This is the user sandbox of Njmcdaniel. A user sandbox is a subpage of the user's user page. It serves as a testing spot and page development space for the user and is not an encyclopedia article. For a sandbox of your own, create it here.
If you are writing an article, and are ready to request its creation:
|Jmol-3D images||Image 1|
|Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)|
|(what is: / ?)|
Reverse triiodothyronine (3,3’,5’-triiodothyronine, reverse T3, or rT3) is an isomer of triiodothyronine (3,5,3’ triiodothyronine, T3). Reverse T3 is the third-most common iodothyronine the thyroid gland releases into the bloodstream, of which 0.9% is rT3; tetraiodothyronine (levothyroxine, T4) constitutes 90% and T3 is 9%. However, 95% of rT3 in human blood is made elsewhere in the body, as enzymes remove a particular iodine atom from T4.
The production of hormone by the thyroid gland is controlled by the hypothalamus and pituitary gland. The physiological activity of thyroid hormone is regulated by a system of enzymes that activate, inactivate or simply discard the prohormone T4 and in turn functionally modify T3 and rT3. These enzymes operate under complex direction of systems including neurotransmitters, hormones, markers of metabolism and immunological signals.
Once believed to be the only significant thyroid hormone, T4 is now known to act primarily as a precursor, having also some non-genomic effects. Formerly considered to have no clinical relevance, T3 is recognized as the active form of thyroid hormone. Until recently considered without function, reverse T3 has been shown to have multiple non-genomic effects and to act as a competitive inhibitor of T3 and its stimulatory effects. There is no doubt that at least one “anti-thyroid hormone” exists, though the exact relations of rT3 to T1AM remain to be clarified.
- 1 Function
- 2 Biosynthesis, clearance, and regulation
- 3 Mechanisms of action
- 4 Clinical significance
- 5 History
- 6 References
Reverse T3 primarily inhibits thyroid signaling. It is commonly thought to have no biological activity, as early studies showed none of the stimulatory effects expected of thyroid hormone (TH). This belief became widely accepted despite contemporaneous work indicating rT3 could inhibit the effects of T4. Even after T4 was discovered to be a prohormone for the potent T3, the conversion of T4 to rT3 was considered simply a deactivation of excessive T4.
This appraisal has been revised. Firstly, surplus T4 is amply cleared by alternative pathways. More importantly, multiple functions for reverse T3 have been revealed – inhibitory functions. Notably, there are several ways (genomic and non-genomic) in which rT3 impedes the actions of thyroid hormone. These can be physiologically significant, depending on the relative proportion of T3 to rT3.
The conversion of T4 to either T3 or rT3 is regulated. The balance of T3 and rT3 is crucial: A shift of the predominant hormone from rT3 to T3 triggers the transition from cellular proliferation to differentiation during embryogenesis and amphibian metamorphosis. Similar effects are apparent in wound healing and tissue repair and in some cancers. Reverse T3 is importantly involved in reducing the metabolic rate during the stress response, which makes the body energy-efficient and prolongs survival in times of crisis.
However, this physiological adaptation, when protracted, can lead to a maladaptive condition called Euthyroid Sick Syndrome (or Non-Thyroidal Illness Syndrome) that is associated with significantly higher morbidity. Some physicians believe Chronic Fatigue Syndrome is a milder form of this illness. By extension, such an imbalance of T3 with rT3 could contribute to diverse other conditions whose apparent relation to thyroid dysfunction was thought to have been ruled-out by normal blood TSH and T4 levels: depression; attention deficit and other cognitive disorders; infertility and more.
The possibility that reverse T3 might have inhibitory effects was proposed in 1974. A review of accumulated research (following) supports this idea; data from many studies show that rT3 is a significant element of thyroid hormone signaling, both genomic and nongenomic. The prohormone T4 can be processed into either T3 or rT3, each an active hormone with opposing effects (a dichotomy analogous to the conversion of testosterone into either estradiol or dihydrotestosterone). The relative balance of T3/ rT3 indicates the physiological effects of thyroid hormone.
Biosynthesis, clearance, and regulation
Intra-thyroidal production, storage and release
About 5% of rT3 in the human body is made in the thyroid gland; the rest is subsequently derived from T4, the gland’s major hormone product. Thyroid gland hormone production is controlled by the hypothalamic-pituitary axis via the pituitary hormone TSH. Thyroid follicular cells increase every aspect of their many functions upon stimulation by TSH, ultimately directed to the manufacture and release of thyroid hormone.
The first step in thyroid hormone production is assembling the scaffolding upon which hormones will be constructed and stored. This is thyroglobulin (formerly called “colloid”), a long protein rich in the amino acid L-tyrosine; it is synthesized in the follicular cells and passes out (“exocytosis”) into a space between cells, the follicle. In this extracellular space, the enzyme thyroid peroxidase (TPO) – also made by the follicular cell – attaches iodine atoms to the aromatic rings virtually bristling from L-tyrosine molecules within the thyroglobulin.
Usually, two iodine atoms are attached to each ring, one apiece to the 3 and 5 carbon atoms. Therefore, the product is called diiodotyrosine (literally, “two-iodine tyrosine,” DIT). Remaining incorporated into thyroglobulin by peptide bonds, DIT is the major precursor of thyroid hormone. Occasionally, only a single iodine atom is attached to an L-tyrosine ring, producing monoiodotyrosine (MIT). MIT Also can be used to make thyroid hormones, the actions of which will be very different.
When thyroglobulin assumes its tertiary structure, appropriately-spaced iodinated tyrosyl rings – most of which are DIT – are brought into proximity. Two are joined (“conjugation”), again by the versatile TPO enzyme, to form one thyroid hormone molecule, still an intrinsic part of thyroglobulin. More than 90% of hormone in thyroglobulin comes from joining two of the abundant DITs; the product, with its four iodine atoms, is called T4 (3,5,3',5'-tetraiodothyronine, levothyroxine).
Less than 10% of thyroid hormone is made by splicing MIT and DIT, creating either of two isomers with only three iodine atoms: rT3 and T3. Reverse T3 has one iodine atom on the inner (tyrosyl) ring; T3 features the single iodine on the outer (phenolic or “prime”) ring. In conjugating MIT and DIT, molecular conformation forces preferentially direct MIT to the outer ring position. is about ten-times more abundant in thyroglobulin than is rT3.
Large amounts of thyroid hormones, a supply sufficient for 2-3 months, are thusly stored as integral parts of the long thyroglobulin molecule, within the capacious extracellular follicles (from Latin: “little bags”). Upon TSH signaling, follicular cells ingest thyroglobulin (“endocytosis”) as cytoplasmic vacuoles and lysosomal enzymes break thyroglobulin’s peptide bonds (“proteolysis”), freeing thyroid hormones into the cytosol. There, liberated hormones promptly encounter deiodinase (DI) enzymes and are altered before they exit the follicular cell – normally to increase T3. In humans, the proportions of thyroid hormones entering the bloodstream are 90% T4; 9% T3, 0.9% rT3 and approximately 0.1% T2, depending on the availability of iodine, the rate of secretion and other variables.
Thyroid hormones in the blood
In the bloodstream, these hormones strongly but reversibly bind to transport proteins. Binding serves multiple purposes: Free hormones are poorly water-soluble but joining to protein allows them to travel easily in the aqueous medium of blood. Protein-carriage also guards hormones against loss by renal clearance and liver breakdown. Finally, a large, inactive reserve of hormone is maintained, as bound hormone cannot enter cells. The equilibrium between bound and free (unattached) hormones leaves just a tiny amount free – in the picomolar range: 0.13% of rT3 is unbound, comparable to T3 (0.3% free) but contrasting with only 0.03% of T4 being free in circulation.
The relative proportions of total (bound and free) thyroid hormones in the bloodstream can be determined. Among carefully-vetted donors, healthy humans have about 56 times more total T4 (tT4) than total T3 (tT3). Though this study didn’t measure reverse T3, its tT4 and tT3 results validate the selection of healthy, normal patients by another group, who did: These investigators determined reference intervals for total rT3 as well as tT4 and tT3. We see tT3 is 7 to 10-times more abundant than rT3 in healthy human serum, using their data to compare tT3 and rT3 at the upper limits of normal and then again at the lower.
Free values are quite different: The amount of biologically-available free T4 is only about 3-times higher than free T3 in healthy serum when measured directly, due to their greatly differing binding affinities noted above. There is no accurate test for free rT3, as its lower normal values fall considerably below the sensitivity of radioimmunoassay (for comparison, so do women’s free estradiol and free testosterone). However, similar binding affinity values for T3 and rT3 noted above indicate the total values will satisfactorily reflect their proportionate free levels.
Whilst 100% of total (bound and free) serum T4 is produced by the thyroid gland, most rT3 and T3 are not, being derived from T4 by enzymatic alterations carried out in other tissues. Approximately 95% of circulating rT3 is made by selectively removing one iodine atom from the inner ring of the prohormone T4 (“5-deiodination”). Similarly, 80% of T3 in the blood comes from T4, when one iodine atom is removed from the outer ring (5’-deiodination). These transformations are performed within the cytoplasm of cells by an elegant system of enzymes and are purposefully directed. This process is now recognized as the primary means of regulating the biological activity of thyroid hormone.
Only free thyroid hormone can enter cells to exert its major effects. Because of membrane-solubility challenges, various transport proteins exist to facilitate this entry. Equipage with specific transporter subtypes is important to the particular activities of individual cell types, tissues and organs. Although genetically defective transporters can cause functional hypothyroidism with severe developmental consequences, this system may play no more than a minor part in adaptively regulating the biological effect of thyroid hormones. That role primarily belongs to thyroid hormone-altering enzymes within the cells.
Arriving just inside the cell membrane, T4 encounters the first of a variety of enzymes by which it can be modified. Some twenty percent of T4 is deactivated by conjugation or other “alternative pathway” (e.g. deamination, decarboxylation, ether-link cleavage) and thusly is cleared away. Evidently, the thyroid gland normally produces an ample surplus of T4. This system is also adaptive: Up to four-fold more T4 can be inactivated by conjugation as necessary.
The remaining unaltered T4 now becomes subject to the leading actors, a family of selenoprotein deiodinase enzymes (DI). There are three major isoforms of DI enzymes, each with different actions: Type-2 converts T4 to T3, making 50-70% of all T3 in the blood. Type-3 changes T4 into rT3. Type-1 is most complex – the first one discovered but the last to be understood; it can act on T4 to produce either T3 or rT3, depending on a variety of biological signals now being revealed by research. Many cell types studied contain DI enzymes, though the types and amounts vary greatly by organ, tissue and cell. Those cells able to convert T4 to T3 supply the blood with T3 for those which cannot.
Reverse T3 is broken down to T2 by 5’-deiodination, removal of an iodine atom from the outer, “prime” ring (Fig. 3). The same step converts T4 to T3. By these two results of the single reaction, types-1 and 2 deiodinase increase the metabolic rate (Fig. 3). People with a healthy metabolism demonstrate a higher ratio of T3 to rT3.
Conversely, 5-deiodination by DI types-1 and 3 removes iodine from the inner ring to deactivate T3 into T2 and convert T4 into rT3. In both ways, this reaction reduces the stimulatory effects of thyroid hormone. Starving, sick and otherwise significantly stressed people have a lower ratio of T3 to rT3. As these findings suggest, deiodinase activity is remarkably important and it is adaptively regulated.
Regulation of biosynthesis and degradation
Peripheral metabolism of T4, T3 and rT3 by deiodination regulates the biological activity of thyroid hormones. Deiodinase enzymes, called the “gatekeepers to thyroid hormone action,” are encoded each in a different DNA location. The deiodination of thyroid hormones is closely controlled by various means, including: Up- or down-regulation of enzyme synthesis; significant variations in substrate preference; differential reaction mechanisms; variable sensitivity to chemical and neuroendocrine messengers and different inactivation mechanisms. These interact to maintain a circumstantially-appropriate level of thyroid hormone signaling.
Mechanisms of action
The hormone T3, largely produced from T4 by outer ring (5’) deiodination, enters the nucleus of the cell and binds to a nuclear receptor (Thyroid Receptor, TR). Thyroid Receptor – and its effect – is also influenced by various other ligands. When T3 joins with TR, the resulting complex is a transcription factor; it attaches to DNA at specialized thyroid response elements. In essence, the T3+TR unit activates DNA programs that increase the metabolic rate and it blocks any DNA message that slows the metabolism. T3 has few effects outside of the cell nucleus. This contrasts again with T4 and rT3, which act significantly upon mitochondria, membranes, ion pumps and more. Though not the only aspect of thyroid signaling, the “genomic” effects (those influencing DNA transcription) of T3 are the most important.
The inhibitory genomic activity of rT3 challenged investigators. Reverse T3 was tested with the same measures used to evaluate the effects and mechanisms of T3. Experimental designs that were, in retrospect, one-dimensional yielded valid but misleading data. Comparing the stimulatory potency of rT3 to other iodothyronines – T4, T3 and T2 and derivatives – revealed it had none: Reverse T3 evoked no calorigenic effect, meaning it did not increase cellular metabolism; neither was it “anti-goiterogenic.” It did not block thyroid iodine uptake nor did it diminish the release of T4 from the thyroid gland. The latter three observations indicate rT3 exerts negligible feed-back inhibition on the hypothalamic-pituitary axis. This was later confirmed in finding T3 reduces TRH-induced TSH secretion at least one hundred-times more potently than does reverse T3. These results led researchers to conclude – and reaffirm for decades afterwards – that reverse T3 had “little or no biological activity.”
The correct conclusion to be drawn from these data is: “Reverse T3 has little or no positive thyroid-mimetic genomic activity.” Another biological effect had been overlooked: rT3 can act as an inhibitor. Using an automotive metaphor, the researchers studied the brake pedal using every appropriate test for an accelerator. Finding it in no way increased the speed of the vehicle, they declared it useless.
Definite effects of rT3 have been demonstrated – anti-thyroid effects: Quite early-on and in several reports, reverse T3 was found to inhibit the action of T4. Subsequent efforts exemplify the difficulties in designing experiments and interpreting their results: Several studies of rT3 binding to nuclear receptors proved reverse T3 incapable of significantly displacing T3 from the Thyroid Receptor. These consistent findings were prematurely interpreted as proof rT3 has but poor affinity to TR. By simply reversing the order of this experiment, the converse also was found to be true: T3 cannot effectively displace Thyroid Receptor-bound rT3 and reverse T3 was indeed shown to have genomic effects– to impede thyroid signaling. When cells are infused with rT3 prior to receiving T3, the effects of T3 are blocked Just as rT3 cannot remove T3 already bound to TR, neither can histamine-receptor antagonists like diphenhydramine (Benadryl®) displace histamine bound to its receptors. However, they have unquestioned antihistaminic action through prophylactically blocking open histamine receptors. A subsequent study of unbound nuclear receptors offered supporting evidence that antagonism between T3 and rT3 alters cellular function.
The presence of more than a single Thyroid Receptor became apparent. A number of groups reported having identified a specialized nuclear rT3-receptor – and also that rT3 had particular genomic effects. Much has been learned about the two groups of thyroid receptor subtypes since these studies were reported. Consequently, earlier conclusions about rT3 receptors should be questioned. Importantly though, recent work has reaffirmed that rT3 exerts significant genomic actions: Injected rT3 blocked a number of known hepatic thyroid-response genes. These researchers wrote in 2007: “That rT3 may function as an inhibitor of T3 offers an interesting new regulatory pathway in the thyroid hormone signaling cascade.”
Beyond activating the thyroid-responsive DNA programs, thyroid hormones influence various cell functions. These are “non-genomic” effects. As their receptors and mechanisms have been identified, the complexity of thyroid hormone signaling – including rT3 activity – has been better understood. Nongenomic receptors include Integrin-αv/β3 on cell membrane surfaces, variants of nuclear TR lingering in the cytosol, mitochondrial and other receptors. Many of these bind T4 and rT3 preferentially, with only poor affinity for T3.
Thyroid hormones can thusly exert multiple actions – sometimes without even entering the cell. Examples of nongenomic thyroid activities include influencing membrane ion pumps (sodium, calcium and protons) and altering the effects of other signaling pathways, such as the adrenergic system and the metabolic-sensing nuclear receptors (e.g. peroxisome proliferator-activated receptors). Also, plasma membrane and cytosolic targets of THs have been strongly, though circumstantially linked to mitogenic and anti-apoptotic signaling pathways.
An important nongenomic function of rT3 – and a plausible explanation for many of its observed inhibitory effects – was identified upon confirming that reverse T3 blocks type-2 deiodinase. This enzyme performs outer-ring (5’) deiodination, converting T4 to the active T3 and clearing rT3 to T2. Eighty percent of the T3 required each day must be produced peripherally by T4-deiodination; of that, type-2 DI provides 50-70%. The functional importance of blocking the greatest source of T3 is obvious but evidence shows there are further significant effects of reverse T3.
Non-genomic receptors can bind rT3, influencing ion pumps and transporter function can be altered:
- The thyroid hormone binding site of apolipoprotein-E was found to accept rT3 with affinity equal to T4 and significantly more than for T3.
- Reverse T3 competitively inhibits – once again, when given as a pre-treatment – effects of T4, T3, 3,5-T2, and DIT on sodium currents in muscle cells, apparently mediated by a non-genomic thyroid hormone receptor.
- The presence of rT3 can influence carrier protein-mediated transport of other thyroid hormones in and out of cells.
Through non-genomic actions, synthetic reactions and enzyme systems are effected to influence metabolic energy and more:
- A study from Japan indicated that rT3 inhibits the metabolism, reporting reduced ATP/ADP ratio in cultured cells under various circumstances – effects that were completely reversed when cells were incubated with T3.
- Reverse T3 may be a physiological modulator of the enzyme inosine monophosphate dehydrogenase with implications for cellular differentiation. This enzyme catalyzes the rate-limiting step in de-novo guanosine triphosphate (GTP) synthesis. GTP is a source of energy or an activator of substrates in metabolic reactions – in addition to being a substrate for the synthesis of DNA and RNA during replication and transcription.
- An rT3-responsive post-translational protein synthesis-dependent pathway has been identified, by which pre-incubation with rT3 increases the antiviral action of interferon-gamma – an effect shared by T4 and T3 but not by T2 or other thyroid derivatives.
- Reverse T3, along with T4, exerts effects essential to normal embryonic central nervous system development. Their non-genomic effects to promote normal granule cell migration and neuronal process outgrowth by influencing actin content and polymerization were markedly attenuated by the presence of T3.
- Other researchers studying the effect of rT3 injections on lipaemia in response to stressors such as endotoxin, adrenaline and dexamethasone write: “Reverse triiodothyronine (rT3) displays hypometabolic properties and antagonizes the hypermetabolic effect of 3,5,3'-triiodothyronine (T3).”
- Reverse T3 effects cancerous cells, stimulating the growth of some and inhibiting the proliferation of others. This may be relevant for normal physiology but could be due to mutated receptors commonly found in such tissues.
Reverse T3 has emerged as a valid indicator in the evaluation and management of patients. For some decades, rT3 had been said to have “little or no biological activity.” It was considered an inactive byproduct of unwanted T4 – a waste product offering no more than iodine atoms for recycling. Blood levels of rT3 were believed to show only the extent to which T4 was directed away from T3 production, as perhaps a more sensitive marker than low T3 itself. Now, the accumulated weight of evidence shows rT3 is an important participant in thyroid signaling, primarily as an inhibitor. There are many clinical situations in which this can be significant.
The last barrier to perceiving rT3 as an inhibitory hormone (besides cognitive habit and orthodoxy) may have fallen with the demonstration that 3-iodothyronamine (T1AM) rapidly exerts a potent anti-thyroid effect. Now, the existence of a thyroid hormone metabolite with effects opposed to thyroid-mimetic signaling is unquestionably proven. This may enhance our ability to conceive of rT3 also as an active, if inhibitory iodothyronine – if only, as suggested by some, as a precursor of T1AM.
Practical assays for rT3 using radioimmunoassay (RIA) technique were reported in the mid-1970s, having been developed by Chopra and others. The range of normal hormone values is determined by testing carefully-selected healthy individuals, whose results analyzed statistically. The reference range (reference interval, RI) is defined as the span of values from -2 to +2 standard deviations – the 2.5th to 97.5th centiles; these include 95% of people expected to be healthy. However, it is difficult to determine the normal range for any thyroid hormone, particularly so for rT3. The many challenges include a non-Gaussian distribution of thyroid values; the prevalence of thyroid problems in apparently healthy populations; variability of binding proteins with the use of hormones such as oral contraceptives and the rapidity with which rT3 can rise in response to stress – in fact, as patients enter a surgical suite or simply with experiencing preoperative anxiety.
The normal range for reverse T3 was found to be 9.1–22.1 ng/dL (0.14–0.34 mmol/L – the conversion factor is 65 for rT3 and T3 both) in a reliable study. Blood tests were taken from a well-selected group of 270 healthy human adults to determine the reference intervals for thyroid hormones by RIA. The similarity of this group’s RIs for TSH (0.4–4.3 μU/dl), tT4 (4.51–9.95 μg/dl) and tT3 (92.8–162.9 ng/dl) with other carefully-executed work, as noted above, supports the validity of these findings.
Commercial laboratories in the United States also offer rT3 tests by liquid chromatography/tandem mass spectrometry (LC/MS-MS), a powerful technique with very high sensitivity and selectivity. Indeed, Laboratory Corporation of America (LabCorp) in 2012 discontinued rT3 RIA in favor of LC/MS-MS; increased demand for rT3 tests had created shortages of reagents and delays in reporting results. Though the limitations of commercial reference intervals have been noted, those for LC/MS-MS are consistent with the best research findings: At LabCorp, the adult RI for rT3 is 9.2–24.1 ng/dL, and at Quest Diagnostics, it is 8–25 ng/dL. However, their RIA reference intervals agree only poorly, using values of 9–35 ng/dL and 11–31 ng/dL. Presently, LabCorp makes a credible effort to present age-adjusted RIs that seem consistent with clinical experience (Table).
Table: Reverse T3 Reference Intervals by Age
- LabCorp USA, LC/MS-MS
|Full Term (2-7d)||33.0-206.0|
|16y and older||9.2-24.1|
The clinical value of an assay for rT3 is not fully established. Commercial laboratories providing rT3 tests offer allowable suggestions: Quest states “the assay may be useful in the diagnosis of nonthyroidal illness (NTI). Patients with NTI have low T3 concentrations and increased concentrations of rT3. RT3 may be useful in neonates to distinguish euthyroid sick syndrome from central hypothyroidism.” LabCorp has written that rT3 is biologically inert and does not stimulate thyroid receptors. They then added, with proper references, that levels of rT3 are elevated in Euthyroid Sick Syndrome and correlate with both the degree of myocardial function impairment in patients with heart failure and shorter survival in elderly people, regardless of other confounding factors.
As the measurement of rT3 became feasible, its remarkably robust presence in healthy amniotic fluid was noted – in stark contrast to the (then) immeasurably-low T3 and very low T4. The use of this assay was suggested to improve the diagnosis of fetal thyroid dysfunction and to identify pregnancies of less than 30 weeks' gestation. Studies of human and animal amniotic fluid soon supported this idea. Although such an approach was subsequently judged unnecessary, many other investigations of fetal and neonatal rT3 have followed. A search of Pub Med for “3,3’,5’-triiodothyronine AND fetus” today yields 168 citations addressing widely varied topics (June 18, 2013).
Reverse T3 levels in human blood are lower than normal in untreated hypothyroidism and elevated in hyperthyroidism. The production of T4 is impaired in hypothyroidism and 95% of rT3 is derived from T4. Also, lower rT3 suggests conversion of T4 preferentially to the active T3, an obviously efficient step in such a shortage. Conversely, higher rT3 in hyperthyroidism is clearly an adaptive response to excessive amounts of T4, regardless of whether rT3 is an inhibitor of high T3 or simply a byproduct of increased T4 deactivation.
Higher than normal levels of rT3 are also found in patients treated with physiological doses of oral levothyroxine (T4). This observation has also been reported in animals given T4, including horses and rats. Given the inhibitory effects of rT3, this finding could have great significance; further discussion follows.
This relative excess of rT3 may be due to the liver’s first pass effect – T4 absorbed from the gut is broken down by a gauntlet of hepatic enzymes before it gains the general circulation. A second possibility is suggested by this fact: The conversion of T4 to rT3 is increased when free T4 levels are high. Whilst the thyroid gland in good health releases hormone at a steady rate and normal blood levels vary but little, once-daily oral doses produce transiently high (supra-physiological) peak free T4 levels some three hours later. This T4 peak may stimulate the excessive rT3 production observed in levothyroxine therapy. An example of the response to a large dose is provided in a case-report: Having taken 20-times her daily T4 dose, a suicidal woman’s blood had very high free and total T4 and rT3 but with well-regulated deiodination, the peak T3 values never exceeded normal. It is easy to consider this an adaptive response to protect against elevated T4, as noted in hyperthyroidism – and that it may be invoked by non-physiological, once-daily T4 doses.
Sufficiently elevated rT3 can be important and ominous. A significant cut-off value of 267 ng/dL (0.41 nmol/L) was determined at Stockholm’s Karolinska Institutet: Death occurred within the first week after myocardial infarction in 10% (16 of 165) of patients whose rT3 levels were above 267 ng/dL; there were no deaths among the 166 patients with lower rT3 levels (P <0.0004). The same elevated reverse T3 levels >267 ng/dL also predicted a significantly increased risk of death within one year – independently of age, previous myocardial infarction, prior angina, heart failure, serum creatinine level and peak serum creatine kinase-MB fraction levels. Serum reverse T3 assay has also been useful in other, less dramatic ways, for instance to predict glucose intolerance in uremia patients on hemodialysis and as an indicator of metabolic control in diabetes mellitus.
The question “what significant value does an rT3 assay convey” invokes an important principle: Due to the complexity of thyroid signaling, the clinical application of any single test of thyroid function is imprecise. Assays for TSH and free T4 are useful indicators of HP-T axis function. The ratio of total T3 to total rT3 additionally - and uniquely - demonstrates the status of peripheral deiodination and in the opinion of some researchers is a better indicator of thyroid function than TSH.
Ratio of T3: rT3
Whilst a value for rT3 is shown to be useful, the ratio of total T3 to reverse T3 has greater worth (rT3 is clinically available only as a “total” measure, so it must be compared to total T3 –in the same units!). Shortly after the rT3 assay became available, clinicians reported their patients had rising rT3 with reciprocally falling T3 during a variety of stressful events, such as operations; acute illness; calorie-restricted diet and myocardial infarction. These changes represent an adaptive response to stress. However, such responses become maladaptive if inappropriately prolonged. The persistence of elevated rT3 with low T3 has been referred to variously as Low T3-Syndrome, Euthyroid Sick Syndrome and Non-thyroidal Illness Syndrome (to be discussed below). Researchers soon found the ratio of tT3 to reverse T3 a clinically useful indicator for these ill patients.
The tT3/rT3 ratio eliminates some common concerns in thyroid testing, particularly their non-Gaussian distribution and vagaries of binding proteins (by comparing total values of both). Since the T4 which is not cleared by “alternative pathways” shall be converted into either T3 or rT3, this measure has proven a useful and sensitive measure of deiodination and thyroid signaling. An accounting metaphor seems relevant: If the prohormone T4 represents a business’ billing (a potential for revenue), T3 would be “collections” and rT3 the “expenses” or “losses.” The tT3/rT3 ratio then represents the profit/loss statement, an essential measure of any corporation’s financial health – as is the tT3/rT3 ratio to quantify thyroid signaling.
The utility of this ratio compared to rT3 alone was powerfully demonstrated in a study of 451 critically ill patients who received intensive care (ICU) for more than 5 days – and of whom 71 (16%) died. Comparing patients whose values fell into the highest vs. lowest quartiles, the tT3/rT3 ratio was strongly predictive of life vs. death, expressed as the odds ratio (OR) of survival = 2.9. In contrast, rT3 alone was a weak indicator, OR = 0.3. Though tT3 values generally rose over time, T3/rT3 increased only in survivors and remained unaltered or declined in the dying.
The clinical significance of the total T3 to rT3 ratio having been demonstrated, determining the range of normal values will be an important step in its clinical application. Although direct evidence among carefully-vetted people is currently lacking, there are several lines of evidence and useful older work. Firstly, T3 and rT3 are released into the bloodstream from the normal thyroid gland in the ratio of 9:1. The same 9:1 ratio is found in the secretions of benign thyroid adenomas. Within the cited studies’ margins of error, the “neutral” or resting-state tT3/rT3 value is 9.0.
However, deiodinase enzymes continually metabolize T4 into either T3 or rT3. What resulting ratio is then enjoyed by healthy people? To determine this, a group of significant number should be properly selected; then, tT3 and rT3 are tested to calculate each individual’s tT3/rT3 ratio. Statistical analysis sets the normal range for these ratios to include 95% (+/- 2 SD, as above). There is some data on people in control groups for various research studies: “Normal” serum tT3: rT3 values – expressed in the same units, of course – were 11.03 in 30 healthy males aged 23-40 years and in two studies by the same authors, 12.2 +/- 0.6 and 12.5 +/- 0.6 Not-really healthy controls matched against people with insulin resistance (IR) by sex, age, body mass index and TSH had tT3/rT3 = 7.33 ± 0.33, while those with IR averaged 8.78 ± 0.47.
We may indirectly infer a “normal” range of tT3/rT3 using the reference intervals determined for tT3 and rT3 separately by Peeters et al. Compare the values for tT3 and rT3 at their lowest limits and again at the upper end: The ranges (given above) suggest tT3/rT3 normally varies from 7 to 10. The lower value of this derived interval is somewhat below the “starting” ratio of 9 upon secretion from the thyroid gland. This result is plausible yet not primary data. Some clinicians’ experience suggests most patients feel best with their tT3/rT3 ratio in the range of 10–14, whilst all thyroid hormone levels are adequate. This impression is gained from including the tT3/rT3 ratio as a data point in following patients’ response to thyroid hormone replacement. The medical literature lacks data regarding such an "optimal" ratio. A recent publication reviewed reports comparing T4, T3 or combinations of both for the treatment of hypothyroidism. As the value of the tT3/rT3 ratio was only recently appreciated, none of the cited studies incorporated this powerful measure into their design.
As should be expected of a system controlled by the up- and down-regulation of enzymes, blood levels of rT3 and the tT3/rT3 ratio can be altered by pharmaceuticals including drugs and hormones. Medications causing elevated reverse T3 levels with low tT3/rT3 balance include the iodine-rich amiodarone; the antithyroid agent propylthiouracil – but not methimazole; the iodinated contrast agent ipodate (iopanoic acid); perhaps tobacco smoking and agents acting on receptors involved in the stress response can raise rT3, below.
Naturally-occurring substances also can increase rT3 levels. Endogenous factors (made within the body) include excessive levels of T4, which can direct the deiodination of T4 to rT3, as above – an appropriate physiological response. A human study showed type-3 DI can be up-regulated by prolonged treatment with T4 in dosses sufficient to suppress TSH; this treatment is usually associated also with elevated levels of T4. Cytokines including tumor necrosis factor alpha, interferon-alpha, NF-κB and interleukin-6 and free (non-esterified) fatty acids increase rT3 by blocking outer-ring (5’) deiodination. Exogenous bacterial endotoxin (lipopolysaccharide) increases rT3 to a greater extent than can be attributed to the cytokines it also provokes.
A few drugs have been observed to lower circulating rT3, including lithium carbonate; phenytoin and carbamazepine. Dithiothreitol reduces serum rT3 by accelerating its deiodination to T2. The antibiotic rifampicin, commonly used to treat tuberculosis, seems also to increase T3 and reduce rT3 by a similar action. Bexarotene, a retinoid specifically-selective for the retinoid X receptor (as opposed to the retinoic acid receptor) can decrease RT3 and increase T3. Agents modifying the stress-response also can lower rT3 levels; see below.
Reverse T3 is reduced by several other signals and stimuli. These include exogenously administered growth hormone and oral – but not intravenous – glucose and carbohydrate feeding.
From the first application of the physics term “stress” to biology, the central role of the adrenal gland in stress responses has been appreciated. The importance of thyroid hormone could not be understood until research had shown deiodination of T4 is regulated, not a random process. Stress hormones, including cortisol and catecholamines, enhance the conversion of T4 preferentially to rT3 instead of T3 during the acute response to stress. Dexamethasone and therapeutic corticosteroids block 5’-deiodination of T4 to T3 and raise rT3 levels. The systemic administration of adrenaline (epinephrine) also increases rT3, though in some tissues, it can increase 5’ (outer ring) deiodination to reduce rT3, acting at least partly at the pre-translational level – chiefly by its beta-agonist effects. Predictably then, while the beta-agonist drug isoproterenol lowers rT3, beta-blockers, especially propranolol inhibit T3 production and increase rT3. This, along with their anti-adrenergic effects, make beta-blockers useful for treating acute symptoms of thyrotoxicosis, though perhaps a concern for hypothyroid patients taking T4.
Cancer (carcinoma) cells, being undifferentiated and rapidly dividing, resemble embryonic or fetal cells. Cancer, like fetal tissue, has long been associated with high circulating levels of rT3 and low T3. This cannot be explained solely by the stress of severe illness (Euthyroid Sick Syndrome). For example, people with hepatitis C virus (HCV)-related cirrhosis of the liver and hepatocellular carcinoma (liver cancer) were found to have significantly higher rT3 than well-matched HCV-cirrhosis patients without carcinoma. Tumor cells themselves abnormally produce deiodinase enzymes. The excessive production of type-3 DI occurs particularly in some brain tumors; basal cell carcinomas; liver cancers and neonatal hemangiomas, the endothelium of which make fetal-levels of 3-DI sufficient to produce “consumptive hypothyroidism.”
These aberrations may create conditions favorable to tumor growth, locally and even systemically. In normal development, T3 stimulates differentiation of fetal cells into their mature adult forms. Research has begun to address the question as to whether conversely, a low T3/rT3 balance supports the proliferation of undifferentiated cells, including cancers: Added reverse T3 increased the growth of several human sarcoma cell lines, leading the investigators to suggest a specific rT3-receptor exists in neoplastic cells. However, when added to cell cultures, reverse T3 inhibits proliferation of certain lines of breast and ovarian cancer cells. If a specific rT3-receptor is responsible, it could be non-genomic – known for mutagenic and anti-apoptotic effects – or a genomic mutated variant.
Mutated thyroid hormone receptors are strongly associated with the onset and growth of cancers, particularly non-T3 binding receptors such as TRα-2 (v-erbA) and mutated TRβ. The DNA programs for these receptors are considered oncogenes and were first identified in birds infected with tumor-inducing retroviruses.Mutated TRβ has been identified in liver, kidney, thyroid and other cancers. Malfunctioning mutated TRβ also is likely to be involved in the process of carcinogenesis and increases cells’ malignant and metastatic potential. A study of clear cell renal carcinoma (ccRCC) was summarized thusly: “…reduced TRβ1 expression (91% less) and tissue hypothyroidism (58% less T3, due to lack of type-1 DI) in ccRCC tumors is likely to be involved in the process of carcinogenesis or in maintaining a proliferative advantage.” Nongenomic actions of thyroid hormone are also observed to activate complex signaling leading to angiogenesis and tumor cell proliferation. It seems further study of rT3 and what effects, if any, it may exert on mutated receptors may be a relevant aspect of cancer research.
Strong evidence that rT3 has biological activity – contributing a tonic inhibition of the metabolic rate – comes from HIV-infected young men who have lost this effect, a situation described as “unique.” Their (total) reverse T3 was observed to decline as their HIV infection advanced, even though their thyroxine-binding globulin became elevated. Whilst low T3 levels correlated with poor survival in advanced AIDS, as can be seen in other severe illnesses, the authors noted the persistence of normal T3 (with falling rT3) may contribute to weight loss.
The finding of low rT3 in HIV patients was soon corroborated and the important association of low rT3 with increased metabolic rate and weight loss was recently validated. Patients with untreated stage-A HIV infections were studied. Their findings confirmed that low rT3 and normal T3 are associated with a hypermetabolic state, featuring increased resting energy expenditure, protein breakdown and 22% greater protein synthesis. Simultaneous findings of low urinary C-peptide and elevated IL-6 and TNF-α were coincidental, not causally-linked and there was no evidence of intestinal malabsorption. These patients apparently prevented Wasting Syndrome (cachexia) by increasing their caloric intake.
Nongenomic explanations for these metabolic effects of low rT3 can be suggested. A Japanese report cited above indicated that rT3 inhibits the metabolism, reducing the ATP/ADP ratio in cultured cells. We’ve also previously noted rT3 blocks type-2 deiodinase: As euthyroid (normal) rT3 levels suppress type-2 DI activity in the brain by 20-30%, this provides a degree of tonic inhibition. The high metabolic rate associated with low rT3 may be due to the loss of these physiological restraints.
This effect also could be genomic: A highly-conserved (suggesting an important function) alternatively-spliced version of Thyroid Receptor alpha exists, called TRα-2; it is known as a “non-T3 binding receptor.” The effects of TRα-2 clearly inhibit T3. If not T3, could this receptor bind rT3? A Pub Med search for “thyroid receptor alpha 2 AND rT3” reveals just 4 articles, none of which actually addresses the question. A review of publications investigating thyroid receptors is similarly unfruitful. Could the “binding protein for reverse T3 (NrT3BP) in the rat liver nuclear extract” described decades ago represent non-T3 binding receptor variants?
Stress and the Euthyroid Sick Syndrome
The stress response, as noted, is a complex adaptation to improve survival chances during life-threatening circumstances. Euthyroid Sick Syndrome (ESS) is its maladaptive prolongation, particularly of altered peripheral deiodination to reduce T3 and increase rT3. There are several associated perturbations: The hypothalamic–pituitary–thyroid axis develops a degree of dysfunction; there is evidence of at least compensatory membrane transporter alterations and cytokine levels are elevated. Euthyroid Sick Syndrome is described primarily among critical care patients, though as above, it has been noted in a variety of other settings associated with severe situational and physiological stress. These patients have normal levels of TSH, so are biochemically “euthyroid.” No intrinsic thyroid disease being involved, EES alternatively may be called “non-thyroidal illness syndrome.” Whereas “low-T3 syndrome” was an early designation for the condition, the term is now little-used because many patients actually have “normal” T3. Most research in this area has disregarded the contribution of rT3, considering it a functionless marker of inappropriate deiodination.
ESS Patients become physiologically hypothyroid as they produce less T3 and more rT3 – both, as above being active and in effect, counter-balancing hormones. This response has a positive survival value at the onset. A report of meningococcal sepsis showed rapidly-fatal cases had paradoxically higher tT3/rT3 than survivors; the authors felt the victims had insufficient time to adapt their thyroid metabolism. However, ESS becomes maladaptive when it is inappropriately continued.
The prolonged condition of ESS is clearly associated with significantly higher death rates and in post-operative patients, prolonged recovery. Ill-effects arise from reverse T3, not just low T3: Well-designed animal research has also shown that infusing rT3 during shock caused significantly higher death rates. Dysfunction of the hypothalamus – itself a target of altered hormone signaling, drugs and cytokines in protracted critical illness – may worsen, causing falling T4 levels. There is an ultimate dichotomy: Improvement in T3/rT3 heralds survival, whilst deterioration predicts a fatal outcome.
ESS is the most severe manifestation of “second level of thyroid control” dysfunction. The role of intervention to supplement T3 (and by some, T4) is not clear. Such efforts have been convincingly advocated by leading experts, while others state “there is no persuasive evidence it is beneficial” for these critically-ill people, though acknowledging thyroid hormone treatment causes no harm. Along with general supportive measures, the use of N-acetyl cysteine has been suggested to prevent ESS by protecting 5’-deiodination against blockade by IL-6 (cytokine). Supplementing the dysfunctional hypothalamus with stimuli to produce TSH and growth hormone (hGH) has shown good results, with the added benefit that hGH allows increased T4 and T3 with no rise in rT3. Euthyroid Sick Syndrome has provided the impetus for much research into the deiodination of T4. To date, though, little of it has esteemed rT3 a functioning hormone.
In thyroid disorders
Altered T4 metabolism can be seen with a variety of thyroidal disorders. Hyperthyroidism has been associated with reduced tT3/rT3 balance in numerous studies. This may be understood as a successful adaptive response to maintain physiological euthyroidism despite elevated thyroid levels. Support for this assertion may be found in reports citing hyperthyroid patients’ normal T3 and lack of clinical symptoms despite the presence of high T4.
Conversely, an increased tT3/rT3 balance could be appropriate when patients lack sufficient thyroid hormone. When tested, this finding is indeed reported in most studies of hypothyroidism. The “second level of thyroid control” adapts to maintain T3 availability should T4 production become insufficient – an effect to which elevated TSH contributes. Deiodination is also adjusted to the supply of iodine, a nutrient required to make thyroid hormone: People living in iodine-deficient areas increase their conversion of T4 to T3. Research has proven frank iodine deficiency increases 5’-deiodination of T4 to T3, particularly effecting enzymes within the thyroid gland itself, whilst iodine excess conversely reduces that action.
Contrary to these expectations, though, an older study reported seventeen hypothyroid patients having significantly lower tT3/rT3 ratios than normal people This study’s authors considered the finding maladaptive and likened it to Euthyroid Sick Syndrome. The probable explanation for these valid comments is impaired deiodination from autoimmune inflammation and this leads to several important associations:
Hypothyroidism is usually caused by autoimmune thyroiditis (AIT). Thyroid glands of patients with Hashimoto’s AIT are infiltrated by lymphocytes, which produce within the gland significantly high levels of inflammatory cytokines (notably TNF-α, IFN-γ, IL-2 and IL-6). These cytokines are known to block outer ring (5’)-deiodination and can increase type-3 DI production, to further reduce T3 and raise rT3. Intra-thyroidal 5’-deiodination significantly compensates for low thyroid production – a consequence of AIT – so its inhibition by locally high concentrations of cytokines can be important. People with autoimmune thyroiditis, as would be expected, have significantly elevated rT3 levels (p<0.00002) and they respond abnormally to TSH, with impaired fT3 and fT4 release and increased rT3 production.
Evidence shows autoimmune thyroiditis patients can have symptoms of hypothyroidism even with normal TSH values: Among women with euthyroid AIT – having diseased glands still capable of functioning normally – higher antithyroperoxidase antibody levels (thusly, more intra-thyroidal cytokines) correlate significantly with a greater symptom load and decreased quality of life. Also, the prevalence of euthyroid AIT is reportedly increased among chronically fatigued patients.
Patients with “subclinical hypothyroidism,” more advanced AIT requiring high TSH to produce T4 normally, have greater rates of dysfunction and death. However, they show little benefit from treatment with T4 alone, so intervention is not encouraged until the elevated TSH exceeds 10 μIU/mL. The classical definition and treatment of subclinical hypothyroidism, it should be noted, do not consider rT3 or even account for T3.
Finally, many frankly hypothyroid patients whose levothyroxine (T4) treatment appears adequate upon testing the HP-T axis with TSH and T4 levels according to prevailing practice standards nevertheless complain they feel no better. Their dissatisfaction – for which they may be offered psychoactive medication – is stated in numerous books in the popular press, some written in quite an angry tone.
These situations are linked by the common thread of autoimmune thyroiditis. As above, AIT effects deiodination to reduce the tT3/rT3 balance and rT3 exerts inhibitory actions. Harvard researchers state such altered deiodination can cause physiological hypothyroidism – “disruption of thyroid hormone signaling” – whilst even T3 levels remain within the normal range. They describe a new thyroid paradigm, hypothyroidism at the second level of regulation and its laboratory hallmark is neither high TSH nor low T4 or T3 but a low tT3/rT3 balance. The condition is loosely analogous to type-2 diabetes, in which abundant hormone nevertheless has inadequate effect. It has been suggested that the Integrative Medicine term “type-2 hypothyroidism”  might appropriately be applied to designate this disorder. The clinical importance of the condition, in its prevalence and severity, is not delineated.
Such a state of low thyroid function, undetectable by the recommended tests for TSH and fT4, has long been postulated. Barnes, Wilson and others noted patients’ symptoms and signs – and response to thyroid treatment incorporating T3 – may not match those test results. Furthermore, studies report that up to sixteen percent of patients do not respond optimally to treatment with T4 alone. Efforts to explain these discrepancies by determining patients’ resting metabolic rate; measuring their body temperature< or by testing the response to TRH stimulation have been, for various reasons, ultimately disappointing. Other mechanisms have been proposed, from “endocrine-disruption” by chemicals, of which the existence is well-supported but the clinical significance is uncertain, to the effects of electromagnetic fields, which can provoke changes characteristic of the stress response and may effect the thyroid.
There are several validated forms of “resistance to thyroid hormone”: The first is Refetoff Syndrome, caused by abnormal Thyroid Receptors  and the second is due to defective trans-membrane thyroid hormone transport These, however, are uncommon hereditary conditions, for which the body compensates with greater thyroid production, elevated blood hormones and often an enlarged thyroid – all inconsistent with the observed clinical problem. The simplest explanation for a common condition of thyroid dysfunction characterized by normal blood TSH and fT4 and poor response to levothyroxine (T4) treatment is low thyroid signaling due to the inappropriate deiodination of T4.
This less severe, “ambulatory” version of ESS can be observed in patients with AIT, subclinical and mild hypothyroidism and those taking levothyroxine, as above. However, just as ESS occurs in critical care patients without co-existing thyroid disease, it has been suggested that chronic dysfunctional deiodination can occur in stressed people with healthy thyroid glands. Despite the disapproval of symptom questionnaires expressed in current guidelines, such patients are said to be identified by their clinical symptoms. The diagnosis is then supported upon demonstrating a low T3/rT3 ratio – regarded by some a better marker of thyroid signaling than TSH – and may be confirmed by their response to treatment.
The best choice of treatment for hypothyroidism has been debated since synthetic-origin levothyroxine (T4) was marketed to compete with desiccated animal thyroid. While T3 constitutes 20% of the latter, the former contains none and its effectiveness depends wholly upon deiodination. A leading textbook states: “A primary advantage of levothyroxine therapy is that the peripheral deiodination mechanisms can continue to produce the amount of T3 required in tissues under the normal physiologic control.”  However, this may not always be possible: Some patients taking sufficient T4 to become euthyroid (normal TSH) nevertheless have low T3. In this study, larger doses of T4 returned T3 levels to normal but that tactic, as above, can result also in higher rT3. While current consensus opinion endorses the use of T4-only as a precursor, conservative and Integrative physicians alike advocate treatment with a “natural” mixture of both T4 and T3. They postulate treatment combining T3 with a reduced amount of T4 (as pharmaceutical liothyronine or “natural” desiccated thyroid) can improve patients’ clinical response. Their ideas are physiologically sound, as 95% of inhibitory rT3 arises from T4 – and are supported by data from an older clinical trial demonstrating added T3 increased the tT3/rT3 ratio and improved outcomes. Renewed interest in combined T3+T4 treatment is indicated by the increased number of recent publications.
Studies comparing treatment with T4 against T3 or both combined yield varied results and despite flaws, the preponderance indicate physiological replacement with both T4 and T3 is superior to T4-only. Basic physiological and design problems can be seen in some reports, including the use of once-daily dosing, particularly an issue with the “brief duration” of T3; the failure to individualize doses – or even adjust them upon causing frank hyperthyroidism with mood impairment (making one study primarily a test of the investigators’ procrustean dosing hypothesis); monitoring therapy only with TSH and finally, neglecting the non-genomic requirements for T4 when providing T3-only treatment. Further support for T3-added treatment – and a genomic rationale – is found in a study of a common (16% prevalence) mutation of the gene (DIO2) coding type-2 deiodinase. People with the mutated gene had impaired deiodination and they fared significantly better taking T4+T3 treatment compared to T4-alone. In its summation, a recent review of combination T3 and T4 treatment concluded: “The outcome of our analysis suggests that it may be time to consider a personalized regimen of thyroid hormone replacement therapy in hypothyroid patients.”
T3-only (liothyronine) treatment has been accepted for use in particular circumstances and is recommended by some physicians for ESS. In humans, treatment with sub-physiological doses of T3 leads to reduced T4 and rT3 in the blood. Since T3 therapy maintains or improves T3 levels, the tT3/rT3 ratio thusly can be increased. Despite thoughtful opposition, treatment with T3 has been suggested for selected symptomatic euthyroid patients and studies old and recent have shown its benefit. A number of T3 intervention trials have been successful also in heart disease patients and Multiple sclerosis research.
Effects on reproduction
Thyroid hormone in appropriate amounts is essential for healthy reproduction. Virtually every aspect depends on thyroid signaling: Male fertility; ovulation; implantation; embryonic organogenesis and differentiation (particularly the central nervous system); intrauterine growth and development and carriage of the pregnancy to term. Of course, thyroid hormone continues to be essential through parturition and into the neonatal phase, when its role in non-shivering thermogenesis may be significant to humans and congenital hypothyroidism will cause tragic consequences if treatment is delayed.
Successful progression from conception through infancy involves changing expressions of deiodinase enzymes and also of Thyroid Receptors. Large shifts in fetal thyroid hormone balance occur first in local tissues and later systemically, particularly so through delivery and early neonatal life. Whilst the precise amount and timing of T3-signaling is known to be absolutely essential to proper fetal development, the exact role of rT3 in this process is uncertain. Reverse T3 is abundantly present in fetal circulation, some 15-times more than found in adult sera. Indeed, it is preponderant and has even been called “fetal thyroid hormone.” That rT3 in the adult can act as an inhibitor is particularly evocative, since ontogeny requires withholding the effects of T3 until a precise moment. The significance of rT3 in reproduction, then, could be great and if so, is likely complex.
The adult uterine lining is one of the few adult tissues to produce type-3 deiodinase, which acts on the inner ring. This suggests the local regulation of thyroid hormones – and a low T3/ rT3 balance – is important to normal uterine function
Following conception, the placenta must invade the maternal uterus to secure the fetal blood supply, an activity facilitated by T3. Promptly, however and afterwards throughout the pregnancy, the placenta produces large amounts of type-3 DI. The resulting placental conversion of T4 into rT3 and deactivation of T3 into T2 greatly reduces TH transfer from mother to fetus, evidently a key regulatory step.
Many or most fetal tissues also produce type-3 DI abundantly. In contrast, little type-2 DI is produced until required for organ-specific differentiation – and type-1 DI only appears after 30 weeks. This sequence of types of deiodination is the reason fetal blood contains mostly rT3, at an order of magnitude greater than normal adult levels; has much conjugated T3 (T3-S) and but very small amounts of T4 and T3. This ensures the proper delivery of the correct type of thyroid signaling when necessary for normal development.
Such great differences from the maternal blood levels have long been understood to allow the fetal thyroid and hypothalamic-pituitary axis to develop and function without suppression by maternal TH. The formation of the brain and neutrally-derived structures, the eyes and ears in particular, has been carefully studied. Their development requires the proliferation of cells to a critical number, during which time T3 must be very low – assured by plentiful type-3 DI production. Then, cells must assume their adult forms, a transition for which T3 is essential. Local synthesis of “prophylactic” type-3 DI ceases and that of type-2 DI begins, which converts available T4 into T3 sufficient to activate cell differentiation.
Organs deprived of T3 fail to differentiate properly. This was learned long ago, when scientists found tadpoles made hypothyroid could not metamorphose into frogs. Conversely, thyroid hormone stimulation in excess – or at the wrong time – causes rushed or imperfect development in amphibians and humans. In particular, disordered neuronal differentiation and skeletal abnormalities are seen when high hormone levels from hyperthyroid mothers overwhelm the protective ability of placental and fetal deiodinases.
The role of nongenomic effects in embryonic organ and tissue development is crucial and reverse T3 has significant nongenomic effects, which must be considered. One such sequence is required for normal cellular migration and brain development. Noting that Down syndrome children have significantly low rT3 values, a causal linkage of low rT3 with their brain and other developmental abnormalities has been suggested. Other nongenomic effects of rT3 noted above may be important. A yet broader view suggests rT3 may substitute for T4 in-utero: Some nongenomic receptors bind rT3 as readily as T4; possibly rT3 maintains their effects during fetal development without the “risk” of prematurely producing T3. Finally, understanding that proper embryogenesis requires orchestrated cellular proliferation and apoptosis (the removal of particular cells – the embryonic webs between fingers, for example), the statement above that nongenomic thyroid effects are characteristically “mitogenic and anti-apoptotic” is provocative.
Effects of rT3 on the embryonic Thyroid Receptors and genome have not been defined. The roles of Thyroid Receptors in embryogenesis are crucial. Thyroid Receptor-alpha (TRα) is most important early in development, when fetal T3 is scarce. If not bound to T3, TRα covers the thyroid response element and actually reduces the transcription of T3-mediated DNA programs. The production of TRα and Thyroid Receptor-beta (TR-β) varies with location (brain, limbs, etc.) and by phase of development. The functions of receptor variants, like non T3-binding TRα-2 and TRα-3 are not yet clarified. Does rT3, which several reports have found to compete with T3 when given as a “pre-treatment,” play a role at the fetal TR? Perhaps it might bind TRα to produce a null-state. Could the “non T3-binding” variants instead have affinity for rT3? The TR is known to be influenced by various co-repressors, including retinoids (vitamin A derivatives); hormones such as estradiol; and other nuclear receptors like the PPARs. A reassessment of possible rT3 participation using modern methods might be useful. This issue also has bearing upon the development and proliferation of cancer.
In terms of human scientific endeavor, Endocrinology is rather recent. The word “hormone” was not coined until 1905, when Starling had proven the intuitively evident: The mysterious lumps of tissue called glands – seemingly anatomically isolated – release potent chemicals into the bloodstream to influence the entire body. This work was, in various ways, propelled by Brown-Séquard’s interest in the adrenal glands and gonads and his well-publicized belief that the glands produced and stored that which came to be called hormones.
The role of the thyroid gland began to be revealed in the 1870s, when surgical science and Theodor Kocher’s skill had advanced sufficiently to allow his complete removal of large, functionally crippling goiters (the cause of which, iodine deficiency, was then unknown). His post-op patients could again easily breathe and swallow but they had become surgically hypothyroid, the unfortunate consequences of which had been prematurely dismissed. The condition was especially obvious in the children, mimicking the syndrome of congenital hypothyroidism and by 1883 was called “artificial Cretinism.” The post-op condition also confirmed that thyroid gland failure caused Gull’s disease or “myxedema,” the contemporary terms for hypothyroidism. Drawing on Brown-Séquard’s work, these patients were injected with extracts of sheep thyroid glands ca. 1890 and restored to health. Kocher’s studies of the thyroid gland were awarded the 1909 Nobel Prize in medicine. Over more than a century, research has further clarified the control of thyroid gland secretion and the roles of its hormones.
It took about 50 years to delineate the HP-T axis. Pioneering neurosurgeon Harvey Cushing appreciated the regulatory function of the pituitary by 1912; after having removed his patients’ glands because of large tumors, he saw them slip into a state similar to hibernation. By 1930, the importance of the pituitary-thyroid axis had been generally acknowledged. Despite obvious anatomical connections between the hypothalamus and the pituitary gland, both direct nerve-linkage and a portal venous system, the hypothalamic-pituitary axis could not be proven until more than 20 years later, in the 1950s. These efforts merited the 1977 Nobel Prize.
Concurrently, of course, thyroid hormones themselves were studied. The most abundant hormone, T4 was isolated by 1915 and its structure was correctly reported in 1927. For some years, researchers did not understand why hormone extracted from the thyroid was more potent than an equal amount of T4. The answer came in 1952, when T3 was identified in humans and its power (to suppress the H-P axis) was found to be some five-times greater than T4. By 1955, T3 was acknowledged as the most active form of thyroid hormone.
The conversion of T4 to T3 had been described in 1951 and again in 1955 but this was retracted – incorrectly – in 1958. The validity and clinical importance of T4 deiodination was not appreciated until 1970. Researchers were then able to accept Gross’ 1953 suggestion that T4 is a prohormone, with little metabolic activity other than that arising from its transformation to T3. Ingbar reiterated this proposal in the 1974 Harrison's Principles of Internal Medicine. Further research was needed to later define non-genomic effects of T4.
The identification and synthesis of reverse T3 was reported in 1955. By 1959, it had been found to inhibit the effects of T4. However, reports both slightly earlier and later stated rT3 had none of the stimulating effects expected of thyroid hormone. Reinforcing perceptions of irrelevance, difficulty measuring rT3 led to the belief it was evanescent and did not linger in normal human serum. Chopra disproved this, demonstrating that deiodination of T4 in humans produces significant amounts of rT3 as well as T3, writing also: “…rT3 may not be just an inactivation product of T4 but that it may be involved in physiological regulation of metabolism and biological action of T4.” Whilst other writers suggested T4 deiodination to T3 might be a “random” process, Chopra asked whether the deiodination of T4 could instead be a physiologically-regulated phenomenon. Time and meticulous research have validated his insights.
Recognition of the proper role of T3 took 18 years, from 1952 to 1970 – at which time the major purpose for T4 was also defined. In 1974, the earliest evidence that the peripheral metabolism of thyroid hormones could be modulated by physiological or physiopathological events was published: Calorie-deprived humans showed decreased circulating T3 relative to T4 with higher rT3 concentrations. The importance of this “second level” of control was stated as fact only around 2005. The inhibitory role of rT3 has also taken decades to define and has yet to be universally acknowledged.
- Chopra IJ (July 1976). "An assessment of daily production and significance of thyroidal secretion of 3, 3', 5'-triiodothyronine (reverse T3) in man". J. Clin. Invest. 58 (1): 32–40. doi:10.1172/JCI108456. PMC 333152. PMID 932209.
- Stasilli NR, v RL, Meltzer RI (January 1959). "Antigoitrogenic and calorigenic activities of thyroxine analogues in rats". Endocrinology 64 (1): 62–82. PMID 13619563.
- Pittman JA, Brown RW, Register HB (January 1962). "Biological activity of 3,3',5'-triiodo-DL-thyronine". Endocrinology 70: 79–83. PMID 14038387.
- Pitman CS, Barker SB (March 1959). "Inhibition of thyroxine action by 3,3',5'-triiodothyronine". Endocrinology 64 (3): 466–8. PMID 13630270.
- Pittman JA, Tingley JO, Nickerson JF, Hill SR (March 1960). "Antimetabolic activity of 3,3',5'-triiodo-DL-thyronine in man". Metab. Clin. Exp. 9: 293–5. PMID 14433319.
- Braverman LE, Ingbar SH, Sterling K (May 1970). "Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects". J. Clin. Invest. 49 (5): 855–64. doi:10.1172/JCI106304. PMC 535757. PMID 4986007.
- Surks MI, Schadlow AR, Stock JM, Oppenheimer JH (April 1973). "Determination of iodothyronine absorption and conversion of L-thyroxine (T4) to L-triiodothyronine (T3) using turnover rate techniques". J. Clin. Invest. 52 (4): 805–11. doi:10.1172/JCI107244. PMC 302327. PMID 4693647.
- Huang SA (August 2005). "Physiology and pathophysiology of type 3 deiodinase in humans". Thyroid 15 (8): 875–81. doi:10.1089/thy.2005.15.875. PMID 16131330.
- Wu SY, Green WL, Huang WS, Hays MT, Chopra IJ (August 2005). "Alternate pathways of thyroid hormone metabolism". Thyroid 15 (8): 943–58. doi:10.1089/thy.2005.15.943. PMID 16131336.
- Peeters RP, Wouters PJ, van Toor H, Kaptein E, Visser TJ, Van den Berghe G (August 2005). "Serum 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities". J. Clin. Endocrinol. Metab. 90 (8): 4559–65. doi:10.1210/jc.2005-0535. PMID 15886232.
- Kuiper GG, Kester MH, Peeters RP, Visser TJ (August 2005). "Biochemical mechanisms of thyroid hormone deiodination". Thyroid 15 (8): 787–98. doi:10.1089/thy.2005.15.787. PMID 16131322.
- St Germain DL, Galton VA, Hernandez A (March 2009). "Minireview: Defining the roles of the iodothyronine deiodinases: current concepts and challenges". Endocrinology 150 (3): 1097–107. doi:10.1210/en.2008-1588. PMC 2654746. PMID 19179439.
- Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR (February 2002). "Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases". Endocr. Rev. 23 (1): 38–89. PMID 11844744.
- Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, Zeöld A, Bianco AC (December 2008). "Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling". Endocr. Rev. 29 (7): 898–938. doi:10.1210/er.2008-0019. PMC 2647704. PMID 18815314.
- Piekiełko-Witkowska A, Nauman A (October 2011). "Iodothyronine deiodinases and cancer". J. Endocrinol. Invest. 34 (9): 716–28. doi:10.3275/7754. PMID 21623154.
- Goode AW, Herring AN, Orr JS, Ratcliffe WA, Dudley HA (May 1981). "The effect of surgery with carbohydrate infusion on circulating triiodothyronine and reverse triiodothyronine". Ann R Coll Surg Engl 63 (3): 168–72. PMC 2493917. PMID 7247276.
- Wartofsky L, Burman KD (1982). "Alterations in thyroid function in patients with systemic illness: the "euthyroid sick syndrome"". Endocr. Rev. 3 (2): 164–217. PMID 6806085.
- Katzeff HL, Powell SR, Ojamaa K (November 1997). "Alterations in cardiac contractility and gene expression during low-T3 syndrome: prevention with T3". Am. J. Physiol. 273 (5 Pt 1): E951–6. PMID 9374681.
- Boelen A, Kwakkel J, Fliers E (October 2011). "Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection". Endocr. Rev. 32 (5): 670–93. doi:10.1210/er.2011-0007. PMID 21791567.
- Economidou F, Douka E, Tzanela M, Nanas S, Kotanidou A (2011). "Thyroid function during critical illness". Hormones (Athens) 10 (2): 117–24. PMID 21724536.
- Wilson ED (1996). Wilson's Syndrome: The Miracle of Feeling Well. Cornerstone Publishing (Va). ISBN 0-9629875-0-6.
- Friedman M, Miranda-Massari JR, Gonzalez MJ (March 2006). "Supraphysiological cyclic dosing of sustained release T3 in order to reset low basal body temperature". P R Health Sci J 25 (1): 23–9. PMID 16883675.
- Premachandra BN, Kabir MA, Williams IK (June 2006). "Low T3 syndrome in psychiatric depression". J. Endocrinol. Invest. 29 (6): 568–72. PMID 16840838.
- Joffe RT (2011). "Hormone treatment of depression". Dialogues Clin Neurosci 13 (1): 127–38. PMC 3181966. PMID 21485752.
- Stagnaro-Green A (February 2012). "Approach to the patient with postpartum thyroiditis". J. Clin. Endocrinol. Metab. 97 (2): 334–42. doi:10.1210/jc.2011-2576. PMID 22312089.
- Poon SH, Sim K, Sum MY, Kuswanto CN, Baldessarini RJ (September 2012). "Evidence-based options for treatment-resistant adult bipolar disorder patients". Bipolar Disord 14 (6): 573–84. doi:10.1111/j.1399-5618.2012.01042.x. PMID 22938165.
- de Cock M, Maas YG, van de Bor M (August 2012). "Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review". Acta Paediatr. 101 (8): 811–8. doi:10.1111/j.1651-2227.2012.02693.x. PMID 22458970.
- Ghassabian A, Bongers-Schokking JJ, de Rijke YB, van Mil N, Jaddoe VW, de Muinck Keizer-Schrama SM, Hooijkaas H, Hofman A, Visser W, Roman GC, Visser TJ, Verhulst FC, Tiemeier H (February 2012). "Maternal thyroid autoimmunity during pregnancy and the risk of attention deficit/hyperactivity problems in children: the Generation R Study". Thyroid 22 (2): 178–86. doi:10.1089/thy.2011.0318. PMC 3271370. PMID 22175242.
- Cakaloz B, Akay AP, Bober E, Yulug B (2011). "Thyroid function and oppositional defiant disorder: more than a coincidence in prepubertal boys with attention-deficit hyperactivity disorder?". J Neuropsychiatry Clin Neurosci 23 (2): E9–E10. doi:10.1176/appi.neuropsych.23.2.E9. PMID 21677236.
- Fumarola A, Grani G, Romanzi D, Del Sordo M, Bianchini M, Aragona A, Tranquilli D, Aragona C (March 2013). "Thyroid Function in Infertile Patients Undergoing Assisted Reproduction". Am. J. Reprod. Immunol. doi:10.1111/aji.12113. PMID 23521347.
- Unuane D, Velkeniers B, Anckaert E, Schiettecatte J, Tournaye H, Haentjens P, Poppe K (February 2013). "Thyroglobulin antibodies: any added value in the detection of thyroid autoimmunity in women consulting for fertility treatment". Thyroid. doi:10.1089/thy.2012.0562. PMID 23405888.
- Blum M, Blum G (December 1992). "The possible relationship between menorrhagia and occult hypothyroidism in IUD-wearing women". Adv Contracept 8 (4): 313–7. PMID 1290333.
- Jackson AJ, Price VH (January 2013). "How to diagnose hair loss". Dermatol Clin 31 (1): 21–8. doi:10.1016/j.det.2012.08.007. PMID 23159173.
- Chopra IJ (September 1974). "A radioimmunoassay for measurement of 3,3',5'-triiodothyronine (reverse T3)". J. Clin. Invest. 54 (3): 583–92. doi:10.1172/JCI107795. PMC 301591. PMID 4211761.
- Bowen R (2006). Synthesis and secretion of thyroid hormones. Colorado State University.
- Jorgensen EC (August 1964). "Stereochemistry of thyroxine and analogues". Mayo Clin. Proc. 39: 560–8. PMID 14198023.
- Molina PE (2004). Endocrine physiology. Lange physiology series. New York, NY: The McGraw-Hill Companies, Inc. p. 83. ISBN 9780071491174.
- Laurberg, P (Dec 1979). "The effect of propylthiouracil on thyroid-stimulating hormone-induced alterations in iodothyronine secretion from perfused dog thyroids.". Biochim Biophys Acta. 588 (3): 351-6. PMID 508809.
- Tegler, L; Gillquist J, Lindvall R, Almqvist S. (Oct 1982). "Secretion rates of thyroxine, triiodothyronine, and reverse triiodothyronine in man during surgery.". Acta Endocrinol (Copenh). 101 (2): 193-8. PMID 6215812. Retrieved 2 June 2013.
- Laurberg, P (Apr 1984). "Mechanisms governing the relative proportions of thyroxine and 3,5,3'-triiodothyronine in thyroid secretion.". Metabolism. 33 (4): 379-92. PMID 6369072.
- Hulbert, AJ (Nov 2000). "Thyroid hormones and their effects: a new perspective.". Biol Rev Camb Philos Soc. 75 (4): 519-631. PMID 11117200. Retrieved 23 April 2013.
- Reed, HL (2001). Ch. 30. Thyroid physiology: Synthesis and release, iodine metabolism, binding and transport. In: Principles and practice of endocrinology and metabolism, 3rd Ed. Becker, KL Ed. Philadelphia PA, USA.: Lippincott Williams & Wilkins. p. 317. ISBN 9780781717502.
- Kratzsch, J; Fiedler GM, Leichtle A et al. (Aug 2005). "New reference intervals for thyrotropin and thyroid hormones based on National Academy of Clinical Biochemistry criteria and regular ultrasonography of the thyroid.". Clin Chem. 51 (8): 1480-6. PMID 15961550. Retrieved 23 March 2013.
- Peeters, RP; van der Geyten S, Wouters PJ, et al. (Dec 2005). "Tissue thyroid hormone levels in critical illness.". J Clin Endocrinol Metab. 90 (12): 6498-507. PMID 16174716. Retrieved 23 March 2013.
- Orozco, A; Valverde-R C, Olvera A, García-G C. (Nov 2012). "Iodothyronine deiodinases: a functional and evolutionary perspective.". J Endocrinol. 215 (2): 207-19. doi:10.1530/JOE-12-0258. PMID 22872760. Retrieved 2 June 2013.
- Peeters, RP; van der Deure WM, Visser TJ. (Nov 2006). "Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases.". Eur J Endocrinol. 155 (5): 655-62. PMID 17062880. Retrieved 2 June 2013.
- Robbins, J; Rall JE. (Jul 1960). "Proteins associated with the thyroid hormones.". Physiol Rev. 40: 415-89. PMID 14437750. Retrieved 18 March 2013.
- Hennemann, G; Roelof D, Friesema EC et al. (Aug 2001). "Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability.". Endocr Rev. 22 (4): 451-76. doi:10.1210/er.22.4.451. PMID 11493579. Retrieved 12 June 2013.
- Visser, WE; Friesema EC, Visser TJ. (Jan 2011). "Minireview: thyroid hormone transporters: the knowns and the unknowns.". Mol Endocrinol. 25 (1): 1-14. doi:10.1210/me.2010-0095. PMID 20660303. Retrieved 2 June 2013.
- Rodriguez-Perez, A; Palos-Paz F, Kaptein E et al. (May 2008). "Identification of molecular mechanisms related to nonthyroidal illness syndrome in skeletal muscle and adipose tissue from patients with septic shock.". Clin Endocrinol (Oxf). 68 (5): 821-7. PMID 17986277.
- LoPresti, JS; Eigen A, Kaptein E et al. (Nov 1989). "Alterations in 3,3',5'-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man.". J Clin Invest. 84 (5): 1650-6. doi:10.1172/JCI114343. PMID 2808705. Retrieved 2 June 2013.
- Orden, I; Pie J, Juste MG et al. (Apr 1987). "Thyroxine in unextracted urine.". Acta Endocrinol (Copenh). 114 (4): 503-8. PMID 3577582. Retrieved 17 March 2013.
- Solis-S, JC; Villalobos P, Orozco A et al. (Jan 2011). "Inhibition of intrathyroidal dehalogenation by iodide.". J Endocrinol. 208 (1): 89-96. PMID 20974636. Retrieved 2 June 2013.
- Araujo, RL; Andrade BM, da Silva ML et al. (May 2009). "Tissue-specific deiodinase regulation during food restriction and low replacement dose of leptin in rats.". Am J Physiol Endocrinol Metab. 296 (5): E1157-63. PMID 19208852. Retrieved 2 June 2013.
- Michalaki, M; Vagenakis AG, Makri M et al. (Sep 2001). "Dissociation of the early decline in serum T(3) concentration and serum IL-6 rise and TNFalpha in nonthyroidal illness syndrome induced by abdominal surgery.". J Clin Endocrinol Metab. 86 (9): 4198-205. PMID 11549650. Retrieved 2 June 2013.
- Lisbôa, PC; Curty FH, Moreira RM et al. (Sep 2001). "Sex steroids modulate rat anterior pituitary and liver iodothyronine deiodinase activities.". Horm Metab Res. 33 (9): 532-5. PMID 11561212. Retrieved 2 June 2013.
- Koppeschaar, HP; Meinders AE, Schwarz F. (Jan 1985). "Metabolic responses during modified fasting and refeeding. The role of sympathetic nervous system activity and thyroid hormones.". Hum Nutr Clin Nutr. 39 (1): 17-28. PMID 3997546.
- Sakurada, T; Rudolph M, Fang SL et al. (Jun 1978). "Evidence that triiodothyronine and reverse triiodothyronine are sequentially deiodinated in man.". J Clin Endocrinol Metab. 46 (6): 916-22. PMID 263472. Retrieved 3 June 2013.
- Köhrle, J (1996). "Thyroid hormone deiodinases--a selenoenzyme family acting as gate keepers to thyroid hormone action.". Acta Med Austriaca. 23 (1-2): 17-30. PMID 8767511.
- Kim, SW; Harney JW, Larsen PR. (Dec 1998). "Studies of the hormonal regulation of type 2 5'-iodothyronine deiodinase messenger ribonucleic acid in pituitary tumor cells using semiquantitative reverse transcription-polymerase chain reaction.". Endocrinology. 139 (12): 4895-905. PMID 9832426. Retrieved 3 June 2013.
- Maia, AL; Kim BW, Huang SA et al. (Sep 2005). "Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans.". J Clin Invest. 115 (9): 2524-33. PMID 16127464. Retrieved 3 June 2013.
- Sanders, JP; Van der Geyten S, Kaptein E et al. (Aug 1999). "Cloning and characterization of type III iodothyronine deiodinase from the fish Oreochromis niloticus.". Endocrinology. 140 (8): 3666-73. PMID 10433225. Retrieved 3 June 2013.
- Moreno, M; Berry MJ, Horst C et al. (May 16 1994). "Activation and inactivation of thyroid hormone by type I iodothyronine deiodinase.". FEBS Lett. 344 (2-3): 143-6. PMID 8187873.
- Chang, Raymond (2005). Physical Chemistry for the Biosciences. Sausalito CA: University Science Books. p. 372-7. ISBN 978-1891389337.
- Gereben, B; Goncalves C, Harney JW et al. (Nov 2000). "Selective proteolysis of human type 2 deiodinase: a novel ubiquitin-proteasomal mediated mechanism for regulation of hormone activation.". Mol Endocrinol. 14 (11): 1697-708. PMID 11075806. Retrieved 3 June 2013.
- Lonard, DM; O'Malley BW (Oct 2012). "Nuclear receptor coregulators: modulators of pathology and therapeutic targets.". Nat Rev Endocrinol. 8 (10): 598-604. doi:10.1038/nrendo.2012.100. PMID 22733267. Retrieved 2 June 2013.
- Cheng, SY; Leonard JL, Davis PJ. (Apr 2010). "Molecular aspects of thyroid hormone actions.". Endocr Rev. 31 (2): 139-70. doi:10.1210/er.2009-0007. PMID 20051527. Retrieved 2 June 2013.
- Chopra, IJ; Carlson HE, Solomon DH. (Aug 1978). "Comparison of inhibitory effects of 3,5,3'-triiodothyronine (T3), thyroxine (T4), 3,3,',5'-triiodothyronine (rT3), and 3,3'-diiodothyronine (T2) on thyrotropin-releasing hormone-induced release of thyrotropin in the rat in vitro.". Endocrinology. 103 (2): 393-402. PMID 105890. Retrieved 2 June 2013.
- Nussey S, Whitehead S (2001). Chapter 3, The thyroid gland. In: Endocrinology: An Integrated Approach.. Oxford: Taylor & Francis, BIOS Scientific Publishers. ISBN 9780203450437.
- Barker SB; Pitman CS, Pittman JA Jr, Hill SR Jr. (Apr 23 1960). "Thyroxine antagonism by partially iodinated thyronines and analogues.". Ann N Y Acad Sci. 86: 545-62. PMID 13796818. Retrieved 18 March 2013.
- Latham, KR; Ring JC, Baxter JD. (Dec 10 1976). "Solubilized nuclear "receptors" for thyroid hormones. Physical characteristics and binding properties, evidence for multiple forms.". J Biol Chem. 251 (23): 7388-97. PMID 12162. Retrieved 2 June 2013.
- Oppenheimer, JH; Schwartz HL, Dillman W, Surks MI. (Dec 10 1973). "Effect of thyroid hormone analogues on the displacement of 125I-L-triiodothyronine from hepatic and heart nuclei in vivo: possible relationship to hormonal activity.". Biochem Biophys Res Commun. 55 (3): 544-50. PMID 4357424. Retrieved 2 June 2013.
- Smith, HC; Robinson SE, Eastman CJ. (Apr 1980). "Binding of endogenous iodothyronines to isolated liver cell nuclei.". Endocrinology. 106 (4): 1133-6. PMID 6244141. Retrieved 10 April 2013.
- Smith HC; Robinson SE, Eastman CJ. (Apr 1980). "Binding of reverse T3 to hepatic nuclear protein.". Aust J Exp Biol Med Sci. 58 (2): 207-12. PMID 7436879.
- du Pont, JS (Aug 1991). "Is reverse triiodothyronine a physiological nonactive competitor for the action of triiodothyronine upon the electrical properties of GH3 cells?". Neuroendocrinology. 54 (2): 146-50. PMID 1766550.
- McCormack, PD; Thomas J, Malik M, Staschen CM. (Jul-Sep 1998). "Cold stress, reverse T3 and lymphocyte function.". Alaska Med. 40 (3): 55-62. PMID 9785613.
- Wiersinga, WM; Chopra IJ, Solomon DH. (Jun 1982). "Specific nuclear binding sites of triiodothyronine and reverse triiodothyronine in rat and pork liver: similarities and discrepancies.". Endocrinology. 110 (6): 2052-8. PMID 7075548. Retrieved 2 June 2013.
- Kobayashi, A; Shimazaki M, Kuwahara H et al. (Nov 1989). "Nuclear binding sites for reverse triiodothyronine in human placenta.". Osaka City Med J. 35 (2): 137-44. PMID 2628841.
- Tagami, T; Nakamura H, Sasaki S, Imura H. (Feb 1990). "Characterization of interaction between nuclear T3 receptors and antiserum against cellular-erb A peptide.". Endocrinology. 126 (2): 1105-11. PMID 2153519. Retrieved 24 March 2013.
- Kobayashi, A; Shimazaki M, Hamada N et al. (May 1990). "Reverse triiodothyronine nuclear binding in rat brain.". Osaka City Med J. 36 (1): 29-35. PMID 2385438.
- Dutkowsky, JP; Smith RA, Calandruccio RA, Carnesale PG. (May 1993). "Effect of fetal thyroid hormone (RT3) on sarcoma cells in culture.". J Orthop Res. 11 (3): 379-85. PMID 8326444.
- Koenig, RJ; Lazar MA, Hodin RA, et al. (Feb 16 1989). "Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing.". Nature. 337 (6208): 659-61. PMID 2537467. Retrieved 23 March 2013.
- Tagami, T; Yamamoto H, Moriyama K et al. (Jun 11 2010). "Identification of a novel human thyroid hormone receptor beta isoform as a transcriptional modulator.". Biochem Biophys Res Commun. 396 (4): 983-8. doi:10.1016/j.bbrc.2010.05.038. PMID 20470753. Retrieved 2 June 2013.
- Katz, D; Lazar MA. (Oct 5 1993). "Dominant negative activity of an endogenous thyroid hormone receptor variant (alpha 2) is due to competition for binding sites on target genes.". J Biol Chem. 268 (28): 20904-10. PMID 8407924. Retrieved 23 March 2013.
- Wondisford, FE (Jul 2003). "Thyroid hormone action: insight from transgenic mouse models.". J Investig Med. 51 (4): 215-20. PMID 12929737.
- Tien, ES; Matsui K, Moore R, Negishi M. (Jan 2007). "The nuclear receptor constitutively active/androstane receptor regulates type 1 deiodinase and thyroid hormone activity in the regenerating mouse liver.". J Pharmacol Exp Ther. 320 (1): 307-13. PMID 17050775. Retrieved 2 June 2013.
- Davis, PJ; Leonard JL, Davis FB. (May 2008). "Mechanisms of nongenomic actions of thyroid hormone.". Front Neuroendocrinol. 29 (2): 211-8. PMID 17983645. Retrieved 31 March 2013.
- Brent, GA (Sep 4 2012). "Mechanisms of thyroid hormone action.". J Clin Invest. 122 (9): 3035-43. doi:10.1172/JCI60047. PMID 22945636. Retrieved 31 March 2013.
- Sukocheva, OA; Carpenter DO (Nov 2006). "Anti-apoptotic effects of 3,5,3'-tri-iodothyronine in mouse hepatocytes.". J Endocrinol. 191 (2): 447-58. PMID 17088414. Retrieved 31 March 2013.
- St Germain DL (Aug 1985). "Metabolic effect of 3,3',5'-triiodothyronine in cultured growth hormone-producing rat pituitary tumor cells. Evidence for a unique mechanism of thyroid hormone action.". J Clin Invest. 76 (2): 890-3. PMID 4031075. Retrieved 2 June 2013.
- Kaiser CA; Goumaz MO, Burger AG. (Aug 1986). "In vivo inhibition of the 5'-deiodinase type II in brain cortex and pituitary by reverse triiodothyronine.". Endocrinology. 119 (2): 762-70. PMID 3732144. Retrieved 2 June 2013.
- Obregon, MJ; Larsen PR, Silva JE. (Nov 1986). "The role of 3,3',5'-triiodothyronine in the regulation of type II iodothyronine 5'-deiodinase in the rat cerebral cortex.". Endocrinology. 119 (5): 2186-92. PMID 3769868. Retrieved 2 June 2013.
- Branco, M; Ribeiro M, Negrão N, Bianco AC. (Jan 1999). "3,5,3'-Triiodothyronine actively stimulates UCP in brown fat under minimal sympathetic activity.". Am J Physiol. 276 (1 Pt 1): E179-87. PMID 9886965. Retrieved 3 June 2013.
- Cettour-Rose P; Visser TJ, Burger AG, Rohner-Jeanrenaud F. (Sep 2005). "Inhibition of pituitary type 2 deiodinase by reverse triiodothyronine does not alter thyroxine-induced inhibition of thyrotropin secretion in hypothyroid rats.". Eur J Endocrinol. 153 (3): 429-34. PMID 16131606. Retrieved 3 June 2013.
- Benvenga, S; Cahnmann HJ, Robbins J. (Sep 1993). "Characterization of thyroid hormone binding to apolipoprotein-E: localization of the binding site in the exon 3-coded domain.". Endocrinology. 133 (3): 1300-5. PMID 8365370. Retrieved 23 May 2013.
- Huang, CJ; Geller HM, Green WL, Craelius W. (Apr 1999). "Acute effects of thyroid hormone analogs on sodium currents in neonatal rat myocytes.". J Mol Cell Cardiol. 31 (4): 881-93. PMID 10329215. Retrieved 23 May 2013.
- Mitchell, AM; Manley SW, Rowan KA, Mortimer RH. (Jan 1999). "Uptake of reverse T3 in the human choriocarcinoma cell line, JAr.". Placenta. 20 (1): 65-70. PMID 9950146. Retrieved 23 May 2013.
- Okamoto, R; Leibfritz D (1997). "Adverse effects of reverse triiodothyronine on cellular metabolism as assessed by 1H and 31P NMR spectroscopy.". Res Exp Med (Berl). 197 (4): 211-7. PMID 9440139.
- Peeters, M; Réthoré MO, de Kermadec S, Lejeune J. (1989). "Correlation between the effects of rT3 and IMP dehydrogenase inhibitors on normal and trisomic 21 lymphocyte cultures.". Ann Genet. 32 (4): 211-3. PMID 2575364.
- Collart FR; Huberman E. (Oct 25 1988). "Cloning and sequence analysis of the human and Chinese hamster inosine-5'-monophosphate dehydrogenase cDNAs.". J Biol Chem. 263 (30): 15769-72. PMID 2902093. Retrieved 24 April 2013.
- Lin, HY; Thacore HR, Davis FB, Davis PJ. (May 1996). "Thyroid hormone analogues potentiate the antiviral action of interferon-gamma by two mechanisms.". J Cell Physiol. 167 (2): 269-76. PMID 8613467.
- Farwell, AP; Dubord-Tomasetti SA, Pietrzykowski AZ, Stachelek SJ, Leonard JL. (Jan 1 2005). "Regulation of cerebellar neuronal migration and neurite outgrowth by thyroxine and 3,3',5'-triiodothyronine.". Brain Res Dev Brain Res. 154 (1): 121-35. PMID 15617761. Retrieved 23 May 2013.
- Bobek, S; Sechman A, Niezgoda J, Jacek T. (Apr 2002). "Reverse 3,3',5'-triiodothyronine suppresses increase in free fatty acids in chickens elicited by dexamethasone or adrenaline.". J Vet Med A Physiol Pathol Clin Med. 49 (3): 121-4. PMID 12019951.
- Martinez, MB; Ruan M, Fitzpatrick LA. (Nov-Dec 2000). "Altered response to thyroid hormones by breast and ovarian cancer cells.". Anticancer Res. 20 (6B): 4141-6. PMID 11205239.
- Rokita SE; Adler JM, McTamney PM, Watson JA Jr. (Sep 2010). "Efficient use and recycling of the micronutrient iodide in mammals.". Biochimie. 92 (9): 1227-35. doi:10.1016/j.biochi.2010.02.013. PMID 20167242. Retrieved 8 May 2013.
- Piehl S; Hoefig CS, Scanlan TS, Köhrle J. (Feb 2011). "Thyronamines--past, present, and future.". Endocr Rev. 32 (1): 64-80. doi:10.1210/er.2009-0040. PMID 20880963. Retrieved 14 June 2013.
- Gompf, HS; Greenberg JH, Aston-Jones G et al. (Sep 10 2010). "3-Monoiodothyronamine: the rationale for its action as an endogenous adrenergic-blocking neuromodulator.". Brain Res. 1351: 130-40. doi:10.1016/j.brainres.2010.06.067. PMID 20615397. Retrieved 28 May 2013.
- Meinhold, H; Wenzel KW, Schürnbrand P. (Dec 1975). "Radioimmunoassay of 3,3',-'-triiodo-L-thyronine (reverse T3) in human serum and its application in different thyroid states.". Z Klin Chem Klin Biochem. 13 (12): 571-4. PMID 1202786.
- Visser, TJ; Docter R, Hennemann G. (May 1977). "Radioimmunoassay of reverse tri-iodothyronine.". J Endocrinol. 73 (2): 395-6. PMID 864376. Retrieved 9 April 2013.
- Dayan, CM; Saravanan P, Bayly G. (Aug 3 2002). "Whose normal thyroid function is better--yours or mine?". Lancet. 360 (9330): 353. PMID 12241772.
- Arunabh; Sarda AK, Karmarkar MG. (Jul-Sep 1992). "Changes in thyroid hormones in surgical trauma.". J Postgrad Med. 38 (3): 117-8. PMID 1303410. Retrieved 9 April 2013.
- Langer P; Balázová E, Vician M et al. (May 1992). "Acute development of low T3 syndrome and changes in pituitary-adrenocortical function after elective cholecystectomy in women: some differences between young and elderly patients.". Scand J Clin Lab Invest. 52 (3): 215-20. PMID 1329184.
- = reverse+T3%2C+serum&x=0&y=0#7_UE4S1I930OGS20IS3O4N2N6680 "reverse T3, serum". LabCorp Test Menu. Retrieved 8 June 2013.
- "T3 Reverse, LC/MS/MS". Quest Diagnostics: Test Center.
- "T3 Reverse". Quest Diagnostics: Test Center. Retrieved 8 June 2013.
- Chopra, IJ; Crandall BF (Oct 9 1975). "Thyroid hormones and thyrotropin in amniotic fluid.". N Engl J Med. 293 (15): 740-3. PMID 1160952.
- Filetti, S; Camus M, Rodesch F et al. (May 1977). "Decreased reverse triiodothyronine (RT3) concentration in amniotic fluid in fetal hypothyroidism.". Arch Dis Child. 52 (5): 430-1. PMID 559476. Retrieved 10 April 2013.
- "PubMed". U.S. National Library of Medicine. Retrieved 14 June 2013.
- Griffiths, RS; Black EG, Hoffenberg R. (Nov 1976). "Measurement of serum 3,3',5'-(reverse) T3, with comments on its derivation.". Clin Endocrinol (Oxf). 5 (6): 679-85. PMID 1009677.
- Laurberg, P; Weeke J. (Dec 1977). "Radioimmunological determination of reverse triiodothyronine in unextracted serum and serum dialysates.". Scand J Clin Lab Invest. 37 (8): 735-9. PMID 601517.
- Faber, J; Kirkegaard BC, Rogowski P et al. (Sep 1978). "Urinary excretion of 3,3',5'-triiodothyronine (reverse T3).". Clin Endocrinol (Oxf). 9 (3): 279-82. PMID 709898.
- Verburg, FA; Smit JW, Grelle I et al. (Apr 2012). "Changes within the thyroid axis after long-term TSH-suppressive levothyroxine therapy.". Clin Endocrinol (Oxf). 76 (4): 577-81. doi:10.1111/j.1365-2265.2011.04262.x. PMID 22017394. Retrieved 3 June 2013.
- Morita, T; Tamai H, Ohshima A et al. (Aug 1989). "Changes in serum thyroid hormone, thyrotropin and thyroglobulin concentrations during thyroxine therapy in patients with solitary thyroid nodules.". J Clin Endocrinol Metab. 69 (2): 227-30. PMID 2753971. Retrieved 10 April 2013.
- Volta, C; Ghizzoni L, Davoli A et al. (1989). "Thyroid function tests in children with congenital hypothyroidism on L-thyroxine treatment.". Horm Res. 32 (4): 109-12. PMID 2625320.
- Sommardahl, CS; Frank N, Elliott SB et al. (Jun 2005). "Effects of oral administration of levothyroxine sodium on serum concentrations of thyroid gland hormones and responses to injections of thyrotropin-releasing hormone in healthy adult mares.". Am J Vet Res. 66 (6): 1025-31. PMID 16008227.
- Banovac, K; Zakarija M, Rabinovitch A. (Feb 1989). "A study of hepatic metabolism of thyroxine in BB/W rats treated with L-thyroxine.". Horm Metab Res. 21 (2): 69-72. PMID 2722130. Retrieved 10 April 2013.
- Sturgess, I; Thomas SH, Pennell DJ et al. (Nov 1989). "Diurnal variation in TSH and free thyroid hormones in patients on thyroxine replacement.". Acta Endocrinol (Copenh). 121 (5): 674-6. PMID 2588938. Retrieved 24 April 2013.
- Ishihara, T; Nishikawa M, Ikekubo K et al. (Jun 1998). "Thyroxine (T4) metabolism in an athyreotic patient who had taken a large amount of T4 at one time.". Endocr J. 45 (3): 371-5. PMID 9790272. Retrieved 10 April 2013.
- Friberg, L; Drvota V, Bjelak AH et al. (Dec 15 2001). "Association between increased levels of reverse triiodothyronine and mortality after acute myocardial infarction.". Am J Med. 111 (9): 699-703. PMID 11747849. Retrieved 10 April 2013.
- De Marchi, S; Cecchin E, Villalta D, Tesio F (Apr 1987). "Serum reverse T3 assay for predicting glucose intolerance in uremic patients on dialysis therapy.". Clin Nephrol. 27 (4): 189-98. PMID 3581526.
- Kabadi, UM (Oct 1986). "Serum T3 and reverse T3 concentrations: indices of metabolic control in diabetes mellitus.". Diabetes Res. 3 (8): 417-21. PMID 3816044.
- Smit, JW; Stokkel MP, Pereira AM et al. (Jul 2007). "Bexarotene-induced hypothyroidism: bexarotene stimulates the peripheral metabolism of thyroid hormones.". J Clin Endocrinol Metab. 92 (7): 2496-9. PMID 17440015. Retrieved 31 March 2013.
- Burr, WA; Black EG, Griffiths RS, Hoffenberg R. (Dec 27 1975). "Serum triiodothyronine and reverse triiodothyronine concentrations after surgical operation.". Lancet. 2 (7948): 1277-9. PMID 54799.
- Burger, A; Nicod P, Suter P et al. (Mar 27 1976). "Reduced active thyroid hormone levels in acute illness.". Lancet. 1 (7961): 653-5. PMID 73636.
- Vagenakis, AG; Burger A, Portnary GI et al. (Jul 1975). "Diversion of peripheral thyroxine metabolism from activating to inactivating pathways during complete fasting.". J Clin Endocrinol Metab. 41 (1): 191-4. PMID 1150863. Retrieved 11 April 2013.
- Westgren, U; Burger A, Levin K et al. (1977). "Divergent changes of serum 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine in patients with acute myocardial infarction.". Acta Med Scand. 201 (4): 269-72. PMID 403745.
- Chrousos, GP; Gold PW (Mar 4 1992). "The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis.". JAMA. 267 (9): 1244-52. PMID 1538563. Retrieved 11 April 2013.
- Banovac K; Solter M, Sekso M et al. (1978). "Relative increase of serum reverse T3 in patients with hypothyroidism.". Ann Endocrinol (Paris). 39 (5): 387-91. PMID 742837.
- Epstein, Y; Udassin R, Sack J. (Nov 1979). "Serum 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine concentrations during acute heat load.". J Clin Endocrinol Metab. 49 (5): 677-8. PMID 489710. Retrieved 12 April 2013.
- Westgren, U; Melander A, Ingemansson S et al. (Feb 1977). "Secretion of thyroxine, 3,5,3'-triiodothyronine and 3,3'5'-triiodothyronine in euthyroid man.". Acta Endocrinol (Copenh). 84 (2): 281-9. PMID 576344.
- Reinwein, D; Durrer H, Emrich D et al. (Aug 1977). "The thyroidal production of reverse triiodothyronine in autonomous adenoma.". Clin Endocrinol (Oxf). 7 (2): 171-3. PMID 891000.
- Banovac, K; Bzik L, Sekso M, Petek M. (Apr 1978). "Decreased ratio of serum T3:rT3 in patients with hyperthyroidism.". Endokrinologie. 71 (2): 159-63. PMID 668639.
- Ruhla, S; Arafat AM, Weickert MO et al. (Feb 2011). "T3/rT3-ratio is associated with insulin resistance independent of TSH.". Horm Metab Res. 43 (2): 130-4. doi:10.1055/s-0030-1267997. PMID 21104580. Retrieved 19 May 2013.
- McDaniel, AB (2011). New endocrinology: new knowledge, new understanding and integrative solutions. Santa Rosa, CA: Electronically, privately.
- Biondi, B; Wartofsky L (Jul 2012). "Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism?". J Clin Endocrinol Metab. 97 (7): 2256-71. doi:10.1210/jc.2011-3399. PMID 22593590. Retrieved 1 July 2013.
- Burger, A; Dinichert D, Nicod P et al. (Aug 1976). "Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin, and thyrotropin. A drug influencing peripheral metabolism of thyroid hormones.". J Clin Invest. 58 (2): 255-9. PMID 783194. Retrieved 28 April 2013.
- Melmed, S; Nademanee K, Reed AW et al. (Nov 1981). "Hyperthyroxinemia with bradycardia and normal thyrotropin secretion after chronic amiodarone administration.". J Clin Endocrinol Metab. 53 (5): 997-1001. PMID 7287882. Retrieved 28 April 2013.
- Westgren, U; Melander A, Wåhlin E, Lindgren J. (Jun 1977). "Divergent effects of 6-propylthiouracil on 3,3',5'-triiodothyronine (RT3) serum levels and in man.". Acta Endocrinol (Copenh). 85 (2): 345-50. PMID 577326. Retrieved 28 April 20013.
- Laurberg, P; Weeke J (Jan 1978). "Opposite variations in serum T3 and reverse T3 during propylthiouracil treatment of thyrotoxicosis.". Acta Endocrinol (Copenh). 87 (1): 88-94. PMID 579537. Retrieved 28 April 2013.
- Laurberg, P; Weeke J (Jan 1980). "Dynamics of serum rT3 and 3,3'-T2 during rT3 infusion in patients treated for thyrotoxicosis with propylthiouracil or methimazole.". Clin Endocrinol (Oxf). 12 (1): 61-5. PMID 7379315.
- Wu, SY; Chopra IJ, Solomon DH, Johnson DE. (Dec 1978). "The effect of repeated administration of ipodate (Oragrafin) in hyperthyroidism.". J Clin Endocrinol Metab. 47 (6): 1358-62. PMID 263735. Retrieved 28 April 2013.
- Suzuki, H; Kadena N, Takeuchi K, Nakagawa S. (Nov 1979). "Effects of three-day oral cholecystography on serum iodothyronines and TSH concentrations: comparison of the effects among some cholecystographic agents and the effects of iopanoic acid on the pituitary-thyroid axis.". Acta Endocrinol (Copenh). 92 (3): 477-88. PMID 517049. Retrieved 28 April 2013.
- Melander, A; Nordenskjöld E, Lundh B, Thorell J. (1981). "Influence of smoking on thyroid activity.". Acta Med Scand. 209 (1-2): 41-3. PMID 7211488.
- Heijckmann, AC; Huijberts MS, Geusens P et al. (Jul 2005). "Hip bone mineral density, bone turnover and risk of fracture in patients on long-term suppressive L-thyroxine therapy for differentiated thyroid carcinoma.". Eur J Endocrinol. 153 (1): 23-9. PMID 15994742. Retrieved 3 May 2013.
- Boelen, A; Platvoet-ter Schiphorst MC, Bakker O, Wiersinga WM. (Sep 1995). "The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice.". J Endocrinol. 146 (3): 475-83. PMID 7595143. Retrieved 5 May 2013.
- van der Poll, T; Endert E, Coyle SM et al. (Feb 1999). "Neutralization of TNF does not influence endotoxin induced changes in thyroid hormone metabolism in humans.". Am J Physiol. 276 (2 Pt 2): R357-62. PMID 9950912. Retrieved 5 May 2013.
- Nicod, P; Burger A, Staeheli V, Vallotton MB. (May 1976). "Radioimmunoassay for 3,3',5'-triiodo-L-thyronine in unextracted serum: method and clinical results.". J Clin Endocrinol Metab. 42 (5): 823-9. PMID 1270576. Retrieved 28 April 2013.
- Hüfner, M; Knöpfle M. (Nov 1 1976). "Pharmacological influences on T4 to T3 conversion in rat liver.". Clin Chim Acta. 72 (3): 337-41. PMID 975586.
- Liewendahl, K; Helenius T, Majuri H et al. (1980). "Effect of anticonvulsant and antidepressant drugs on iodothyronines in serum.". Scand J Clin Lab Invest. 40 (8): 767-74. PMID 7280555.
- Visser, WE; de Rijke YB, van Toor H, Visser TJ. (Sep 2011). "Thyroid status in a large cohort of patients with mental retardation: the TOP-R (Thyroid Origin of Psychomotor Retardation) study.". Clin Endocrinol (Oxf). 75 (3): 395-401. doi:10.1111/j.1365-2265.2011.04089.x. PMID 21535074.
- Hüfner, M; Grussendorf M (1980). "Studies on the deiodination of 3,3',5'-T3 (reverse T3) to 3,3'-T2 (diiodothyronine) in rat liver.". Acta Biol Med Ger. 39 (2-3): 169-75. PMID 7424338.
- Borges, M; LaBourene J, Ingbar SH. (Dec 1980). "Changes in hepatic iodothyronine metabolism during ontogeny of the chick embryo.". Endocrinology. 107 (6): 1751-61. PMID 7428690. Retrieved 28 April 2013.
- Ohnhaus, EE; Bürgi H, Burger A, Studer H. (Oct 1981). "The effect of antipyrine, phenobarbitol and rifampicin on thyroid hormone metabolism in man.". Eur J Clin Invest. 11 (5): 381-7. PMID 6800809.
- Rezvani, I; DiGeorge AM, Dowshen SA, Bourdony CJ. (Jan 1981). "Action of human growth hormone (hGH) on extrathyroidal conversion of thyroxine (T4) to triiodothyronine (T3) in children with hypopituitarism.". Pediatr Res. 15 (1): 6-9. PMID 7208169.
- Gács, G; Bános C (Apr 1981). "The effect of growth hormone on the plasma levels of T4, free-T4, T3, reverse T3 an TBG in hypopituitary patients.". Acta Endocrinol (Copenh). 96 (4): 475-9. PMID 6782790. Retrieved 3 May 2013.
- Westgren, U; Ahrén B, Burger A, Melander A. (Jul 1977). "Stimulation of peripheral T3 formation by oral but not by intravenous glucose administration in fasted subjects.". Acta Endocrinol (Copenh). 85 (3): 526-30. PMID 577337. Retrieved 3 May 2013.
- Danforth, E Jr; Burger AG, Wimpfheimer C. (1978). "Nutritionally-induced alterations in thyroid hormone metabolism and thermogenesis.". Experientia Suppl. 32: 213-7. PMID 348487.
- Selye, H (July 4 1936). "A Syndrome produced by Diverse Nocuous Agents.". Nature. 138 (3479): 32-32. doi:10.1038/138032a0. Retrieved 15 June 2013.
- Chopra, IJ; Williams DE, Orgiazzi J, Solomon DH. (Nov 1975). "Opposite effects of dexamethasone on serum concentrations of 3,3',5'-triiodothyronine (reverse T3) and 3,3'5-triiodothyronine (T3).". J Clin Endocrinol Metab. 41 (5): 911-20. PMID 1242390. Retrieved 28 April 2013.
- Burr, WA; Ramsden DB, Griffiths RS et al. (Jul 10 1976). "Effect of a single dose of dexamethasone on serum concentrations of thyroid hormones.". Lancet. 2 (7976): 58-61. PMID 59147. Retrieved 28 April 2013.
- Gamstedt, A; Järnerot G, Kågedal B, Söderholm B. (1979). "Corticosteroids and thyroid function. Different effects on plasma volume, thyroid hormones and thyroid hormone-binding proteins after oral and intravenous administration.". Acta Med Scand. 205 (5): 379-83. PMID 108922.
- Nauman, A; Kamiński T, Herbaczyńska-Cedro K. (Jun 1980). "In vivo and in vitro effects of adrenaline on conversion of thyroxine to triiodothyronine and to reverse-triiodothyronine in dog liver and heart.". Eur J Clin Invest. 10 (3): 189-92. PMID 6783414.
- Soutto, M; Guerrero JM, Molinero P. (1996). "Beta- and alpha-adrenergic mechanisms are involved in regulating type II thyroxine 5'-deiodinase in rat thymus.". Life Sci. 58 (1): 1-8. PMID 8628106.
- Yasuzawa-Amano, S; Toyoda N, Maeda A et al. (Dec 2004). "Expression and regulation of type 2 iodothyronine deiodinase in rat aorta media.". Endocrinology. 145 (12): 5638-45. PMID 15345674. Retrieved 30 April 2013.
- Verhoeven, RP; Visser TJ, Doctor R et al. (May 1977). "Plasma thyroxine, 3,3',5-triiodothyronine and 3,3',5'-triiodothyronine during beta-adrenergic blockade in hyperthyroidism.". J Clin Endocrinol Metab. 44 (5): 1002-5. PMID 576870. Retrieved 28 April 2013.
- Lumholtz, IB; Busch-Sørensen M, Faber J et al. (1979). "The influence of propranolol on the extrathyroidal metabolism of 3,3',5'-triiodothyronine (reverse T3).". Acta Med Scand Suppl. 624: 31-34. PMID 284711.
- Nilsson, OR; Melander A, Tegler L. (Oct 1980). "Effects and plasma levels of propranolol and metoprolol in hyperthyroid patients.". Eur J Clin Pharmacol. 18 (4): 315-20. PMID 7439251.
- Tagami, T; Yambe Y, Tanaka T et al. (2012). "Short-term effects of β-adrenergic antagonists and methimazole in new-onset thyrotoxicosis caused by Graves' disease.". Intern Med. 51 (17): 2285-90. PMID 22975536. Retrieved 30 April 2013.
- Adami, HO; Rimsten A, Thorén L et al. (1978). "Thyroid disease and function in breast cancer patients and non-hospitalized controls evaluated by determination of TSH, T3, rT3 and T4 levels in serum.". Acta Chir Scand. 144 (2): 89-97. PMID 665106.
- Ratcliffe, JG; Stack BH, Burt RW et al. (Jan 28 1978). "Thyroid function in lung cancer.". Br Med J. 1 (6107): 210-2. PMID 620266. Retrieved 15 May 2013.
- Adami, HO; Hansen J, Rimsten A, Wide L. (1979). "Thyroid function in breast cancer patients before and up to two years after mastectomy.". Ups J Med Sci. 84 (3): 228-34. PMID 543051.
- Rose, DP; Davis TE. (Aug 1981). "Plasma thyronine levels in carcinoma of the breast and colon.". Arch Intern Med. 141 (9): 1161-4. PMID 6789787. Retrieved 15 May 2013.
- Sorvillo, F; Mazziotti G, Carbone A, et al. (Feb 2003). "Increased serum reverse triiodothyronine levels at diagnosis of hepatocellular carcinoma in patients with compensated HCV-related liver cirrhosis.". Clin Endocrinol (Oxf). 58 (2): 207-12. PMID 12580937.
- Romitti, M; Wajner SM, Zennig N et al. (Sep 2012). "Increased type 3 deiodinase expression in papillary thyroid carcinoma.". Thyroid. 22 (9): 897-904. doi:10.1089/thy.2012.0031. PMID 22823995.
- Piekielko-Witkowska, A; Master A, Wojcicka A, et al. (Oct 2009). "Disturbed expression of type 1 iodothyronine deiodinase splice variants in human renal cancer.". Thyroid. 19 (10): 1105-13. doi:10.1089/thy.2008.0284. PMID 19534619.
- García-Solís, P; Aceves C (Mar 28 2003). "5'Deiodinase in two breast cancer cell lines: effect of triiodothyronine, isoproterenol and retinoids.". Mol Cell Endocrinol. 201 (1-2): 25-31. PMID 12706290. Retrieved 23 March 2013.
- Mori, K; Yoshida K, Kayama T et al. (Nov 1993). "Thyroxine 5-deiodinase in human brain tumors.". J Clin Endocrinol Metab. 77 (5): 1198-202. PMID 8077312.
- Calvo, RM; Roda JM, Obregón MJ, Morreale de Escobar G. (Aug 10 1998). "Thyroid hormones in human tumoral and normal nervous tissues.". Brain Res. 801 (1-2): 150-7. PMID 9729351.
- Dentice, M; Luongo C, Huang S et al. (Sep 4 2007). "Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes.". Proc Natl Acad Sci U S A. 104 (36): 14466-71. PMID 17720805. Retrieved 27 April 2013.
- Sato, K; Robbins J. (Aug 10 1980). "Thyroid hormone metabolism in cultured monkey hepatocarcinoma cells. Monodeiodination activity in relation to cell growth.". J Biol Chem. 255 (15): 7347-52. PMID 6771290. Retrieved 24 March 2013.
- Huang, SA; Fish SA, Dorfman DM et al. (Oct 2002). "A 21 year old woman with consumptive hypothyroidism due to a vascular tumor expressing type 3 iodothyronine deiodinase.". J Clin Endocrinol Metab. 87 (10): 4457-61. PMID 12364418. Retrieved 24 May 2013.
- Vigone, MC; Cortinovis F, Rabbiosi S, et al. (2012). "Difficult treatment of consumptive hypothyroidism in a child with massive parotid hemangioma.". J Pediatr Endocrinol Metab. 25 (1-2): 153-5. PMID 22570966.
- Chen, RN; Huang YH, Yeh CT, et al. (Mar 15 2008). "Thyroid hormone receptors suppress pituitary tumor transforming gene 1 activity in hepatoma.". Cancer Res. 68 (6): 1697-706. doi:10.1158/0008-5472.CAN-07-5492. PMID 18339849. Retrieved 20 March 2013.
- Master, A; Wójcicka A, Piekiełko-Witkowska A, et al. (Nov 2010). "Untranslated regions of thyroid hormone receptor beta 1 mRNA are impaired in human clear cell renal cell carcinoma.". Biochim Biophys Acta. 1802 (11): 995-1005. doi:10.1016/j.bbadis.2010.07.025. PMID 20691260. Retrieved 15 May 2013.
- Jazdzewski, K; Boguslawska J, Jendrzejewski J, et al. (Mar 2011). "Thyroid hormone receptor beta (THRB) is a major target gene for microRNAs deregulated in papillary thyroid carcinoma (PTC).". J Clin Endocrinol Metab. 96 (3): E546-53. doi:10.1210/jc.2010-1594. Retrieved 15 June 2013.
- LoPresti, JS; Fried JC, Spencer CA, Nicoloff JT. (Jun 15 1989). "Unique alterations of thyroid hormone indices in the acquired immunodeficiency syndrome (AIDS).". Ann Intern Med. 110 (12): 970-5. PMID 2567143. Retrieved 23 March 2013.
- Lambert, M; Zech F, De Nayer P et al. (Dec 1990). "Elevation of serum thyroxine-binding globulin (but not of cortisol-binding globulin and sex hormone-binding globulin) associated with the progression of human immunodeficiency virus infection.". Am J Med. 89 (6): 748-51. PMID 2147539.
- Crenn, P; Rakotoanbinina B, Raynaud JJ, et al. (Sep 2004). "Hyperphagia contributes to the normal body composition and protein-energy balance in HIV-infected asymptomatic men.". J Nutr. 134 (9): 2301-6. PMID 15333720. Retrieved 23 March 2013.
- Huang, SA; Bianco AC (Mar 2008). "Reawakened interest in type III iodothyronine deiodinase in critical illness and injury.". Nat Clin Pract Endocrinol Metab. 4 (3): 148-55. doi:10.1038/ncpendmet0727. PMID 18212764. Retrieved 8 May 2013.
- Bello, G; Ceaichisciuc I, Silva S, Antonelli M. (Nov 2010). "The role of thyroid dysfunction in the critically ill: a review of the literature.". Minerva Anestesiol. 76 (11): 919-28. PMID 20935602. Retrieved 5 May 2013.
- Mebis, L; Debaveye Y, Ellger B et al. (2009). "Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness.". Crit Care. 13 (5): R147. doi:10.1186/cc8043. PMID 19747372. Retrieved 5 May 2013.
- Hennemann, G; Krenning EP. (Jun 2007). "The kinetics of thyroid hormone transporters and their role in non-thyroidal illness and starvation.". Best Pract Res Clin Endocrinol Metab. 21 (2): 323-38. PMID 17574011. Retrieved 5 May 2013.
- Mebis, L; Paletta D, Debaveye Y et al. (Aug 2009). "Expression of thyroid hormone transporters during critical illness.". Eur J Endocrinol. 161 (2): 243-50. doi:10.1530/EJE-09-0290. PMID 19439506. Retrieved 5 May 2013.
- Chopra, IJ; Sakane S, Teco GN. (May 1991). "A study of the serum concentration of tumor necrosis factor-alpha in thyroidal and nonthyroidal illnesses.". J Clin Endocrinol Metab. 72 (5): 1113-6. PMID 2022711. Retrieved 5 May 2013.
- Boelen, A; Platvoet-Ter Schiphorst MC, Wiersinga WM (Dec 1993). "Association between serum interleukin-6 and serum 3,5,3'-triiodothyronine in nonthyroidal illness.". J Clin Endocrinol Metab. 77 (6): 1695-9. PMID 8263160. Retrieved 5 May 2013.
- Kwakkel, J; Wiersinga WM, Boelen A. (Apr 2006). "Differential involvement of nuclear factor-kappaB and activator protein-1 pathways in the interleukin-1beta-mediated decrease of deiodinase type 1 and thyroid hormone receptor beta1 mRNA.". J Endocrinol. 189 (1): 37-44. PMID 16614379. Retrieved 5 May 2013.
- De Groot, LJ (Jan 2006). "Non-thyroidal illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of current evidence, should be treated with appropriate replacement therapies.". Crit Care Clin. 22 (1): 57-86, vi. PMID 16399020. Retrieved 5 May 2013.
- Langouche, L; Vander Perre S, Marques M et al. (Mar 2013). "Impact of early nutrient restriction during critical illness on the nonthyroidal illness syndrome and its relation with outcome: a randomized, controlled clinical study.". J Clin Endocrinol Metab. 98 (3): 1006-13. doi:10.1210/jc.2012-2809. PMID 23348400. Retrieved 8 May 2013.
- den Brinker, M; Joosten KF, Visser TJ et al. (Oct 2005). "Euthyroid sick syndrome in meningococcal sepsis: the impact of peripheral thyroid hormone metabolism and binding proteins.". J Clin Endocrinol Metab. 90 (10): 5613-20. PMID 16076941. Retrieved 5 May 2013.
- Slag, MF; Morley JE, Elson MK et al. (Jan 2 1981). "Hypothyroxinemia in critically ill patients as a predictor of high mortality.". JAMA. 245 (1): 43-5. PMID 7431627. Retrieved 5 May 2013.
- Tognini, S; Marchini F, Dardano A et al. (Jan 2010). "Non-thyroidal illness syndrome and short-term survival in a hospitalised older population.". Age Ageing. 39 (1): 46-50. doi:10.1093/ageing/afp197. PMID 19917633. Retrieved 5 May 2013.
- Kwakkel, J; Fliers E, Boelen A. (May 2011). "Illness-induced changes in thyroid hormone metabolism: focus on the tissue level.". Neth J Med. 69 (5): 224-8. PMID 21646671. Retrieved 13 April 2013.
- Haas, NA; Camphausen CK, Kececioglu D. (2006). "Clinical review: thyroid hormone replacement in children after cardiac surgery--is it worth a try?". Crit Care. 10 (3): 213. PMID 16719939. Retrieved 13 April 2013.
- Shigematsu, H; Smith RA, Shatney CH. (Oct 1987). "Detrimental effect of reverse triiodothyronine in hemorrhagic shock.". Crit Care Med. 15 (10): 933-8. PMID 3652709.
- Dagan, O; Vidne B, Josefsberg Z et al. (May 2006). "Relationship between changes in thyroid hormone level and severity of the postoperative course in neonates undergoing open-heart surgery.". Paediatr Anaesth. 16 (5): 538-42. PMID 16677263.
- Mebis, L; van den Berghe G (Nov 2009). "The hypothalamus-pituitary-thyroid axis in critical illness.". Neth J Med. 67 (10): 332-40. PMID 19915227. Retrieved 5 May 2013.
- Bello, G; Paliani G, Annetta MG et al. (Aug 2009). "Treating nonthyroidal illness syndrome in the critically ill patient: still a matter of controversy.". Curr Drug Targets. 10 (8): 778-87. PMID 19702524. Retrieved 8 May 2013.
- Wajner, SM; Goemann IM, Bueno AL et al. (May 2011). "IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells.". J Clin Invest. 121 (5): 1834-45. doi:10.1172/JCI44678. PMID 21540553. Retrieved 8 May 2013.
- Van den Berghe, G; de Zegher F, Baxter RC et al. (Feb 1998). "Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues.". J Clin Endocrinol Metab. 83 (2): 309-19. PMID 9467533. Retrieved 5 May 2013.
- Dorfman, SG; Young RL. (Jun 1978). "T4-thyrotoxicosis.". Arch Intern Med. 138 (6): 1016-7. PMID 580554. Retrieved 28 April 2013.
- Smallridge, RC; Wartofsky L, Desjardins RE, Burman KD. (Aug 1978). "Metabolic clearance and production rates of 3,3',5-triiodothyronine in hyperthyroid, euthyroid, and hypothyroid subjects.". J Clin Endocrinol Metab. 47 (2): 345-9. PMID 263302. Retrieved 28 April 2013.
- Schlienger, JL; Chabrier G, Stephan F, Sapin R. (Jan 5 1980). ". [Thyrotoxicosis with low T3 and high reverse T3 levels. 9 cases (author's transl)]. [Article in French]". Nouv Presse Med. 9 (1): 30. PMID 7355063.
- Chabrier, G; Schlienger JL, Stephan F, Reville P. (Apr 8-15 1980). "[Clinical and biological patterns of hyperthyroidism in elderly patients (author's transl)]. [Article in French]". Sem Hop. 56 (13-14): 629-34. PMID 6246589.
- Amico, JA; Derubertis FR. (May-Jun 1981). "Hyperthyroxinemia and hypotriiodothyroninemia with clinical euthyroidism.". Am J Med Sci. 281 (3): 157-63. PMID 7246597.
- Faase, EM; Meacham LR, Novack CM et al. (Jan-Feb 1997). "Decreased reverse T3 levels in neonates with central hypothyroidism.". J Perinatol. 17 (1): 15-7. PMID 9069058.
- Chopra, IJ; Sack J, Fisher DA. (Jun 1975). "Circulating 3,3',5'-triiodothyronine (reverse T3) in the human newborn.". J Clin Invest. 55 (6): 1137-41. PMID 1133163. Retrieved 1 May 2013.
- Laurberg, P (Mar 1978). "Non-parallel variations in the preferential secretion of 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) from dog thyroid.". Endocrinology. 102 (3): 757-66. PMID 743992. Retrieved 1 May 2013.
- Riccabona, G; Glatzl J, Platzer S et al. (1981). "[Endemic goiter in Austria's youth?]. [Article in German]". Padiatr Padol. 16 (2): 189-94. PMID 7243330.
- Lavado-Autric, R; Calvo RM, de Mena RM et al. (Jan 2013). "Deiodinase activities in thyroids and tissues of iodine-deficient female rats.". Endocrinology. 154 (1): 529-36. doi:10.1210/en.2012-1727. PMID 23142811. Retrieved 1 May 2013.
- Liu, N; Zuo A, Liang D et al. (Winter 2006). "Effect of iodine supplement on iodine status and 5'-deiodinase activity in the brain of neonatal rats with iodine deficiency.". Biol Trace Elem Res. 114 (1-3): 207-15. PMID 17206003. Retrieved 6 May 2013.
- Zaletel, K; Gaberšček S (Dec 2011). "Hashimoto's Thyroiditis: From Genes to the Disease.". Curr Genomics. 12 (8): 576-88. doi:10.2174/138920211798120763. PMID 22654557. Retrieved 1 May 2013.
- Panciera, DL; Helfand SC, Soergel SA. (Jan 1995). "Acute effects of continuous infusions of human recombinant interleukin-2 on serum thyroid hormone concentrations in dogs.". Res Vet Sci. 58 (1): 96-7. PMID 7709069. Retrieved 1 May 2013.
- Poncin, S; Lengelé B, Colin IM, Gérard AC. (Apr 2008). "Differential interactions between Th1/Th2, Th1/Th3, and Th2/Th3 cytokines in the regulation of thyroperoxidase and dual oxidase expression, and of thyroglobulin secretion in thyrocytes in vitro.". Endocrinology. 149 (4): 1534-42. doi:10.1210/en.2007-1316. PMID 18187547. Retrieved 1 May 2013.
- Orlická, E; Vondra K, Hill M et al. (2008). "TRH test in patients with diabetes mellitus type 1 and/or autoimmune thyroiditis. Changes in the pituitary-thyroid axis, reverse T3, prolactin and growth hormone levels.". Physiol Res. 57 (Suppl 1): S109-17. PMID 18271686. Retrieved 1 May 2013.
- Ott, J; Promberger R, Kober F et al. (Feb 2011). "Hashimoto's thyroiditis affects symptom load and quality of life unrelated to hypothyroidism: a prospective case-control study in women undergoing thyroidectomy for benign goiter.". Thyroid. 21 (2): 161-7. doi:10.1089/thy.2010.0191. PMID 21186954.
- Greenfield, JR; Samaras K (Jan 2006). "Evaluation of pituitary function in the fatigued patient: a review of 59 cases.". Eur J Endocrinol. 154 (1): 147-57. PMID 16382004. Retrieved 1 May 2013.
- Cignini, P; Cafà EV, Giorlandino C et al. (Oct 2012). "Thyroid physiology and common diseases in pregnancy: review of literature.". J Prenat Med. 6 (4): 64-71. PMID 23272277. Retrieved 29 June 2013.
- Gencer, B; Collet TH, Virgini V et al. (Jan 15. 2013). "Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies.". Endocr Metab Immune Disord Drug Targets. [Epub ahead of print]. PMID 23369133.
- Donnay, S; Balsa JA, Alvarez J et al. (Jun 15. 2013). "Burden of illness attributable to subclinical hypothyroidism in the Spanish population.". Rev Clin Esp. [Epub ahead of print]. doi:10.1016/j.rce.2013.04.009. Check
|doi=value (help). PMID 23773909.
- Garber, JR; Cobin RH, Gharib H et al. (Nov-Dec 2012). "Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association.". Endocr Pract. 18 (6): 988-1028. PMID 23246686. Retrieved 8 May 2013.
- Surks, MI; Ortiz E, Daniels GH et al. (Jan 14 2004). "Subclinical thyroid disease: scientific review and guidelines for diagnosis and management.". JAMA. 291 (2): 228-38. PMID 14722150. Retrieved 3 May 2013.
- Reid, SM; Middleton P, Cossich MC et al. (May 31 2013). "Interventions for clinical and subclinical hypothyroidism pre-pregnancy and during pregnancy.". Cochrane Database Syst Rev. 5: CD007752. doi:10.1002/14651858.CD007752.pub3. Check
|doi=value (help). PMID 23728666.
- Col, NF; Surks MI, Daniels GH. (Jan 14 2004). "Subclinical thyroid disease: clinical applications.". JAMA. 291 (2): 239-43. PMID 14722151. Retrieved 3 May 2013.
- Shomon, MJ (2000). Living well with hypothyroidism: what your doctor doesn’t tell you…that you need to know. New York, NY: Avon Books Inc. ISBN 0-380-80898-6.
- Kharrazian, D (2011). Why do I still have thyroid symptoms? When my lab tests are normal. Garden City, NY.: Morgan James Publishing LLC. ISBN 1600376703.
- Bowthorpe, JA (2011). Stop the thyroid madness: a patient revolution against decades of inferior thyroid treatment. 2nd Edition. Fredericksburg, TX: Laughing Grape Publishing, LLC. ISBN 978-0-615-47712-1.
- Starr, M. (2013). Hypothyroidism Type 2: The Epidemic. Revised 2013 edition. Irvine, CA: New Voice Publications. ISBN 978-0975262405.
- McDaniel, AB (April 17-18, 2013.). "Thyroid physiology and dysfunction: Diagnosis and treatment. Instruction course part IV: The new endocrinology.". American Academy of Environmental Medicine. Retrieved 29 June 2013.
- Barnes, BO, Galton L. (1976). Hypothyroidism: the unsuspected illness. New York, NY.: Harper & Row. ISBN 0-690-01029-X.
- Solter, D; Solter M. (Feb 2012). "Benefit of combined triiodothyronine (LT(3)) and thyroxine (LT(4)) treatment in athyreotic patients unresponsive to LT(4) alone.". Exp Clin Endocrinol Diabetes. 120 (2): 121-3. doi:10.1055/s-0031-1297253. PMID 22187290.
- Panicker, V; Saravanan P, Vaidya B et al. (May 2009). "Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients.". J Clin Endocrinol Metab. 94 (5): 1623-9. doi:10.1210/jc.2008-1301. PMID 19190113. Retrieved 23 June 2013.
- Rowe, AH (Sep 1920). "Basal metabolism in thyroid disease, as an aid to diagnosis and treatment, with notes on the utility of the modified Tissot apparatus.". Cal State J Med. 18 (9): 332-6. PMID 18738275. Retrieved 6 May 2013.
- Gold MS, MS; Pottash AL, Extein I. (May 15 1981). "Hypothyroidism and depression. Evidence from complete thyroid function evaluation.". JAMA. 245 (19): 1919-22. PMID 7230383. Retrieved 6 May 2013.
- Jackson, IM (Oct 1998). "The thyroid axis and depression.". Thyroid. 8 (10): 951-6. PMID 9827665.
- Zoeller, TR (Jan-Mar 2010). "Environmental chemicals targeting thyroid.". Hormones (Athens). 9 (1): 28-40. PMID 20363719. Retrieved 7 May 2013.
- Vandenberg, LN; Colborn T, Hayes TB et al. (Jun 2012). "Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses.". Endocr Rev. 33 (3): 378-455. doi:10.1210/er.2011-1050. PMID 22419778. Retrieved 7 May 2013.
- Udintsev, NA; Serebrov VIu, Tsyrov GI. (Nov 1978). "[Effect of an industrial frequency alternating magnetic field on the functional state of the thyroid gland and thyroxine absorption by the organs of rats]. [Article in Russian]". Biull Eksp Biol Med. 86 (11): 544-6. PMID 719146.
- Zagorskaia, EA (Sep-Oct 1981). "[Effect of a permanent magnetic field on the endocrine system]. [Article in Russian]". Kosm Biol Aviakosm Med. 15 (5): 14-7. PMID 7026894.
- Becker RO and Selden G (1985). The body electric: electromagnetism and the foundation of life. New York, NY: Quill; William Morrow. ISBN 0-688-06971-1.
- Koyu, A; Cesur G, Ozguner F et al. (Jul 4 2005). "Effects of 900 MHz electromagnetic field on TSH and thyroid hormones in rats.". Toxicol Lett. 157 (3): 257-62. PMID 15917150. Retrieved 12 May 2013.
- Mortavazi, S; Habib A, Ganj-Karami A et al. (Oct 2009). "Alterations in TSH and Thyroid Hormones following Mobile Phone Use.". Oman Med J. 24 (4): 274-8. doi:10.5001/omj.2009.56. PMID 22216380. Retrieved 12 May 2013.
- Udintsev, NA; Moroz VV (Dec 1974). "Response of the pituitary-adrenal system to the action of a variable magnetic field.". Bull Exp Biol Med. 77 (6): 641-2. PMID 4441704. Retrieved 12 May 2013.
- Refetoff, S; DeWind LT, DeGroot LJ. (Feb 1967). "Familial syndrome combining deaf-mutism, stippled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone.". J Clin Endocrinol Metab. 27 (2): 279-94. PMID 4163616. Retrieved 6 May 2013.
- Visser, TJ (2013). "Thyroid hormone transporters and resistance.". Endocr Dev. 24: 1-10. doi:10.1159/000343695. PMID 23392090. Retrieved 6 May 2013.
- Dumitrescu, AM; Refetoff S. (Jul 2013). "The syndromes of reduced sensitivity to thyroid hormone.". Biochim Biophys Acta. 1830 (7): 3987-4003. doi:10.1016/j.bbagen.2012.08.005. PMID 22986150. Retrieved 6 May 2013.
- Gilman AG, Murad F. (1975). Thyroid and antithyroid drugs. Goodman LS, Gilman A. The pharmacological basis of therapeutics. 5th Ed. New York, NY.: MacMillan Publishing Co., Inc. p. 1408. ISBN 0-02-344781-8.
- Mandel, SJ; Brent GA, Larsen PR. (Sep 15 1993). "Levothyroxine therapy in patients with thyroid disease.". Ann Intern Med. 119 (6): 492-502. PMID 8357116.
- Brent GA, Larsen PR, Davies TF. (2008). Hypothyroidism and thyroiditis. In: Krnoenberg HM, Melmed S, Polonsky KS, Larsen PR. Williams textbook of endocrinology, Ed 11. Philadelphia PA.: Saunders Elsevier. p. 397. ISBN 9781416029113.
- Jonklaas, J; Davidson B, Bhagat S, Soldin SJ. (Feb 20 2008). "Triiodothyronine levels in athyreotic individuals during levothyroxine therapy.". JAMA. 299 (7): 769-77. doi:10.1001/jama.299.7.769. Check
|doi=value (help). PMID 18285588.
- Hertoghe T. (2006). The hormone handbook. Windhof, Luxembourg: International Medical Books. ISBN 978-2-9599713-0-3.
- Mori, T; Inoue D, Kosugi S et al. (Aug 1988). "Effects of low dose L-triiodothyronine administration on mental, behavioural and thyroid states in elderly subjects.". Endocrinol Jpn. 35 (4): 585-92. PMID 3215145. Retrieved 17 May 2013.
- Saravanan, P; Siddique H, Simmons DJ et al. (Apr 2007). "Twenty-four hour hormone profiles of TSH, Free T3 and free T4 in hypothyroid patients on combined T3/T4 therapy.". Exp Clin Endocrinol Diabetes. 115 (4): 261-7. PMID 17479444.
- Siegmund, W; Spieker K, Weike AI et al. (Jun 2004). "Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism.". Clin Endocrinol (Oxf). 60 (6): 750-7. PMID 15163340.
- Celi, FS; Zemskova M, Linderman JD et al. (Nov 2011). "Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine.". J Clin Endocrinol Metab. 96 (11): 3466-74. doi:10.1210/jc.2011-1329. PMID 21865366. Retrieved 17 May 2013.
- Roti, E; Minelli R, Gardini E et al. (1993). "The use and misuse of thyroid hormone.". Endocr Rev. 14: 401-23. PMID 8223339. Retrieved 29 June 2013.
- Gerdes, AM; Iervasi G. (Jul 27 2010). "Thyroid replacement therapy and heart failure.". Circulation 122 (4): 385-93. doi:10.1161/CIRCULATIONAHA.109.917922. PMID 20660814. Retrieved 17 May 2013.
- Harsan, LA; Steibel J, Zaremba A et al. (Dec 24 2008). "Recovery from chronic demyelination by thyroid hormone therapy: myelinogenesis induction and assessment by diffusion tensor magnetic resonance imaging.". J Neurosci. 28 (52): 14189-201. doi:10.1523/JNEUROSCI.4453-08.2008. PMID 19109501. Retrieved 23 June 2013.
- D'Intino, G; Lorenzini L, Fernandez M et al. (Sep 2011). "Triiodothyronine administration ameliorates the demyelination/remyelination ratio in a non-human primate model of multiple sclerosis by correcting tissue hypothyroidism.". J Neuroendocrinol. 23 (9): 778-90. doi:10.1111/j.1365-2826.2011.02181.x. PMID 21707794.
- Oki, N; Matsuo H, Nakago S, et al. (Oct 2004). "Effects of 3,5,3'-triiodothyronine on the invasive potential and the expression of integrins and matrix metalloproteinases in cultured early placental extravillous trophoblasts.". J Clin Endocrinol Metab. 89 (10): 5213-21. PMID 15472228. Retrieved 19 March 2013.
- Krassas, GE; Poppe K, Glinoer D (Oct 2010). "Thyroid function and human reproductive health.". Endocr Rev. 31 (5): 702-55. doi:10.1210/er.2009-0041. PMID 20573783. Retrieved 2 April 2013.
- van den Boogaard, E; Vissenberg R, Land JA et al. (Sep-Oct 2011). "Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review.". Hum Reprod Update. 17 (5): 605-19. doi:10.1093/humupd/dmr024. PMID 21622978. Retrieved 2 April 2013.
- van Marken Lichtenbelt, WD; Schrauwen P (Aug 2011). "Implications of nonshivering thermogenesis for energy balance regulation in humans.". Am J Physiol Regul Integr Comp Physiol. 301 (2): R285-96. doi:10.1152/ajpregu.00652.2010. PMID 21490370. Retrieved 3 April 2013.
- Silva, JE (Apr 2006). "Thermogenic mechanisms and their hormonal regulation.". Physiol Rev. 86 (2): 435-64. PMID 16601266. Retrieved 3 April 2013.
- Donaldson, M; Jones J (Mar 4 2013). "Optimising outcome in congenital hypothyroidism; current opinions on best practice in initial assessment and subsequent management.". J Clin Res Pediatr Endocrinol. 5 (Suppl 1): 13-22. doi:10.4274/jcrpe.849. PMID 23154163. Retrieved 13 June 2013.
- Chan, S; Kachilele S, Hobbs E et al. (Sep 2003). "Placental iodothyronine deiodinase expression in normal and growth-restricted human pregnancies.". J Clin Endocrinol Metab. 88 (9): 4488-95. PMID 12970328. Retrieved 19 March 2013.
- Pascual, A; Aranda A (Jul 2013). "Thyroid hormone receptors, cell growth and differentiation.". Biochim Biophys Acta. 1830 (7): 3908-16. doi:10.1016/j.bbagen.2012.03.012. PMID 22484490. Retrieved 3 June 2013.
- Ishizuya-Oka, A; Hasebe T, Shi YB (Mar 2010). "Apoptosis in amphibian organs during metamorphosis.". Apoptosis. 15 (3): 350-64. doi:10.1007/s10495-009-0422-y. PMID 20238476. Retrieved 3 April 2013.
- Brown, DD; Cai L (Jun 1 2007). "Amphibian metamorphosis". Dev Biol. 306 (1): 20–33. PMID 17449026. Retrieved 3 June 2013.
- Forhead, AJ; Jellyman JK, Gardner DS, et al. (Feb 2007). "Differential effects of maternal dexamethasone treatment on circulating thyroid hormone concentrations and tissue deiodinase activity in the pregnant ewe and fetus.". Endocrinology. 148 (2): 800-5. PMID 17110425. Retrieved 3 June 2013.
- Byfield, PG; Bird D, Yepez R et al. (Aug 1978). "Reverse triiodothyronine, thyroid hormone, and thyrotrophin concentrations in placental cord blood.". Arch Dis Child. 53 (8): 620-4. PMID 101154.
- Huang, SA; Dorfman DM, Genest DR et al. (Mar 2003). "Type 3 iodothyronine deiodinase is highly expressed in the human uteroplacental unit and in fetal epithelium.". J Clin Endocrinol Metab. 88 (3): 1384-8. PMID 12629133. Retrieved 19 March 2013.
- Wasco, EC; Martinez E, Grant KS et al. (Oct 2003). "Determinants of iodothyronine deiodinase activities in rodent uterus.". Endocrinology. 144 (10): 4253-61. PMID 12959985. Retrieved 6 April 2013.
- McKinnon, B; Li H, Richard K, Mortimer R. (Dec 2005). "Synthesis of thyroid hormone binding proteins transthyretin and albumin by human trophoblast.". J Clin Endocrinol Metab. 90 (12): 6714-20. PMID 16159939. Retrieved 19 March 2013.
- Hernandez, A; Martinez ME, Fiering S et al. (Feb 2006). "Type 3 deiodinase is critical for the maturation and function of the thyroid axis.". J Clin Invest. 116 (2): 476-84. PMID 16410833. Retrieved 6 April 2013.
- Santini, F; Chiovato L, Ghirri P, et al. (Feb 1999). "Serum iodothyronines in the human fetus and the newborn: evidence for an important role of placenta in fetal thyroid hormone homeostasis.". J Clin Endocrinol Metab. 84 (2): 493-8. PMID 10022406. Retrieved 19 March 2013.
- Mortimer, RH; Galligan JP, Cannell GR et al. (Jun 1996). "Maternal to fetal thyroxine transmission in the human term placenta is limited by inner ring deiodination.". J Clin Endocrinol Metab. 81 (6): 2247-9. PMID 8964859. Retrieved 3 April 2013.
- No Authors Listed (Apr 27 1957). "Maternal and foetal thyroid.". Br Med J. 1 (5025): 996-7. PMID 13413274. Retrieved 3 June 2013.
- Santini, F; Pinchera A, Ceccarini G, et al. (Jun 2001). "Evidence for a role of the type III-iodothyronine deiodinase in the regulation of 3,5,3'-triiodothyronine content in the human central nervous system.". Eur J Endocrinol. 144 (6): 577-83. PMID 11375791. Retrieved 19 March 2013.
- Lejeune, J; Peeters M, de Blois MC et al. (1988). "[Thyroid function and trisomy 21. TSH increase and rT3 deficiency]. [Article in French]". Ann Genet. 31 (3): 137-43. PMID 2975939.
- Toledo, C; Alembik Y, Dott B et al. (Feb 1997). "[Anomalies of thyroid function in children with Down syndrome]. [Article in French]". Arch Pediatr. 4 (2): 116-20. PMID 9097820. Retrieved 24 April 2013.
- Lejeune, J (1991). "[Pathogenesis of mental impairment in trisomy 21]. [Article in French]". Ann Genet. 34 (2): 55-64. PMID 1836122.
- Grimaldi, A; Buisine N, Miller T et al. (Jul 2013). "Mechanisms of thyroid hormone receptor action during development: Lessons from amphibian studies.". Biochim Biophys Acta. 1830 (7): 3882-92. doi:10.1016/j.bbagen.2012.04.020. PMID 22565053. Retrieved 3 June 2013.
- Bernal, J; Morte B (Jul 2013). "Thyroid hormone receptor activity in the absence of ligand: Physiological and developmental implications.". Biochim Biophys Acta. 1830 (7): 3893-9. doi:10.1016/j.bbagen.2012.04.014. PMID 22554916. Retrieved 3 June 2013.
- Henderson, J (Jan 2005). "Ernest Starling and 'Hormones': an historical commentary.". J Endocrinol. 184 (1): 5-10. PMID 15642778. Retrieved 18 May 2013.
- Aminoff, MJ (2011). Brown-Séquard: an improbable genius who transformed medicine. New York, NY: Oxford University Press, Inc. ISBN 978-0-19-974263-9.
- Friedman, DM (2001). A mind of its own: a cultural history of the penis. New York, NY: The Free Press, Simon & Schuster, Inc. ISBN ISBN 0-684-85320-5 Check
- Hintzsche, E (Apr 25 1970). "[August Fetscherin (1849-1882), unjustly forgotten general practitioner]. [Article in German]". Schweiz Med Wochenschr. 100 (17): 721-7. PMID 4924042.
- Schlich, T (Oct 1994). "Changing disease identities: cretinism, politics and surgery (1844-1892).". Med Hist. 38 (4): 421-43. PMID 7808101. Retrieved 18 May 2013.
- Osler, W (1901). The principles and practice of medicine, 4th Ed. Edinburgh & London: Young J. Pentland. p. 841-3.
- Pearce, JM (2006). "Sir William Withey Gull (1816-1890).". Eur Neurol. 55 (1): 53-6. PMID 16479123. Retrieved 19 May 2013.
- Pearce, JM (May 2006). "Un cas de myxeodème traité par la greffe hypodermique du corps thyroïde d‘un mouton. Sem Medicale. 1890; 10:294. Cited in: Myxoedema and Sir William Withey Gull (1816-1890).". J Neurol Neurosurg Psychiatry. 77 (5): 639. PMID 16614024. Retrieved 19 May 2013.
- Murray, GR (Oct 10 1891). "Note on the Treatment of Myxoedema by Hypodermic Injections of an Extract of the Thyroid Gland of a Sheep.". Br Med J. 2 (1606): 796-7. PMID 20753415. Retrieved 18 May 2013.
- "The Nobel Prize in Physiology or Medicine 1909". The Nobel Foundation.
- Cushing, H (1912. Digitized Feb 1, 2007.). The pituitary body and its disorders: clinical states produced by disorders of the hypophysis cerebri.. Philadelphia & London: J. B. Lippincott Company.
- Cushing, H; Goetsch E. (Jul 1 1915). "Hibernation and the pituitary body.". J Exp Med. 22 (1): 25-47. PMID 19867901. Retrieved 18 May 2013.
- Crew, FA; Wiesner BP (Apr 26 1930). "On the existence of a fourth hormone, thyreotropic in nature, of the anterior pituitary.". Br Med J. 1 (3616): 777-778. PMID 20775412. Retrieved 19 May 2013.
- Schally, AV; Saffran M, Zimmermann B. (Sep 1958). "A corticotrophin-releasing factor: partial purification and amino acid composition.". Biochem J. 70 (1): 97-103. PMID 13584307. Retrieved 19 May 2013.
- "The Nobel Prize in Physiology or Medicine 1977". The Nobel Foundation.
- Kendall, EC (Aug 1919). "Isolation of the iodine compound which occurs in the thyroid: first paper.". J. Biol. Chem. 39 (1): 125-147. Retrieved 18 May 2013.
- Harington, CR; Barger G. (1927). "Chemistry of Thyroxine: Constitution and Synthesis of Thyroxine.". Biochem J. 21 (1): 169-83. PMID 16743801. Retrieved 18 May 2013.
- Frieden, E; Winzler RJ (Jul 1948). "Comparative parenteral thyroxine-like activity of natural and synthetic thyroporteins studied with the goiter prevention method.". Endocrinology. 43 (1): 40-7. PMID 18871461. Retrieved 22 May 2013.
- Gross, J; Pitt-Rivers R. (Mar 22 1952). "Physiological activity of 3:5:3'-L-triiodothyronine.". Lancet. 1 (6708): 593-4. PMID 14909477.
- Roche, J; Lissitzky S, Michel R. (Mar 1952). "[Triiodothyronine and its presence in thyroid proteins]. [Article in French]". Ann Pharm Fr. 10 (3): 166-72. PMID 14953049.
- Gross, J; Pitt-Rivers R. (Mar 1953). "3:5:3'-triiodothyronine. 2. Physiological activity.". Biochem J. 53 (4): 652-7. PMID 13032125. Retrieved 18 May 2013.
- Sterling, K; Lashof JC, Man EB. (Jul 1954). "Disappearance from serum of I131-labeled l-thyroxine and l-triiodothyronine in euthyroid subjects.". J Clin Invest. 33 (7): 1031-5. PMID 13174660. Retrieved 9 March 2013.
- Sprott WE, WE; Maclagan NF (Feb 1955). "Metabolism of thyroid hormones; the deiodination of thyroxine and triiodotyronine in vitro.". Biochem J. 59 (2): 288-94. PMID 14351194. Retrieved 8 May 2013.
- Gross, J; Leblond CP (Apr 1951). "Metabolites of thyroxine.". Proc Soc Exp Biol Med. 76 (4): 686-9. PMID 14844312.
- Pitt-Rivers, R; Stanbury JB, Rapp B. (May 1955). "Conversion of thyroxine to 3-5-3’-triiodothyronine in vivo.". J Clin Endocrinol Metab. 15 (5): 616-20. PMID 14367478. Retrieved 4 June 2013.
- Lassiter, WR; Stanbury JB (Aug 1958 Aug). "The in vivo conversion of thyroxine to 3:5:3'triiodothyronine.". J Clin Endocrinol Metab. 18 (8): 903-6. PMID 13563619. Retrieved 19 May 2013.
- Sterling, K; Brenner MA, Newman ES. (Sep 11 1970). "Conversion of thyroxine to triiodothyronine in normal human subjects.". Science. 169 (3950): 1099-100. PMID 5449321. Retrieved 19 May 2013.
- Schwartz, HL; Surks MI, Oppenheimer JH. (May 1971). "Quantitation of extrathyroidal conversion of L-thyroxine to 3,5,3'-triiodo-L-thyronine in the rat.". J Clin Invest. 50 (5): 1124-30. PMID 5552409. Retrieved 19 May 2013.
- Ingbar SH, Woeber KA. (1974). Diseases of the thyroid. In: Wintrobe MW, Thorn GW, Adams RD et al., Eds. Harrison’s principles of internal medicine, 7th Ed. New York, NY.: McGraw Hill. p. 465-84. ISBN 0-07-071133-X.
- Roche, J; Michel R, Wolf W. (Jan 10 1955). "[Probable presence of 3,3',5'-triiodothyronine in thyroglobulin].[Article in French]". C R Hebd Seances Acad Sci. 240 (2): 251-3. PMID 14352480. Retrieved 8 March 2013.
- Surks, MI; Oppenheimer JH (Oct 1971). "Metabolism of phenolic- and tyrosyl-ring labeled L-thyroxine in human beings and rats.". J Clin Endocrinol Metab. 33 (4): 612-8. PMID 5093766. Retrieved 19 May 2013.
- Portnay, GI; O'Brian JT, Bush J et al. (Jul 1974). "The effect of starvation on the concentration and binding of thyroxine and triiodothyronine in serum and on the response to TRH.". J Clin Endocrinol Metab. 39 (1): 191-4. PMID 4835133. Retrieved 18 May 2013.