Lately, there has been heated debate among menopause experts on social media (what else is new...) regarding hormone therapy and whether or not it decreases the risk of cardiovascular disease. As always, the conversation is nuanced, so get ready for a deep dive into it!
In a previous post, I discussed the women’s health initiative (WHI) and how it changed the course of the use of menopausal hormone therapy (MHT). Interestingly, the original purpose of that large study was to determine if MHT should be used in all women in menopause in order to reduce cardiovascular risk. It's been a while, so some of the content in this post may be the same or similar to the prior post - but here we will focus on the effect of hormone therapy on prevention of cardiovascular disease.
In the 1980s and 1990s, multiple observational studies were showing a possible link of MHT use with decreased rates of heart disease, osteoporosis, and dementia. At that point, MHT use exploded, and many doctors were prescribing MHT for all postmenopausal patients, including asymptomatic ones, for disease prevention. Along came the women’s health initiative (WHI). A HUGE and important study that made a HUGE impact on the treatment of menopause.
The WHI was one of the largest and most expensive NIH-funded trials on women ever conducted. There were multiple objectives of the study, but one was to answer the following question (READ THIS PART - THE CLINICAL QUESTION ASKED IS IMPORTANT!!!): “Does MHT use in asymptomatic menopausal women reduce the risk of cardiovascular disease and osteoporosis fractures?”
Note - this is NOT the same question as “is menopausal hormone therapy safe and effective for women with bothersome symptoms of menopause?”
In the WHI, the average age of women enrolled was 63! And ages ranged from 50-79. The average BMI was 28 (overweight). Majority of patients (83%) were white. 30% were on medication for hypertension, 50% were either former or current smokers, and 13% had elevated lipids. The medication used was CEE/premarin 0.625mg and MPA/(Provera) 2.5mg in a combined oral pill. The primary outcome (main finding) they were looking for was cardiovascular events such as MI (heart attack) or stroke
They looked for Cardiovascular disease, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death due to other causes.
The study was halted earlier than planned (6.8years) after they found that actually cardiovascular disease seemed to be increasing and they found a small increased risk of breast cancer in women that were taking the CEE and MPA combination. This made HUGE HEADLINES and caused widespread fear about taking hormones. Many women stopped them without talking to their doctors, and many doctors stopped prescribing them for fear of backlash or because they were not fully aware of the data.
Let's dive into the numbers a bit in that study.
The risk of cardiovascular disease (mostly in the form of non-fatal MI) went from 3 events in 1,000 women to 3.7events in 1,000 women (which is a 29% increase) for women taking CEE/MPA. This was statistically significant (p=.05) There was no significant increase in deaths due to CV disease. Similar increased rates of stroke and blood clots (VTE) were seen.
For the numbers people: stroke risk went from 2.1 in 1000 to 2.9 in 1000, and VTE went from 1.6/1000 to 3.4/1000. The rates of breast cancer went from 3/1000 to 3.8/1000
So what does this tell us?
This particular study tells us that it is not recommended to use oral CEE 0.625mg and oral MPA 2.5mg for the purpose of CV disease prevention in menopausal white women of average age 63 years. Sound specific? It is. Very specific.
By the way… there was another whole arm of the WHI trial that looked at the same outcomes for women without a uterus who used ONLY CEE 0.625mg, and no MPA since they did not need it for uterine protection. And what did that find?
-similar small increased risks stroke, and VTE
-DECREASED RISK OF BREAST CANCER
-NO INCREASED RISK OF CHD
-decreased risk of fracture
Yea, this one didn't make headlines. Less exciting, I guess. (I would beg to differ)
In that same follow up study, they looked at the risk of each outcome stratified by age group.
When they looked at the 50-59 age group, or early menopause group for CEE alone, we see LOWER rates of cardiovascular disease (bypass surgeries, MI) and LOWER all cause mortality!
There is a large and growing body of evidence that shows a cardioprotective effect of estrogens when started in early menopause. While breast cancer seems scarier, in reality, far more women die of heart disease. Women are underrepresented historically in cardiovascular disease research, and womens heart attacks are more likely to be missed due to “atypical” symptoms. (although I think by “atypical” they really mean “not a symptom a man usually has”)
After menopause, a woman’s risk of heart disease rapidly approaches their male counterparts’. In the absence of estrogen, blood vessels stiffen, blood pressure increases, LDL numbers increase, and inflammation increases. All of which are major risk factors for atherosclerosis.
Interestingly, hot flashes themselves are strongly correlated with cardiovascular risk. It is thought that they may represent or perhaps even cause dysfunction in the endothelium (the inner cell layer of blood vessels) which can accelerate atherosclerosis.
From the WHI, it seemed that estrogen/MHT given later in life either has no effect or possibly a detrimental effect to existing cardiovascular disease.
To date, there have been no long-term (~20year) prospective studies of MHT, and certainly not in a randomized controlled trial. And unfortunately I’m not sure we'll ever get one. (I know I’m not signing up for it! I don’t want to be randomized to placebo!) What we have to go on is animal studies, shorter prospective studies, and retrospective data, which are inferior but still important to examine.
A recent MASSIVE retrospective study was done using medicare data, that looked at women >65 who have used MHT long term. It separated out by type of hormones used, method of delivery, and dose, and looked at correlations with outcomes. I am fascinated by this data and find it extremely compelling! Take a look:
Source: Baik et al, Menopause may 2024: “Use of menopausal hormone therapy beyond age 65 years and its effects on women's health outcomes by types, routes, and doses”
I know it's a busy chart, so I highlighted the routes that are commonly used by most menopause specialists today: transdermal estradiol (alone, if no uterus) or transdermal estradiol with progesterone. Interestingly, those that had the addition of progesterone did not seem to have any correlation with either increased or decreased risk of heart disease. Transdermal estrogen alone, seemed to be the only preparation with favorable inverse correlations with heart disease. Again, this is retrospective data, but its a BIG dataset, and possibly the best we have right now. This paper needs to be discussed more!!! Another part of this study was showing outcomes with cancer where almost across the board MHT seemed to be correlated with decreased rates of cancers including breast, lung, colorectal, ovarian. Also decreased rates of all cause mortality! (they did, however, find increased rates of breast cancer in patients who took estrogen + either progesterone or a synthetic progestin.)
There have been quite a few prospective randomized/controlled trials done. Looking at the data from many of them together, it seems that estrogen alone consistently helps prevent CVD when started early in menopause. However, the picture gets fuzzier when we need to add in a progestogen in women with a uterus.
Ok so what do we do with all of this information, and lack thereof? Well, here is my take, given all the data together:
Estrogen, when started early, can help to prevent cardiovascular disease.
It is unclear whether estrogen PLUS progestin/progesterone protects against CVD in the long term. If it does, it is certainly best when started early in menopause.
Oral estrogens can increase the risk of blood clots and stroke, and high blood pressure - this may be partly why some of the net long-term effects are not positive.
These risks are mitigated when using transdermal estradiol (patch, cream, spray), but we have less prospective data on transdermal.
My favorite form of MHT: Estrogen patch in a woman without a uterus, or patch + progestin-containing IUD in women with a uterus.
With regards to the IUD, yet again, we don’t have all the data we need. What we do know is this: A Mirena IUD protects the uterus, and causes blood plasma levels of the synthetic progestin to be around 150-200pg/mL. This is 1/10th of the amount in the blood you would get from an oral progestin.
Dose matters! With such a low dose, the likelihood of negative health effects are lower. So for women with a uterus, an IUD can be a great way to go. But many women choose not to have this, and progesterone and progestins are also safe and effective alternatives for symptoms. But the jury is still out for long term benefits for CVD and alzheimers/dementia. We do know it helps to prevent many types of other cancers aside from breast!
The decision to take MHT must be individualized, especially when considering it for health benefits alone. We don’t yet have all the answers we need, but the future seems promising given our current wave of advocacy.
To see Dr. Mandelberger as a patient, please contact our office at 516.853.7891 or email info@balancedmedicalny.com
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