20 Jan The 3 Pathways of Estrogen Metabolism and Hormone Recycling with Dr. Betty Murray
You’re doing everything right. You started hormone replacement therapy, you’re following your doctor’s protocol, but something still feels off. The brain fog lingers. The weight won’t budge. Maybe you’re even experiencing new symptoms you didn’t have before. Here’s what almost no one is talking about: the problem might not be the hormones you’re taking or even the hormones your body makes. It could be how your body packages and eliminates them.
I recently sat down with Dr. Betty Murray, a nutrition biochemist who spent nearly four years researching this exact puzzle for her PhD. What she discovered challenges everything most clinicians understand about hormone replacement therapy and explains why some women thrive on HRT while others struggle despite doing “everything right.”
The Missing Piece in Women’s Health Research
Here’s something that should make you angry: we’ve been doing hormone replacement therapy since 1942, yet we have a 22 to 23-year gap in meaningful research about how it actually works in women’s bodies. Dr. Murray explains that after the Women’s Health Initiative study in 2002 (which misrepresented data and caused unnecessary panic), research funding for hormone studies essentially dried up overnight.
That means an entire generation of women in their 40s, 50s, 60s, and 70s have been navigating menopause without the robust scientific support they deserve. The good news? Researchers like Dr. Murray are working to close that gap by examining what happens after hormones enter your system.
It’s Not Just About What You Take, It’s About What You Eliminate
Think about your body’s hormone system like a river system flowing down from a mountain. At the top, you have cholesterol (yes, you actually need some LDL) that gets converted into various hormones. These hormones flow through different pathways in your body, doing their jobs, and then they need to exit the system. This is where things get interesting and where most women (and their doctors) stop paying attention.
Dr. Murray uses a brilliant analogy: imagine you’re trying to get to a spa. You don’t take a straight shot. You make right turns, left turns, encounter toll bridges, and sometimes hit traffic. Your hormone detoxification pathways work the same way. There are multiple steps, multiple pathways, and multiple places where things can get blocked or rerouted.
The Three Estrogen Pathways: Your Porridge Problem
Remember Goldilocks and the Three Bears? Dr. Murray explains that when your body processes estrogen for elimination, it has three main pathway options and, just like the porridge, one is too hot, one is too cold, and one is just right.
The “Just Right” Pathway (2-hydroxy): This is controlled by a gene called CYP1A1. When estrogen goes down this pathway, it gets packaged safely and exits your body without causing problems. This is where you want most of your estrogen to go.
The “In-Between” Pathway (16-alpha-hydroxy): Controlled by the CYP3A4 gene, this pathway is acceptable but not ideal. Some older studies suggest that if too much estrogen goes this route without proper conversion, it might have proliferative effects (meaning it could encourage cell growth in ways you don’t want).
The “Problematic” Pathway (4-hydroxy): This one’s controlled by CYP1B1, and here’s where things get concerning. When estrogen gets stuck in this pathway, it creates compounds that can damage your DNA over time. Breast tissue is particularly rich in CYP1B1 enzymes, which is why this pathway matters so much for breast health.
Everyone processes some estrogen through all three pathways. The question is: what’s your ratio? Are you primarily using the “just right” pathway, or is your body defaulting to the problematic one?
Why Genetics Aren’t Your Destiny
Here’s where Dr. Murray drops a truth bomb that should relieve a lot of anxiety: your genes are not deterministic. Yes, you inherit genes from both parents that influence which pathways work better or worse for you. But these genes don’t seal your fate.
She uses Keith Richards as an example (yes, the Rolling Stones guitarist). The man has famously treated his body like what Dr. Murray calls “a human trash can” for decades (drugs, alcohol, smoking) yet he’s still going strong. Why? Probably because his genetics gave him really efficient detoxification pathways. But here’s the thing: not all of us won the genetic lottery like Keith Richards. If you have less favorable genetics and live a similar lifestyle (or even just deal with the toxic load of modern life), you’re going to struggle.
The empowering news? You have significant control through nutrition, lifestyle, and targeted support. Your genes might load the gun, but your choices pull the trigger or keep the safety on.
The Wrappers: How Your Body Packages Hormones for Disposal
Dr. Murray uses another helpful analogy: think of a used highlighter. It’s out of ink, and you need to throw it away. Your body doesn’t break hormones into tiny pieces to eliminate them. Instead, it wraps them in different colored wrappers to prepare them for disposal.
First, your hormones get wrapped in one of three colors (red, blue, or green, representing those three pathways we discussed). This MUST happen. There’s no skipping this step. Then, depending on the hormone and pathway, additional wrappers get added:
The Pink Wrapper (Methylation): This involves a gene called COMT and requires nutrients like B12, B6, B2, and B9. If you’re what’s called a “slow COMT” (which many people are), you’ll have trouble adding this wrapper. This doesn’t just affect estrogen, it also impacts how you process dopamine, norepinephrine, and epinephrine.
The Black Wrapper (Glucuronidation): This is particularly important for estradiol. Your liver wraps the hormone, binds it to bile, stores it in your gallbladder (or sends it straight to your intestines if you don’t have a gallbladder), and prepares it for elimination through your stool. But here’s a critical detail: your gut bacteria produce an enzyme called beta-glucuronidase that can unwrap this package and send the hormone back into circulation.
The Orange Wrapper (Sulfation): This is the pathway Dr. Murray spent much of her research investigating, and it’s where many women run into trouble. Estrone particularly needs to go through sulfation. If you can’t add this wrapper efficiently, hormones get stuck in your system.
The Wine Test: A Clue About Your Detox Pathways
Here’s a simple way to get insight into your sulfation capacity: what happens when you drink wine? If you’re someone who gets a runny nose, headaches, or turns red in the neck after a mimosa or glass of wine, that’s a sign your sulfation pathways might not be working optimally.
Wine (particularly American wine) contains high levels of sulfites. If your body can’t efficiently convert sulfites to sulfate through the SULT gene, you’ll experience allergic responses. Many women report that they could drink wine in their 20s without issues, but by their 40s, everything went haywire. Dr. Murray explains this happens because you have more estrogen flowing through these pathways during perimenopause, competing with the sulfites for processing.
Another clue? If you feel amazing after taking an Epsom salt bath, it’s not just the magnesium. Epsom salt is magnesium sulfate, and when you absorb it through your skin, it provides sulfate your body desperately needs for that orange wrapper.
Why Blood Tests Miss the Most Important Information
Most doctors rely solely on blood tests to monitor hormone levels, but Dr. Murray explains this gives you an incomplete picture. In blood, hormones travel around in what she calls a “taxi cab”: a carrier protein called sex hormone binding globulin (SHBG). Blood tests can’t distinguish between hormones sitting inside the taxi cab (bound and unavailable) versus hormones that have gotten out and are free to act in your tissues.
You might have perfectly adequate hormone levels on a blood test, but if most of your hormones are trapped in the taxi cab, you won’t feel the benefits. This explains why some women on hormone replacement therapy have “good numbers” but still feel terrible.
For a complete picture, Dr. Murray recommends looking at multiple testing methods:
Blood tests are valuable for seeing what other hormones are doing (thyroid, insulin, cortisol) since these all influence your hormone picture. Blood also has research backing for protective levels, we know what estradiol levels correlate with bone protection, for instance.
24-hour urine testing has historically been the gold standard because it captures your full hormone output over an entire day, accounting for natural fluctuations. You collect all your urine for 24 hours, shake it up, and send a sample to the lab.
Dried urine tests (like DUTCH) are more accessible. You pee on special paper at different times throughout the day and night. This gives insight into your diurnal rhythm, especially for cortisol, and shows how you’re processing hormones.
Only urine testing shows you the complete picture: the hormones you make, the hormones you take, and critically, how you package and eliminate them. This is information you simply cannot get from blood or saliva.
The Downstream Problem: When the Toilet Is Backed Up
Dr. Murray uses a plumbing analogy that makes perfect sense: if you notice water backing up in your sink and toilet, you don’t start messing with the sink and toilet. You go all the way to where the pipes exit your house and start there. Your detoxification pathways work the same way.
If your elimination pathways are blocked downstream, it doesn’t matter how much you optimize the upstream pathways. You’re not going to get anywhere. This is why she sees so many people supplementing with things like DIM or other detox support without results. They’re messing with the sink when the main sewer line is clogged.
The key is working backwards: first, ensure your final elimination pathways are working (proper hydration, good gut health, regular bowel movements). Then optimize the “wrapper” steps (methylation, glucuronidation, sulfation). Only after those are functioning well does it make sense to influence which of the three main pathways your estrogen preferentially uses.
The Microbiome Connection You Haven’t Heard About
Here’s something fascinating: your gut bacteria change naturally as you go through perimenopause and menopause. Specifically, bacteria that produce beta-glucuronidase (the enzyme that unwraps the black wrapper and recycles estrogen back into your system) increase in number.
Why would your body do this? Dr. Murray explains it’s an adaptive mechanism. When your ovaries start producing less estrogen, your body tries to conserve whatever estrogen it can by recycling it. This was probably protective before we lived in a world saturated with industrial chemicals that mimic estrogen (phthalates, pesticides, and others).
But now, this same mechanism can work against us. If you’re not pooping regularly, if your gut bacteria are imbalanced, or if you’re not eating enough fiber, those hormones (and hormone-like chemicals from the environment) get unwrapped and recirculated instead of being eliminated.
When Everything You Try Makes Things Worse
Some women fall into what Dr. Murray calls the “canary” category: they’re highly sensitive to hormone changes and detoxification challenges. These are often women who experienced intense symptoms even when their cycles first started as teenagers, who had heavy or unpredictable periods, or who had terrible reactions to birth control pills.
If you’ve been diagnosed with PCOS (or suspect you have it, since it’s vastly underdiagnosed), you’re more likely to be walking a razor’s edge with hormone replacement therapy. This doesn’t mean you can’t do HRT, but you can’t follow the same protocol as everyone else. You need more careful monitoring and individualized dosing.
Signs you might be in this category:
- You’re extremely sensitive to medications in general
- SSRIs or pain medications gave you terrible side effects
- Birth control was a nightmare
- You had crime scene periods, fibroids, or severe PMS in your 40s
- You react strongly to wine, beer, or alcohol
- You’ve been diagnosed with IBS, anxiety, or depression that worsens around your cycle
Medications Compete for the Same Pathways
Here’s something most doctors don’t consider: many common medications process through the same detoxification pathways as your hormones. Antidepressants, pain medications, statins, and anticoagulants all flow through these same rivers Dr. Murray described.
If you’re on multiple medications (polypharmacy), you’re creating traffic jams in your detoxification system. Your body can only handle so much at once. This is why some women start hormone therapy and suddenly their other medications don’t work the same way, or they develop new symptoms they can’t explain.
This doesn’t mean you should stop necessary medications. It means you need to be aware of this competition and work with practitioners who understand these interactions. It also highlights why optimizing your foundational elimination pathways becomes even more critical when you’re taking multiple medications.
The Cholesterol Paradox: Why Your Hormones and Heart Health Are Connected
Dr. Murray shares her personal experience with cholesterol, and it’s illuminating. She has genetic predispositions for cardiovascular issues, and when she went through perimenopause and menopause, her cholesterol (particularly a compound called ApoB that causes arterial plaque) skyrocketed.
She tried statins, which caused liver damage (her liver enzymes went up). She tried Zetia, which works in the gut instead of the liver, but it still processed through the same estrogen pathways, and again, her liver enzymes increased.
Finally, she found success with a PCSK9 inhibitor called Repatha, which works completely differently. It doesn’t process through the liver’s detoxification pathways the way statins do. This allowed her to manage her cardiovascular risk without competing with her hormone pathways or damaging her liver.
The lesson? If you’re struggling with both hormone issues and cardiovascular concerns, the solution isn’t always a statin. There are alternatives that work through different mechanisms, and finding the right one for your body’s unique detoxification capacity matters enormously.
What About Going “Natural”?
Dr. Murray is refreshingly balanced on this topic. She acknowledges that some women genuinely feel fine without hormone replacement therapy and that’s totally valid. But she also wants women to understand what “natural” actually means in this context.
In 1900, the average woman’s lifespan was about 48 years (and if you take out deaths during childbirth, women generally lived into their mid-50s or early 60s). Menopause was a relatively short-lived experience. Now, women live a third of their lives or more in menopause.
Going natural can absolutely be done, but you need to understand that no amount of soy, flax, herbs, or supplements can replace your estrogen and progesterone to physiological levels. They might help manage some symptoms, but they’re not creating the hormonal environment your body had premenopausal.
More importantly, current research shows that starting hormone replacement therapy early in the transition or within the first couple years of menopause provides protective effects for osteoporosis, osteopenia, dementia, Alzheimer’s disease, and cardiovascular health. This is especially relevant if you have family history of any of these conditions.
The Path Forward: Becoming Your Own Health Detective
Dr. Murray is building technology platforms and data capture systems through her company Minerva specifically to address the massive gap in women’s health research. She went back to school at 49 for her PhD because she wanted to understand complex research models well enough to collapse what she calls “the 100-year gap in women’s research” in less than five years.
But you don’t have to wait for those solutions to start taking action. Here’s what you can do now:
Get comprehensive testing. Don’t rely on blood work alone. Consider 24-hour urine or dried urine testing to see the complete picture of how you’re making, using, and eliminating hormones.
Look at your entire health picture. Your hormones don’t exist in isolation. If you’re pre-diabetic with high insulin, or hypothyroid and undertreated, or dealing with chronic stress and elevated cortisol, these all impact your hormone function.
Optimize your elimination pathways. Before adding more supplements or changing your hormone doses, ensure you’re:
- Staying well hydrated
- Having regular, complete bowel movements
- Supporting your gut microbiome with fiber and fermented foods
- Managing stress to keep cortisol balanced
Consider genetic testing, but understand that your genes are not your destiny. They show tendencies, not certainties. Knowing you have a slow COMT or challenges with CYP1B1 can guide your nutrition and supplementation choices, but it doesn’t doom you to poor outcomes.
Work with practitioners who understand the complexity. If your doctor thinks hormone replacement is as simple as writing a prescription and checking blood levels once a year, you need a more sophisticated approach. Look for practitioners trained in functional medicine who understand hormone metabolism.
Be patient with yourself. Finding the right hormone protocol isn’t like flipping a light switch. It requires observation, testing, adjustment, and sometimes trial and error. But when you find what works for your unique body and metabolism, the transformation can be remarkable.
The Real Women’s Health Initiative
The original Women’s Health Initiative study that scared an entire generation away from hormone therapy was deeply flawed. It massaged data to make hormone therapy look dangerous when it really wasn’t. The single component that carried risks (a synthetic progestin called Provera) isn’t even widely used anymore. Yet that black box warning stayed on all estrogen products for over two decades, and research funding evaporated.
Dr. Murray and researchers like her are working to create the REAL women’s health initiative: comprehensive studies that look at hormone replacement therapy, hormone metabolism, and women’s health across the lifespan. They’re asking questions like: Why do some women get menstrual migraines? Why does one woman develop PCOS while another doesn’t? What causes osteoarthritis to develop? Why do detoxification pathways fail?
We don’t have those answers yet because we haven’t been asking the questions or collecting the data. But when enough women demand better, when we refuse to accept “it’s just aging” or “just take this pill” as adequate answers, when we become true health detectives investigating our own bodies’ signals – that’s when real change happens.
Your Body Isn’t Broken…It Just Needs the Right Support
If hormone replacement therapy isn’t working the way you hoped, or if you’re experiencing symptoms that don’t make sense, I want you to hear this: your body isn’t broken. You’re not failing. You’re not doing anything wrong.
You’re navigating an incredibly complex system that even most doctors don’t fully understand. You’re dealing with decades of research gaps, environmental toxins our ancestors never encountered, and a medical system that often treats symptoms rather than investigating root causes.
But armed with knowledge about how hormones actually move through your body, how they get packaged for elimination, and what can go wrong along the way, you can start asking better questions. You can seek out practitioners who understand these mechanisms. You can test what needs testing. You can optimize what can be optimized.
The conversation about menopause and hormone health is finally changing. Women like Dr. Betty Murray are dedicating their careers to getting us the answers we deserve. And women like you: asking questions, demanding better, refusing to accept “it’s just aging” as an answer, are driving that change forward.
Your most vibrant years aren’t behind you. They’re waiting for you to claim them, armed with the knowledge and support you need to thrive.
The contents of the Midlife Conversations podcast is for educational and informational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always consult with a qualified healthcare provider. Some episodes of Midlife Conversations may be sponsored by products or services discussed during the show. The host may receive compensation for such advertisements or if you purchase products through affiliate links mentioned on this podcast.
