Thyroid T3/T4 Combination Therapy vs T4-Monotherapy
by Jeffrey Dach MD
Susan is a 42-year-old Professor of Literature at the local college. About four years ago, she was treated with radioactive iodine (thyroid ablation) for Graves’ Disease. Susan now requires lifelong thyroid replacement. After seeing four different endocrinologists who prescribed various doses of thyroid medication, Susan is still unhappy with her treatment. The last endocrinologist prescribed 175 mcg of Levothyroxine, and Susan’s TSH is suppressed down to a very low 0.01. However, Susan continues to suffer from chronic fatigue, depression, weight gain, foggy thinking, and constipation, all typical symptoms of a low thyroid condition. Susan was crying in my office as she told her story of frustration. Above left image: thyroid ultrasound courtesy of wikimedia commons.
T4 Only Medication Cannot Guarantee Euthyroid State
T4 medication (Levothyroxine) is a prohormone and must be converted to its active form, T3. This is done by the D2 deiodinase enzyme system inside the cells of the peripheral tissues. The assumption made by the endocrinologist when using T4 monotherapy with Levothyroxine, generic Synthroid, is this:
It is assumed T4-only medication (Levothyroxine) is converted to T3 by the peripheral tissues at the proper rate to produce normal thyroid levels. This assumption is incorrect as shown by studies at Rush Medical Center in Dr. Antonio Bianco’s lab. The paradigm shift in thyroid endocrinology is understanding the conversion of T4 to its active form, T3, is controlled by the deiodinase enzyme system at the cellular level. This has been ignored by mainstream endocrinology, leading to a number of errors, one of which is the dogmatic perpetuation of T4-monotherapy. (2)(38-40)(43-44)
In 2011, Dr Damiano Gullo from Italy reported T4 to T3 conversion is defective in about 20% of patients treated with Levothyroxine (T4 monotherapy) after thyroid ablation (athyreotic patients). Dr. Gullo writes:
Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.(21)(3)
Indeed, Susan’s labs showed a high Free T4 of 1.6 and a low Free T3 of 240 indicating poor conversion of T3 to T4, “reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion”. A number of animal studies have been done to answer this question of why peripheral conversion of T4 to T3 is reduced. (21)
Left image chemical structure of levothyroxine courtesy of wikimedia commons
T4 – Monotherapy Explained
The key to understanding the failings of T4-monotherapy lies with the D2 deiodinase enzyme system which resides in our cells, and plucks an iodine molecule off of T4, converting it to T3, the active form of the hormone. In a 2013 report, Dr. Antonio Bianco says this intracellular D2 deiodinase enzyme system is the master controller for thyroid levels and creates a new paradigm in our understanding of thyroid function:
Thyroid hormone–responsive metabolic processes are turned on and off by thyroid hormone via deiodination pathways that are taking place inside the target cells, seemingly invisible from the plasma viewpoint…. deiodination supports a new paradigm in which hormones are activated or inactivated in a controlled fashion in specific thyroid hormone-target tissues. (38)
D2 in the Pituitary Acts Differently from D2 in Periphery
According to a 2015 animal study by Dr De Castro, the D2 deiodinase enzyme system in the pituitary acts differently from the D2 in the peripheral tissues. In the peripheral tissues, D2 is inactivated by T4. This is a safety mechanism to protect the cells from hyperthyroidism with dangerously high T4 levels. T4 inactivates the D2 enzyme in the peripheral tissues, thereby preventing conversion of T4 to its active form, T3.
However, the D2 in the hypothalamus and pituitary is a different type of D2 which is not inactivated by T4. In the hypothalamus and pituitary, the abundant T4 in circulation is promptly converted to intracellular T3 which will then suppress the TSH to low levels. This results in the pattern we see with Susan’s, labs, relatively higher serum T4 and relatively lower serum T3. In the periphery, cells are starved of T3 because of inactivation of the D2 enzyme by T4, which inhibits conversion of T4 to T3 in the peripheral tissues. In his mouse study, Dr De Castro found that only constant infusion of both T4 and T3 normalized thyroid levels. Dr De Castro writes:
in contrast to other D2 expressing tissues, the hypothalamus is wired to have increased sensitivity to T4… only constant delivery of L-T4 and L-T3 fully normalizes T3 -dependent metabolic markers and gene expression profiles in thyroidectomized rats. (39)
In most tissues, exposure to T4 inactivates the D2 deiodinase, which decreases conversion of T4 to T3, and decreases peripheral production of T3. Similarly, this also occurs in the brain, where the elevated serum T4/T3 ratio results in hypothyroid brain cells. However, the exception to this rule is the hypothalamus where the D2 deiodinase is less susceptible to T4 induced inactivation, causing suppression of TSH with Levothyroxine T-4 monotherapy, while in the periphery, T4 conversion to T3 via D2 is inhibited by T4, creating a hypothyroid state. This explains the findings in thyroidectomized mice in which T4 treatment normalizes TSH, yet there is reduced peripheral T3. This also explains the failings of Susan’s T4-only monotherapy with levothyroxine which suppresses her TSH, while leaving the peripheral tissues in a hypothyroid state. (38-40)
Combination Treatment with T3 andT4
If T4-monotherapy leads to cellular hypothyroidism in the periphery while centrally, a suppressed TSH, what is the solution? Combined therapy with both T3 and T4 may resolve this problem. The past dogmatic insistence on T4 monotherapy seems to be changing, as more and more endocrinologists are embracing combination T3 and T4 therapy. In 2014, Dr Wilmar Wiersinga writes:
Levothyroxine plus liothyronine [generic Cytomel] combination therapy is gaining in popularity….in some of the 14 published trials this combination was definitely preferred by patients and associated with improved metabolic profiles. (1) Note: liothyronine is T3.
Perhaps the research using thyroidectomized mice from 1995 and 1996 by Dr Escobar is convincing. In studies using thyroidectomized mice, Dr Escobar found that T3 and T4 levels could not be normalized with T4 monotherapy alone. Rather, a steady infusion of both drugs, T3 and T4, were needed to maintain a euthyroid state. In addition, a number of human studies show that patients prefer combination therapy. (1)(3,4)
Adverse Effects of Thyroid Pills
Adverse effects of thyroid excess are similar for all three types of thyroid medication, levothyroxine, NDT and combination therapy. Rapid heart rate at rest (tachycardia), is the symptom we are most concerned about, and the patient is instructed to watch for this and hold the thyroid pill if this is noted. Other symptoms of thyroid excess to watch out for include anxiety, insomnia and loose stools.
Which type of thyroid pill do you prefer?
1) Synthetic T4 andT3. Mainstream endocrinology uses Levothyroxine (T4) combined with Cytomel (T3) in a ratio of (12:1).
2) T4 plus a slow release compounded T3 to avoid supraphysiologic dosing of T3 which peaks 2 hours after ingestion.
3) NDT, Natural Desiccated Thyroid which contains T4:T3 in ratio of 4:1.
4) NDT plus T4 Levothyroxine. Some patients prefer a 12:1 ratio of T4 to T3, so adding an appropriate dose of T4 to NDT will do the trick.
Here is a sample dosing schedule:
Half Grain tablet of NDT twice a day provides 4.5 mcg of T3 twice a day (total 9 mcg), and a total T4 dosage of 76 Mcg. Add another daily 25 Mcg of (T4) Levothyroxine to obtain the desired T4:T3 ratio of (101: 9) = (11.2:1).
We have found a few patients after thyroid ablation may prefer adding T4 to obtain this combination.
Option 1) Combined T3 and T4 (Levothyroxine and Cytomel)
This option is discussed by Dr Colin Dayan in 2018 Thyroid Research. Dr. Dayan prefers a T4:T3 ration of (14:1) because this closely matches the natural secretion rate for T4 and T3 by the human thyroid gland. In 2018, Dr Dayan writes:
“The doses (for NDT) give a T4:T3 ratio of 4.2:1, significantly more T3 than the 14:1 secreted by the normal thyroid and the doses recommended above. This makes dosing difficult as displayed by several studies which have shown supraphysiological T3 doses post dose, fluctuating T3 levels during the day and more hyperthyroid symptoms in subjects taking DTE compared to LT4 monotherapy.” … “Furthermore, it has also been shown that the majority of circulating T3 comes from peripheral conversion of T4 to T3 and not secretion of T3 from the thyroid , hence a T4:T3 secretion ratio of approximately 14:1 appears average in humans, suggesting only a small role for secreted T3…Practicing clinicians will be able to identify a group of patients not satisfied on LT4 monotherapy which makes up a small subset of all their patients on LT4…. Both ATA and ETA suggest that in an appropriate clinical setting (see below) combination therapy may be trialed to determine if it is beneficial for the individual patient…. despite recommendations and guidelines from various specialist bodies, use of combination T4/T3 therapy appears significant in most developed countries.”(37)
Dr Colin Dayan’s routine is to give a T3 (generic Cytomel) to a patient already on “adequate LT4 monotherapy ” (usually 75-150 mcg levothyroxine), yet still having symptoms of hyopothyroidism. Dr Dayan will then remove some of the T4 dose (usually 50-75 mcg T4) and replace it with (5 – 20) mcg of T3, usually generic Cytomel (Liothyrronine) in a split dose given twice a day to avoid or reduce “supraphysiologic dosing”.
Option 2 Slow Release T3
Dr Martin Milner describes his routine using compounded slow release T3 in his article in the Townsend Letter 2005. In order to avoid supraphysiologic dosing with T3, Dr Milner suggests using slow release compounded T3.(36)
Option 3: Synthetic T3 and T4 Combination
Which T4:T3 Ratio do You Prefer 14:1 or 4:1 ? As mentioned above, a major objection to NDT, Natural Desiccated Thyroid) is the T4:T3 ratio which is 4:1, providing a much larger T3 bolus compared to the 14: 1 ration (T4:T3) ratio discussed by Dr Colin Dayan in his 2018 article .(37)
Others such as Dr Martin Milner disagree, and actually prefer to use the 4:1 (T4:T3) ratio commonly found in NDT. Perhaps Dr Milner is right, since this 4:1 (T4:T3) ratio is closer to the serum (T4:T3) ratios for the average patient which is 3.3:1. Dr. Jernej Grmek, in the 2015 Slovenian Medical Journal, studied the free thyroxine to free triiodothyronine ratios (FT4:FT3) in 225 patients, reporting this mean ratio was 2.86 ± 0.52.(41) This discrepancy between serum T4:T3 (3.3:1) ratio and secreted T4:T3 (14:1) ratio can be explained by the fact that 80% (most) of our T3 comes from peripheral conversion of T4 to T3 via the intra-cellular D2 Deiodinase Enzyme. Of the circulating Free T3, only 20 % comes from thyroid secretion, the remaining 80% from peripheral conversion of T4 to T3 via the Type 2 De-Iodinase Enzyme.(36-37)
5:1 Ratio Combination T3 and T4 Wins the Contest
in 2005, Dr. Bente Appelhof studied two different T4:T3 synthetic combination ratios, 5:1 and 10:1 ratios and compared them to T4 monotherapy in a randomized double blind study in 141 patients with Hashimoto’s hypothyroidism. About 47 patients were randomized to each treatment group, T4 monotherapy, 5:1 or 10:1 combination therapy. The 5:1 ratio was most preferred by the patients. Please note, this 5:1 ratio most closely approximates the 4:1 ratio found in NDT, Natural Desiccated Thyroid. (16)
Which Thyroid Pill is Best, Synthetic Combination or NDT?
In 2018 by Dr. Anam Tariq from Johns Hopkins examined this question. Dr Tariq performed a retrospective observational study of 100 patients from an endocrinology clinic in Pennsylvania over six years comparing T4 monotherapy to both synthetic T3, T4 combination therapy and NDT, Natural Desiccated Thyroid. Patients on T4 monotherapy for a year continuing to complain of hypothyroid symptoms were candidates for combination therapy. Starting dose for T3 was “5 μg in conjunction with an appropriate decrease of 12.5 μg in LT4 to achieve the standard physiological circulating FT4:FT3 ratio of nearly 14:1.“ The maximum dose of T3 was 12.5 mcg. Starting dose for NDT was 15mg (quarter grain) then titrated up. T4:T3 ratio was, of course, 4:1 for NDT. The authors also checked and optimized B12 and Vitamin D levels in all patients.
The average dose of DTE (NDT) was 30 mg. The average LT4/LT3 dose was 75 μg/5 μg to obtain physiologic thyroid levels. Fifty-two percent had Hashimoto disease, 22% had surgical hypothyroidism, 10% had ablation for either Graves’ disease or thyroid cancer, and 16% had miscellaneous etiologies. (30)
I found it remarkable that the mean TSH for all treated patients was in the 1.8 to 1.9 range, regardless of the particular combination of thyroid medication. Likewise, the Free T3 and Free T4 levels were remarkably similar across all treatment modalities. Adverse effects of synthetic combination therapy were:
6.7% of the 100 patients complained of palpitations and anxiety and had confirmed TSH <0.35 μIU/mL but without atrial arrhythmias. (30)
Many of the patients reported feeling better on combination therapy (either NDT or Synthetic T3,T4) compared to Levothyroxine monotherapy. Both combination therapies seemed equally safe and effective. The authors conclude:
Combination therapy of LT4 and LT3 has remained an experimental treatment that can be used at the physician’s discretion. Our observational study concludes that for a subset of patients who feels suboptimal on LT4 monotherapy, synthetic therapy is beneficial and safe in controlling hypothyroid symptoms and improving quality of life. (30)
Genetic Mutations in the D2 Deioidinase
As mentioned above, the D2 Deiodinase enzyme is the master control mechanism for tissue level conversion of T4 to T3. What if the patient harbors a polymorphism (mutation) in the D2 deiodinase gene? Will this affect the T4 to T3 peripheral conversion ability? And if so, would these patients prefer combination therapy? Dr Allan Carle says yes, of course. In 2017, Dr Carle studied 45 autoimmune hypothyroid patients on Levothyroxine using genetic analysis of the D2 gene. 60 per cent of patients harboring D2 gene polymorphisms preferred combination therapy with both T3 and T4. If two SNPs (single nucleotide polymorphisms) were present, all of these (100%) patients preferred combination therapy. (42-46)
Major Objection to NDT – High peak T3 levels
Mainstream Endocrinology’s major objection and reason for rejecting NDT is the high T3 peak for a few hours after ingestion of the pill. (5) However, this argument also applies to combination therapy with Levothyroxine and generic Cytomel which has recently become acceptable for mainstream endocrinologists. In 2012, Dr Wiersinga writes about combination T4 and T3 therapy:
It is suggested to start combination therapy in an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. (5-6)
This argument seems rather vacuous, since many patients do well with NDT which contains a T4:T3 ratio of 4:1. In addition, many patients do well on synthetic combination T3 and T4 with the 5:1 ratio as described above by Dr. Bente Appelhof in 2005. This is very similar and essentially the same ratio as found in NDT, which has a 4:1 ratio for T4/T3. If one objects to the T3 in NDT, then one must object equally to T3 in synthetic combinations used by conventional endocrinologists. The reality is that many patients do well on both. (16)
Back to the Patient
Susan was switched to NDT, Natural Desiccated Thyroid, starting with half grain daily and gradually increasing dosage by half grain weekly increments until reaching maintenance dose of 3 grains a day. Susan’s labs at 3 grains showed a suppressed TSH of 0.25, and both the serum T3 and T4 were in normal range. The Serum T3 was 320, and serum T4 was 1.1. More importantly, Susan was now feeling back to her normal self with resolution of hypothyroid symptoms, and no adverse effects of thyroid excess.
Conclusion: Of the 7%-10% of the population suffering from hypothyroidism, most will do well on T4 only thyroid medication such as Levothyroxine with the local endocrinologist. However, a subset (10-20%) of these patients will continue to suffer from low thyroid symptoms, and will do much better on a combination of T3 and T4, either synthetic T3 and T4 at their local endocrinologist, or NDT, natural desiccated thyroid used by integrative medical practitioners. The 5:1 ratio of T4 to T3 seems to be preferred. However, a smaller subset of patients will prefer the 12:1 ratio which can be obtained by adding T4 to NDT, or a synthetic combination of T4 and T3 in the proper ratio.
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Jeffrey Dach MD
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Davie, Florida 33314
Articles with Related Interest
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2) Abdalla, Sherine M., and Antonio C. Bianco. “Defending plasma T3 is a biological priority.” Clinical endocrinology 81.5 (2014): 633-641.
3) Escobar-Morreale, Hector F., et al. “Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats.” The Journal of clinical investigation 96.6 (1995): 2828-2838.
4) Escobar-Morreale, Héctor F., et al. “Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.” Endocrinology 137.6 (1996): 2490-2502.
5) Surks, Martin I., Alan R. Schadlow, and Jack H. Oppenheimer. “A new radioimmunoassay for plasma L-triiodothyronine: measurements in thyroid disease and in patients maintained on hormonal replacement.” The Journal of clinical investigation 51.12 (1972): 3104-3113.
6) Wiersinga, Wilmar M., et al. “2012 ETA guidelines: the use of L-T4+ L-T3 in the treatment of hypothyroidism.” European thyroid journal 1.2 (2012): 55-71.
7) Panicker, Vijay, et al. “Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients.” The Journal of Clinical Endocrinology & Metabolism 94.5 (2009): 1623-1629.
8) Hoang, Thanh D., et al. “Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study.” The Journal of Clinical Endocrinology & Metabolism 98.5 (2013): 1982-1990.
9) Biondi, Bernadette, and Leonard Wartofsky. “Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism?.” The Journal of Clinical Endocrinology & Metabolism 97.7 (2012): 2256-2271.
10) Snyder, Scott. “Bioidentical thyroid replacement therapy in practice: Delivering a physiologic T4: T3 ratio for improved patient outcomes with the Listecki-Snyder protocol.” Int J Pharm Compd 16 (2012): 376-380.
11) Escobar-Morreale, Héctor F., José I. Botella-Carretero, and Gabriella Morreale de Escobar. “Treatment of hypothyroidism with levothyroxine or a combination of levothyroxine plus L-triiodothyronine.” Best Practice & Research Clinical Endocrinology & Metabolism 29.1 (2015): 57-75.
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24) Montero-Pedrazuela, Ana, et al. “Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior.” Molecular psychiatry 11.4 (2006): 361.
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26) Beard, John L., et al. “Plasma thyroid hormone kinetics are altered in iron-deficient rats.” The Journal of nutrition 128.8 (1998): 1401-1408.
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31) Peterson, S. J., et al. “An Online Survey of Hypothyroid Patients Demonstrates Prominent Dissatisfaction.” Thyroid: official journal of the American Thyroid Association (2018).
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42) Carlé, Allan, et al. “Hypothyroid patients encoding combined MCT10 and DIO2 gene polymorphisms may prefer L-T3+ L-T4 combination treatment–data using a blind, randomized, clinical study.” European Thyroid Journal 6.3 (2017): 143-151.
43) Jo, Sungro, et al. “Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain.” The Journal of clinical investigation 129.1 (2019): 230-245.
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