Still Exhausted On Medication? This Might Be Why.
What the evidence actually says about T3, NDT, and the conversion problem nobody explained to you
You did everything right.
You got diagnosed. You started medication. You take it every morning, thirty minutes before food, away from your supplements, exactly as instructed.
Your TSH came back normal at your last appointment.
And you still feel terrible.
Exhausted. Foggy. Cold. Gaining weight despite trying. Not yourself.
Your doctor says your levels are fine. You nod. You go home. You wonder if this is just what your life is now.
It doesn’t have to be.
There is a real, biological explanation for why a meaningful number of people on levothyroxine — doing everything correctly — still feel symptomatic. And there is a medication conversation worth having that most doctors either don’t bring up, or actively resist.
Today I want to walk you through what the evidence actually says. Not to tell you what to take. But so that when you sit in that appointment, you understand your options well enough to ask the right questions.
FIRST: WHAT LEVOTHYROXINE ACTUALLY IS 🎯
T4 — The Storage Hormone
Levothyroxine is synthetic T4.
T4 is not the active thyroid hormone. It’s a storage hormone — a precursor that your body is supposed to convert into T3, the hormone your cells actually use.
T3 is what:
Drives your metabolism
Regulates your energy
Controls your body temperature
Supports brain function, mood, and cognition
Maintains gut motility
Affects heart rate and cardiovascular function
Your brain runs on T3. Your gut runs on T3. Your hair follicles run on T3. Almost every cell in your body has T3 receptors.
T4 alone does nothing until it’s converted.
The assumption behind T4-only treatment is that your body will reliably convert T4 into adequate T3.
For many people, that assumption holds. For a significant number — it doesn’t.
THE CONVERSION PROBLEM
Why T4 Doesn’t Always Become T3
The conversion of T4 to active T3 happens primarily in the liver, kidneys, gut, and peripheral tissues. It depends on enzymes called deiodinases — particularly DIO2.
Conversion is impaired by:
Low ferritin
Iron is essential for the enzyme activity that converts T4 to T3. Ferritin below 70 ng/mL meaningfully impairs conversion — which is why optimizing ferritin is often the first step before anything else.
Chronic inflammation
Hashimoto’s — an autoimmune condition — creates systemic inflammation that directly impairs deiodinase enzyme function. This is one reason why Hashimoto’s patients are more likely to struggle with T4-only treatment than those with non-autoimmune hypothyroidism.
High cortisol / chronic stress
Elevated cortisol inhibits T4-to-T3 conversion and simultaneously raises Reverse T3 — a mirror image of T3 that binds to T3 receptors without activating them, effectively blocking active T3 from doing its job.
Selenium deficiency
Selenium is a cofactor for the deiodinase enzymes. Low selenium = impaired conversion. Common in Hashimoto’s patients and often overlooked.
Gut dysfunction
Approximately 20% of T4-to-T3 conversion happens in the gut. Dysbiosis, intestinal permeability, or inflammatory bowel conditions (like colitis) impair this pathway significantly.
A genetic variant in the DIO2 gene
A portion of the population carries a genetic polymorphism that reduces the efficiency of the DIO2 enzyme — meaning they structurally convert T4 to T3 less effectively, regardless of how well everything else is optimized. Studies suggest this group may respond better to combination T4/T3 therapy than to T4 alone.
How to Know If Conversion Is Your Problem
You can’t see conversion issues on a TSH test.
TSH reflects the pituitary’s signal to the thyroid. It doesn’t tell you how much active T3 is reaching your cells.
The test you need: Free T3
Free T3 shows the amount of active, unbound T3 available to your tissues.
What to look for:
Free T3 in the lower third of the reference range = likely conversion issue
Free T3 at the floor of range = significant conversion problem
Normal TSH + low Free T3 = classic conversion problem pattern
Also worth testing: Reverse T3
Reverse T3 (rT3) is the inactive mirror of T3. When conversion is impaired, T4 can be shunted toward rT3 instead of active T3. High rT3 with low Free T3 = conversion problem confirmed.
The ratio that matters:
Free T3 divided by Reverse T3. Ask your doctor to interpret this in context of your symptoms — not just each number in isolation.
THE OPTIONS: WHAT THE EVIDENCE SAYS
Option 1: Optimize First
Before changing medication, several things are worth addressing — because they directly affect conversion:
✅ Ferritin to 70-90 ng/mL — iron supplementation if needed
✅ Selenium 200mcg daily — supports deiodinase enzyme function
✅ Vitamin D to 50-80 ng/mL — deficiency worsens both thyroid function and conversion
✅ Address gut inflammation — especially relevant for Hashimoto’s
✅ Cortisol regulation — chronic stress is a direct conversion inhibitor
For some people, optimizing these factors alone brings Free T3 into a better range and resolves residual symptoms without any medication change.
This is always worth trying first — before moving to more complex medication options.
Option 2: Adding T3 (Combination Therapy)
Liothyronine (synthetic T3) added to levothyroxine — rather than replacing it.
What it does:
Bypasses the conversion step entirely. Provides direct T3 alongside T4, rather than relying on the body to convert all its T3 from T4.
What the evidence says:
Studies are mixed — which is worth being honest about.
Some trials show no significant benefit of combination therapy over T4-alone for the average patient. Others show meaningful improvements in mood, cognitive function, and wellbeing in a specific subset — particularly those with the DIO2 polymorphism, low Free T3 despite normal TSH, or residual symptoms after optimization.
A 2019 study found that patients with a specific DIO2 variant showed significantly greater improvements on combination therapy compared to T4-alone. This suggests the benefit isn’t universal — but it is real for the subset who need it.
What the risks are:
T3 is fast-acting. It peaks and clears quickly — which is why it’s usually prescribed twice daily. Dosing errors or too-high doses can cause:
Heart palpitations
Anxiety
Insomnia
In serious cases, arrhythmia
This is not a medication to self-prescribe or self-adjust. The risks are real and the dosing requires careful titration with medical supervision.
How to have this conversation:
“My TSH is optimized but my Free T3 is in the lower third of the reference range and I’m still symptomatic. I’ve read about combination T4/T3 therapy and I’d like to discuss whether I might be a candidate — specifically whether the DIO2 polymorphism might be relevant to me.”
Bringing Free T3 results + specific residual symptoms + the DIO2 research gives your doctor something concrete to engage with.
Option 3: Natural Desiccated Thyroid (NDT)
NDT — brand names include Armour Thyroid, NP Thyroid, Erfa — is derived from dried porcine (pig) thyroid glands. It contains both T4 and T3 in a fixed ratio, alongside T2, T1, and calcitonin.
What it does:
Provides the full spectrum of thyroid hormones in a single tablet, rather than synthetic T4 alone.
What the evidence says:
This is where the controversy is most acute — and where intellectual honesty requires acknowledging the limitations.
The evidence base for NDT is thin. Not because it definitively doesn’t work — many patients and a number of integrative physicians report significant improvements — but because the large, well-designed clinical trials simply don’t exist. The trials needed to prove or disprove NDT’s advantages over T4 alone have never been adequately funded or conducted.
What exists: smaller studies and patient surveys. A 2013 study found that patients preferred NDT over levothyroxine and lost more weight on it. But preference and outcomes in small studies don’t substitute for robust RCT evidence.
The concerns:
The T3:T4 ratio in NDT is higher than what the human thyroid naturally produces. This means some patients on NDT may get more T3 than is physiologically ideal — which can cause the same cardiovascular risks as excess synthetic T3 if not carefully monitored.
Dosing can also be less consistent than synthetic hormones — though pharmaceutical-grade NDT from reputable manufacturers is more standardised than it was historically.
The honest position:
NDT works meaningfully for some people — particularly those who feel better with a natural T4/T3 combination and who haven’t done well on synthetic options. It is not appropriate for everyone. It requires careful monitoring. And it should be prescribed and managed by a doctor — not self-sourced.
How to have this conversation:
“I’ve heard about natural desiccated thyroid and I’d like to understand whether it might be worth discussing for my situation. What’s your view on it?”
Some conventional endocrinologists will decline to prescribe it. Integrative physicians, functional medicine doctors, and some GPs are more open. If it’s something you want to explore and your current doctor won’t discuss it — finding a provider who will is a legitimate option.
WHAT THIS DOES NOT MEAN
A few things worth being direct about:
It does not mean levothyroxine is bad.
For the majority of people with hypothyroidism, T4-only treatment works well. The goal here isn’t to cast doubt on a medication that genuinely helps most people — it’s to provide information for the subset for whom it hasn’t been enough.
It does not mean you should change your medication without medical guidance.
Thyroid medication changes require monitoring. TSH, Free T3, Free T4 all need to be rechecked after any dose or medication change. The risks of getting this wrong — in either direction — are real.
It does not mean your doctor is wrong or negligent.
Most doctors prescribing T4-only are following the established standard of care. The evidence base genuinely does support T4-alone as first-line treatment. What this newsletter is arguing is that the conversation shouldn’t stop there when someone remains symptomatic — not that the starting point is wrong.
Thyroid medication decisions — including whether to add T3, switch to combination therapy, or try NDT — should always be made with a qualified healthcare provider. This newsletter does not constitute medical advice. Never adjust, add to, or discontinue thyroid medication without medical supervision. The risks of incorrect thyroid hormone dosing are real and include cardiovascular complications.
QUICK WIN ⚡
Before your next appointment:
Request Free T3 and Reverse T3 alongside your usual TSH
Note your specific residual symptoms (fatigue, brain fog, cold intolerance, weight) and how long you’ve had them on your current dose
Check your ferritin — if below 70, address this before anything else
Check your selenium intake — are you supplementing?
Write down this phrase: “My TSH is optimized but I have persistent symptoms. I’d like to discuss whether my Free T3 level might explain this and whether there are other medication options worth considering.”
If your doctor isn’t open to the conversation — that’s information too. A second opinion from an integrative physician or functional medicine doctor is a legitimate next step.
READER QUESTION 💬
Q: “I’ve been on 100mcg levothyroxine for three years. My TSH is 1.2 — which my doctor says is perfect. But I’m still exhausted and my brain fog hasn’t lifted. My doctor says there’s nothing more to do. Is that true?”
A: No — but there’s a right way to push further.
First: get Free T3 tested.
TSH of 1.2 is genuinely good. But it tells you your pituitary is happy with the amount of T4 circulating. It doesn’t tell you how much active T3 is reaching your tissues. That’s what Free T3 shows.
If your Free T3 is in the lower third of the reference range — even with a perfect TSH — you have a conversion issue. That’s the next conversation to have.
Second: check ferritin, selenium, and vitamin D.
Low ferritin (below 70) is one of the most common causes of persistent fatigue and brain fog in hypothyroid patients on otherwise optimized medication. It’s also one of the most commonly missed. If you haven’t had ferritin specifically checked — and been told the optimal range is 70-90, not just “>12” — this is the first thing to address.
Third: if Free T3 is low and optimization hasn’t helped:
This is the point at which the combination T3/T4 conversation becomes appropriate. Ask specifically: “My Free T3 is [X], which is in the lower third of range. I’ve addressed ferritin and selenium. I’d like to discuss whether combination therapy might be appropriate for me.”
Fourth: if your doctor won’t engage:
A second opinion from an integrative physician or a doctor who specialises in thyroid is not a betrayal of your current doctor. It’s appropriate patient advocacy.
Three years of persistent symptoms on optimized TSH is not “nothing more to do.” It’s a signal that something hasn’t been found yet.
RESOURCE CORNER 📚
Useful reading:
Why Do I Still Have Thyroid Symptoms? by Datis Kharrazian — the most accessible book on conversion issues and Hashimoto’s
The Thyroid Connection by Amy Myers MD — covers both conventional and functional approaches
For tracking Free T3, symptoms, and patterns daily: https://get.allvihealth.com/
WHAT’S HELPING ME THIS WEEK 🌱
I had my Free T3 tested alongside my TSH for the first time last month. My TSH was optimal. My Free T3 was in the lower quarter of the reference range. That single additional test told me more about why I was still symptomatic than three years of TSH monitoring had. If you haven’t had Free T3 tested — it’s the one thing I’d prioritise this week.
YOUR NEXT STEP
Request Free T3 at your next appointment. Not TSH alone. Free T3.
If it’s in the lower third of range alongside persistent symptoms — you now know what conversation to have next.
Need complete thyroid resources?
THYROID RESOURCES
Want your Free T3, symptoms, and patterns tracked daily so you walk into every appointment with real data?
We’re running a 90-day programme — daily tracking, pattern analysis, lab interpretation, and a structured report for your doctor. https://tally.so/r/LZ0bEj
Have a question about T3, NDT, or conversion? Hit reply. I read every response personally.
Your partner in hormonal health,
Rashmi
Founder, Allvi
P.S. The most common response I get when women share their Free T3 results for the first time is: “Nobody ever told me this test existed.”
TSH tells you your pituitary is satisfied.
Free T3 tells you whether your cells are.
They are not the same thing.
If you take one action from this newsletter — request Free T3 at your next appointment. Everything else follows from knowing that number.
Allvi | https://get.allvihealth.com/
Allvi provides comprehensive care for women with complex health conditions. This newsletter contains educational information and is not medical advice. Consult your healthcare provider for diagnosis and treatment. Thyroid medication decisions should always be made with a qualified healthcare provider.