Combination thyroid tablets cluster around two ratios. Cynoplus is 4:1 T4 to T3 by weight in both its strengths. Novothyral is 5:1. Slow-release combination formulations are commonly built at 4:1.
The explanation usually offered is that these ratios approximate what the thyroid gland produces. That explanation is wrong, and it is wrong in an interesting direction: combination tablets are far more T3-weighted than the gland, not similar to it. Understanding by how much requires noticing something that most discussion of this topic skips entirely, which is that a ratio quoted by weight and a ratio quoted in molar terms are different numbers for the same tablet.
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SRT4+T3-120 Slow Release T4+T3 (120/30mcg)
The practical arithmetic of moving between doses and ratios is covered in the T4 to T4/T3 conversion reference. This piece is about where the ratios come from.
Weight Ratios Are Not Molar Ratios
T4 and T3 differ by one iodine atom. That single atom carries substantial mass, and it makes T4 the heavier molecule: approximately 776.9 g/mol against approximately 651.0 g/mol for T3 as the free acids.
The consequence is that a milligram of T4 contains fewer molecules than a milligram of T3. So when a tablet is described as 4:1 by weight, the ratio of actual hormone molecules is not 4:1.
Working it through for a 120/30 tablet:
- T4: 120 mcg ÷ 776.9 g/mol = 0.1545 micromoles
- T3: 30 mcg ÷ 651.0 g/mol = 0.0461 micromoles
- Molar ratio: 0.1545 ÷ 0.0461 = 3.35 : 1
A 4:1 tablet by weight is a 3.35:1 tablet by molecule count. The weight figure systematically understates how T3-heavy the formulation is, by about sixteen percent.
The same calculation for a 5:1 weight ratio, as in Novothyral 100/20, gives approximately 4.19:1 molar.
This matters because the clinical literature frequently specifies ratios in molar terms while product labelling and forum discussion specify them by weight. Comparing a tablet's weight ratio against a study's molar ratio without converting is comparing two different quantities, and it makes formulations look closer to the research than they are.
What the Gland Actually Does
A healthy adult thyroid secretes on the order of 100 micrograms of T4 per day against roughly 5 micrograms of T3. That is approximately 20:1 by weight, or close to 17:1 in molar terms.
Crucially, direct secretion is not where most circulating T3 comes from. The large majority is produced outside the gland, by deiodination of T4 in liver, kidney and other tissues. The thyroid's own contribution to the T3 pool is a minority share.
This is why the "combination tablets mimic the gland" explanation collapses on inspection. If a tablet genuinely reproduced glandular output it would be roughly 20:1 by weight, and it would be relying on the recipient's peripheral conversion to generate most of their T3, which is exactly what levothyroxine monotherapy already does.
A 4:1 tablet is doing something different on purpose.
The Actual Rationale
Combination tablets exist because peripheral conversion is suspected of being the limiting step in some individuals. If the conversion machinery is the bottleneck, supplying more T4 does not fix the problem, because the constraint is downstream of the T4 supply. Supplying pre-converted T3 bypasses it.
Bypassing a step that normally generates the majority of circulating T3 requires delivering considerably more T3 than the gland ever secretes directly. That is the whole logic, and it is why the ratio departs from physiology rather than approximating it.
There is documented genetic support for the premise. Polymorphism in DIO2, encoding type 2 iodothyronine deiodinase, has been associated with reduced enzyme activity and lower serum T3 in thyroid-deficient individuals. A subgroup with impaired conversion is a plausible population for whom a T3-weighted preparation would behave differently from a T4-only one. The mechanism is set out in the deiodinase dysfunction guide.
Whether that subgroup can be identified in advance, and whether combination therapy actually helps them, is where the evidence becomes genuinely difficult.
Where Desiccated Thyroid Sits
Desiccated thyroid is the format synthetic combination tablets were built to replace, and its ratio is the historical reason combination products look the way they do.
Porcine thyroid tissue carries a T4 to T3 proportion considerably richer in T3 than human glandular secretion. It also contains T2, T1 and calcitonin, which synthetic combinations do not reproduce and whose contribution, if any, is not established. The NDT comparison covers the format difference in detail.
Two properties matter for a discussion about ratios specifically.
The first is that desiccated thyroid's ratio is not a designed number. It is whatever the source tissue contained, standardised to a total hormone activity rather than to a fixed proportion of each hormone. Batch-to-batch variation in the ratio is therefore intrinsic to the format rather than a manufacturing failure.
The second is that synthetic combination products inherited the general shape of that profile rather than deriving a ratio from first principles. When a 4:1 tablet is described as more physiological than levothyroxine alone, what is usually meant, whether or not the speaker knows it, is that it resembles desiccated thyroid more closely than levothyroxine does. That is a comparison against another pharmaceutical product, not against the human thyroid.
The Trial That Complicates the Story
If ratios closer to physiology were better, a trial testing one should show it.
A randomised study of replacement therapy using levothyroxine plus triiodothyronine at a bioavailable molar ratio of 14:1, chosen specifically to approximate physiological proportions, reported that the combination was not superior to thyroxine alone. The title states the result plainly.
That finding cuts in an awkward direction for both camps. It undermines the argument that combination therapy fails because the ratios used are unphysiological, since a physiological ratio was tested and did not outperform. And it equally undermines any assumption that a near-glandular ratio is the target formulations should be aiming at.
A separate randomised comparison of T4 plus T3 against T4 monotherapy, a consensus document on evidence-based use of the combination, and a 2026 network meta-analysis of additional treatment strategies all bear on the same question without settling it. A 2025 systematic review examined liothyronine safety specifically. The honest summary is that the field has not established which ratio, if any, is correct, and that includes the ratios currently manufactured.
Ratio and Dose Are Independent
A recurring confusion in protocol discussion is treating the ratio as though it described the dose.
Cynoplus 60/15 and Cynoplus 120/30 hold exactly the same 4:1 proportion. One delivers twice the hormone of the other. A researcher saying "I am on a 4:1 protocol" has communicated the proportion and nothing about the quantity, which is the variable that determines effect.
| Preparation | T4 | T3 | Weight ratio | Molar ratio |
|---|---|---|---|---|
| Cynoplus 60/15 | 60 mcg | 15 mcg | 4:1 | 3.35:1 |
| Cynoplus 120/30 | 120 mcg | 30 mcg | 4:1 | 3.35:1 |
| Novothyral 100/20 | 100 mcg | 20 mcg | 5:1 | 4.19:1 |
| SRT4+T3-120 | 120 mcg | 30 mcg | 4:1 | 3.35:1 |
| Self-assembled 95/10 | 95 mcg | 10 mcg | 9.5:1 | 7.96:1 |
| Thyroid gland (daily) | ~100 mcg | ~5 mcg | ~20:1 | ~16.8:1 |
The self-assembled row is worth attention. A researcher substituting 10 mcg of T3 into a 125 mcg levothyroxine protocol lands near 9.5:1 by weight, which is far closer to physiological than any manufactured combination tablet. Moving from that self-assembled ratio to a 4:1 product roughly doubles the T3 fraction, which is a larger change than the phrase "switching to a combination tablet" suggests.
Ratio Drift in Self-Assembled Protocols
Anyone dosing two separate preparations rather than a fixed-ratio tablet is running a ratio, whether or not they are tracking it, and it moves whenever either component changes.
Consider a protocol that starts at 125 mcg levothyroxine with 10 mcg T3, a ratio of 12.5:1. A series of ordinary adjustments follows.
| Adjustment | T4 | T3 | Resulting weight ratio |
|---|---|---|---|
| Starting point | 125 | 10 | 12.5 : 1 |
| T3 raised to 15 | 125 | 15 | 8.3 : 1 |
| T4 reduced to 100 | 100 | 15 | 6.7 : 1 |
| T3 raised to 20 | 100 | 20 | 5.0 : 1 |
| T4 reduced to 88 | 88 | 20 | 4.4 : 1 |
Four routine adjustments have moved the protocol from 12.5:1 to 4.4:1 without any decision ever being taken about the ratio. It has arrived near a manufactured combination proportion by accumulation rather than by design.
Neither endpoint is wrong. The point is that the ratio is a variable that changes silently in a two-component protocol, and someone who has never calculated it may be running something quite different from what they believe. Recording the ratio alongside the doses at each adjustment costs nothing and makes the drift visible.
This is also the practical argument for a fixed-ratio product where a specific proportion is actually wanted: a fixed ratio cannot drift, because the proportion is a property of the tablet rather than of a sequence of decisions.
Why Manufacturers Land on 4:1 and 5:1
Three constraints push in the same direction, and none of them is a claim about optimal physiology.
Manufacturability. Both hormones are dosed in micrograms, and content uniformity gets harder as the smaller component shrinks. A ratio of 20:1 at a normal replacement T4 dose would put the T3 component around 5 mcg per tablet, at which point reliable, reproducible content becomes a genuine formulation problem. Four to one keeps both components in a range that can be manufactured consistently.
Divisibility. 120 and 30 are convenient numbers. So are 60 and 15, and 100 and 20. They halve and quarter into figures that remain whole or cleanly fractional, which matters for a product people divide.
Historical precedent. Desiccated thyroid, the format combination tablets were designed to replace synthetically, carries a considerably higher T3 fraction than glandular secretion. Synthetic combination products inherited the general shape of that profile. The comparison is examined in the NDT versus slow-release T3 analysis.
None of these is a physiological argument. They are engineering and inheritance, which is worth knowing when a ratio is presented as though it encoded a clinical finding.
What the Evidence Establishes, and What It Does Not
Established. The molecular weights, and therefore the arithmetic converting weight ratios to molar ratios. That the thyroid secretes far more T4 than T3 and that most circulating T3 arises from peripheral deiodination. That manufactured combination tablets are several times more T3-weighted than glandular output. That DIO2 polymorphism is associated with reduced deiodinase-2 activity.
Contested. Whether combination therapy is superior to monotherapy in any identifiable population. A trial at a near-physiological 14:1 molar ratio found no superiority; other randomised work and a 2026 network meta-analysis reach no consensus.
Not established. That 4:1 is optimal, or better than 5:1, or better than 9:1. That any manufactured ratio was selected on outcome evidence rather than on formulation practicality. That a more physiological ratio would perform better, which is the specific proposition the 14:1 trial tested and did not support.
Frequently Asked Questions
What does a 4:1 T4:T3 ratio actually mean?
Four micrograms of levothyroxine for every one microgram of liothyronine, by weight. In molar terms, accounting for T4 being the heavier molecule, it works out at approximately 3.35 molecules of T4 per molecule of T3.
Is 4:1 the same as what my thyroid produces?
No, and not close. A healthy thyroid secretes roughly 20:1 by weight, and most circulating T3 is produced outside the gland by conversion rather than secreted directly. A 4:1 tablet carries about five times the T3 fraction of glandular output.
Why is the molar ratio different from the weight ratio?
Because T4 and T3 have different molecular weights, T4 being heavier by roughly one iodine atom. A given weight of T4 therefore contains fewer molecules than the same weight of T3, so weight ratios always understate how T3-heavy a preparation is.
Is a more physiological ratio better?
The available evidence does not support that assumption. A randomised trial using a bioavailable molar ratio of 14:1, deliberately close to physiological, reported no superiority over thyroxine alone.
Why do Cynoplus and Novothyral use different ratios?
Cynoplus is 4:1 and Novothyral 5:1, a difference that reflects formulation choices rather than any established outcome advantage for either. Neither ratio has been demonstrated superior to the other.
Does the ratio tell me my dose?
No. Ratio and dose are independent. Cynoplus 60/15 and 120/30 share the same 4:1 ratio while delivering twice the hormone, so stating a ratio communicates proportion and nothing about quantity.
Should I match my current ratio when switching products?
Matching the ratio preserves the proportion but not necessarily the totals, and matching the totals does not necessarily preserve the ratio. Both need calculating separately, which is covered in the conversion reference.
Why not manufacture a 20:1 combination tablet?
At a normal replacement T4 dose, a 20:1 ratio puts the T3 component near 5 mcg per tablet, where reliable content uniformity becomes a real manufacturing constraint. It would also deliver so little T3 that it would function much like levothyroxine monotherapy.
Closing Note
The 4:1 ratio is not a physiological finding, an optimum, or an imitation of the thyroid gland. It is a formulation convention that keeps two microgram-dosed hormones in a range that can be manufactured reliably and divided cleanly, sitting several times more T3-heavy than glandular secretion because bypassing the conversion step is the entire point of the format.
That is a perfectly reasonable basis for a product. It is not the same as evidence that the proportion is correct, and the most useful thing a researcher can take from the literature here is that the one trial specifically designed to test a physiological ratio did not find it superior.
Where a protocol calls for a 4:1 preparation at the full replacement range, the SRT4+T3-120 slow release T4+T3 is manufactured at 120 mcg T4 with 30 mcg T3. Where a different proportion is wanted, T4 levothyroxine at 100 mcg alongside the slow-release T3 range allows any ratio to be built from two components rather than accepting a fixed one.
All compounds discussed here are research chemicals supplied for laboratory research use only. Nothing in this article is medical advice, a treatment protocol, a dosing recommendation, or a recommendation for human or animal consumption. Thyroid hormone dosing carries genuine cardiovascular risk and the clinical evidence on combination therapy remains actively contested. Researchers should consult the primary literature cited below and appropriate qualified professionals.