Which Thyroid is Best, Natural, Synthetic or Combination?

Susan is a 42 year old Professor of Literature at the local college (left image).  4 years ago, she had thyroid ablation with radioactive iodine for her Graves’ Disease.  Susan now requires lifelong thyroid replacement because the radioactive iodine treatment rendered her severely hypothyroid.  After seeing four different endocrinologists who prescribed trying 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 is crying as she tells her story of frustration.  Left image Professor with Glasses courtesy of Psychology Today.

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 De-iodinase Enzyme inside the cells of the peripheral tissues.  The assumption made by the endocrinologist when using T4 only medication such as Synthroid or Levothyroxine is this: The T4 medication is converted to T3 by the peripheral tissues at the proper rate to produce normal thyroid levels.  However, Dr Daminano Gullo from Italy reported in 2011 this is not the case for about 20% of patients after thyroid ablation (athyreotic patients). (21)(3)

“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)

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”.(21)  A number of animal studies have been done to to answer this question of why peripheral conversion of T4 to T3 is reduced.

T4 – Monotherapy Explained

The key to understanding the failings of T4-monotherapy lies with the Deiodinase Enzyme (D2) 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 Bianco says this intracellular Deiodinase Enzyme is the master controller for thyroid levels and creates a new paradigm in our understanding of thyroid function :(38)

“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)

According to an animal study by Dr De Castro from 2015, the D2 (Deiodinase enzyme) in the pituitary acts differently from the D2 in the peripheral tissues. (39)   In the peripheral tissues, D2 is inactivated by T4.  This is a safety mechanism to protect the cells from hyperthyroidism in which we have very 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  the hypothalmus and pituitary is a different type of D2 which is relatively insensitive to inactivation 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. The cells are starved of T3 because of inactivation of the D2 enzyme which inhibits conversion of T4 to T3 in the peripheral tissues.  In his mouse animal model, Dr De Castro found that only constant infusion of both T4 and T3 normalized thyroid levels. Dr De Castro says:

‘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 D2 Deiodinase, which decreases conversion of T4 to T3, and decreases peripheral production of T3.  Similarly in the brain, where the elevated serum T4/T3 ratio results in hypothyroid brain bells.  However the exception to this rule is the Hypothalamus.   Hypothalamic Deiodinase-D2 is less susceptible to T4 induced inactivation, and is so effective in this tissue that T4-induced D2 inactivation is insignificant.  This causes a suppressed TSH.   In the periphery however, 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 production.(38-40)  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.

Combination Treatment with T3 andT4

Ten years ago in the past, endocrinologists were very dogmatic, and offered only T4 monotherapy.  This seems to be changing, as more and more endocrinologists are embracing combination T3 and T4 therapy.   Dr Wilmar Wiersinga writes in 2014 (1):

“Levothyroxine plus liothyronine 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)

Perhaps the research using thyroidectomized mice  from 1995 and 1996 by Dr Escobar has them convinced.  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. (3,4)  In addition, a number of human studies show that patients prefer combination therapy. (1)

Which Flavor Thyroid Pill ?

I explain to my patients that thyroid pills are like ice cream.  We have different flavors of vanilla, chocolate and strawberry, yet they are all ice cream.  Likewise, adverse effects of thyroid excess are similar for all three flavors.   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.  Left Image Chocolate Vanilla And Strawberry Ice cream.

Which flavor 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  of T4 to T3, so adding an appropriate dose of T4 to NDT will do the trick.  We have found a few patients after thyroid ablation who may prefer this combination.

Option 1) Combined T3 and T4 (Levothyroxine and Cytomel)

This option is discussed by Dr Colin Dayan in 2018 Thyroid Research. (37)  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.(37)  Dr Dayan in 2018 Thyroid Research says :

“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 [8], 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 [5, 6]….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, T4 combination 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 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.(36)  Perhaps Dr Milner is right, since this 4:1 (T4:T3) ratio is closer to the serum (T4:T3) ratios  reported by Dr. Jernej Grmek in the 2015 Slovenian Medical Journal, who 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 ratio and secreted T4:T3 (14:1) ratio can be explained by 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.

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 Hashimotos hypothyroidism.  About 47 patients were randomized to each treatment group, T4 monotherapy, 4:1 combination or 10:1 T4:T3 synthetic combination therapy.(16)  The 5:1 ratio was most preferred by the patients. See Data Chart Below:

Above Image Fig 2, courtesy of Appelhof 2005 (16) Number of patients preferring combination therapy compared to usual treatment. Note greater preference for the T4:T3 (5:1) ratio T4:T3 (52% RED bar on right) compared to T4:T3 (10:1) ( 41% GREEN Bar in Middle)  and T4 monotherapy (29% YELLOW bar on LEFT).  This Combination T4:T3(5:1) ratio is similar to the 4:1 ratio found in NDT  Natural Desiccated Thyroid(which was not used in this study)

Please note, this T4:T3 (5:1) ratio synthetic combination most closely approximates the 4:1 ratio found in NDT Natural Desiccated Thyroid.

Which Flavor Thyroid Pill is Best,  Synthetic Combination or NDT?

As of this writing, the only study to examine this question was published in 2018 by Dr. Anam Tariq from Johns Hopkins.(30)  This was a retrospective observational study of 100 patients in an endocrinology clinic in Pennsylvania over six years comparing T4 monotherapy to both synthetic T3, T4 combination therapy and NDT (natural Desiccated Thyroid) therapy.  Patients on T4 monotherapy for a year who continued to complained 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.“(30)  Maximum dose of T3 was 12.5 mcg.  Starting dose for NDT was 15mg (quarter grain) and the 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 or “flavor” of thyroid medication. Likewise the Free T3 and Free T4 levels were remarkably similar across all treatment modalities.  Adverse effects of combination therapy: “ 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)

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 cytomel which has recently become acceptable for mainstream endos.(5)  Dr Wiersinga writes about combination T4 and T3 therapy  in 2012:(6)

“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.(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. Appelhof in 2005.(16)  This is very similar and essentially the same ratio as found in Natural Desiccated Thyroid which is 4:1.  If one objects to the T3 in NDT, then one must also equally object to the T3 in synthetic combinations used by conventional endocrinologists.  The reality is that patients do well on both.

Back to the Patient

Susan was switched to Natural Desiccated Thyroid , starting with half grain daily and gradually increasing to 3 grains a day.  Susan’s labs at 3 grains showed a suppressed TSH of .25, and the both 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  her hypothyroid symptoms, and no adverse effects of thyroid excess.

Conclusion: Of the 5% of the population suffering from hypothyroidism, most will do well on T4 only thyroid medication such as Levothyroixine 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 holistic doctors.  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.

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Fl 33314
954 792-4663

References

1)  Wiersinga, Wilmar M. “Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism.” Nature Reviews Endocrinology 10.3 (2014): 164.
Impaired psychological well-being, depression or anxiety are observed in 5-10% of hypothyroid patients receiving levothyroxine, despite normal TSH levels. Such complaints might hypothetically be related to increased free T₄ and decreased free T₃ serum concentrations, which result in the abnormally low free T₄:free T₃ ratios observed in 30% of patients on levothyroxine. Evidence is mounting that levothyroxine monotherapy cannot assure a euthyroid state in all tissues simultaneously, and that normal serum TSH levels in patients receiving levothyroxine reflect pituitary euthyroidism alone. Levothyroxine plus liothyronine combination therapy is gaining in popularity; although the evidence suggests it is generally not superior to levothyroxine monotherapy, in some of the 14 published trials this combination was definitely preferred by patients and associated with improved metabolic profiles. Disappointing results with combination therapy could be related to use of inappropriate levothyroxine and liothyronine doses, resulting in abnormal serum free T₄:free T₃ ratios. Alternatively, its potential benefit might be confined to patients with specific genetic polymorphisms in thyroid hormone transporters and deiodinases that affect the intracellular levels of T₃ available for binding to T₃ receptors. Levothyroxine monotherapy remains the standard treatment for hypothyroidism. However, in selected patients, new guidelines suggest that experimental combination therapy might be considered.

2) Abdalla, Sherine M., and Antonio C. Bianco. “Defending plasma T3 is a biological priority.” Clinical endocrinology 81.5 (2014): 633-641.  Most T3 is produced outside the thyroid gland via deiodination of T4, with <20% being secreted directly from the thyroid

The molar ratio of T4 to T3 in the human thyroglobulin is 15:1, and some estimates put the thyroidal secretion as containing a molar ratio of 11:1, which is supportive of thyroidal deiodination of T4.

It is estimated that healthy adult subjects produce about 30 µg T3/day, of which about 5 µg are secreted directly from the thyroid and the rest is produced outside of the thyroid parenchyma via T4 deiodination.

T3 production via deiodination is an intracellular event.

current forms of liothyronine replacement, that is, tablets, do not ensure stable serum T3 levels throughout the day. Given the relatively short T3 half-life and the relatively fast absorption of liothyronine, patients receiving a tablet of liothyronine experience a transient increase in serum T3 that subsides during the next few hours.85 In fact, it has been reported that at least three tablets daily of liothyronine are necessary to avoid peaks of serum T3 that are above the normal range, which makes this approach impractical.

For example, oral administration of 3,5,3′-triiodothyronine sulphate (T3S) that banks on the lack of biological activity of T3S and the endogenous desulphating pathway that slowly produces T3 from T3S. In hypothyroid humans, T3S is absorbed following oral administration and results in steady state serum T3 levels for 48 h.87

Conclusion Disruption of key elements in the hypothalamus–pituitary–thyroid axis as well as the deiodinase system in animals suggests that maintaining a stable serum T3 within normal range is a biological priority. At the same time, an analysis of a large number of hypothyroid patients maintained on levothyroxine replacement therapy indicates that monotherapy restores serum TSH levels without normalizing serum T3 in a portion of patients. The clinical relevance of a relatively lower serum T3 is unknown. Many clinical trials comparing monotherapy vs combination therapy might not have been useful, given limitations to normalize serum T3 with a single tablet of liothyronine daily.

3) J Clin Invest. 1995 Dec;96(6):2828-38.
Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats.
Escobar-Morreale HF1, Obregón MJ, Escobar del Rey F, Morreale de Escobar G.
Author information Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas y Universidad Autónoma, Madrid, Spain.

We have studied whether, or not, tissue-specific regulatory mechanisms provide normal 3,5,3′-triiodothyronine (T3) concentrations simultaneously in all tissues of a hypothyroid animal receiving thyroxine (T4), an assumption implicit in the replacement therapy of hypothyroid patients with T4 alone. Thyroidectomized rats were infused with placebo or 1 of 10 T4 doses (0.2-8.0 micrograms per 100 grams of body weight per day). Placebo-infused intact rats served as controls. Plasma and 10 tissues were obtained after 12-13 d of infusion. Plasma thyrotropin and plasma and tissue T4 and T3 were determined by RIA. Iodothyronine-deiodinase activities were assayed using cerebral cortex, liver, and lung. No single dose of T4 was able to restore normal plasma thyrotropin, T4 and T3, as well as T4 and T3 in all tissues, or at least to restore T3 simultaneously in plasma and all tissues. Moreover, in most tissues, the dose of T4 needed to ensure normal T3 levels resulted in supraphysiological T4 concentrations. Notable exceptions were the cortex, brown adipose tissue, and cerebellum, which maintained T3 homeostasis over a wide range of plasma T4 and T3 levels. Deiodinase activities explained some, but not all, of the tissue-specific and dose related changes in tissue T3 concentrations. In conclusion, euthyroidism is not restored in plasma and all tissues of thyroidectomized rats on T4 alone. These results may well be pertinent to patients on T4 replacement therapy.

4) Endocrinology. 1996 Jun;137(6):2490-502.
Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.
Escobar-Morreale HF1, del Rey FE, Obregón MJ, de Escobar GM.
Author information1 Molecular Endocrinology Unit, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Spain. hescobar@mvax.fmed.uam.es

We have recently shown that it is not possible to restore euthyroidism completely in all tissues of thyroidectomized rats infused with T4 alone. The present study was undertaken to determine whether this is achieved when T3 is added to the continuous sc infusion of T4. Thyroidectomized rats were infused with placebo or T4 (0.80 and 0.90 microgram/100 g BW.day), alone or in combination with T3 (0.10, 0.15, or 0.20 microgram/100 g BW.day). Placebo-infused intact rats served as euthyroid controls. Plasma and 12 tissues were obtained after 12 days of infusion. Plasma TSH and plasma and tissue T4 and T3 were determined by RIA. Iodothyronine deiodinase activities were assayed using cerebral cortex, pituitary, brown adipose tissue, liver, and lung. Circulating and tissue T4 levels were normal in all the groups infused with thyroid hormones. On the contrary, T3 in plasma and most tissues and plasma TSH only reached normal levels when T3 was added to the T4 infusion. The combination of 0.9 microgram T4 and 0.15 microgram T3/100 g BW.day resulted in normal T4 and T3 concentrations in plasma and all tissues as well as normal circulating TSH and normal or near-normal 5′-deiodinase activities. Combined replacement therapy with T4 and T3 (in proportions similar to those secreted by the normal rat thyroid) completely restored euthyroidism in thyroidectomized rats at much lower doses of T4 than those needed to normalize T3 in most tissues when T4 alone was used. If pertinent to man, these results might well justify a change in the current therapy for hypothyroidism.

5) J Clin Invest. 1972 Dec;51(12):3104-13.
A new radioimmunoassay for plasma L-triiodothyronine: measurements in thyroid disease and in patients maintained on hormonal replacement.
Surks MI, Schadlow AR, Oppenheimer JH.
A new procedure for the radioimmunoassay of l-triiodothyronine (T(3)) in human plasma is described in which the iodothyronines are separated from the plasma proteins before incubation with a specific antiserum to T(3). The antibody bound and free T(3) are separated with dextran-coated charcoal. In this system, the mean recovery of T(3) added to plasma was 97.9% and both in vitro conversion of l-thyroxine (T(4)) to T(3) and cross-reaction between T(4) and the anti-T(3) antibody were undetectable (less than 0.1%). The assay procedure allowed the measurement of T(3) in up to 0.5 ml of plasma resulting in improved assay sensitivity (6 ng/100 ml). The mean plasma T(3) in normal subjects was 146+/-24 ng/100 ml (sd). Mean T(3) concentration was increased in hyperthyroidism (665+/-289 ng/100 ml) and decreased in hypothyroidism (44+/-26 ng/100 ml). In patients with severe hypothyroidism, plasma T(3) was between 7 and 30 ng/100 ml. Plasma T(3) concentration was relatively constant throughout the day in three euthyroid subjects. In contrast, in hypothyroid subjects on replacement therapy with T(3), a T(4): T(3) combination or desiccated thyroid plasma T(3) was markedly elevated for several hours after ingestion of the medication. Plasma T(3) was unchanged throughout the day in patients treated with T(4). Thus, insofar as plasma T(3) levels are concerned, replacement therapy with T(4) appears to mimic the euthyroid state more closely than other preparations.

6) Eur Thyroid J. 2012 Jul;1(2):55-71.2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism. Wiersinga WM1, Duntas L2, Fadeyev V3, Nygaard B4, Vanderpump MP5.

Data suggest symptoms of hypothyroidism persist in 5-10% of levothyroxine (L-T4)-treated hypothyroid patients with normal serum thyrotrophin (TSH). The use of L-T4 + liothyronine (L-T3) combination therapy in such patients is controversial. The ETA nominated a task force to review the topic and formulate guidelines in this area.
METHODS:Task force members developed a list of relevant topics. Recommendations on each topic are based on a systematic literature search, discussions within the task force, and comments from the European Thyroid Association (ETA) membership at large.
RESULTS:SUGGESTED EXPLANATIONS FOR PERSISTING SYMPTOMS INCLUDE: awareness of a chronic disease, presence of associated autoimmune diseases, thyroid autoimmunity per se, and inadequacy of L-T4 treatment to restore physiological thyroxine (T4) and triiodothyronine (T3) concentrations in serum and tissues. There is insufficient evidence that L-T4 + L-T3 combination therapy is better than L-T4 monotherapy, and it is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism. L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothyroid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously received support to deal with the chronic nature of their disease, and associated autoimmune diseases have been excluded. Treatment should only be instituted by accredited internists/endocrinologists, and discontinued if no improvement is experienced after 3 months. 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. Close monitoring is indicated, aiming not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Suggestions are made for further research.

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.” (2009).

Animal studies suggest that up to 80% of intracellular T(3) in the brain is derived from circulating T(4) by local deiodination. We hypothesized that in patients on T(4) common variants in the deiodinase genes might influence baseline psychological well-being and any improvement on combined T(4)/T(3) without necessarily affecting serum thyroid hormone levels.
METHODS: We analyzed common variants in the three deiodinase genes vs. baseline psychological morbidity and response to T(4)/T(3) in 552 subjects on T(4) from the Weston Area T(4) T(3) Study (WATTS). Primary outcome was improvement in psychological well-being assessed by the General Health Questionnaire 12 (GHQ-12).
RESULTS: The rarer CC genotype of the rs225014 polymorphism in the deiodinase 2 gene (DIO2) was present in 16% of the study population and was associated with worse baseline GHQ scores in patients on T(4) (CC vs. TT genotype: 14.1 vs. 12.8, P = 0.03). In addition, this genotype showed greater improvement on T(4)/T(3) therapy compared with T(4) only by 2.3 GHQ points at 3 months and 1.4 at 12 months (P = 0.03 for repeated measures ANOVA). This polymorphism had no impact on circulating thyroid hormone levels.
CONCLUSIONS: Our results require replication but suggest that commonly inherited variation in the DIO2 gene is associated both with impaired baseline psychological well-being on T(4) and enhanced response to combination T(4)/T(3) therapy, but did not affect serum thyroid hormone levels.

“subjects on a stable dose of T4 therapy 100 μg or more per day were recruited from 28 primary care practices in the Weston-superMare and Bristol areas of the United Kingdom and randomized to either combination T4/T3 therapy (original dose minus 50 μg of T4 and added 10 μg T3) or original dose of T4 alone.

8) J Clin Endocrinol Metab. 2013 May;98(5):1982-90. Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. Hoang TD1, Olsen CH, Mai VQ, Clyde PW, Shakir MK.1
Department of Endocrinology, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, Maryland 20889-5600, USA.

Patients previously treated with desiccated thyroid extract (DTE), when being switched to levothyroxine (L-T₄), occasionally did not feel as well despite adequate dosing based on serum TSH levels.
OBJECTIVE:  Our objective was to investigate the effectiveness of DTE compared with L-T₄ in hypothyroid patients.
DESIGN AND SETTING:  e conducted a randomized, double-blind, crossover study at a tertiary care center.
PATIENTS: Patients (n = 70, age 18-65 years) diagnosed with primary hypothyroidism on a stable dose of L-T₄ for 6 months were included in the study.
INTERVENTION: Patients were randomized to either DTE or L-T₄ for 16 weeks and then crossed over for the same duration.
OUTCOME MEASURES: Biochemical and neurocognitive tests at baseline and at the end of each treatment period were evaluated.
RESULTS: There were no differences in symptoms and neurocognitive measurements between the 2 therapies. Patients lost 3 lb on DTE treatment (172.9 ± 36.4 lb vs 175.7 ± 37.7 lb, P < .001). At the end of the study, 34 patients (48.6%) preferred DTE, 13 (18.6%) preferred L-T₄, and 23 (32.9%) had no preference. In the subgroup analyses, those patients who preferred DTE lost 4 lb during the DTE treatment, and their subjective symptoms were significantly better while taking DTE as measured by the general health questionnaire-12 and thyroid symptom questionnaire (P < .001 for both). Five variables were predictors of preference for DTE.
CONCLUSION: DTE therapy did not result in a significant improvement in quality of life; however, DTE caused modest weight loss and nearly half (48.6%) of the study patients expressed preference for DTE over L-T₄. DTE therapy may be relevant for some hypothyroid patients.

======================================================================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. Combination treatment with T4 and T3 in hypothyroidism Biondi Bernadette Leonard Wartofsky J Clinical Endo Metab 2012

We do not fully understand why some hypothyroid patients given replacement therapy with L-T4 appear to achieve a satisfactory functional level when biochemical euthyroidism is restored, whereas others continue to complain of persistent symptoms of thyroid hormone deficiency such as mood changes, decreased psychomo-tor performance, cognitive disturbances, weight gain, fatigue, lethargy, and depression. Physicians do not ex-
pect these symptoms to continue with adequate replace-ment L-T4 dosage reflected by normal TSH levels and normal thyroid hormones and become frustrated with the management of these patients and their ongoing complaints.

Experimental and clinical evidence suggests that a TSH level within the reference range is not a sufficiently optimal marker of adequate thyroid hormone replacement therapy in hypothyroid patients.

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.

Effective thyroid replacement therapy may be elusive to some patients, and compounding pharmacists have an opportunity to deliver more effective therapy. Goodman & Gilman’s The Pharmacological Basis of Therapeutics 12th edition states that the body usually secretes T4:T3 in an 11:1 ratio but cautions against pursuing combined thyroid replacement due to the short halflife of T3 that necessitates multiple daily dosing; no commercial availability and lack of benefit were shown in trials. Commercial combinations of T4/T3 such as Armour Thyroid and Nature-Throid have a 4.22:1 T4:T3 ratio. Applying the same concept as bioidentical hormone replacement therapy, compounding pharmacists can deliver an 11:1 ratio using a commercial T4 product and taking into account oral bioavailability of each entity. The short half-life of T3 can be remedied by taking the patient’s daily T3 dose and dividing it into two slow-release capsules to be dosed every 12 hours.

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.

At present, the drug of choice for the treatment of hypothyroidism is levothyroxine sodium, even though the thyroid gland secretes both thyroxine and 3′,3,5-triiodothyronine; the latter is the more active of the two at the cellular level because of its higher affinity for the nuclear thyroid hormone receptors. To date, combined levothyroxine plus liothyronine treatment for hypothyroidism has been evaluated in 15 clinical trials in humans. In two studies, combined therapy seemed to have beneficial effects on mood, quality of life, and psychometric performance of patients, compared with levothyroxine alone; in some of these studies, the patients preferred levothyroxine plus liothyronine combinations. This preference should be balanced against the possibility of adverse events resulting from the addition of liothyronine to levothyroxine. Until clear advantages of levothyroxine plus liothyronine are demonstrated, the administration of levothyroxine alone should remain the treatment of choice for replacement therapy of hypothyroidism.

12) Schmidt, Ulla, et al. “Peripheral markers of thyroid function: the effect of T4 monotherapy versus T4/T3 combination therapy in hypothyroid subjects in a randomized cross-over study.” Endocrine connections (2013): EC-12.

13) Benvenga, Salvatore. “When thyroid hormone replacement is ineffective?.” Current Opinion in Endocrinology, Diabetes and Obesity 20.5 (2013): 467-477.

14) Samuels, Mary H., et al. “The effects of levothyroxine replacement or suppressive therapy on health status, mood, and cognition.” The Journal of clinical endocrinology and metabolism 99.3 (2014): 843.

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15) Hennemann, G., et al. “Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: proof of principle.” Thyroid 14.4 (2004): 271-275.Thyroxine plus low-dose slow-release triiodothyronine replacement in hypothyroidism Hennemann G Thyroid 2004

16) Appelhof, Bente C., et al. “Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial.” The Journal of Clinical Endocrinology & Metabolism 90.5 (2005): 2666-2674. Combined therapy with levothyroxine and liothyronine in two ratios in primary hypothyroidism Appelhof J Clin Endo 2005

17) Escobar-Morreale, Hector F., et al. “Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine.” The Journal of Clinical Endocrinology & Metabolism 90.8 (2005): 4946-4954.

18) Escobar-Morreale, Héctor F., et al. “Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone.” Annals of internal medicine 142.6 (2005): 412-424.

19) 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.

20) Saravanan, Ponnusamy, et al. “Partial substitution of thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial.” The Journal of Clinical Endocrinology & Metabolism 90.2 (2005): 805-812.

21) Gullo, Damiano, et al. “Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients.” PLoS One 6.8 (2011): e22552.

22) J Clin Invest. 1973 May;52(5):1010-7.  Effects of replacement doses of sodium L-thyroxine on the peripheral metabolism of thyroxine and triiodothyronine in man. Braverman LE, Vagenakis A, Downs P, Foster AE, Sterling K, Ingbar SH.

Studies of the effect of L-thyroxine administration (0.3 mg daily for 7-9 wk) on the peripheral metabolism of (131)I-labeled triiodothyronine (T(3)) and (125)I-labeled thyroxine (T(4)) and on the concentration and binding of T(4) and T(3) in serum were carried out in 11 euthyroid female subjects. Administration of L-thyroxine led to consistent increases in serum T(3) concentration (137 vs. 197 ng/100 ml), T(3) distribution space (39.3 vs. 51.7 liters), T(3) clearance rate (22.9 vs. 30.6 liters/day) and absolute T(3) disposal rate (30 vs. 58 mug/day), but no change in apparent fractional turnover rate (60.3 vs. 60.6%/day). The proportion and absolute concentration of free T(3) also increased during L-thyroxine administration. Increases in serum total T(4) concentration (7.3 vs. 12.8 mug/100 ml) and in both the proportion and absolute concentration of free thyroxine also occurred. In five of the subjects, the kinetics of peripheral T(4) turnover were simultaneously determined and a consistent increase in fractional turnover rate (9.7 vs. 14.2%/day), clearance rate (0.84 vs. 1.37 liters/day), and absolute disposal rate (64.2 vs. 185.0 mug/day) occurred during L-thyroxine administration. Despite these increases in the serum concentration and daily disposal rate of both T(4) and T(3), the patients were not clinically thyrotoxic. However, basal metabolic rate (BMR) values were marginally elevated and, as in frank thyrotoxicosis, T(4)-binding capacities of thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA) reduced, suggesting that subclinical thyrotoxicosis was present. Thus, the often recommended replacement dose of 0.3 mg L-thyroxine daily may be greater than that required to achieve the euthyroid state. The studies have also provided additional evidence of the peripheral conversion of T(4) to T(3) in man and have permitted the calculation that approximately one-third of exogenously administered T(4) underwent deiodination to form T(3). To the extent that a similar fractional conversion occurs in the normal state, it can be calculated that a major fraction of the T(3) in serum derives from the peripheral deiodination of T(4) and that only a lesser fraction derives from direct secretion by the thyroid gland.

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23) Desouza, Lynette A., et al. “Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain.” Molecular and Cellular Neuroscience 29.3 (2005): 414-426.

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.

25) Burmeister, Lynn A., John Pachucki, and Donald L. St. Germain. “Thyroid hormones inhibit type 2 iodothyronine deiodinase in the rat cerebral cortex by both pre-and posttranslational mechanisms.” Endocrinology 138.12 (1997): 5231-5237.

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.

27) Martínez-Iglesias, Olaia, et al. “Hypothyroidism enhances tumor invasiveness and metastasis development.” PloS one 4.7 (2009): e6428.

2017

28) Curr Opin Endocrinol Diabetes Obes. 2017 Oct;24(5):356-363. Persistent hypothyroid symptoms in a patient with a normal thyroid stimulating hormone level. Jonklaas J1. Division of Endocrinology, Georgetown University, Washington, District of Columbia, USA.

A subset of patients being treated for hypothyroidism do not feel well while taking levothyroxine (LT4) replacement therapy, despite having a normal serum thyroid stimulating hormone level. Pursuing a relative triiodothyronine deficiency as a potential explanation for patient dissatisfaction, has led to trials of combination therapy with liothyronine (LT3), with largely negative outcomes. This review attempts to reconcile these diverse findings, consider potential explanations, and identify areas for future research.
RECENT FINDINGS: Patients being treated with LT4 often have lower triiodothyronine levels than patients with endogenous thyroid function. Linking patient dissatisfaction with low triiodothyronine levels has fueled multiple combination therapy trials that have generally not shown improvement in patient quality of life, mood, or cognitive performance. Some trials, however, suggest patient preference for combination therapy. There continues, moreover, to be anecdotal evidence that patients have fewer unresolved symptoms while taking combination therapy.
SUMMARY: The 14 trials completed to date have suffered from employing doses of LT3 that do not result in steady triiodothyronine levels, and having insufficient power to analyze results based on baseline dissatisfaction with therapy and patient genotype. Future trials that are able to incorporate such features may provide insight into what thyroid hormone preparations will most improve patient satisfaction with therapy.

secondary analysis of the largest combination therapy trial suggested that patients with a particular genetic variation, the Thr92Ala variant of the type 2 deiodinase responded differently to combination therapy (43). Not only did these individuals have worse scores on the general health questionnaire while taking LT4, but they also had a better response to combination therapy in which 50 mcg LT4 was replaced by 10 mcg LT3.

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2018

29) Hennessey, James V., and Ramon Espaillat. “Current evidence for the treatment of hypothyroidism with levothyroxine/levotriiodothyronine combination therapy versus levothyroxine monotherapy.” International journal of clinical practice 72.2 (2018): e13062.

Hypothyroidism is relatively common, occurring in approximately 5% of the general US population aged ≥12 years. Levothyroxine (LT4) monotherapy is the standard of care. Approximately, 5%‐10% of patients who normalise thyroid‐stimulating hormone levels with LT4 monotherapy may have persistent symptoms that patients and clinicians may attribute to hypothyroidism. A long‐standing debate in the literature is whether addition of levotriiodothyronine (LT3) to LT4 will ameliorate lingering symptoms. Here, we explore the evidence for and against LT4/LT3 combination therapy as the optimal approach to treat euthyroid patients with persistent complaints.

Methods:  Recent literature indexed on PubMed was searched in March 2017 using the terms “hypothyroid” or “hypothyroidism” and “triiodothyronine combination” or “T3 combination.” Relevant non‐review articles published in English during the past 10 years were included and supplemented with articles already known to the authors.
Findings: Current clinical evidence is not sufficiently strong to support LT4/LT3 combination therapy in patients with hypothyroidism. Polymorphisms in deiodinase genes that encode the enzymes that convert T4 to T3 in the periphery may provide potential mechanisms underlying unsatisfactory treatment results with LT4 monotherapy. However, results of studies on the effect of LT4/LT3 therapy on clinical symptoms and thyroid‐responsive genes have thus far not been conclusive.
Conclusions:  Persistent symptoms in patients who are biochemically euthyroid with LT4 monotherapy may be caused by several other conditions unrelated to thyroid function, and their cause should be aggressively investigated by the clinician.

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30) Tariq, Anam, et al. “Effects of Long-Term Combination LT4 and LT3 Therapy for Improving Hypothyroidism and Overall Quality of Life.” Southern medical journal 111.6 (2018): 363.

Hypothyroidism results in decreased mood and neurocognition, weight gain, fatigue, and many other undesirable symptoms. The American Association of Clinical Endocrinologists, the American Thyroid Association (ATA), and The Endocrine Society recommend levothyroxine (LT4) monotherapy as the treatment for hypothyroidism; however, after years of monotherapy, some patients continue to experience impaired quality of life. Combination LT4 and synthetic liothyronine (LT3) therapy or the use of desiccated thyroid extract (DTE), has not been suggested for this indication based on short-duration studies with no significant benefits. Our first observational study examined the role of combination therapy for 6 years in improving quality of life in a subset of a hypothyroid population without adverse effects and cardiac mortality.
An observational retrospective study examining patients prescribed thyroid replacements with serum triiodothyronine (FT3), LT4 with LT3 (synthetic therapy) or DTE (natural therapy), compared with LT4 alone in the United States from 2010 to 2016. Thyroid-stimulating hormone (TSH), serum thyroxine (FT4), and FT3 levels were documented for each patient in addition to any admissions of myxedema coma, thyrotoxicosis, or cardiovascular complications, such as arrhythmias, atrial fibrillation, and mortality. At the conclusion of the study, a cross-sectional interview assessed quality of life for each combination therapy through the Medical Outcomes Study Short Form-20 questionnaire.
Compared with patients taking only LT4, 89.47% using synthetic therapy had therapeutic TSH (P < 0.05). Similarly, 96.49% using natural therapy had therapeutic TSH (P < 0.05). Less than 5% of patients had supratherapeutic FT3. None of the patients who had abnormally low TSH or elevated FT3 or FT4 levels had hospitalizations for arrhythmias or thyrotoxicosis. On the Medical Outcomes Study Short Form-20 questionnaire, >92% answered feeling “excellent, very good, or good” when questioned about their health while undergoing thyroid replacement compared with levothyroxine alone.

This is the only retrospective study reported to use long-term (mean 27 months) thyroid replacements with combination therapy and to compare between the two forms of therapy: synthetic and natural. For patients undergoing either therapy, we did not identify additional risks of atrial fibrillation, cardiovascular disease, or mortality in patients of all ages with hypothyroidism.

31) Peterson, S. J., et al. “An Online Survey of Hypothyroid Patients Demonstrates Prominent Dissatisfaction.” Thyroid: official journal of the American Thyroid Association (2018).

BACKGROUND: Approximately 15% more patients taking levothyroxine (LT4) report impaired quality of life compared to controls. This could be explained by additional diagnoses independently affecting quality of life and complicating assignment of causation. This study sought to investigate the underpinnings of reduced quality of life in hypothyroid patients and to provide data for discussion at a symposium addressing hypothyroidism.
METHODS: An online survey for hypothyroid patients was posted on the American Thyroid Association Web site and forwarded to multiple groups. Respondents were asked to rank satisfaction with their treatment for hypothyroidism and their treating physician. They also ranked their perception regarding physician knowledge about hypothyroidism treatments, need for new treatments, and life impact of hypothyroidism on a scale of 1-10. Respondents reported the therapy they were taking, categorized as LT4, LT4 and liothyronine (LT4 + LT3), or desiccated thyroid extract (DTE). They also reported sex, age, cause of hypothyroidism, duration of treatment, additional diagnoses, and prevalence of symptoms.
RESULTS: A total of 12,146 individuals completed the survey. The overall degree of satisfaction was 5 (interquartile range [IQR] = 3-8). Among respondents without self-reported depression, stressors, or medical conditions (n = 3670), individuals taking DTE reported a higher median treatment satisfaction of 7 (IQR = 5-9) compared to other treatments. At the same time, the LT4 treatment group exhibited the lowest satisfaction of 5 (IQR = 3-7), and for the LT4 + LT3 treatment group, satisfaction was 6 (IQR = 3-8). Respondents taking DTE were also less likely to report problems with weight management, fatigue/energy levels, mood, and memory compared to those taking LT4 or LT4 + LT3.
CONCLUSIONS: A subset of patients with hypothyroidism are not satisfied with their current therapy or their physicians. Higher satisfaction with both treatment and physicians is reported by those patients on DTE. While the study design does not provide a mechanistic explanation for this observation, future studies should investigate whether preference for DTE is related to triiodothyronine levels or other unidentified causes.

32) Wiersinga, W. M. “THERAPY OF ENDOCRINE DISEASE: T4+ T3 combination therapy: is there a true effect?.” European journal of endocrinology 177.6 (2017): R287.

About 5%-10% of hypothyroid patients on T4 replacement therapy have persistent symptoms, despite normal TSH levels. It was hoped that T4 + T3 combination therapy might provide better outcomes, but that was not observed according to a meta-analysis of 11 randomized clinical trials comparing T4 monotherapy with T4 + T3 combination therapy. However, the issue is still subject of much research because normal thyroid function tests in serum may not necessarily indicate an euthyroid state in all peripheral tissues. This review evaluates recent developments in the field of T4 + T3 combination therapy. T4 monotherapy is associated with higher serum FT4 levels than in healthy subjects, and subnormal serum FT3 and FT3/FT4 ratios are observed in about 15% and 30% respectively. T4 + T3 combination therapy may mimic more closely thyroid function tests of healthy subjects, but it has not been demonstrated that relatively low serum FT3 or FT3/FT4 ratios are linked to persistent symptoms. One study reports polymorphism Thr92Ala in DIO2 is related to lower serum FT3 levels after thyroidectomy, and that the D2-Ala mutant reduces T4 to T3 conversion in cell cultures. Peripheral tissue function tests such as serum cholesterol reflect thyroid hormone action in target tissues. Using such biochemical markers, patients who had a normal serum TSH during postoperative T4 monotherapy, were mildly hypothyroid, whereas those with a TSH 0.03-≤0.3 mU/L were closest to euthyroidism. Peripheral tissue function tests suggest euthyroidism more often in patients randomized to T4 + T3 rather than that to T4. Preference for T4 + T3 combination over T4 monotherapy was dose-dependently related to the presence of two polymorphisms in MCT10 and DIO2 in one small study. It is not known if persistent symptoms during T4 monotherapy disappear by switching to T4 + T3 combination therapy. The number of patients on T4 + T3 therapy has multiplied in the last decade, likely induced by indiscriminate statements on the internet. Patients are sometimes not just asking but rather demanding this treatment modality. It creates tensions between patients and physicians. Only continued research will answer the question whether or not T4 + T3 combination therapy has true benefits in some patients.

33) Hannoush, Zeina C., and Roy E. Weiss. “Thyroid hormone replacement in patients following thyroidectomy for thyroid cancer.” Rambam Maimonides medical journal 7.1 (2016).
Thyroid hormone replacement therapy in athyreotic patients with a history of thyroid cancer is a straightforward clinical problem that needs to take into account the form of TH used, the timing of the blood tests to assess TSH concentrations, and other factors that affect the absorption and/or biologic availability of this important hormone. While the majority of patients have no difficulty being maintained with THR, there will predictably be special patients who find themselves in the doctor’s office, or make contact by phone or email, with the concern that they are not being properly replaced with TH. This may not correlate with the serum TSH level and may reflect yet unidentified molecular mechanisms of thyroid hormone action that do not tell the entire story of what it takes to replace the body’s production of thyroid hormone.

34) Jonklaas, Jacqueline, et al. “Single Dose T3 Administration: Kinetics and Effects on Biochemical and Physiologic Parameters.” Therapeutic drug monitoring 37.1 (2015): 110.

35) Ling, C., et al. “Does TSH Reliably Detect Hypothyroid Patients?.” Annals of thyroid research 4.1 (2018): 122.
Objectives To evaluate the reliability of normal Thyroid Stimulating Hormone (TSH) as a thyroid function test and assess the effect of Adrenocorticotropic Hormone (ACTH) on serum TSH concentration.
Patients presenting to the National Institutes of Health Department of Endocrinology outpatient clinic with symptoms consistent with hypothyroidism were identified. Thyroid hormone concentrations were measured by liquid chromatography/tandem mass spectrometry and immunoassay. Patients with normal TSH concentrations were assessed for both clinical and biochemical hypothyroidism.
We evaluated the effect of ACTH stimulation (performed on patients for assessment of adrenal function) on TSH concentration.
Patients with symptoms consistent with hypothyroidism but with normal TSH values in the range of 1–4 IU/mL and normal free T4 (FT4) values by immunoassay measurements were confirmed to be biochemically hypothyroid following measurements of thyroid hormones by mass spectrometry. We present case studies of two patients, a 76-year-old male and a 58-year-old female. Improvement in the male patient’s hypothyroid symptoms, including afternoon fatigue, constipation, alopecia, dry skin and high cholesterol, was documented after initiating thyroid hormone replacement.

ACTH stimulation resulted in an average decrease of 17% in TSH between time 0 and 60 minutes post stimulation.

Although measurement of TSH is a convenient screen for thyroid function, it is influenced by many factors which may affect its overall reliability. We believe thyroid function should be assessed by more than a single test. We recommend measurement of thyroid hormone concentrations by mass spectrometry if the patient’s clinical presentation is discordant with their TSH levels.

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36) Milner, Martin. “Hypothyroidism: Optimizing medication with slow-release compounded thyroid replacement.” International journal of pharmaceutical compounding 9.4 (2005): 268.

From the Townsend Letter February/March 2007
Hypothyroidism:Optimizing Medication with Slow-Release Compounded Thyroid Replacement by Martin Milner, ND National College of Naturopathic Medicine

2018 Combination T4 and T3 Cytomel

37) Dayan, Colin, and Vijay Panicker. “Management of hypothyroidism with combination thyroxine (T4) and triiodothyronine (T3) hormone replacement in clinical practice: a review of suggested guidance.” Thyroid research 11.1 (2018): 1.

hence a T4:T3 secretion ratio of approximately 14:1 appears average in humans
There are also several studies showing that on LT4 monotherapy serum T3 levels are significantly lower for the same TSH in euthyroid patients [11–16], although the clinical significance of this is unknown. Another study showed it was not possible to normalise serum TSH, T3 and T4 levels or tissue T3 levels in laboratory animals giving them LT4 monotherapy [17].

Because of this there have now been at least 13 randomized controlled trials (RCT) comparing efficacy of combination LT4/LT3 therapy versus LT4 monotherapy for thyroid hormone replacement [18–30].

there is no significant benefit of combination LT4/LT3 therapy compared to LT4 monotherapy in terms of mood, health-related quality of life or cognitive function.

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 trialled to determine if it is beneficial for the individual patient [5, 6].

despite recommendations and guidelines from various specialist bodies, use of combination T4/T3 therapy appears significant in most developed countries.

Practice point: Alternatives to LT4 monotherapy for thyroid hormone replacement are being used in a small percentage of hypothyroid patients and it appears frequently without specialist oversight and appropriate monitoring. If specialists are willing to discuss the available evidence, possible benefits and adverse effects of such therapy with patients, it is likely to make this practice safer.

Practice point: starting dose in a patient on adequate LT4 monotherapy will always require removal of part of the LT4 dose and replacement with LT3. In practice the dose of LT3 will usually be a dose of 5 – 20 mcg a day in a split dose, by necessity often determined by the availability of low dose formulations of LT3.

it is reasonable to measure TSH, free T4 and free T3 2–4 h post dose as this is the expected peak of serum T3 post dose.

None of the 13 RCTs comparing combination therapy to T4 monotherapy showed any increase in adverse events in the combination group, however the follow up was generally short ranging from 5 to 52 weeks.

Practice point: whilst all major endocrine and thyroid societies advise against the use of DTE for hypothyroidism, it is clear that its use remains significant.

Although there is convincing evidence that there is no benefit of combination T4/T3 therapy over T4 monotherapy for management of hypothyroidism at a population level, there remains a population of patients who do not feel well on T4 monotherapy. There are several possible reasons for this, one of which is an inability to use T4 effectively in a group of patients who may respond better to combination T4/T3 therapy.

Deiodinase Enzyme D2

38) Bianco, Antonio C. “Cracking the code for thyroid hormone signaling.” Transactions of the American Clinical and Climatological Association 124 (2013): 26.

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.

39) De Castro, Joao Pedro Werneck, et al. “Differences in hypothalamic type 2 deiodinase
ubiquitination explain localized sensitivity to thyroxine.” The Journal of clinical investigation 125.2 (2015): 769.

40) Bianco, Antonio C., and Brian W. Kim. “Deiodinases: implications of the local control of thyroid hormone action.” Journal of Clinical Investigation 116.10 (2006): 2571.

41) Grmek, Jernej, et al. “Usefulness of free thyroxine to free triiodothyronine ratio for diagnostics of various types of hyperthyroidism.” Slovenian Medical Journal 84.5 (2015). Usefulness of free thyroxine to free triiodothyronine ratio for diagnostics of various types of hyperthyroidism Grmek Jernej Slovenian Medical Journal 2015.

225 pts 44 y/o Free T4 to Free T3 ratio = 2.86 ± 0.52

The mean fT4/fT3 ratio in HS (2.86 ± 0.52)

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