Journal Club: Why Your Estradiol Patch Might Not Be Doing What You Think It Is

Welcome to Journal Club — a recurring series from Camel City Women's Wellness where I break down research that is changing how I think about and practice menopause care. These are the studies I find myself referencing in patient conversations, and I want you to have access to them too.

The Study

Glynne S, et al. "The range and variation in serum estradiol concentration in perimenopausal and postmenopausal women treated with transdermal estradiol in a real-world setting: a cross-sectional study." Menopause. 2025;32:103–111. DOI: 10.1097/GME.0000000000002459

Why This Study Caught My Attention

One of the most common conversations I have with patients goes something like this: you started your estradiol patch, you gave it time, and you still feel terrible. Hot flashes, poor sleep, brain fog, mood instability — still present. You wonder if hormone therapy just isn't going to work for you.

This study offers a different explanation — and it is one that has significant implications for how we dose, monitor, and individualize transdermal estrogen therapy.

What the Researchers Did

This was a cross-sectional study conducted at a specialist menopause clinic in the United Kingdom. Researchers analyzed serum estradiol levels from 1,508 perimenopausal and postmenopausal women who were already using transdermal estradiol — patches or gels — at various doses, both licensed and off-label. The goal was to understand how much variation actually exists in blood estradiol levels among women using the same doses, and to identify what proportion of women on the highest licensed doses were still not achieving therapeutic estradiol levels.

What They Found

The findings are striking — and clinically important.

The range of estradiol levels was enormous. Across all transdermal estradiol users, the reference interval spanned from 54.62 to 2,050.55 pmol/L. The median was 355.26 pmol/L, but the interquartile range — where the middle half of patients fell — stretched from 198 to 646 pmol/L. That is a more than threefold difference between the 25th and 75th percentiles. Women using the same dose were achieving wildly different blood levels.

One in four women on the highest licensed dose had subtherapeutic levels. Among women using the maximum licensed dose of transdermal estradiol, 24.84% — nearly one in four — had serum estradiol below 200 pmol/L (approximately 54 pg/mL), which the researchers defined as subtherapeutic. These women were on the highest dose available within standard prescribing guidelines and still not reaching levels associated with adequate symptom control and tissue protection.

Approximately one in six women on high off-label doses also had subtherapeutic levels. Even among women whose providers had already gone above licensed dosing thresholds, a significant minority were still not absorbing adequately.

Older women and patch users were at higher risk for low levels. Women aged 50 and older were significantly more likely to have low estradiol levels compared to younger perimenopausal women (odds ratio 1.77). Patch users were more likely to have low levels than gel users (odds ratio 1.51). Interestingly, gel users showed greater variability — higher highs and lower lows — while patches tended to produce lower but somewhat more consistent absorption patterns.

Younger women and gel users showed greater variance. This means that while gel may achieve higher average levels, the unpredictability is also greater — a clinical tradeoff worth understanding.

Why This Matters for Your Care

This study confirms something that experienced menopause clinicians have long suspected but had limited data to support: the dose on the label does not equal the dose in the body.

Transdermal estradiol absorption is affected by skin thickness, hydration, application site, body composition, age, and individual metabolic differences that we cannot fully predict in advance. Two women applying the same patch to the same area of skin will achieve different serum estradiol concentrations — sometimes dramatically so.

This has three major clinical implications:

1. Symptom persistence on hormone therapy is not always a treatment failure — it may be an absorption problem. If you are still symptomatic on a standard dose, the first question should not be "does hormone therapy work for you?" It should be "what is your actual serum estradiol level?" Checking a level removes the guesswork and tells us whether the dose is reaching your bloodstream in the concentration needed to produce the effects we are aiming for.

2. Standard licensed doses are a starting point, not a ceiling. The fact that one in four women on the highest licensed dose remained subtherapeutic makes a strong case that off-label dosing — when clinically indicated and monitored appropriately — is not excessive practice. It is individualized care. A woman who is symptomatic, whose serum estradiol is subtherapeutic despite maximum licensed dosing, and who has no contraindications deserves a provider willing to titrate to her actual physiology.

3. Monitoring estradiol levels is clinically meaningful. This study adds to a growing body of evidence that serum estradiol monitoring in women on hormone therapy is not unnecessary testing — it is the tool that allows us to distinguish adequate from inadequate dosing, to explain persistent symptoms, and to customize therapy in a way that symptom reporting alone cannot achieve.

How We Apply This at CCWW

This research reinforces our practice philosophy: hormone therapy is not a one-size-fits-all prescription. When a patient on transdermal estradiol is not responding as expected, checking a serum estradiol level is one of our first steps — not a last resort. We use that level alongside symptom assessment to make informed, individualized decisions about dose, formulation, and delivery route.

We also discuss delivery method with patients in the context of their individual clinical picture. Patches and gels have different absorption profiles, and for some women — particularly older postmenopausal women where this study showed elevated risk of subtherapeutic levels with patches — gel formulations may achieve more consistent therapeutic concentrations.

If you have been told your hormone therapy "isn't working" without ever having your estradiol level checked, that is a conversation worth having. The therapy may not be failing you. The dose may simply not be reaching you.

The Bottom Line

This study makes a simple but powerful argument: real-world transdermal estradiol absorption is far more variable than we typically acknowledge, a meaningful proportion of women are undermedicated on standard doses, and serum estradiol monitoring is a legitimate and important clinical tool. Individualizing hormone therapy based on both symptoms and levels — not just on what the package insert recommends — is not overcautious. It is good medicine.

Journal Club posts summarize published research for educational purposes and reflect my independent clinical interpretation. They do not constitute medical advice. Full citation: Glynne S, et al. Menopause. 2025;32:103–111.