levels during menopause, many women experience uncomfortable symptoms and a loss of the wellness and protection that these hormones provide. Replacing these hormones often does wonders for how a woman feels, looks and enjoys her life.
Estrogen is known to protect against depression, mood disorders, insomnia, loss of memory and cognition, dementia, colon cancer, reduction in bone fractures, dry vaginal tissue, wrinkles, and loss of teeth. Estrogen also contributes to the prevention of urogenital atrophy, the improvement of lipid metabolism and increasing libido. Overall, estrogen improves wellbeing and general symptoms of malaise.
The benefits of progesterone include improved sleep, reduced anxiety, and protection against breast cancer, coronary artery disease, and osteoporosis.
Does HRT increase the risk of breast cancer? Does HRT cause cancer? What about increase strokes, heart disease, and blood clots? What are the risks of hormone replacement therapy?
These are the most common questions I get from women when discussing HRT.
The reason for their concern is still firmly etched in everyone’s mind from when the conclusions of the Women’s Health Initiative (WHI) study were published in 2002. This showed that women on HRT had increased rates of breast cancer of 34 percent, strokes of 37 percent, blood clots and pulmonary emboli of 24 percent, and heart disease of 27 percent. When these figures were published, there was a huge media frenzy highlighting HRT risks, patients were immediately taken off HRT, and all research into this type of therapy was seriously curtailed.
Since that time, there’s been considerable research, some carried out by the same WHI group, that actually refutes aspects of these findings and also examines some of the pitfalls and perils of the original WHI publication. However, none of the same fanfare and publicity has been given to these new findings. Many patients and doctors are still influenced by the 2002 guidelines initiated after this trial was first published.
Keep in mind that when we prescribe HRT for women in the postmenopausal years, the hormones that we use include, but are not limited to, estrogen, progesterone, testosterone, DHEA, pregnenolone, thyroid, oxytocin, hydrocortisone, and melatonin. However, the WHI study was concerned with oral Premarin, a synthetic, non-bioidentical estrogen made from horse urine, along with oral Progestin, which is also a synthetic progestin rather than bioidentical progesterone HRT. The elucidation of these distinctions is vital to understanding these results, as we’ll explore later.
With breast cancer incidences, it’s well established in oncology that anti-estrogen approaches to breast cancer, such as oophorectomy (removal of one or both ovaries), tamoxifen (a medication that blocks estrogen), or aromatase inhibitors (medication that blocks the conversion of testosterone to estrogen), are all beneficial for breast cancer response, survival, and even prevention.
So, if these anti-estrogenic approaches are beneficial, by inference estrogen must be carcinogenic. However, as mentioned above, with recent updated publications on breast cancer and hormone replacement therapy, the results reflect that this may not be the case.
In fact, recent data suggests the exact opposite: Estrogen-based hormone replacement therapy appears to reduce breast cancer and all-cause mortality rates.
How can this be? Let’s explore this conundrum and the history of breast cancer and HRT.
Here are the results from some historical studies outlining forty years of research on this very question, with some surprisingly new observations that will require our serious attention.
The relationship between hormones and breast cancer dates back to the late nineteenth century. At that time a George Beatson, a British surgeon, was the first to postulate an association between the hormonal action of the ovaries and the proliferation of breast cells, first discovering the relationship in lactating sheep. He wondered if removing the ovaries, that produce estrogen and progesterone, could be a treatment for breast cancer. He tested his theory in June of 1895.
A thirty-three-year-old woman had noticed a small lump on her left breast while she was breast-feeding her first child. This lump became larger after the birth of her second baby. A large tumor was successfully removed from her breast, but the cancer was already far advanced. She was referred to Dr. Beatson who removed both her ovaries. He reported the case to the Edinburgh Medico-Chirurgical Society and published details in the Lancet in July 1896. The woman survived for nearly four years before dying of recurrent disease. Thus, the removal of the ovaries as therapy for breast cancer was born and continues in present day. What’s so interesting is this discovery was made thirty years before estrogens were identified.
But, Dr. Beatson didn’t know what the full function of the ovaries was. In the 1920s, researchers Edgar Allen and Edward A. Doisy from St. Louis University identified, extracted, and characterized the molecule of estrogen from a pig’s ovarian follicle. This was a major scientific breakthrough and explained the success of oophorectomy. Once estrogen was isolated from the ovaries and an oophorectomy induced a positive breast cancer response, it implied that estrogen is most likely breast carcinogenic.
Indeed, when anti-estrogens such as tamoxifen and aromatase inhibitors were subsequently developed in the 1970s and 1980s, with tamoxifen as the best example of a dedicated, specialized antiestrogen, a positive response rate of between 20 and 50 percent was seen in stage IV breast cancer. In the 1980s, when aromatase inhibitors were used, a 25 to 30 percent reduction of breast cancer mortality was noted and a reduction in new breast cancer incidence was determined to be between 30 and 40 percent.
Estrogen HRT has been used since the 1940s, became popular in the 1960s then gained a very high level of popularity in the 1990s. It was primarily used to reduce hot flashes, the classic sign of menopause. Yet, in the very beginning their use was also tied to the issues of femininity and sexuality, very well described by Masters and Johnson in the early 1970s. After the seventies, more science emerged within HRT research, confirming that the therapy improved energy, reduced the incidence of bone loss and bone fractures, reduced cholesterol, and had many potential benefits for the cardiovascular system and the risk for heart attacks.
There are approximately fifty-nine observational studies summarized by the Oxford Group on the question of HRT and breast cancer mortality over the past forty years. These studies show an increase in breast cancer mortality with HRT, ranging from 30 to 80 percent, meaning that HRT increases the risk by a considerable amount. Let’s dive more into what this means and the limitations of this type of study.
In observational studies, participants aren’t randomly assigned to a treatment or a control group. Instead, they’re simply observed over time to see whether a particular treatment or intervention helped, harmed, or did nothing. The results are then compared to a similar group that received a placebo or no treatment at all. In the HRT studies, women selected themselves to receive treatment. After twenty years, the researchers would eventually follow up and study these self-selected HRT users against the general population of non-HRT users in a non-randomized fashion.
The benefit of observational studies is that they’re less expensive, can be done more quickly, and can include a broader range of patients. They’re often used when a randomized trial would be impossible or unethical.
The Collaborative Group on Hormonal Factors in Breast Cancer, in Oxford in the UK, the leading authorities recognized in this particular field of epidemiological studies, summarized the observational studies of the previous thirty years of research and published their findings in the Lancet Journal in September 2019, using the comparative analysis of users against non-users. They showed that taking Premarin or progestins had double or a 208 percent increase in the risk of breast cancer.
With estrogen alone, for women after hysterectomy, the risk is lower but incidence is still increased by almost a third or 33 percent. Progestin is used along with estrogen in women who still have a uterus to prevent the risk of endometrial cancer, since estrogen alone stimulates the growth of the endometrial lining.
When looking at mortality rates or death cases with estrogen alone HRT versus non-users, there was a 35 percent increase in mortality. For estrogen plus progestin, there was an almost 64 percent increase in breast cancer mortality. This is the present understanding of the HRT outcomes, when you examine observational non-randomized studies, as reported by the Oxford overview group.
Indeed, from these studies it appears that the incidence and mortality of breast cancer associated with HRT was definitely increased and thus by deduction, estrogen is undoubtedly breast carcinogenic. This information, understandably, would raise caution in a woman looking for symptom relief and anti-aging benefits in menopause. Luckily, there is more to the story.
Other researchers have looked into the issue of potential flaws in these studies, particularly when new studies have shown that estrogen use alone has shown a reduced incidence of breast cancer, with many added benefits of estrogen HRT. Dr. Ragaz’s group has raised the issue that in non-randomized studies like the Oxford overview, with self-selection of HRT users, a potential bias could be created in that women with high-risk of breast cancer were selected. One bias was that more affluent women take HRT. Therefore, the question arises regarding the link between affluence and breast cancer risk.
Affluence and higher socio-economic status have been associated in many studies with an increased risk of breast cancer.
Affluent women have:
There’s plenty of data indicating that all these particular factors are very much linked with higher breast cancer rates.
What’s most important is that randomization is essential when attempting to analyze breast cancer risk in HRT users. Researchers must use a sampling of women from all socioeconomic groups in order to equivalize as many variables as possible.
Randomized controlled trials (RCTs) are considered the gold standard and an ideal method when it comes to medical research. In an RCT, women are randomly assigned to receive hormones, or any other treatment being studied, or a placebo. If the study is double-blinded, neither the patient nor the investigators know which patient is taking what.
The start of large randomized HRT trials began with the WHI studies. The Women’s Health Initiative (WHI) was established in the 1990s under the leadership of Bernadine Healy, the first female director of the National Institute of Health. In 1992, the WHI project conducted a series of four randomized trials examining issues of women’s health, two of which were aimed at the HRT issue.
The Women’s Health Initiative is the most active epidemiological group in USA. Unfortunately, soon after the beginning of these WHI studies, Bernadine Healy died of brain tumors resulting from glioblastoma. She sadly never saw the result of her initiative.
The biggest randomized study to date was initiated by the WHI and called Trial 1. In routine randomized studies the numbers usually amount to a few hundred, but in this study group there were 16,000, a huge amount by routine standards.
In the WHI Trial 1, 16,608 women with an intact uterus were randomised to Arm 1 using estrogen (Premarin) plus a progestin (Provera). Arm 2 received a placebo only. This was the first study looking at both estrogen and progestin and showed a 44 percent increase in breast cancer mortality.
The WHI Trial 1 was terminated prematurely and the results published in JAMA 2002. As mentioned earlier, there was a substantial media frenzy. The media and television networks were full of the data and publicity was aggressive and prolific. This study showed an almost 27 percent increase in heart attacks, 34 percent increase in breast cancer, 37 percent increase in strokes, and a 24 percent increase in pulmonary emboli or blood clots in the lungs. There were some benefits, as quality of life markedly improved and bone fractures were reduced quite significantly. The interpretation by the lead investigators of the WHI Trail 1 dramatically changed guidelines for HRT.
With HRT discredited as a therapy, sales dropped by 50 percent in one month and all the major clinical organizations, such as the American Association of Clinical Endocrinologists (AACE), the American College of Obstetricians and Gynecologists (ACOG), and the North American Menopause Society (NAMS) recommended only using HRT for a very short time and solely for the control of menopausal symptoms.
With regards to the cardiovascular risk factors, some of the initial criticisms of the study declared that most of the women studied were much older and already had significant baseline coronary artery disease. In addition, they were given oral estrogen which is known, particularly in the first year of taking it, to increase clotting factors in the liver.
Soon after the WHI Trial 1 findings were made public, Dr. Lobo published the findings from four large randomized trials in Family Practice News in 2003. These showed that that the risk of cardiovascular diseases is extremely low in healthy women in early menopause and that the results of the WHI didn’t apply to younger women between fifty and sixty years of age who initiate HRT around menopause.
There was overwhelming evidence that the anti-atherosclerotic effect of HRT depends on the time of initiation and that early initiation is protective. The Nurses’ Health Study (NHS), which has produced the most data for observational studies for risk factors for major chronic disease causation in women, didn’t find any association between coronary artery disease (CAD) and HRT. It was hypothesised that once CAD is established, HRT has no protective or beneficial effect, but estrogen given to menopausal women significantly retards progression of CAD by its positive effects on lipids and endothelial functioning, which is related to the inner lining of blood vessels. However, oral estrogen given to women over sixty with CAD may make the condition worse.
A second study by WHI, called Trial 2, using estrogen hormone replacement therapy alone, showed astounding results, but in the other direction.
In the WHI Trial 2, 10,739 women, after hysterectomy, were randomized to estrogen against placebo. Arm 1 used estrogen-based HRT alone, while Arm 2 was a placebo only.
In 2004, the first publication of the WHI Trial 2was released regarding the estrogen-alone arm, which has continued onwards until the present. These results were from women under the age of sixty.
The WHI Trial 2 mostly indicated benefits, including a 40 percent reduction in breast cancer mortality! Remember, in WHI 1 there was an increase in breast cancer, but here we have a 40 percent reduction in breast cancer mortality with the use of estrogen HRT alone. It’s very important to note in this case that progestin wasn’t used.
Furthermore, there was a 25 percent reduction of diabetes, a 26 percent reduction of Alzheimer’s dementia mortality, a 55 percent reduction in myocardial infarction among patients between fifty and fifty-nine years old, a 21 percent reduction in all-cause mortality, and a 32 percent reduction in bone fractures with an 80 percent improvement in quality-of-life benefits. This is remarkable and the findings are very different from the WHI Trial 1 results.
However, unlike the WHI Trial 1, which according to these publications had revealed mostly remarkable benefits, there was no publicity. There wasn’t a single article or television report. Not a thing. From 2004 to 2020, the WHI has updated this study, with the same benefits being shown, but they’ve entirely suppressed their own publicity. Consequently, nobody knows much about these outcomes.
So, when patients inevitably ask me if HRT therapy is safe or inform me that their doctor has told them to stop using HRT because it isn’t safe, I immediately know that they aren’t aware of the WHI Trial 2 studies, which have refuted the majority of the WHI Trial 1 findings.
These findings are completely opposite to the WHI Trial 1 studies, which incorporated estrogen and progestin. A further WHI Trail 2 study published by Stefanick et al in 2006 showed a reduction in the estrogen-alone HRT group, the breast cancer incidence reduced by between 20 and 43 percent. However, nobody has heard about these outcomes. There was no publicity at all. As a result, the consensual opinion of patients and the majority of health practitioners continue to be based on the WHI Trail 1 findings.
With continuation of the WHI Trial 2, published by Andersen et al in Lancet Oncology 2012, showed the persistence of benefit with estrogen alone. There was a 23 percent reduction in breast cancer incidence with a 63 percent reduction in breast cancer mortality and a 38 percent reduction in all-cause mortality with estrogen alone. This is unbelievable.
Almost twenty years later, the WHI Trial 2 continues to publish data. An updated study, published by Manson J. et al in JAMA 2017 showed a 45 percent mortality reduction with estrogen alone and the 2020 Chlebowski R. et al JAMA 2020 publication showed mortality for breast cancer reduced by 40 percent.
Please note that the conclusions from the WHI Trial 2 findings from all studies from 2004 to date show a very statistically significant 40 percent breast cancer mortality reduction with estrogen.
So here we have to ask how is it possible that estrogen, which for decades has been linked to breast cancer, provides benefits?
There’s some evidence for the biological impact of estrogen on breast cancer cells. Research by Dr. Joseph Ragaz’s group has shown the following:
As far back as 2010, Dr. Ragaz’s group presented the potentially very important concept of estrogen duality, which shows that exogenous estrogen in HRT is protective, whereas endogenous estrogen made by the body proliferates the breast cancer cells. We know that exogenous estrogen in HRT is protective as the WHI Trial 2 data above attests.
We also know that because of the endogenous estrogen, we can remove the ovaries and administer anti-estrogens such as tamoxifen, with these being aimed against endogenous estrogen. These studies show that suppression of endogenous estrogen is breast cancer beneficial. Therefore, endogenous estrogen stimulates and remains carcinogenic.
The message is that now there’s clear evidence of exogenous estrogen emerging as a potent, powerful anti-estrogen to the endogenous estrogen. This is basically the information that needs to be published, publicised, and the message spread amongst the lay and medical communities.
The other question is why there’s so much difference between the two trials. The evidence very clearly appears to be centered on the issue of the synthetic progestins used. It’s been known for some time and there’s adequate evidence to show that the progestin/Provera used is actually carcinogenic and inflammatory and can erase the benefit of estrogen.
In Trial 1 with estrogen and Provera, the incidence of breast cancer mortality was increased by 44 percent. In the WHI Trial 2, with no progesterone but estrogen alone, there was a 45 percent reduction in breast cancer mortality. However, the new generation of bioidentical progesterone, including Prometrium and compounded bioidentical progesterone rather than progestin, don’t appear to be as harmful to breast cancer. That’s a very important concept as most patients and many doctors equate the two, meaning progestins such as Provera and bioidentical progesterone, as being the same.
Progesterone was isolated and produced in the 1930s and so named because it’s the hormone that supports pregnancy and is pro-gestation. Today, the word progesterone is often misleadingly applied to many different forms of this hormone, rather than the natural progesterone that the body produces. Prometrium is the most common bioidentical micronized form of progesterone used in North America.
In contrast, progestins are synthetic compounds, not bioidentical to what your body produces. The most frequently prescribed synthetic progestin in North America is called methoxy progesterone acetate (MPA), which has the trade name Provera. Prempro is a combination of synthetic estrogen and synthetic progestin and was the one used in the WHI Trial 1.
Progestins are known to adversely affect mood, fatigue, edema, anxiety, bloating, depression, breast swelling, and reduce HDL levels. Progesterone is devoid of these side effects, unless given in amounts above what’s normal for the body.
All this to say that the form of HRT really matters and bioidentical is the most beneficial with the least risk.
Estrogen has an impact on all-cause mortality, referring to the health of women and the cause of death for all other conditions other than breast cancer, and is decreased considerably in those who take estrogen-only HRT.
Dr. Ragaz and his group obtained data from the WHI and transformed the numbers into crude, absolute numbers of deaths that could be avoided each year by women taking estrogen-only HRT. Their final aim was to influence the HRT prescribing guidelines, because the current HRT guidelines haven’t yet taken into consideration the updated data or results since 2004, which have been explained above.
In the 2017 overview from Mason’s WHI Trial 2 publication, breast cancer mortality reduction was 45 percent, Alzheimer dementia mortality reduction was 26 percent, and all-cause mortality reduction was 21 percent. This includes every other cause of death, other than dementia and breast cancer. They took the annualized mortality rates for these three conditions, applied the reduction in deaths from them as published in the WHI Trial 2 and came up with the following figures. The results were stunning!
Every year in the United States, with the use of estrogen-only HRT, there would be 9,292 fewer breast cancer deaths, 18,966 fewer Alzheimer’s dementia deaths, and 21,750 fewer deaths from other causes, such as diabetes, bone fractures, or from cardiac factors. In total, the lower mortality rates amounted to 50,008 fewer deaths from all causes every year by using estrogen-only HRT.
The evidence is clear that we see an unexpected numerical HRT benefit with avoidance or breast cancer cases, Alzheimer’s dementia, and all-cause mortality.
Dr. Ragaz’s recommendation is to adopt and implement HRT, without synthetic progestins, to the current medical guidelines in order to pass on the benefit to millions of women. This means that hundreds or even thousands of deaths could be avoided worldwide. In the USA alone, 50,000 deaths could be prevented and many more women could be saved if these recommendations are adopted worldwide.
In summary, the absence of randomization in the previous observational studies highlights the fact that these studies were methodologically flawed and the conclusions they reached have to be viewed from this perspective. Secondly, because of the carcinogenicity of progestin/Provera included in the randomized WHI Trial No 1, this trial’s conclusion can’t be applied to modern prescribing of HRT, which excludes progestin/Provera in favour of bioidentical progesterone.
As a result, the estrogen-alone based HRT evaluated in the WHI Trial 2constitutes the new gold standard. This is a basic constituent for present HRT regimens to be recommended in new guidelines, with the new generation of progesterone, which aren’t carcinogenic, to be applied for most women approaching menopause.
There’s hope that breast cancer prevention is possible and that estrogen will likely play a larger role. If you’d like to explore if HRT is a good fit for you, please contact my office to schedule a consultation.
