Does Estrogen Cause Uterine Cancer?

In the late 1960’s estrogen therapy became available as a treatment for hot flashes.  Millions of women received prescriptions from their doctors and welcomed this remedy for their troublesome symptoms. However, in the following several years problems emerged.  Many women began to experience abnormal bleeding, and in some cases this was due to uterine cancer. This led to a concern that hormone replacement therapy (HRT) can cause cancer. Obviously, this was alarming but it soon became apparent that this problem was caused by the fact that women were given estrogen alone, without its partner-hormone, progesterone. 

What occurs is that estrogen causes progressive thickening of the lining of the uterus.  Eventually this buildup inside the uterus causes bleeding as well other changes that can trigger a uterine cancer.  However, if progesterone is administered along with the estrogen, abnormal thickening of the lining doesn’t occur. This prevents the abnormal bleeding and other negative effects due to taking estrogen alone.  Doctors subsequently started to prescribe both hormones for women for menopausal hormone therapy.

In hindsight, this should have been obvious, because estrogen was doing exactly what it is supposed to do.  During most of a woman’s life when she is ovulating, the estrogen produced by the ovaries builds up the lining of the uterus, getting it ready to host a fertilized egg.  If a woman doesn’t get pregnant, the ovaries start making progesterone, whose job it is to interrupt estrogen effects and block any further buildup of the lining. The lining then sheds, which causes the monthly menstrual period. 

Once it was realized that women who have a uterus need to take two hormones for HRT, the standard of care since the late 1970’s has been to always recommend that a progesterone-like drug be taken concurrently with an estrogen. This prevents the estrogen from continuously stimulating the uterine cells. And, as will be described below, also eliminates the potential that uterine cancer can develop.

Why might estrogen lead to cancer?

If continual estrogen replacement without progesterone increases the risk of cancer, does this mean that estrogen causes cancer?  Intuitively it doesn’t seem logical, since women have very high levels of estrogen throughout their lives – much higher levels than what occurs in postmenopausal women being treated with estrogen for HRT.  Yet it is uncommon to see uterine cancer in young, premenopausal women.

The answer comes down to the issue of whether estrogen actually causes uterine cancer, or whether it promotes it.  This is an important distinction, so let me expand on this question.  Below is a diagram of normal female anatomy.

As I noted earlier, ongoing estrogen administration without progesterone causes a buildup of the lining of the uterus.  We call this unopposed estrogen treatment.  The unopposed estrogen stimulates the lining cells to continuously divide.  If you look at a slice of the uterine lining under a microscope, it normally is only a couple of layers thick. However, if you examine a sample from a woman on unopposed estrogen therapy you would see layers and layers of cells piled up on each other. 

In most cases, these cells are simply normal lining cells. However, in some cases one of these cells can become abnormal and can become cancerous.

Why would this happen?

To answer this question, we need to review the process of cell division.  Every cell in our body replaces itself by dividing.  This process involves the DNA in the cell to unwind itself and split into two, and each strand then serves as the blueprint for the DNA in each new cell.  Each of these “blueprints” needs to make a mirror image of itself.  This requires the units making up the DNA to pair up with its counterpart unit, piece by piece.  This is a complex undertaking given that our DNA is comprised of about 3 billion of these units.  Inevitably, errors occur, and one unit is mismatched.  This creates a mutated piece of DNA. This mutation then stays with the new cell and its progeny, and can affect how these cells function. It is estimated that millions of mutations occur every day in the more than 50 trillion cells that make up the human body. 

Most of the time these mutations do not lead to problems because there are mechanisms within the cell that are able to identify and correct most of these errors.  And if a mutation does escape this proofreading system, our immune cells can intercept and destroy an abnormal cell before it can reproduce.  However, at times a mutated cell survives and potentially can be one that goes on to cause cancer.

As an aside, it’s not undesirable that genetic mutations occur. This phenomenon is the basis for evolution.  We are witnessing this occur in real time with the Coronavirus. As this virus mutates, we are seeing one strain after another appear, each slightly different.  Most of these mutations, like those that occur in our body, don’t affect the virus to a major degree, but when multiple mutations significantly change the virus’s character it can affect its ability to spread or make us sicker.

Let’s now turn our attention back to estrogen and the uterus.  Continual estrogen administration, without progesterone, stimulates the cells to rapidly divide.  This creates a situation where more mutations are likely to occur and thus a greater likelihood that a cancerous mutation will develop. This cell could then escape the body’s defense mechanisms and begin to grow, causing a cancerous tumor in the uterus.

In this scenario, it does not seem appropriate to classify estrogen as a carcinogen because it is simply stimulating the cells to grow rather than directly damaging the cell’s DNA. More correctly estrogen should be regarded as a “promoter” because the cancerous cell appeared due to a mistake of nature.  However, there is some controversy about this.  Research in animals has shown that some by-products of estrogen metabolism may be directly toxic to DNA and therefore carcinogenic.  However, whether this mechanism plays a role in human uterine cancer is unclear.

While more research is needed in this area, women need to understand that it is well documented that women who take estrogen along with a progesterone-like drug do not face an increased risk of uterine cancer.  In fact, studies show that the overall risk of uterine cancer is lower in women who take HRT compared to women who don’t!

Ways that estrogen and progesterone are administered for HRT

After it was discovered that both estrogen and progesterone should be used for HRT, the logical approach was to mimic the hormone changes that occur naturally during the premenopausal years.  This would entail having women take estrogen throughout the month, adding a progesterone drug the second half of the month.  In this way, the estrogen would build up the lining and the progesterone would ensure the lining breaks down – resulting in it being discharged from the uterus.

This basically causes a monthly menstrual flow.  This is not exactly welcome by many postmenopausal women (after all, for many, the cessation of monthly periods is viewed as a positive aspect of menopause!)  So, an alternative method of taking HRT has become popular.  This entails having women take estrogen daily along with a half-dose of progesterone daily, rather than a full dose of progesterone the last two weeks of the month.  In this way, the combined action of the hormones does not cause any buildup of the uterine lining.  Thus, there is nothing to shed and no bleeding occurs. Furthermore it has been determined that this method does not increase the risk of uterine cancer.  There are many different types of estrogen and progesterone-like products used in HRT regimens.  For further information on this topic see my post about these HRT options.

Does the type or amount of progesterone matter?

As mentioned, studies show that postmenopausal women who take HRT have a lower risk of uterine cancer than women who do not take hormones.  However, it is important that the amount of progesterone balance the amount of estrogen. Any drug that has progesterone activity counteracts estrogen effects, as long as it is given in adequate doses.

For many years the only progesterone-like drugs available were synthetic drugs known as progestins.  We now are able to produce natural progesterone, which is identical to the progesterone the ovaries make.  It is becoming increasingly desirable to offer women natural progesterone for HRT because the synthetic progestins can have some adverse effects.  (See my blog that describes the types of progesterone drugs.)

Natural progesterone is considerably less potent than the synthetic progestins so it is important that women be given appropriate doses.  Typically if a woman is taking the average dose of estrogen (which would be the equivalent of 1 mg oral estradiol or 0.05 mg estradiol patch), she would take 100 mg progesterone daily or 200 mg progesterone 12-14 days per month (in the form of oral pills). Currently there are no reliable natural progesterone patches or creams for HRT because natural progesterone is poorly absorbed through the skin.

In conclusion – the bottom line

Estrogen treatment, if not accompanied by progesterone, can increase a woman’s risk of uterine cancer.  However, combined estrogen and progesterone taken in appropriate doses does not increase the risk of uterine cancer and, in fact, decreases the risk.

Interestingly, the rates of uterine cancer are on the rise.  This raises a number of interesting issues that I will be sharing in a follow-up blog about estrogen and uterine cancer.  Stay tuned!