For many decades, we have been led to believe that this particularly important hormone that makes us women, fosters reproduction, and propagates our human species wants to harm us by causing breast cancer. It’s such a strange and unintuitive thought. Does estrogen cause breast cancer? The answer to this question can be confusing, even for physicians. I hope to shed some light to this constantly misunderstood topic.

To do this topic justice, I have to start with the Women’s Health Initiative (WHI) trial where the confusion seems to stem. The WHI was a randomized trial started in 1992. It used drugs like oral conjugated estrogens (CEE - brand name Premarin) and medroxyprogesterone (MPA - brand name Provera). These drugs have hormone like affects and are synthetic in nature when comparing them to the hormones produced by the body.

The WHI was abruptly stopped in 2002. This was due to an increased risk of breast cancer in the study arm of postmenopausal women who had not had a hysterectomy or who still had a uterus. This population of women was using both oral CEE with daily MPA. As mentioned above, MPA contains hormone like effects, but is not the hormone progesterone. Progesterone is a naturally produced hormone by women and is responsible for maintaining the endometrium during pregnancy.

This is in contrast to the other trial arm which contained postmenopausal women who were hysterectomized (did not have a uterus). This population of women was given daily oral CEE alone for almost 6 years and resulted in a decreased risk (>20%) of breast cancer versus placebo. These results held strong 20 years later! (JAMA. July 28, 2020). To address our primary question, estrogen replacement alone for 6 years does not cause breast cancer. Using estrogen REDUCES the risk of breast cancer.

At 10-15 years, the picture changes. Observational data of women who continue to use CEE alone tend to see an increased rate of breast cancer. These cancers, however, were noted to be small according to mammogram screening and strongly estrogen receptor positive (ER+). Estrogen receptor positive tumors tend to have good outcomes. (Nurses’ Health Study)

Let us diverge for a moment. People tend to think that if a woman has an ER+ breast cancer that the cancer is caused by estrogen. Please know that all normal breast tissues are full of many receptors: estrogen, progesterone, androgen, and more. Generally speaking, the more receptor strength, the better the prognosis. Just like the uterus that develops low grade uterine cancer with unopposed estrogen (estrogen without progesterone therapy), I believe the low-grade breast cancers in women who used CEE alone are similar. Progesterone is needed with estrogen, uterus or not. So yes, the unopposed use of estrogen for greater than 10 years may increase the risk of breast cancer.

Another bit of information is that estrogen has been identified as a major driver of cancer growth in about 40-45% of estrogen receptor positive breast cancers as researched by Biotheranostics and the Breast Cancer Index test. That means that almost 55-60% of ER+ breast cancers grow from other causes! Research has not identified all the drivers, but I assume factors from weight gain are part of it. Cancer is really, more a metabolic disease than a hormonal problem!

Back to the WHI: the women using CEE and MPA daily experienced an increased risk of breast cancer after 6 years. The risk was 26% higher than placebo meaning an absolute number of 8 more breast cancers in that group. What is known now is that development of cancer takes time. Those breast cancers were already present and tumor growth was possibly fostered by the combination, allowing the cancers to be diagnosed sooner. Twenty years later, the risk of death in the women using daily CEE and MPA group compared to women using CEE alone are the same. So no, even these drugs with hormone like effects may not cause breast cancer

Physiologic Restoration, also known as rhythmic dosing for hormone replacement, uses compounded estradiol and progesterone applied transdermally twice a day in dosing patterns attempting to mimic a cycle of a young healthy reproductive woman. The compounded product allows an easy adjustment and change in doses as needed. This is as close to nature as one gets without transplanting a functional ovary (which is being studied!).

So, do not be afraid of estrogen! Estrogen is needed for a healthy body and if we are to live to be 100, you will want estrogen for the ride. How hormones are replaced has yet to have consensus, but for most women, some is better than none, and Physiologic Restoration makes the most biological sense!