Lifetime estrogen exposure and the different roads of estrogen

Bright-eyed and bushy-tailed out of undergrad, my first job was as a Health Promotion Specialist for a large hospital. My job was to help hospital employees stay healthy through education, outreach, and community engagement. I loved my work, and because of its nature, I was more motivated than ever to care for my own health.

I made an appointment with a highly regarded OBGYN within the hospital system to discuss my very heavy and painful periods. She confidently wrote me a prescription for the Ortho Evra patch and assured me this would take care of my problems.

A few months into the patch, I was feeling terrible. My menstrual cycles were worse; I was bloated, battling headaches, irritable, and had gained a few pounds. 

One afternoon, I was dragging in the office, trying to focus on a creative wellness newsletter project in Microsoft Publisher (if you remember Microsoft Publisher, you are likely in peri- or menopause), when I decided to get a coffee.

The barista was busy whipping up my double soy mocha with whip (soy was the only available alternative milk in the early 2000’s) while the local pop radio station was playing in the corner. The DJ was reporting breaking news that the Women’s Health Initiative Study was halted due to an increased risk of breast cancer and no cardioprotection among the participants. 

Note: the WHI was a large scale, long-term series of Randomized Controlled Trials and other studies following menopausal women who were and were not taking hormone replacement therapy to see whether they had a decreased risk of cardiovascular disease, and/or an increased risk of breast cancer specifically.

Rather than going right back to my work project, I sat down in the cafeteria and sipped my mocha while pondering what I had just heard. I reasoned and intuited that if exogenous hormones were increasing one’s risk of breast cancer, then the Ortho Evra patch probably was not a good idea. I took it off that night and never looked back.

Sure enough, just a few years later, the FDA issued a warning about the Ortho Evra patch, citing 60% increased systemic estrogen exposure over oral contraceptive pills and increased risk of blood clots, strokes, and heart attacks. The Ortho Evra patch was discontinued altogether in 2014.

Now, there is a lot to say about the WHI - the hormones they used were different from today’s hormones, they studied specific populations, the increased risk of breast cancer may have been due to the progestin rather than the estrogen, and we can’t extrapolate many of the conclusions to today. But one thing I do know is that I was absolutely right to be concerned about unnecessary exposure to estrogens.

How lifetime estrogen exposure affects health risks

Estrogen is a wonderful thing. It protects our heart and bones; it allows for menstrual cycles and fertility; it improves brain health, mood, and sleep; and it supports our skin, collagen, tendons, and ligaments. But just like any wonderful thing on this side of heaven, there are downsides. And as I mentioned above, the downsides include concerns about breast (and endometrial) cancer, heart attacks, blood clots, and strokes.

There is a “sweet spot” with estrogen. We could map lifetime estrogen exposure as a graphical curve. It would spike in puberty, be cyclical before menopause, except during pregnancy (when it would be elevated but lack surges), then become more erratic in perimenopause, and finally drop to near childhood levels in menopause. The area under the curve is the amount of estrogen one has been exposed to in their lifetime. The greater the area under the curve, the higher their risk for estrogen-related diseases like stroke and breast cancer.

As you can see, various factors affect lifetime estrogen exposure, including age at puberty and menopause, cycle regularity, pregnancy and lactation, use of oral contraceptives and hormone therapy, BMI (estrogen is stored in fat cells), genetics, and xenoestrogens (estrogens in our environment, foods, skincare, etc.).

Women who had a full-term pregnancy before the age of 25 have a 38% decreased risk of breast cancer, and lactation offers additional risk protection.

Women who have hysterectomies before menopause have a decreased risk of breast cancer, and those who already have breast cancer who undergo hysterectomies have a lower risk of recurrence.

Women who start menarche early or enter menopause late are at increased risk of breast cancer.

The common theme here is estrogen exposure over decades. 

Menopausal hormone therapy effectively extends estrogen exposure beyond menopause, so it follows that health care providers should discuss individual estrogen exposures with their patients in the hormone therapy conversation.

The different roads of estrogen

Your body doesn’t just make estrogen; it has to clear it. Your liver has to break down and recycle estrogen so that it doesn’t build up into more harmful forms.

There are different roads that estrogen can take, and some are more harmful than others. The 2-OH estrogen is the more protective route, as it’s easily cleared by your body. The 4-OH estrogen is the riskier route that can form reactive compounds that damage your DNA and are associated with cancer.

If you had insights into which road your body takes to push estrogen down, would that help inform your decision about MHT?

CYP1A1 is an enzyme that converts estrogen into a gentler version (2-OH) that is much less likely to stimulate the breast or uterine tissue or form damaging DNA byproducts. You may produce more or less of this enzyme genetically.

CYP1B1 is an enzyme that converts estrogen into the 4-OH metabolite that creates more reactive and inflammatory byproducts and can damage DNA. Increased 4-OH metabolites over time are linked to a higher risk of breast and uterine cancers, especially when antioxidant and detox systems are weak. You may produce more or less of this enzyme genetically.

CYP17A1 is an enzyme that helps determine your starting estrogen levels, and hence, can be factored into your lifetime estrogen exposure.

The cleanup crew

Two of your most important “cleanup crew” enzymes for estrogen are CYP3A4 and COMT. They work at different stages of the process — one in the liver, the other in the final cleanup and recycling phase.

CYP3A4 in the liver helps remove estrogen from your body and maintain its balance. Pharmaceuticals, alcohol, toxic burdens, and genetics can slow down this pathway, keeping toxic estrogens in circulation.

COMT neutralizes estrogen by adding a methyl group. If the COMT enzyme is slow, toxic estrogens can build up in the body and lead to DNA damage.

Understanding your genetics can help to fill in the gaps in your risk profile and help you make an educated decision as to whether hormone therapy is right for you.

Hormone therapy is FDA-approved for the relief of moderate to severe hot flashes and night sweats, vaginal and urogenital issues, and prevention of postmenopausal osteoporosis (caveat here: osteoporosis risk increases to the levels of women who never started HT - within a few years after stopping HT).

If you are experiencing any of these concerns, your health care provider should offer HT as an option. As with any informed consent, you should also discuss your individual risk/benefit profile (ideally including personal and family history, lifetime estrogen exposure, and your genetics) and be aware of alternative therapies, including non-hormonal pharmaceuticals and herbs, as well as lifestyle interventions.

Starting HT is a nuanced and personal decision, and you are the one who ultimately should decide what is best for your body.

Given my own family history and genetics, I know that I am not a good candidate for estrogen therapy, and I am grateful there are so many other options to move through menopause comfortably. Thank God I ripped that Ortho Evra patch off after a few months in my early twenties.

Considering the fact that cancers are projected to rise by up to 77% by 2050, and that we are exposed to more xenoestrogens than ever before, I believe it is prudent for women to know their individual risks and all of their options before starting MHT.

We will discuss the alternatives for MHT in the next blog post.

About the Author: Dr. April Graham is a Naturopathic Doctor and Exercise Physiologist, Owner of Avra Health. She is passionate about helping women transition through menopause healthfully and gracefully.

Acknowledgments:

I credit Dr. Penny Kendall-Reid for enlightening me in these matters through her GeneRx.ca platform and her mentorship.

Resources:

Many resources are linked directly in the article.

Kendall-Reid, P. (2025, July 11). Moving Through Perimenopause/Menopause: Why we need to rethink treatment![Conference presentation]. AANP 2025 Convention, Palm Springs, CA, United States.

Disclaimer:

This isn’t medical advice — just information. Please talk with your healthcare provider before making changes to your health plan.