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Is Menopausal hormone replacement therapy safe?

by | Aug 21, 2020

This article was written by our Chief Medical Advisor Deborah Matthew MD. An internationally recognized leader in her field, she is a Diplomat of the American Board of Anti-Aging and Regenerative Medicine (ABAARM), and the American Board of Integrative Medicine (ABOIM).

Are you having menopausal symptoms, but you are worried about hormone replacement because you have heard that it is dangerous? 

You may have heard that it causes breast cancer or heart attacks, and maybe your doctor has even advised against it. 

So you suffer with hot flashes, vaginal dryness, fatigue, depressed mood, irritability, poor sleep, changes in your hair, your skin, your sex life and the shape of your body.   How you feel may be affecting your family, your career and your quality of life. 

Hearing that women are suffering like this makes me very frustrated, because the risks of estrogen have been over-stated, mis-construed and mis-understood  – resulting in unnecessary suffering as well as unnecessary deaths. 

Did you know that consistently, across many studies, estrogen replacement has NOT been associated with an increase in the risk of breast cancer? 

Estrogen has also been shown to reduce the risk of heart attacks and death!

But wait a minute, how many times have you heard that it increases risks?  How can this be?

A study done at Yale looked at women aged 50-59 who had had a hysterectomy. Estrogen therapy (ET) was actually associated with a REDUCTION in deaths from heart attacks and breast cancer in these women. They estimated that 90,000 women have died because they did NOT continue on hormone replacement therapy.  Pretty shocking!

Philip M. Sarrel, Valentine Y. Njike, Valentina Vinante, and David L. Katz.  The Mortality Toll of Estrogen Avoidance: An Analysis of Excess Deaths Among Hysterectomized Women Aged 50 to 59 Years. American Journal of Public Health: September 2013, Vol. 103, No. 9, pp. 1583-1588.

The Women’s Health Initiative Trial (or WHI) is the study that started the controversy.  In this study women were given a pill that contained estrogen that was not bio-identical (meaning it wasn’t exactly the same as the estrogen that your ovaries make) and a synthetic progestin (a man-made chemical that mimics human progesterone).  The progestin in the pill was the main problem – it contributed to an increase in breast cancer and heart disease risks (more on that later). 

For now, lets focus on estrogen, since that is the one that seems to have gotten a bad rap.

Here is what we know.  Estrogen is good for your bones (it helps reduce the risk of osteoporosis) and is the most effective therapy for hot flashes.  These facts are not in question.

Here is what else we know: 

  1. WHEN you start hormone replacement matters.
  2. HOW you take your hormone replacement matters.
  3. What FORM of hormone replacement you take matters

Let’s explore each of these issues, so you can become an expert.

WHEN you start hormone replacement matters.

1.  In the WHI study, some women were given estrogen only (these women had had a hysterectomy).  They were all given the same form of estrogen (it was not bioidentical) and took it the same way (an oral pill).  But WHEN they started it varied, and made a big difference.

Women who were given estrogen only, and started it between age 50-59 had LESS Heart disease, LESS strokes, LESS breast cancer, and LESS risks of death

Women on estrogen only, who started between age 60-69 had less heart disease and less breast cancer, but they had a slightly increased risk of blood clots and stroke.  There was no statistical change in overall mortality (no increase or decrease in death compared with women who did not receive hormone replacement).

Women on estrogen only, who started when they were older, between ages 70-79 had  increased blood clots, stroke and heart disease, and increased overall mortality, but no increased risk of breast cancer.

Starting estrogen within 10 years of menopause gives the best results.  Starting when you are less than than 60 can decrease the risk of heart attacks, strokes and death! 

Here is how the Endocrine Society interprets this information:

“Heart attacks, heart failure and death are reduced by 40% when HRT is initiated in women aged less than age 60 or within 10 years of menopause. “

Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement. JCEM July 1, 2010 vol. 95 no. 7 Supplement 1

And note that women had a decrease in breast cancer no matter how old they were when they started! This data is from the same WHI study that trumpeted all over the news that hormones increase breast cancer.  Remember, this was due to the progestin, and this info is coming up.  But let’s talk a little more about the timing of estrogen use.

For women who start on oral estrogen over the age of 60, there is an increased risk of heart attacks in the first year.  If you haven’t taken hormone replacement (probably because you were told it was dangerous!) then in the years since menopause you may have had plaque building up in your arteries.  Oral estrogen increases matrix metalloprotein, which is a compound that causes the plaque to become “unstable” and increase the risk of plaque rupture causing a stroke or heart attack. 

The risk of plaque rupture is increased in the first year of starting oral estrogen, but if you don’t have a stroke or heart attack in the first year, then over time your risk decreases because the estrogen affects the plaque making it gradually smaller.   By year 5, the risk of heart attacks and strokes is less than in women who are not on hormone replacement. 

This remains controversial and research is still ongoing, but the risks are less if you transdermal estrogen instead of oral estrogen.  So we can still use estrogen even if you are over 60, but we want to consider your heart disease risk factors,  will recommend transdermal estrogen, and need to have a more in depth discussion of this topic so you can make an informed decision.

woman with menopause and depression
HOW you take your hormone replacement matters.

Oral estrogen increases the risk of blood clots, especially when it is not bioidentical (like the one in the WHI study).  Using oral estrogen with a synthetic progestin increases the risk even further.  Other things that further increase the risk including being older, obese, and smoking.  There are other less common risk factors that can be considered (such as a genetic factor called Factor V leiden). 

Transdermal (absorbed through the skin) estrogen does NOT increase the risk of blood clots.  So avoiding estrogen pills can reduce this risk, especially in women with additional risk factors.

What FORM of hormone replacement you take matters

In addition to increasing blood clot risk, synthetic progestins all increase the risk of breast cancer slightly.  This includes the progestin that was used in the WHI study.  Estrogen with bio-identical progesterone (meaning it is the same as your ovaries used to make) does NOT increase the risk.  Estrogen alone (without progesterone) DECREASES the risk of breast cancer. 

There is some concern that using estrogen alone for more than 10 years can cause a slight increase in breast cancer, and it is well known that using estrogen alone can increase the risk of uterine cancer, so I recommend combining estrogen with bioidentical progesterone (which prevent uterine cancer).

Dr Josh Trutt did a great job writing a blog to help his patients understand how to make sense of studies that seem to show risks of hormone replacement. This is the gist of how he explained things:

Was there an increase in blood clots?  They used oral estrogen instead of transdermal in women with other risk factors like hypertension, obesity, or smoking, or the oral estrogen was combined with a synthetic progestin.  Blood clot risk doesn’t go up if transdermal estrogen is used.

Was there an increase in heart attacks?  They used oral estrogens in women who were more than 10 years from menopause,  and they had other risk factors like smoking, hypertension and obesity.  If they had used transdermal estrogens in women less than 10 years after menopause then the risk of heart disease would have gone DOWN.

Did breast cancer incidence go up?  They used synthetic progestins instead of bio-identical progesterone.  Breast cancer does not increase if bio-identical progesterone is used.

Did breast cancer risks decrease?  They either used estrogen alone, or with bioidentical progesterone.

What about dementia?  We know that estrogen protects your memory, and they tried to prove that in the WHI study.  But instead they found women had an increase in dementia as early as 12 months after starting HRT.  But there was no increase in mild cognitive impairment (which happens in the early stages of Alzheimers).  This suggests that the dementia may not have been due to Alzheimers.  So what is the explanation?

All of the women in the arm of the WHI study looking at Alzheimers were over 65.  Since we know that older women starting hormones have a greater risk for blood clots and unstable plaque (especially with oral estrogen and synthetic progestins, which is what they were given), they were likely having mini-strokes and this was causing the fairly sudden onset of dementia.  Studies have shown that using transdermal estrogen (less risk for blood clots) and starting estrogen at a younger age actually results in a significant reduction in dementia. 

Let’s look at some of the studies that showed the benefits of hormone replacement.

1.  In Denmark, they studied 1000 women who were within a few years of menopause.  Half the women received hormone replacement with an oral estrogen (that was bioidentical) and if they had a uterus they also received a synthetic progestin (not bioidentical) 10 days out of the month to protect their uterus.  The other half of the women were the control group and did not receive hormone replacement.  The women were treated for 10 years, but when WHI study results came out they were told to stop because of safety concerns.  The women were followed for another 6 years even after stopping (16 years total).

Did they have a rash of breast cancer diagnoses?  Were they dropping from heart attacks?  Not in the least.  In fact, they had a 50% reduction in heart attacks, heart failure and death.

Women on estrogen only (the ones without a uterus) had a decrease in breast cancer, women on combined estrogen/progestin had no increase in breast cancer (they only took the progestin for 10 days per month, so we did not see the increase in breast cancer risk that is seen in women who take progestins daily).

In total, 26 women in the control group died, compared with 15 women on HRT = 42% reduction in the risk of death in the women on hormone replacement (even though they used oral estrogen and a synthetic progestin).

After stopping HRT for 6 years, the reduction in death dropped to only 33% (in other words, after the women stopped the hormone replacement the benefits started to diminish)

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e6409  Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial

2.  Researchers in Finland looked at the effect of estradiol (bio-identical estrogen) on longterm health in postmenopausal women.  Almost half a million women were studied.  The results were pretty convincing.

Risk of death from heart disease was reduced by 18-54%.  The longer the women had used hormone replacement, the lower their risk, that is why there is such a large range.

Risk of stroke death was reduced by 18-39%.  There was no change in the risk based on duration of treatment.

Risk of all cause mortality (death from ANY cause) was reduced by 12-28%, in an almost linear relationship with duration of exposure – meaning the longer the women used the hormones, the lower their risk of death.


In this study, all of these reductions were comparable in women starting hormone replacement before 60 years and women starting at 60 years or older.

In absolute numbers, there were 19 fewer heart disease deaths and 7 fewer stroke deaths per 1000 women using hormone replacement for at least 10 years.

Menopause. 2015 Mar 23.

Here are several more:

3.  “Over-interpretation and misrepresentation of the WHI findings have damaged the health and well-being of menopausal women by convincing them and their health professionals that the risks of HT outweigh the benefits.”

Climacteric. 2014 Jun;17(3):215-22.

4.  “For healthy women aged 50-59 years, estrogen therapy decreases coronary heart disease and all-cause mortality”

Climacteric. 2014 Oct;17(5):540-56. doi: 10.3109/13697137.2014.933411

5. “Breast cancer risk increased marginally with estrogen/progestogen therapy, related to duration of use, but with estrogen-alone therapy, breast cancer risk decreased significantly, as did mortality. For younger women receiving estrogen alone, there is great consistency between all randomized trials, including the WHI and observational data showing a coronary benefit and a decrease in all-cause mortality.”

Climacteric. 2014 Dec;17 Suppl 2:12-7.

6.  “In this paper, we review data supporting the use of HT administered to postmenopausal women, showing it to have more benefit than risk for symptom control, prevention of bone mineral loss and fracture, and improvement of the metabolic profile in women who began HT when they were less than 60 years of age and had their last menstrual period less than ten years previous. In hysterectomized women treated with estrogen only, a reduction in breast cancer risk was noted in all age groups”

J Steroid Biochem Mol Biol. 2014 Jul;142:4-11.

7.  “The totality of data converges to show a consistency between randomized trials and observational studies that when started in women at or near menopause and continued long-term, HRT decreases CHD and overall mortality compared with women who do not use HRT.”

J Steroid Biochem Mol Biol. 2014 Jul;142:68-75. doi: 10.1016/j.jsbmb.2013.06.011.

8.  “Unlike oral estrogens, transdermal estradiol has been shown not to increase the risk of blood clot or stroke, and to confer a significantly lower risk for gallbladder disease. Unlike some progestogens, [bioidentical] progesterone is also not associated with an increased risk of blood clot, or with an increased risk of breast cancer. “

CLIMACTERIC 2012;15(Suppl 1):3–10

Hormone replacement has important benefits for women. In the media, all types of hormone replacement therapy have been lumped together as though they have the same risks, with the message being HRT increases the risk for breast cancer and heart disease.  

But now YOU understand that there are lots of variations in HOW hormones are prescribed, and the risks are NOT the same.  There are important benefits to hormones, and starting early makes a big difference.  It’s important to have a conversation with your doctor to understand your personal risks and benefits. For most women, there is no need to suffer with symptoms of hormone imbalance due to fear!  Empower yourself with information, make smart choices and you can feel like yourself again!

Yours in health,

Dr Deb Matthew MD

The Happy Hormones Doctor

 GET YOUR FREE COPY OF INTRODUCTION TO BIOIDENTICAL HRT FOR MEDICAL PROVIDERS EBOOK

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