Dr. Brian Lawenda

03/27/2026

Transdermal Estrogen for Prostate Cancer: Rediscovering an Old Therapy with Modern Delivery

⸻

Introduction

For decades, androgen deprivation therapy (ADT) has been the backbone of treatment for advanced prostate cancer. Since researchers first showed (in 1941) that prostate cancer is hormonally driven, the goal has been straightforward: suppress testosterone.

We’ve gotten very good at doing that.

Luteinizing hormone–releasing hormone (LHRH) agonists reliably shut down the hypothalamic-pituitary axis and drive testosterone to castrate levels. But they also suppress estrogen. That part is often overlooked, and it matters.

In men, roughly 80% of estrogen is derived from testosterone via aromatization. When testosterone falls, estrogen falls with it. What we call “androgen deprivation” is actually dual hormone deprivation.

And many of the side effects patients experience are driven just as much by estrogen loss as by testosterone loss.

This is where transdermal estradiol (tE2) becomes interesting.

Estrogen therapy for prostate cancer is not new. Oral estrogen was widely used decades ago but was abandoned because of cardiovascular toxicity. The issue was not the hormone itself. It was the delivery.

Oral estrogen undergoes first-pass hepatic metabolism, increasing coagulation factors and thrombotic risk. Transdermal delivery bypasses that.

That changes the equation.

⸻

Oncologic Efficacy: It Does the Same Job

The Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial finally gives us high-level data.
https://www.nejm.org/doi/full/10.1056/NEJMoa2511781

More than 1,300 men with locally advanced (non-metastatic, M0) prostate cancer were randomized to transdermal estradiol (tE2) or LHRH agonists.

The result is straightforward.
📌 3-year metastasis-free survival (MFS): 87.1% (tE2) vs 85.9% (LHRH)
📌 5-year overall survival (OS):
81.1% vs 79.2%
📌 Castrate testosterone levels achieved: 85% in both groups

In practical terms, disease control is the same.

⸻

Quality of Life: Where This Actually Matters

The real difference is not oncologic. It is physiologic.

Hot flashes are one of the most disruptive side effects of ADT. They affect sleep, concentration, and daily functioning.

With LHRH agonists, they are almost universal.

With transdermal estradiol, they are not.
📍 Any hot flashes: 44% (tE2) vs 89% (LHRH)
📍 Moderate to severe (grade ≥2): 8% vs 37%
📍 Patients significantly bothered: 8% vs 46%

That is a major quality-of-life difference.

⸻

The Trade-off: Gynecomastia

The downside is predictable.

If you give estrogen, you stimulate breast tissue.
⚠️ Gynecomastia (any grade): 85% (tE2) vs 42% (LHRH)
⚠️ Grade ≥2: 37% vs 9%

This is common and needs to be addressed upfront.

Prophylactic breast radiation therapy (RT) is a can be used strategy to reduce gynecomastia risk/severity. 1-2 treatment sessions are commonly used with minimal to no side effects.

⸻

Bone and Metabolic Health: The Quiet Advantage

Estrogen is the dominant regulator of bone health in men.

With LHRH therapy, bone density declines.

With transdermal estradiol, it improves.
📌 Lumbar spine bone mineral density (BMD) change: +7.9% (tE2) vs −3.0% (LHRH)…Absolute difference: ~9%

💥 That is a large effect.

The metabolic profile also moves in a different direction:
📍 Fasting glucose: decreases with tE2, increases with LHRH
📍 Total cholesterol: decreases vs increases
📍 Blood pressure: trends down vs up

These are not just lab differences. Over time, they likely translate into differences in cardiovascular risk.

⸻

Cardiovascular Risk: The Question Everyone Had

The historical concern with estrogen therapy has always been cardiovascular toxicity.

That concern was valid for oral estrogen.

It does not appear to apply to transdermal delivery.

That is a critical distinction. It suggests the toxicity we saw historically was route-dependent, not intrinsic to estrogen itself.

⸻

Cognition: Plausible, Not Proven

There is growing attention on the cognitive effects of ADT.

Some studies suggest LHRH therapy is associated with a 20–25% increased risk of dementia. Other analyses show increased subjective cognitive complaints, though objective deficits are less consistent.

Biologically, estrogen has neuroprotective effects.

There is small, early data suggesting potential cognitive benefit with estradiol, but nothing definitive.

This is an area where the mechanism makes sense, but the clinical proof is still evolving.

⸻

Forward to the Past

We tend to think of progress in medicine as linear.

It is not.

We used estrogen for prostate cancer decades ago. We abandoned it because of toxicity. Now we are revisiting the same concept with a different delivery method.

The results look very different.

The therapy did not fail.

The formulation did.

⸻

What This Means in Practice

Transdermal estradiol is now a legitimate alternative to standard ADT.

For some patients, it may be the better option.

If a patient prioritizes:
📌 Avoiding hot flashes
📌 Preserving bone density
📌 Minimizing metabolic effects

This approach offers clear advantages.

If gynecomastia is a major concern, that needs to be addressed upfront and managed proactively.

This is not about replacing LHRH agonists.

It is about expanding the conversation.

⸻

Conclusion

The PATCH trial highlights something we do not emphasize enough.

ADT is not just testosterone suppression. It is estrogen depletion.

And that has consequences.

Transdermal estrogen offers a different way to achieve the same oncologic goal while preserving part of the underlying physiology.

The trade-offs are real. The benefits are real.

This is not a new idea.

It is an old idea, used more intelligently.

And for the right patient, it may be the better one.

03/22/2026

Breast cancer care is not a straight line. It’s a series of connected decisions across surgery, radiation, and systemic therapy, all influenced by biology, stage, and response to treatment.

So I built something to help with this complexity.

👉 Breast Cancer Tumor Board-AI

It’s a clinical decision support tool for stage I–III breast cancer that brings everything into one place.

You enter the patient’s data and it generates structured, evidence-based recommendations across:
• Medical oncology (chemo, endocrine, targeted therapy)
• Surgery (lumpectomy vs mastectomy, axilla management)
• Radiation decisions

It also:
• Flags high-risk features and medical comordities
• Accounts for prior treatments and pharmacogenomics
• Provides rationale + supporting trials (Z0011, AMAROS, TAILORx, etc.)
• Highlights gray zones and uncertainty (which is where most real decisions live)

There’s also a built-in AI chat, so you can ask:
“Why this regimen?”
“What data supports this?”
“What changes if this patient was premenopausal?”

This isn’t about replacing clinical judgment. It’s about organizing it. Because the hardest part of modern oncology isn’t access to information. It’s making sense of it for the patient sitting in front of you.

Link: https://breast-cancer-tumor-board-ai.base44.app/Home

03/22/2026

One of the most important things patients can do during radiation is protect the skin barrier.

I typically recommend:
• Lipikar 2–3x daily during treatment
• Transition to Cicaplast B5 if you start to see dryness or peeling
(both widely at Target and many other retailers)

Early, consistent care makes a real difference.

03/19/2026

A lot of women are going to see headlines about this new hormone therapy study and come away frightened.

They shouldn’t.

This is a good example of why one study, especially an observational one, should never be allowed to override decades of better evidence.

The new Israeli study looked at more than 83,000 women and concluded that starting hormone therapy after age 65 was associated with higher risks of cancer and vascular events. That part is not especially shocking. It is broadly consistent with what we already believed about late initiation of hormone therapy. 

But that is not the part that caught my attention.

What stood out was how extreme the reported risks were in women who started hormone therapy between ages 50 and 65. In that group, the study reported a 749% higher cancer risk, a 1,569% higher stroke risk, and an 817% higher risk of ischemic heart disease or heart attack. For women who started after age 65, the reported increases were actually much smaller: about 122% higher cancer risk, 170% higher stroke risk, and roughly 139% higher risk of ischemic heart disease or heart attack. 

Think about that for a second.

The study is basically implying that starting hormone therapy at ages 50 to 65 was far more dangerous than starting it after 65.

That does not make physiologic sense. It does not fit clinical experience. And it does not fit the larger body of evidence we already have. 🙄

That is a giant red flag 🚩

This was not a randomized trial. It was a retrospective observational study. Women were not randomly assigned to hormones or no hormones. Doctors prescribed treatment based on symptoms, baseline health, prior hysterectomy status, cardiovascular risk, and many other factors that are hard to fully account for in a database. The authors also acknowledged missing historical information before 2000, which makes confounding even harder to sort out. 

That is how you can end up with numbers that look statistically polished but clinically implausible.

In fact, the Menopause Society’s summary of the study makes the problem pretty obvious. In crude analyses, women who started hormone therapy between 50 and 65 actually had lower rates of ischemic heart disease and MI before adjustment. Then, after adjustment, that apparent benefit flipped into massive harm. When a model reverses the story that dramatically and spits out huge risk estimates, you have to question whether the model is correcting for confounding or creating distortion. 

And this is exactly why one large study should not bulldoze decades of better evidence.

The broader literature has been much more consistent. When hormone therapy is started in women younger than 60, or within 10 years of menopause, the benefit-risk profile is generally the most favorable. Multiple reviews and scientific statements have supported the idea that earlier initiation is associated with lower coronary heart disease risk and lower all-cause mortality, while later initiation looks less favorable. 

The breast cancer story is also far more nuanced than most headlines suggest.

In the long-term follow-up of the Women’s Health Initiative, women with prior hysterectomy who took estrogen alone had lower breast cancer incidence and LOWER breast cancer mortality than women assigned to placebo. There were 238 breast cancers in the estrogen-alone group versus 296 in the placebo group, and 30 breast cancer deaths versus 46. That translated to a 22% lower breast cancer incidence and a 40% lower breast cancer mortality with estrogen alone. 

That is not a trivial detail. That is one of the most important and most misunderstood findings in this entire field.

By contrast, combined estrogen plus progestin is different. In the same long-term WHI follow-up, combined therapy was associated with higher breast cancer incidence, 584 cases versus 447 with placebo, or about a 28% increase. Breast cancer mortality, however, was not significantly increased. 

So the type of hormone therapy matters. A lot.

And age at initiation matters. A lot.

The bottom line is that this new Israeli study does not overturn the existing evidence base. If anything, it reinforces the point that starting hormone therapy later in life is riskier. But the dramatic findings in the 50 to 65 age group should be viewed with real skepticism, because they clash with biology, clinical experience, and much stronger prior evidence. 

📌 If you are under 60, or within about 10 years of menopause, and you have bothersome symptoms, hormone therapy remains a very reasonable option for many women after an individualized discussion of risks and benefits. If you have had a hysterectomy, estrogen-alone therapy may actually LOWER your breast cancer risk. If you are older, especially beyond 65, the decision becomes more cautious and more individualized. 

This is the bigger lesson.

Large studies are not automatically good studies.

If a result does not make clinical sense, it deserves scrutiny, not blind acceptance.

Good medicine means looking at the totality of evidence, understanding who the patient is in front of you, and not letting one flawed study drive the entire conversation.

Study: https://journals.lww.com/menopausejournal/fulltext/9900/health_outcomes_of_hormone_therapy_initiated_or.608.aspx

03/18/2026

Presenting the nuances of axillary surgery and radiation nodal management in breast cancer. Thankfully, we are able to treat less aggressively in many more patients in the modern era. This translates into fewer patients with long term side effects, such as lymphedema.

03/17/2026

A really interesting study just came out looking at a simple, inexpensive way to reduce nerve damage from chemotherapy.

👉 https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.70124

This focuses on paclitaxel, a very common chemotherapy drug.

One of its biggest side effects is neuropathy
→ numbness
→ tingling
→ burning pain

Sometimes severe enough that treatment has to be reduced or stopped.

⸻

Why this study matters

This was a randomized trial.

Patients were randomly assigned to either receive losartan or not. That helps ensure the groups are similar at the start, so differences seen later are much more likely due to the drug itself, not bias or chance.

This is one of the strongest types of clinical evidence we have.

⸻

The result

Patients who took losartan (a common blood pressure medication) had:

• 86% rate of significant neuropathy without it
• 33% with it

That’s over a 50% absolute reduction.

That’s a very large effect in medicine.

⸻

How does this even work?

Chemotherapy damages nerves…
but a lot of the problem comes from the body’s inflammatory response to that damage.

The body releases inflammatory signals that actually make the nerve injury worse.

Losartan helps by:

• Blocking a receptor (AT1) that drives inflammation
• Activating PPAR-γ, which calms inflammation and protects cells
• Reducing harmful cytokines (like IL-1, TNF, IL-6) around nerves
• Helping preserve nerve structure and function

So instead of the body overreacting…
…it responds in a more controlled, less damaging way.

⸻

What about dosing?

In the study:

• Losartan 100 mg once daily
• Started at the same time as chemotherapy
• Continued throughout the entire treatment course (12 weeks)

It was not timed to the infusion.
Just taken once daily like a typical medication.

⸻

Why timing matters

This is not a treatment after neuropathy develops.

It’s preventive.

Starting early:

• Helps delay or prevent nerve damage
• Works best when given from the beginning of chemotherapy

⸻

Safety and reality check

Losartan is:

• Widely used
• Generally well tolerated
• Inexpensive

But…

This is still early data.

• One randomized trial
• Not yet part of standard guidelines
• Larger studies are needed

⸻

Bottom line

This is not ready to be routine for everyone.

But when you see:

• A randomized trial
• A strong biological explanation
• A very large reduction in side effects
• Using a safe, familiar medication

…it gets your attention.

02/28/2026

I wrote The Cancer Tightrope to help patients and their loved ones through one of the most difficult times of their lives,

Cancer doesn’t just affect your body, it upends everything. Your breath. Your identity. Your relationships. Your sense of safety. Whether you’ve been diagnosed, are caring for someone you love, or navigating life after treatment, it can feel like walking a wire with no net. The Cancer Tightrope is a steady, compassionate guide through that instability. Written by Dr. Brian Lawenda, a Harvard-trained radiation oncologist and nationally recognized expert in integrative and functional medicine, this book offers short, practical chapters to help you stay grounded. At its core is “The Four Pillars of Stability,” a whole-person framework to support your mind, body, and relationships through every stage of the cancer journey. You’ll find tools for managing scanxiety, fear, and emotional overwhelm; strategies to restore sleep, energy, and recovery; support for caregivers and life after treatment; and language for hard conversations with loved ones and doctors.

Available in print and ebook: https://a.co/d/0fL313W7

Listen to the audiobook on Eleven Labs: https://elevenreader.io/audiobooks/the-cancer-tightrope-audiobook/pj:5AtenPaZB5OQVWh11qtu

Cancer doesn’t just affect your body—it upends everything. Your breath. Your identity. Your relationships. Your sense of safety. ...

02/16/2026

Tired of conflicting information on anti-cancer supplements and off-label drugs? OncoIntegrate offers a unique lens, focusing on preclinical evidence to help you understand underlying mechanisms, not proven clinical outcomes. We empower researchers and patients to see the full evidence landscape. Explore the evidence: https://oncointegrate.com

02/14/2026

Many of our patients use this drug to fight cancer. It’s great to see the NCI funding research to investigate this inexpensive generic medicine. We need data not anecdotes.
https://kffhealthnews.org/news/article/ivermectin-cancer-treatment-nih-study-dewormer-offlabel-drug/

02/12/2026

Why do I keep posting about something called VeloNote?
Most of you have known me for years through health education, research updates, and my books. So I understand why this might feel like a shift.
Here’s why it isn’t.
When you see a physician for something serious, you assume we have carefully reviewed your entire story. Every scan. Every biopsy. Every prior note. Every treatment recommendation.
That’s what you deserve.
But medical records today are often scattered across different systems. Notes don’t always agree with each other. Dates can conflict. Important details can be buried in 30 or 40 pages of documentation.
Before a complex visit, I used to spend 30 to 45 minutes reading and organizing everything so I could walk into the room fully prepared. I did that because I believe patients should never feel like their doctor is figuring out the case while they’re talking.
But that level of preparation is time-intensive.
So I worked with a healthcare software development team to build something that helps me synthesize records quickly and systematically. Now I can upload the relevant documents and generate a structured draft note and draft plan in minutes. It organizes the timeline and can even flag inconsistencies across records so I can address them before the visit.
The result is simple.
When I sit down with a patient, I already understand their case.
The conversation is about decisions and goals, not reconstructing history.
That is why I talk about this.
It’s not a tech project. It’s a workflow that helps me stay prepared and focused on the person in front of me.
If you’re curious, I wrote more about it in my latest Substack article:
https://brianlawenda.substack.com/p/seven-minutes-to-prepare-a-complex
Prepared care is better care.

02/09/2026

☕🧠 Coffee, Caffeine, and Dementia Risk

A large new JAMA study (Feb 2026) reports that caffeinated coffee ☕️ (but NOT DECAF) is associated with a 19% lower risk of dementia and better long-term cognitive outcomes compared to non-drinkers. The strongest association was seen at 2–4 cups per day, with benefits flattening at higher intakes.

This likely isn’t about coffee as a beverage. It’s about caffeine and underlying brain biology.

Caffeine blocks adenosine (2A) receptors. Adenosine signaling increases with aging and neurodegeneration and is linked to synaptic dysfunction, neuroinflammation, and amyloid/tau pathology. Chronic A2A antagonism appears to preserve synaptic plasticity and cognitive resilience over time.

Caffeine also improves neurovascular function. Dementia is not purely a neurodegenerative disease; it is also a vascular one. Better cerebral blood flow and neurovascular coupling may help protect white matter integrity and cognitive reserve.

There is also evidence for long-term anti-inflammatory effects. Regular caffeine intake is associated with lower systemic inflammatory markers and may modulate microglial activation toward a less harmful phenotype.

Metabolic signaling likely plays a role as well. Insulin resistance is a major risk factor for cognitive decline, and moderate caffeine intake improves insulin sensitivity, lipid metabolism, and mitochondrial efficiency.

The fact that decaffeinated coffee did not show the same association strongly implicates caffeine itself rather than polyphenols or coffee rituals. Similar protective signals seen with tea further support this.

The nonlinear curve makes biological sense. At higher intakes, caffeine can impair sleep, increase cortisol, and raise sympathetic tone, all of which work against long-term cognitive health.

Bottom line:
This is observational data, not proof of causation, and coffee is not a dementia therapy. But taken together, moderate caffeine intake appears to act as a slow neurovascular and neurometabolic protective signal over decades, layered on top of the fundamentals that still matter most: sleep, exercise, metabolic health, and vascular risk control.

For people who tolerate it well, 2–4 cups of caffeinated coffee per day may be a small but meaningful contributor to long-term brain health.

https://jamanetwork.com/journals/jama/fullarticle/2844764

02/07/2026

Chart prep shouldn't be a second shift. I built VeloNote to do the heavy lifting for you.
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