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A Deep Dive into Menopausal Hormone Therapy and Breast Cancer

Updated: Jan 3




Part 1 - History of MHT and breast cancer


Here are some “facts” you may come across when reading about MHT (menopausal hormone therapy, sometimes referred to as HRT or hormone replacement therapy)


MHT causes breast cancer

MHT prevents breast cancer

MHT causes heart disease

MHT prevents heart disease

MHT reduces risk of dementia

MHT decreases chances of dementia

MHT improves bone health

MHT helps sexual function

MHT does nothing for libido

MHT will not help you lose weight

MHT will lessen weight gain


No wonder women don’t know what to do when it comes to MHT!!!!

So what is the truth? Well, the answer is convoluted, as the history of MHT is convoluted. So let me attempt to briefly explain the history of MHT and why it is SO controversial.


Here's the summary if you want just the key points of the information that's outlined below:

  • MHT has been on a rollercoaster ride over the last century

  • The media frenzy that followed the WHI did a major disservice to women’s menopausal health that persists to this day

  • Oral conjugated equine estrogens (CEE or Premarin) alone have been shown to decrease the risk of breast cancer

  • Synthetic oral progestins may increase the risk of breast cancer

  • Oral progesterone (Prometrium) does not appear to increase the risk of breast cancer

  • Talk to your [menopause-trained] doctor to see if you are a good candidate for MHT


A BRIEF HISTORY OF HRT


Estrogen therapy has been around since the 1930s, mainly in the form of conjugated equine estrogens, or CEE. CEE is also known as Premarin, which stands for pregnant mare’s urine (the estrogen is derived from the urine of pregnant horses.) CEE contains a mixture of at least 10 different estrogens, some of which are naturally found in premenopausal women and some of which are not.


In the 1970s, once MHT (Premarin) was widely used for menopausal symptoms, an increased rate of endometrial cancer was identified, and lack of progesterone was found to be a cause. In menstruating women, estrogen builds the uterine lining, and progesterone, produced by a post-ovulation follicle called a corpus luteum or corpus luteum cyst, helps to stabilize that lining. It is now well known that an excess of estrogens in the absence of adequate progesterone is a significant risk factor for endometrial cancer. We know that if estrogen is being used for MHT symptoms, a progestogen (progesterone or progesterone-like compound) must also be used to protect the uterus if a woman has not had a hysterectomy.


In the 1980s and 1990s, multiple observational studies suggested a possible link between MHT use and 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.


Then 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 TRIAL


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: “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).

The 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) the researchers were looking for was cardiovascular events such as MI (heart attack) or stroke.


They also 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 the researchers found that cardiovascular disease actually seemed to be increasing, and they found a small increased risk of breast cancer in women who 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 familiar with the data.






















After the WHI blew up, it is likely that a generation of symptomatic women were denied or counseled against MHT for symptoms due to poor information, and fear. There was also significant backlash and an entire counterculture arose, spearheaded by the late Suzanne Somers. Women were demanding their hormones so they wouldn’t have to suffer (and rightfully so!)! Unfortunately, this led to many alternative, untested, and unstudied treatments becoming widespread such as the use of compounded “bioidentical” hormones, hormone pellets, and hormone-related supplements. Some of these treatments have some serious potential dangers. (I will save my deep dive into those for a later post).


WHAT DID THE WHI TELL US ABOUT HORMONES AND BREAST CANCER?



Let's dive into the numbers a bit:


The risk of cardiovascular disease (mostly in the form of non-fatal MI) went from 3 events in 1000 women to 3.7 events in 1,000 women (which is a 29% increase) among 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 an average age of 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? A DECREASED RISK OF BREAST CANCER!!!


Yeah, this one didn't make headlines. Less exciting, I guess. (I would beg to differ)


There was a long-term follow-up study (20 years later) of the women in the WHI trial after they were instructed to stop taking the meds.


In this follow-up study of women without a uterus that was previously assigned to CEE alone, there was a significantly lower rate of breast cancer. In women that were in the CEE+MPA group compared to placebo, there was a significantly increased rate of breast cancer but no increase in breast cancer mortality.


When stratified by age, the results become non-significant but still demonstrate a fairly obvious trend towards LOWER rates in the CEE-only group and HIGHER rates in the CEE+MPA group compared to placebo.


DOES ALL PROGESTERONE CAUSE BREAST CANCER?


How can we interpret this? First, it is important to distinguish between different types of progestins. There are synthetic progestins that the body does not make naturally, such as MPA, levonorgestrel or norethindrone, and there is “natural” or “bioidentical” progesterone - oral micronized progesterone, that is equivalent to that made by our bodies during the reproductive cycle for the 2 weeks following ovulation.


It seems as though the progesterone and synthetic progestins may have differing and possibly opposite effects on breast cancer proliferation. When studied at the cellular level, it appears as though progesterone does NOT have an adverse effect on breast tissue whereas synthetic progestins do. A study out of Sweden actually randomized 77 healthy women to oral CEE+MPA vs transdermal E2 + oral micronized progesterone and did multiple breast biopsies to see the before and after effect on breast tissue. In the women who took CEE+MPA they showed significantly increased proliferation whereas they did not see as strong of an effect in the transdermal E2 + micronized P arm. While this was not a cancer outcome, it is plausible that this would increase the risk of cancer.


The data on a larger scale seems to agree with this. The E3N French cohort (French gov’t and nonprofits) study looked at almost 100k women, about half of whom were postmenopausal and qualified for their HRT and breast cancer study. The majority of the patients who used HRT used transdermal estradiol and oral MPA (60%) and about 20% used oral micronized progesterone. Their finding in those who took MPA for an average of 2 years was similar to the WHI trial, whereby they had a relative risk of breast cancer of 1.5 (1.5x as likely to report a breast cancer diagnosis) which was significant.


However, the women who used oral micronized progesterone with their estrogens had no increased risk of breast cancer over baseline.


Oral micronized progesterone (often referred to by brand name Prometrium) is now a preferred route for MHT in women with a uterus who are on estrogen. Another favorite of mine is a levonorgestrel IUD (intrauterine device, such as Mirena or Liletta). While this does contain a synthetic progestin, the absorbed amounts are much lower than any oral preparation and can mitigate any potential progesterone-related side effects. The chances of it increasing the risk of any significant health concerns are low given the low systemic absorption, and added bonus of not having to take a pill on a daily basis. We know that it protects the uterus against cancer, and it has been used safely in women throughout the life cycle for other purposes such as endometrial cancer or hyperplasia, so we do have some long-term safety data, though as of yet there are no long term studies to my knowledge looking at progesterone IUDs for MHT long term.

(side note/PSA: vaginal or topical preparations of micronized progesterone have NOT been well studied or proven as an adequate form of endometrial protection for MHT, and it is likely that the absorption is not high enough to adequately protect the uterus from cancer. I would not recommend these forms in women taking systemic estrogen who have a uterus)


Also, keep in mind - synthetic progestins are not all bad! I still use them frequently for birth control in my patients, as there is a large body of evidence showing safety in that population. I even still use it in some menopausal women for MHT if they have failed or declined the other forms for various reasons. All with proper counseling, of course. Just because something increases the risk for breast cancer, does not mean that this risk would outweigh the potential benefit for all patients. Every patient is unique and there is no one-size-fits-all treatment.


So while there is still much more research that needs to be done, we do know a lot about how to safely use MHT and some of the significant benefits it can bring! For most patients who are candidates and want MHT, I start with a transdermal estrogen patch combined with oral micronized progesterone or a progesterone IUD to optimize the risk/benefit ratio.


As always, please reach out to me with any questions and make sure you sign up for my email list to stay up to date on information and services at Balanced Medical.



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