Rationale: L-T3-T4 combination therapies

Updated 2018-07-09

In clinical practice, combination therapy is usually attempted only after L-T4 monotherapy has brought insufficient relief from hypothyroid symptoms despite an increase in dosage, and when T3-T4 conversion is chronically poor. When thyroid scientists recommend T3 medication, it is usually for patients who do not convert T4 hormone into sufficient T3 hormone to alleviate low-T3 symptoms; it may also be preventive of disorders associated with lower levels of T3 (see our sections on Free T3 and the T3:T4 ratio). [26, 32, 177 178, 179]

In the standard L-T4 therapy, an increased dosage can paradoxically result in lowering T3 levels or leaving them relatively unchanged because of the role T4 plays in reciprocally downregulating Deiodinase Type 2 and upregulating Deiodinase Type 3. This is the natural result when the body perceives “excess” T4 above its more specific set point within the statistical normal range (see the section on Reverse T3 and Deiodinase Type 3).

In view of this drawback of L-T4 monotherapy, combination therapy offers promise: administering a combination of T4 and T3 hormone can make it possible to achieve a healthier hormonal balance in some patients.

Research studies of L-T3-T4 combination therapy, although very enlightening about the modality’s many variations and effects, are difficult to review as a collective body of literature because of their methodological limitations and wide variety.  The issue of “added benefit” for this therapy has not yet been properly assessed or concluded.  Doctors are not merely considering their patients’ health but looking for an incentive worthy of the extra effort of learning about a new treatment modality.

The major flaw of most of these studies, which hinders their ability to show “superiority” over L-T4 for particular patients, is the random recruitment model. Studies have not often targeted individuals who would benefit the most, such as those with low T3 levels in serum, or DIO2 polymorphisms. [100]

However, in 2018, a study did investigate genetic relationships and discovered a significant preference for combination among those with DIO2 and MCT10 genetic polymorphisms, but it did not measure signs or biomarkers of peripheral T3 effects, and individual patients’ variation was hidden underneath the cohort averages.[180]

As of 2017-2018, there are two crucial “negative” findings. Studies do not show reduced efficacy in combination therapy, and they do not raise any objection from the perspective of safety. Therefore, they pose no insurmountable barrier to its use in clinical practice with a specific individual who may benefit from it. The main challenge is for the practitioner to understand its unique qualities as a therapy and to use it judiciously. [31]

To the degree that L-T4 hormone therapy may contribute to low T3 in some individuals, including T3 within therapy may correct it. By changing the ratio of T4 to T3 in serum to achieve the same overall effect as L-T4 therapies, a moderate T4 deficiency will upregulate its conversion to T3 via Deiodinase type 2. The resulting serum may have a higher T3:T4 ratio than in untreated controls, but this can help symptomatic patients’ peripheral tissues from experiencing T3 deficiency especially if they have genetic limitations to hormone conversion, transport, receptor stimulation, or other reasons science has yet to discover.

The DIO1 and DIO2 genetic defects can lower T4-T3 conversion efficiency and have been associated with low T3:T4 levels in serum and in tissues, respectively. [133] Another challenge some patients face is in the genes responsible or hormone transport. The MCT8 gene, MCT10, and several other genes are responsible for ensuring the transport of T3 hormone molecules across cell membrane, and MCT8 is predominant in heart tissue.[65] It has therefore been suggested that patients with genetic defects in DIO2 as well as MCT10 may benefit from T3-T4 combination therapy. 136 (p8)

Combination therapy may be preferable in hypothyroid patients who have health conditions exacerbated by higher T4 levels. These associations have been discovered from time to time and reported in research. For example, one recent study that measured TSH, T4 and T3 found a positive association between T4 levels and the severity of depression.[181]

Currently there is debate about the “natural” or best ratio of T3 to T4 within combination therapy. Some have approached the ideal T3:T4 dosage ratio based on the approximate normal ratio found in serum in patients without thyroid disease, while others point to the ratio of hormones theorized to be secreted from a normal thyroid gland. A common criticism of animal-sourced combination therapy is that its T3:T4 ratio of 1:4 (20% T3 and 80% T4) in most animal-derived formulations of desiccated thyroid offers an “unnaturally” high T3/T4 ratio. [31] Proponents of desiccated thyroid like to point out in response that T4-monotherapy is equally unnatural since it contains no T3, yet many patients can and do adapt to unnatural monotherapy.

Ultimately these ideas about ratios are rather fruitless debates based on impractical comparisons. Dose ratio can only be a starting place or a suggestion. The ratio of hormones found within the pharmaceutical dose is only the raw input into the system. Each patient’s body will respond in a different way to a given hormone ratio as well as dose, and this was discovered as early as 1977. [182] Clearly, patients vary in their ability to absorb them, to transport them, and to convert the T4 given with the T3. The LT3:T4 dose ratio may need to increase in combination therapy to the degree that an individual patient is a poor converter of T4 hormone and/or symptoms resolve only when serum is in a T3-dominant state. Some patients may need a higher ratio of T3 intake than others in order to produce a similar Free T3 level in serum, and some may have a higher T3 set-point.

Where should patients’ serum levels be if they are euthyroid? Since few recent studies exist on desiccated thyroid therapy, we may consider patient experience to be a vast collection of diverse N=1 experiments. Decades of patients’ experience with desiccated thyroid combination therapy has led to the general understanding that for most patients, a euthyroid state occurs most often when the TSH is near the bottom of normal reference range or even below reference range, the Free T3 is near the top of its range, and the Free T4 is near the middle of range. [183]

Endocrinologist and thyroid researcher Dr. Rudolf Hoermann and co-authors have given this useful guide to those attempting a transition to combination therapy:

“When adding L-T3 to a hypothyroid patient’s medication, is should be noted that available conversion tables wrongly show that 100 mcg of L-T4 = one grain of NDT = 25 mcg of L-T3. This implies that 100 mcg of L-T4 is equivalent to 25 mcg of L-T3, a ratio of 4 to 1. If that were the case then one grain of NDT would be equivalent to only 75 mcg of L-T4, since it contains 39 mcg of T4 and 9 mcg of T3 (39 + (9 times 4) = 75). Furthermore, studies have reported that the correct ratio of T4 to T3 is closer to 3 to 1; consequently one grain of NDT is equivalent to only 66 mcg of L-T4.

It should be noted that higher L-T3 medication doses should best be split in half for a morning and early afternoon dose. Since L-T3 reaches peak effect in 3 to 4 hours, and then drops off, this split dose may provide a more consistent effect over the full day. In addition, the guidelines recommend that “blood for assessment of serum FT4 should be collected before dosing because the level will be transiently increased by up to 20% after Levothyroxine (L-T4) administration.” For the same reason, L-T3 medications should be deferred until after the blood draw for FT3 testing in order to avoid false high results.” [158 (p12)]

The strongest benefit of synthetic combination therapy is its flexibility, and the short-acting effect of T3 enable a patient him or herself to adapt the doses and ratios of L-T4 and L-T3 to the their metabolic and symptomatic response. This can be done either by prescribing the two hormones as separate pills and doses, or arranging a pharmacy to compound a precise mcg dose of both in one customized capsule.



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