Untangling the Complexities of Breast Cancer and Endometrial Cancer Risks with Menopausal Hormone Therapy

Ask Dr. Jen

“I have a question that I've never seen an answer to anywhere. Women are always told that they need to take progesterone if they're on HRT and they still have a uterus in order to decrease their chance of getting endometrial cancer. However, adding progesterone to the mix increases your chance of breast cancer per the large studies such as the WHI where those women who were on only estrogen actually had a decrease in incidence of breast cancer, while those who were also taking progesterone had an increased risk of breast cancer. So why is it OK to increase your chance of breast cancer by adding in the progesterone, but it's not OK to just increase your chance of endometrial cancer by taking only estrogen? Aren't you just trading one cancer risk for another with the progesterone?”

Via the Vajenda

Short Take

That’s a great question!

The short answer is that with menopausal hormone therapy (MHT) the risk of endometrial cancer from estrogen given without progesterone/progestin far exceeds the risk of breast cancer with an estrogen plus progesterone/progestin. Also, 60% of people will eventually bleed irregularly if they have a uterus and take estrogen without progesterone/progestin, which is of course problematic.

But there is more to the story. And it’s especially important to discuss as it is complicated, and on top of that, there is a lot of disinformation.

Go On…

Come take a deeper dive with me. I promise, it’s not too heavy on the statistics!

First, why do people need progesterone/progestins? Estrogen causes the endometrium (lining of the uterus) to grow, and progesterone/progestins stops that growth. Uncontrolled growth can lead to cancer, hence why estrogen is always paired with a progesterone/progestin for people with a uterus. This is often called combination hormone therapy and is also sometimes abbreviated as E + P or EP.

Breast Cancer Risk with Progesterone/Progestins

The risk of breast cancer with menopausal hormone therapy (MHT) does vary based on whether someone needs progesterone/progestin (a synthetic hormone similar to progesterone).

We rely heavily on the Women’s Health Initiative (WHI), primarily using the group who were ages 50-59 at enrollment, to calculate the risk of breast cancer. This is because the WHI is the only large randomized controlled trial with long-term follow up. In the WHI, women took Premarin (conjugated equine estrogens or CEE) by itself if they had previously had a hysterectomy and Premarin plus medroxyprogesterone acetate as the progestin if they had a uterus. Both of these are oral therapy. There were also placebo arms for both groups.

In the WHI, for women who took Premarin plus medroxyprogesterone acetate for 5 years there were 51 additional cases of breast cancer per 10,000 women compared with those who took placebo. The risk of breast cancer didn’t start before year three of the study. Often risks are explained in very complex ways in studies that make great sense statistically, but aren’t reality useful in the office. Because of this, the risk of breast cancer from the WHI has been calculated as 3 additional cases for every thousand women who take Premarin plus medroxyprogesterone acetate for five years. The risk does continue for up to 15 years even after the hormones are stopped. We’ll tackle that in a later post on the long-term safety of MHT. But right now, for simplicity, let’s stick with the risk at five years.

One issue with using the WHI is that the way the hormones were prescribed and the medications used rarely applies to how we practice medicine today. The average age of starting hormones in the WHI was 63, but now we advise against starting after age 60 or more than 10 years from the last period. In fact, many women now start hormones before their final period (meaning in their menopause transition) or shortly after their last period. Another difference is transdermal estradiol and oral progesterone are the starting medications of choice. Meaning, we can’t necessarily rely on the WHI to tell us what the risk of breast cancer is with transdermal estrogen and oral progesterone or a progestin IUD (like the Mirena) started a few years before or after the final period.

There are several observational studies, some with tens of thousands of participants and followed for a good length of time, that also give us data. They all tell us that the estrogen/progestin regimens have a fairly similar breast cancer risk as seen in the WHI. However, one of these studies is the E3N cohort from France, which enrolled over 80,000 women and then followed them for an average of 8 years. Some women elected to be on menopausal hormones and others did not (they were not randomly started, this was just the medical care they received). Several different hormone regimens were used, but there was enough data to suggest that using estradiol with progesterone did not increase the risk of breast cancer compared with women who didn’t take hormones. Many women in the study were also using transdermal estradiol, which is especially helpful.

While observational data can have issues, it is from this observational data that we hypothesize that transdermal estradiol is the safest blood-clot wise. And it is this data that led everyone to suggest that progesterone is the drug of choice to protect the uterus because it seems to offer a lower risk of breast cancer (we don’t have enough data on the progestin IUD to comment).

Why might progesterone result in a lower risk of breast cancer than medroxyprogesterone acetate? One theory is that medroxyprogesterone acetate is inflammatory, but we don’t really know for sure.

Endometrial Cancer Risk

Now let’s look at the risk of endometrial cancer.

Look at this stunning graph of biopsy results from the lining of the uterus from a study using Premarin 0.625 mg with and without micronized progesterone (Prometrium, this graph is from the package insert). Hyperplasia means changes in the lining of the uterus that indicate there is too much estrogen. You can see the line for Premarin plus progesterone is barely above placebo (not statistically significant). Now contrast that with the line headed for the sky, which is Premarin alone.

Taking Premarin 0.625 mg alone led to 64% of women developing hyperplasia within three years, and 35% (about half of those with hyperplasia) had changes that indicated they were at increased risk of becoming cancerous.

Not all of these changes will become cancer, and overall the risk of cancer from estrogen alone is conservatively estimated at 1 additional woman per 100 for each year of use and this risk persists for at least 5 years, and possibly 10, after the estrogen is stopped. In some studies the risk of cancer is six times higher than expected when estrogen is taken for five years or more without a progesterone/progestin. We don’t have that much data for 5 years or longer, so let’s stick with a conservative 5% at five years and we’ll also use the three year data from the study above to tell us that 35% will also have concerning changes that could potentially become cancer. As you can see from the graph above, it just gets worse over time.

The risk of endometrial cancer is so significant with what we called unopposed estrogen (no progesterone/progestin), that in the United States the FDA requires all drugs that have any hint of a suggestion that they could act like an estrogen to be tested for their safety on the uterus just in case they have some unanticipated effect. This should ring alarm bells for those who are taking MHT in pellets and for those taking more than the licensed dose of a prescription estrogen, because the risk of cancer of the uterus is directly related to the amount of estrogen and duration of use. Unstudied high doses of estrogen prescribed in this manner are a very real concern. If you are getting hormone pellets or taking higher than the recommended dose of estrogen, your doctor or nurse practitioner needs a plan for how they will screen you for precancer and cancer.

The other big issue is that when women in menopause just take an estrogen, they will eventually develop a 60% chance of nuisance bleeding, which could over time become quite heavy.

Putting it All Together

If we say the WHI breast cancer data applies to all forms of estrogen and progesterone/progestin then we assume that 0.3% of people will develop breast cancer related to combined MHT in the first five years of use, but if we consider the observational data then it seems likely the risk is lower for those taking estradiol and progesterone. The risk of endometrial cancer at five years is 5% for those who take estrogen without progesterone/progestin and at least another 35% will develop potentially concerning changes in their uterus. Also, about 60% of women taking estrogen without progesterone/progestin will have irregular bleeding.

Therefore, the balance of risks far favors giving estrogen with progesterone/progestin (and preferably progesterone) for those with a uterus.

However…

Before you think, “I should just have a hysterectomy so I don’t have to worry at all about breast cancer with my menopausal hormone therapy,” there is observational data that suggests the way we prescribe hormones today may mean that there could also be a small breast cancer risk with estradiol when it is given without progesterone/progestin. Remember, transdermal estradiol started at an average age of 50 (typical therapy of today) is NOT the same as Premarin started at an average age of 63 (the WHI).

If we assume the observational studies are right about the safety of transdermal estradiol over oral hormones for blood clots and that the data from observational studies is right about oral progesterone being safer for the breast, we can’t really cherry pick and ignore what the observational data has to say about the breast cancer risk with estradiol given without progesterone/progestin. No one should panic, the risk in these studies appears to be less than the risk seen with Premarin and medroxyprogesterone acetate in the WHI, but I think it’s worth mentioning because I know there are some doctors who tell people if they get a hysterectomy they can push their estrogen doses with no concern. There are some interesting hypothesis about the difference in results from the WHI vs. the observational studies, and so I will probably address it down the road in another post. So stay tuned for more!

If you want to read more about the dangers of pellets, click here. You could not pay me enough to get one.

Here is a link to the post on the risk of blood clots.

Some of you have asked about hormone levels. If that is you, you may find this post helpful (and it also covers some of the potential concerns with the VC backed menopause start ups).

And thank you for all of your questions! Things I am working on:

• All-cause mortality on the pill, a lot of people over on Instagram were fascinated to find it’s lower!

• Long-term use of MHT.

References

1. Santen RJ, et. al. Underlying Breast Cancer Risk and Menopausal. J Clin Endocrinol Metab 2020;105: e2299–e2307.

2. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause 2022;29:767-794.

3. Stute P, et. al. The impact of micronized progesterone on the endometrium: a systematic review. Climacteric 2016;19:316-328

4. Weiderpass E, et. al. Risk of Endometrial Cancer Following Estrogen Replacement With and Without Progestins. Journal of the National Cancer Institute 1999;91:1131-1137.

5. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019; 394: 1159–68.

6. Fournier A, et. al. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103–111.

7. Henderson BE. The cancer question: An overview of recent epidemiologic and retrospective data. Am J Obstet Gynecol 1989;161:1859-64.

8. Chlebowski RT, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials. JAMA 2020;324:369–380.

9. Prometrium package insert.