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Thyroid Therapy

Thyroid Functions

Thyroid Functions

Thyroid Therapy
Thyroid Functions
Thyroid Hormone Replacement Defy Medical 02

If you struggle with fatigue, unexplained weight gain, decreased metabolism or other symptoms of a thyroid condition, Defy Medical can help you diagnose and treat this condition. As a concierge clinic, we offer a personalized approach to thyroid replacement therapy with access to a variety of affordable treatment options.

Defy Medical is a leading clinic in both preventative and restorative therapies that focus on the entire person and not just the symptoms. We work with our patients to help improve quality of life, overall health and promote longevity by combining proven treatment models for thyroid replacement therapy and hormone imbalance.

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Brief overview of Thyroid function

The thyroid is an important hormone producing gland located in the neck that continually releases hormones into the blood stream. The primary function of the thyroid gland is to synthesize and secrete thyroxine (3,5,3′,5′-tetraiodothyronine, also known as T4).*

*Thyroid Gland, Anatomy and Physiology. Wilmar M. Wiersinga, in Encyclopedia of Endocrine Diseases, 2004

Synthesis and Secretion of thyroid hormones:

  • Thyroid Releasing Hormone (TRH) is released by the hypothalamus.
  • TRH stimulates cells in the anterior pituitary to secrete Thyroid Stimulating Hormone (TSH).
  • TSH travels to the thyroid and stimulates the synthesis and secretion of thyroxine (T4).
  • Thyroxine converts to triiodothyronine (T3) and reverse triiodothyronine (rT3) through a process called deiodination.
  • The physiologic actions of thyroid hormones are produced predominately by T3, the majority of which (approximately 80%) is derived from T4 by deiodination (removal of iodine) in peripheral tissues.

Function of Thyroid hormones:

  • enhance oxygen consumption by most tissues of the body
  • increase the basal metabolic rate and the metabolism of carbohydrates, lipids and proteins
  • exert a profound influence on every organ system in the body
  • important for the development of the central nervous system

Thyroid hormones regulate our body's metabolism and influence virtually every organ system in the body. They tell organs how fast or slow they should work. Thyroid hormones also regulate the body's consumption of oxygen and production of heat. Thyroid problems, such as an overactive or an underactive thyroid, can severely affect metabolism.

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How the body maintains balance:

Thyrotropic feedback control

Hormone levels are controlled by a feedback loop mechanism that regulates the release of TSH from the anterior pituitary based upon the amount of thyroid hormone detected in the bloodstream. As thyroid hormone levels rise, the release of TRH from the hypothalamus is inhibited, preventing the release of TSH. Without TSH stimulation, the thyroid stops the release of thyroid hormones. This mechanism prevents the thyroid from overproducing thyroid hormones to maintain consistent levels. As circulating thyroid hormones are used and levels fall, the thyroid axis resumes normal production, allowing the thyroid to secrete more hormone.  

Hypothalamus - Pituitary - Thyroid Axis (HPT)

The hypothalamus-pituitary-thyroid (HPT) axis determines the set point of thyroid hormone (TH) production. Hypothalamic thyrotropin-releasing hormone (TRH) stimulates the synthesis and secretion of pituitary thyrotropin (thyroid-stimulating hormone, TSH), which acts at the thyroid to stimulate all steps of TH biosynthesis and secretion. The THs thyroxine (T4) and triiodothyronine (T3) control the secretion of TRH and TSH by negative feedback to maintain physiological levels of the main hormones of the HPT axis. Reduction of circulating TH levels due to primary thyroid failure results in increased TRH and TSH production, whereas the opposite occurs when circulating THs are in excess. (Compr Physiol. 2016 Jun 13;6(3):1387-428. doi: 10.1002/cphy.c150027. Hypothalamus-Pituitary-Thyroid Axis. Ortiga-Carvalho TM1, Chiamolera MI2, Pazos-Moura CC1, Wondisford FE3.)

Thyroid Hormone Summary

L-Thyroxine (T4)

  • L-thyroxine is the major hormone derived from the thyroid gland.
  • Thyroxine is synthesized via the iodination of tyrosines (MONOIODOTYROSINE) and the coupling of iodotyrosines (DIIODOTYROSINE) in the THYROGLOBULIN.
  • Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood.
  • pproximately 70% of secreted thyroxine (T4) is deiodinated to equal amounts of triiodothyronine (T3) and reverse triiodothyronine (rT3). (source:

Triiodothyronine (T3)

  • T3 is the primary hormone responsible for producing most of the effects associated with thyroid hormones; basal metabolic rate, body temperature, nutrient metabolism, etc.
  • 20% of daily supply is released directly from the thyroid, while 80% is produced from thyroxine. Thyroid Gland, Anatomy and Physiology. Wilmar M. Wiersinga, in Encyclopedia of Endocrine Diseases, 2004.
  • Thyroxine (T4) is peripherally deiodinated (removal of iodine) to form triiodothyronine (T3).
  • T3 exerts a broad spectrum of stimulatory effects on cell metabolism.
  • T3 is roughly 4 times more potent than T4 in its effects on target tissues.

Reverse T3 (rT3)

  • Reverse T3 is another product of thyroxine that is believed to be inactive.
  • Reverse T3 is formed through removal of iodine from the 5 position of T4 or thyroxine (deiodination).
  • 70% of thyroxine converts to equal amounts of T3 and rT3
  • Think of rT3 as a mirrored opposite of T3, attaching to T3 receptor sites “backwards” without producing any activity, thereby blocking the metabolic effects of T3.
  • One purpose of rT3 is to protect against hyperthyroidism resulting from too much T3 attaching to receptor sites, especially when patients are over prescribed thyroid medications. Serves as a counter-balance to T3 levels. (Arch Dis Child. 1984 Jan; 59(1): 30–35.

PMCID: PMC1628409. The importance of reverse triiodothyronine in hypothyroid children on replacement treatment. M Desai, A J Irani, K Patil, and C S Pandya) .

  • Stress appears to refocus deiodination functions with the conversion of T4 to rT3 being favored over the production of T3.
  • Too much rT3 can result in decreased metabolic function and symptoms associated with low thyroid hormone levels.

3,5-diiodothyronine (T2)

  • Both T3 and reverse T3 are thought to deiodinate into a metabolite called 3,5-diiodothyronine (T2) within peripheral tissues.
  • T2 is a poorly understood metabolite of T3, and previously believed to be relatively inert.
  • Several rat model studies provide evidence that T2 may possess its own influence on energy (lipid and carbohydrate) metabolism separate from T3.
  • Recent research has promoted interest in the use of T2 supplementation for the treatment of obesity and metabolic disorder. The academic community appears to realize this data and as there are a few published articles discussing T2’s potential effects in humans and the need for more comprehensive human studies to assess any risks.
  • Emerging evidence revealing the function of T2 supports
    • the need for more research and better understanding of thyroid hormone function
    • the importance of taking a holistic approach to thyroid diagnosis and treatment
    • the continued development and availability of thyroid replacement products
  • 3,5-diiodothyronine is an ingredient found in several over the counter products marketed to consumers as a fat loss agent and metabolic enhancer. There is a risk taking these OTC supplements since the contents cannot be verified and the dose needed to provide efficacy in humans in unknown. Taking a dosage that is too low will result in negative feedback and reduction of endogenous thyroid hormones. 

Other metabolites

  • Monoiodothyronine (T1) is a hormone precursor and byproduct of thyroid hormone synthesis. It has unknown physiological effects
  • Calcitonin regulates levels of calcium and phosphate in the blood, opposing the action of parathyroid hormone

Biologic effects of Thyroid Hormones (T3 and T4):

  • Triiodothyronine (T3) primarily responsible for effects
  • Increase in thyroid hormones =
    • increase in body temperature
    • increase in cardiac output
    • increase ventilation
    • increase food intake requirements
    • increase in the breakdown of energy stores (carbohydrates, fat, protein)
    • thyroid hormones also maintain alertness, responsiveness, and emotional state

T3 Calorigenic Effects

  • Protein Metabolism
    • T3 stimulates protein synthesis. It also increases the rate of protein degradation, and, in excess, the rate of protein degradation exceeds the rate of protein synthesis causing loss of muscle tissue
  • Glucose Metabolism
    • T3 potentiates the effects of the β-adrenergic receptors on the metabolism of glucose; increases the rate of glycogen breakdown; increases glucose synthesis
  • Lipid Metabolis
    • T3 stimulates an increase in lipolysis; Increase oxidation of free fatty acids(FFA); decreases serum cholesterol (excretion into GI)

Effects on CNS and Brain Function

  • Thyroid hormones have a significant influence on the development and maturation of the central nervous system.
  • Both decreased and increased concentrations of thyroid hormones lead to alterations in mental state. Too little thyroid hormone, and the individual tends to feel mentally sluggish, while too much induces anxiety and nervousness.
  • Subclinical thyroid dysfunctions may cause cognitive deficits and mood disorders.
  • One study’s findings provide evidence of neuropsychological impairment in patients with differentiated thyroid carcinoma treated with chronic TSH-suppressive therapy.*
  • Thyroid hormones seem to have a regulatory role with regard to life span.

CNS References:

  • J. Endocrinol. Invest. 35: 760-765, 2012*
  • Thyroid Hormones and the Central Nervous System. Dev Neurosci 1994;16:1–8.

Thyroid Hormone Metabolism

How Thyroid Hormones are made from other hormones

Thyroid hormone is indispensable for normal development and metabolism of most cells and tissues. Thyroid hormones are metabolized by different pathways: glucuronidation, sulfation, and deiodination, the latter being the most important. Basically, thyroid hormones are created by adding or removing iodine molecules from chemicals produced within the thyroid gland.
Iodine is an important nutritional element that the thyroid stores and uses to create its primary hormone Thyroxine (T4). A protein within the thyroid gland called thyroglobulin reacts with the stored iodine to create precursors used to produce thyroid hormones. These precursor products are called iodotyrosines and include monoiodotyrosine and diiodotyrosine. Triiodothyronine is formed when diiodotyrosine is combined with monoiodotyrosine within in the colloid of the thyroid follicle (follicles are located within the thyroid gland). Two molecules of diiodotyrosine combine to make the thyroid hormone thyroxine. Remember, roughly 20% of the daily triiodothyronine supply is secreted by the thyroid after being synthesized through this process. The other 80% is produced from thyroxine within peripheral tissues through a process called deiodination, or the removal of iodine, from a specific location on the molecule. Only a small amount of T3 is secreted directly from the thyroid compared to thyroxine, which is the primary hormone produced and released. Therefore, the process of diodination is a critical for achieving adequate levels of T3. Patients who have disruption of this process may continue to experience symptoms of hypothyroidism while taking levothyroxine monotherapy, since they are unable to convert the T4 into T3. 

Deiodination: Necessary for healthy thyroid hormone balance

Deiodination = the removal or release of iodine from an attached chemical
Deiodination is the process by which an iodine molecule is removed from Iodotyrosines that make up thyroxin, basically reversing the iodination process that created it. Diodination converts T4 into equal amounts of T3 and reverse T3, depending on the location where the iodine was removed. Diodination occurs again down the pathway to release iodine from Iodotyrosines that make up T3 and rT3, converting a % of each hormone into a metabolite known as 3,5-diiodothyronine (T2). The process of deiodination, or the release of iodine, is an important aspect of thyroid hormone metabolism and the synthesis of physiogically active hormones including T3.

References for the above paragraph:

  • Metabolism of Thyroid Hormone Robin P Peeters, M.D. Ph.D. and Theo J Visser, Ph.D.
  • Thyroid Gland, Anatomy and Physiology Wilmar M. Wiersinga, in Encyclopedia of Endocrine Diseases, 2004

Thyroid Hormone Gene: Why it’s important to seek personalized thyroid care 

Studying the gene identified as DIO2 (IDII) has shown that treating all cases of hypothyroidism with the same conventional methodology might not be the most effective treatment. These are two populations that react very differently to levothyroxine sodium monotherapy: while one group achieves the desired T3 levels, the other does not. For these individuals, levothyroxine sodium (T4) alone is incapable of fully remedying the symptoms of hypothyroidism: these people cannot convert their new stores of T4 into T3 (and having too much T4 without enough IDII can even make the problem worse — T4 that that doesn’t become T3 is more likely to become reverse T3 which decreases thyroid function. Adding T3, in theory and in practice, essential for these individuals. (Gavin L, Castle J, McMahon F, Martin P, Hammond M, Cavalieri R. “Extrathyroidal Conversion of Thyroxine to 3, 3’, 5’-Triiodothyronine (Reverse-T3) and to 3, 5, 3’-Triiodotyronine. Journal of clinical endocrinology and Metabolism. 1977;44(4):733-42.)

DIO2 Gene: “The protein encoded by this gene belongs to the iodothyronine deiodinase family. It catalyzes the conversion of prohormone thyroxine (3,5,3',5'-tetraiodothyronine, T4) to the bioactive thyroid hormone (3,5,3'-triiodothyronine, T3) by outer ring 5'-deiodination. This gene is widely expressed, including in thyroid, placenta, pituitary and brain. It is thought to be responsible for the 'local' production of T3, and thus important in influencing thyroid hormone action in these tissues. It has also been reported to be highly expressed in thyroids of patients with Graves disease, and in follicular adenomas. The intrathyroidal T4 to T3 conversion by this enzyme may contribute significantly to the relative increase in thyroidal T3 production in these patients.” (DIO2 iodothyronine deiodinase 2 [ Homo sapiens (human) ]

Gene ID: 1734, updated on 5-Nov-2017)
Resource: Metabolism of Thyroid Hormone. Robin P. Peeters, M.D. Ph.D.
Dept. of Endocrinology, Room D-442, Erasmus University Medical Center, Wytemaweg, 3015 CE, Rotterdam The Netherlands