Each modality of thyroid hormone therapy, including standard L-T4 therapy, has the power to artificially shift the TSH-T4-T3 relationship. For example, one cannot simply increase L-T4 dose and assume it will convert into more T3, especially if T4 is already fairly high in range. Deiodinase 2 activity is reduced by higher levels of T4 in patients, as we discuss in the section on Reverse T3 and Deiodinase Type 3.
The T3 hormone, whether taken as synthetic L-T3 or natural desiccated thyroid (DTE) also has its unique effects on hormone levels in blood.
In a study of the properties of a fast-acting L-T3 therapy, Jonklaas et al (2015) confirmed what has been known since the 1950s: upon oral ingestion, there is a sharp rise and fall in T3 levels that occurs in the first 5-7 hours. After the peak serum T3 level, which occurs on average 2.5 hours post-dose for women and 3 hours post-dose for men, T3 levels may sharply drop off, especially if the dose is mostly “supraphysiological,” as it was in Jonklaas’s study, which tested the effects of T3 by significantly overdosing euthyroid subjects on 50mcg of T3 hormone. The sharp drop in T3 level occurs far sooner than expected and may be due to a physiological safety mechanism not yet understood, such increased binding of free hormone or the conversion of excess T3 into T2.
Normally, TSH takes weeks to adjust to T4 hormone dose changes. In contrast, as shown in a 2015 pharmacokinetic study by Jonklaas et al, oral ingestion of T3 hormone has an exaggerated suppressive effect on TSH within the first hour, even before T3 reaches its peak level in bloodstream at 2.5-3 hours. This has also been known since the 1950s, when a low TSH was not feared as barrier to its use. 
This TSH-suppressive effect is partly because the short-acting hormone is absorbed in pulses via the GI tract, rather than gradually through thyroidal secretion and T4 hormone conversion. 
It may also partly be due to the ratio of free versus bound molecules of T3 that are released into the bloodstream from this synthetic formulation.
Most of all, it is likely due to the ability of T3 hormone in particular to suppress Thyrotropin Releasing Hormone (TRH), which is the hormone from the hypothalamus that triggers the pituitary gland to secrete TSH. As researchers have stated, “Regulation of TRH transcription by thyroid hormone is relatively rapid because the exogenous administration of thyroid hormone can suppress transcription of the TRH gene in the PVN [the hypothalamic paraventricular nucleus] within 5 hours.” 
As shown in Jonklaas et al’s study, after approximately 7 hours post-dose, T3 levels in serum gradually decrease closer to baseline (pre-dose) levels. TSH levels then remain suppressed for up to 3 days after a single 50mcg dose, which means that TSH levels do not reflect the average level of T3 in serum any longer. Research on Thyrotropin Releasing Hormone (TRH) has similarly shown this delayed restoration of TSH: “restoration of circulating levels of T3 to normal levels in hypothyroid rats without the administration of T4 does not normalize TRH gene expression in the PVN [the hypothalamic paraventricular nucleus].” 
Given the peaks shown in Jonklaas et al’s study, contemporary doctors are concerned that T3 levels will spike far above the reference range and harm the patient. However, the degree to which T3 levels rise above “normal” reference range depends on at least two factors: the patient’s pre-dose level of Free T3, and the size of the dose. To even out the peaks and troughs, patients often multi-dose throughout the day, splitting their total daily dose into smaller doses every 5-12 hours.
Although some researchers have lamented that L-T3 dosing is not feasible for patients because it is inconvenient to dose too often, this is a factor that depends on patient education and their desire to manage their hypothyroidism. Diabetes patients are educated and entrusted to manage their own monitoring and medication. A patient who actively seeks L-T3 therapy is more likely to give it their best effort.
Some doctors, out of their fear of T3 peaks, advise patients to take a dose of L-T3 a few hours before a lab test in order to measure the peak dose.  However, this approach emphasizes the short-term peak more than the long-term troughs, and the fear of overdose is exaggerated by our unfounded fear of Low TSH (see our section on TSH suppression). Despite decades of use, we have no evidence that shows these transient peaks are harmful in the long term. The patient, who if rational, does not wish to be overdosed, can be trusted to keep records of their metabolic signs and symptoms at the dose and at the peak time in order to discover whether adverse heart rate or body temperature responses occur at the peak.
Even in Jonklaas’s study, there was a significant tall T3 peak because “euthyroid” test subjects were given a significant dose of 50mcg of extra T3 that they certainly did not need. Yet the study was did not reveal a significantly raised metabolic rate to confirm true cardiovascular hyperthyroidism. This is possibly due to biological compensatory mechanisms like hormone binding. 
There is a fear of cardiovascular problems with the use of T3 hormone in therapy because of its power to affect heart rate. Yet research even on fragile cardiovascular patients had not discovered any safety concerns as of 2016:
“T3 treatment does not produce untoward effects when administered in either physiological or short-term pharmacologic doses to patients with concomitant cardiac disease. There have been no reported episodes of supraventricular arrhythmias, increases in heart rate, or worsening of cardiac ischemia in any of the reported series to date.” [164 (p. 87)]
A 2018 study of combination therapy over the long term also revealed no adverse cardiovascular symptoms—even when the thyroid hormones verged into their lab-defined hyperthyroid ranges for 95% of the population. 
Next page: Rationale: L-T3-T4 Combination therapies
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