Thyroid gland function is controlled by a feedback loop involving the hypothalamus and the pituitary. Both brain centers monitor thyroid hormone levels in the bloodstream to maintain a steady-state gland function.
Thyroid Hormone Conversion
When blood levels fall, the hypothalamus produces Thyroid Releasing Hormone (TRH) to signal the pituitary to produce Thyroid Stimulating Hormone (TSH). TSH prompts the thyroid gland to increase its production of hormones T4 and T3.
The selenoenzyme family of deiodinases regulates the activity of thyroid hormones by their converting process: removing an iodide from various positions on the relatively inactive T4 molecule to produce primarily T3—or reverse T3.
Iodothyronine 5′-deiodinase has 3 isoforms:
- Types one (D1)
- two (D2)
- and three (D3)
Role of D1, D2, and D3
The role of D1 is primarily to provide T3 in the serum, and is highly expressed in the liver and kidney.
D2 is expressed in many tissues, including the Central Nervous System, (especially the pituitary), brown adipose tissue, and skeletal muscle.
The third, deiodinase, is D3 and converts T4 to reverse T3 (rT3), considered a competitive inhibitor of active T3.
Thyroid Feedback and Conversion Issues: Pituitary
As the pituitary deiodinase, pituitary levels of D2 are essential for feedback regulation of TSH by T4.
According to Dr. Kent Holtorf, founder and medical director of the National Academy of Hypothyroidism, pituitary D2 is 1000 times more efficient at converting T4 to T3 than is D1, acting in the periphery.
The pituitary also lacks D3. This means that none of pituitary T4 becomes rT3. Therefore, conversion to active T3 in the pituitary is much more efficient.
Additionally, D1 (and therefore serum thyroid hormone) is known to be suppressed by stress, low mood, dieting, weight issues, PMS, poor blood sugar regulation, leptin, fatigue, inflammation, an immune issues.
Upregulation of D2
However, this is not true for D2—in fact, it is upregulated by these conditions.
Upregulation of D2 produces optimal intra-pituitary levels of T3, which consequently reduce TSH. Thus, while peripheral conversion is suppressed (hypothyroidism), pituitary conversion is enhanced by the above conditions.
The common practice of using TSH as an indicator for the body’s overall thyroid status assumes that the T3 levels in the pituitary directly correlate with T3 levels in the periphery. According to Dr. Holtorf, this is an incorrect assumption. Though almost universally used, TSH is an ineffective measure of whole body thyroid status. Serum fT3, fT4 and serum rT3 must also be evaluated to know overall thyroid status.
 Marsili A, Aguayo-Mazzucato C, Chen T, et al. (2011). Mice with a Targeted Deletion of the Type 2 Deiodinase Are Insulin Resistant and Susceptible to Diet Induced Obesity. PLoS One. 2011; 6(6): e20832.
 Luongo C, Martin C, Vella K, et al. (2015). The selective loss of the type 2 iodothyronine deiodinase in mouse thyrotrophs increases basal TSH but blunts the thyrotropin response to hypothyroidism. Endocrinology. Feb;156(2):745-54.
 National Academy of Hypothyroidism, op. cit.