Thyroid-stimulating hormone
Abbreviation TSH
Molecular formula Glycoprotein (~28 kDa); two subunits (α and β) with complex carbohydrate chains
Type Pituitary glycoprotein hormone
Administration Endogenous only
Bioavailability N/A, regulated by hypothalamic TRH and feedback from T3/T4
Synonyms Thyrotropin, Thyrotropic hormone
Source Anterior pituitary gland (thyrotrope cells)
Ray's verdict Generally hurts
Strongly negative, TSH itself is harmful, not just a marker, inflammatory and tissue-damaging


Thyroid-stimulating hormone (TSH), also known as thyrotropin, is a glycoprotein hormone produced by the anterior pituitary gland. It serves as the primary regulator of thyroid gland activity, stimulating the thyroid to produce thyroxine (T4) and triiodothyronine (T3). TSH is commonly measured in clinical settings as a marker of thyroid function, though its interpretation and the appropriateness of current reference ranges remain subjects of significant debate.

History

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Etymology

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The name is descriptive: it is the pituitary hormone that stimulates the thyroid gland. It is also called thyrotropin, using the "-tropin" suffix for pituitary hormones that act on another gland.

Bennett Allen and Philip Smith identified the pituitary's role in stimulating thyroid activity in 1916, though TSH wasn't isolated in pure form until decades later.

The TSH test became widely adopted as the "gold standard" for evaluating thyroid function after replacing the protein-bound iodine (PBI) test, which was abandoned in the 1960s when it was proven to be irrelevant to thyroid function [1]. Prior to the 1940s, hypothyroidism was diagnosed on the basis of basal metabolic rate (BMR) and clinical signs and symptoms, with approximately 40% of the American population meeting the diagnostic criteria [2].

The PBI test, introduced in the late 1940s, suggested that only 5% of the population was hypothyroid [3]. This dramatic reduction from 40% to 5% shaped the statistical norms for subsequent tests. When TSH measurement became available, its "normal" ranges were established using these already artificially narrowed expectations, resulting in what some researchers consider pathologically high TSH levels being defined as normal [4].

The reference ranges for TSH have undergone numerous revisions: while 7.0 microIU/mL was once considered normal, the cutoff was later lowered to 6.4, then 5.5, and then 4.2 [5]. In 2003, the American Association of Clinical Endocrinologists changed their guidelines for the normal range to 0.3 to 3.0 microIU/mL [6].

Structure/Chemical properties

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TSH is a glycoprotein hormone consisting of two non-covalently linked subunits: an alpha subunit common to other pituitary hormones (FSH, LH, hCG) and a beta subunit unique to TSH that confers its biological specificity. The hormone is synthesized in the thyrotroph cells of the anterior pituitary gland under the control of hypothalamic thyrotropin-releasing hormone (TRH) [7].

The molecular structure enables TSH to bind to TSH receptors on thyroid follicular cells, initiating a cascade of intracellular signaling that promotes thyroid hormone synthesis and release.

Function/Mechanism of Action

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TSH operates within the hypothalamic-pituitary-thyroid (HPT) axis through a negative feedback loop. The hypothalamus secretes TRH, which stimulates TSH release from the pituitary. TSH then acts on the thyroid gland to promote the synthesis and release of T4 and T3. When circulating thyroid hormone levels rise, they suppress further TSH secretion; when they fall, TSH increases [8].

Approximately 90% of TSH suppression occurs through circulating T4, which is converted to T3 within the cells of the pituitary. This intrapituitary conversion is what primarily signals to the pituitary that the thyroid has done its job [9].

Beyond its effects on the thyroid, TSH has direct actions on many cell types including fibroblasts, fat cells, pigment cells in the skin, mast cells, and bone marrow cells [10][11]. This widespread action suggests TSH functions as more than simply a thyroid-regulating hormone.

"TSH has direct actions on many cell types other than the thyroid, and probably contributes directly to edema, fibrosis, and mastocytosis." [10]

TSH is increased by stress hormones and serotonin. Low thyroid individuals often exhibit elevated serotonin, which in turn raises both TSH and prolactin. This creates a self-perpetuating pattern of high TSH, high prolactin, and high serotonin that suppresses mitochondrial respiration and carbon dioxide production [12].

Increasingly, TSH (the pituitary thyroid stimulating hormone) has been treated as if it meant something independently; however, it can be brought down into the normal range, or lower, by substances other than the thyroid hormones.

— Ray Peat[13]

Medical uses/Effects

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Pro-inflammatory actions

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TSH itself is considered pro-inflammatory, with direct tissue-irritating effects wherever it has been studied. It promotes inflammation in blood vessels and bone marrow, and contributes to hypertension and circulatory problems [14]. The TSH molecule creates inflammation in the blood vessels, working alongside parathyroid hormone to calcify blood vessels and shift calcium out of bones [15].

"The TSH goes around irritating or creating inflammation, for example, in the blood vessels... TSH in excess works in that same direction, calcifying the blood vessels, increasing blood pressure." [15]

TSH contributes to atherosclerosis, increased blood lipids, and increased blood pressure [16]. High TSH is associated with increased production of mucopolysaccharides, the accumulation of which is a hallmark of hypothyroidism (myxedema) [5].

Bone metabolism

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TSH reduces bone turnover indicators, which has been misinterpreted as protective against osteoporosis. However, TSH, like estrogen, increases osteoprotegerin, which is closely associated with bone loss, osteoporosis, osteopenia, and calcification of soft tissues [17]. TSH increases the movement of calcium into arteries and heart while depleting it from bones [17].

Cancer associations

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Chronic exposure of the thyroid gland to TSH is carcinogenic, leading to nodule formation and ultimately increased risk of thyroid cancer [18]. Populations with TSH below 0.4 show the lowest incidence of thyroid cancer [5]. Some types of thyroid cancer can be controlled by keeping TSH completely suppressed [19].

TSH's role may extend to other cancers as well. Its action on diverse cell types including pigment cells suggests a potential involvement in melanoma development [20].

Cardiovascular effects

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One study found that TSH levels of 1.5 to 3.5 (within the "normal" range) were associated with developing fatal coronary heart disease [5]. TSH increases fibrinogen in the blood, making it more viscous and harder to circulate [21].

Relationship to stress

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TSH functions as an indicator of stress as much as it indicates thyroid status. Stress hormones like cortisol and adrenaline can suppress TSH, making a person appear euthyroid on tests while remaining functionally hypothyroid [14]. Conversely, stress conditions that increase the need for thyroid production tend to increase TSH, while simultaneously producing cortisol and adrenaline that suppress it defensively [15].

Dosing

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Produced endogenously, you wouldn't want to supplement an inflammatory and tissue damaging hormone anyway

Instead look at Supplementing T3/T4

Reference ranges and optimal values

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The current accepted range of 0.3 to 3.0 microIU/mL is considered too lenient by some researchers. Ray has observed that over a period of several years, he never saw a person whose TSH was over 2 microIU/mL who was "comfortably healthy," forming the impression that the normal or healthy quantity was probably something less than 1.0 [22].

Thyroid specialists at the University of California Medical Center in San Francisco prefer to see corrected TSH levels around 0.2, slightly below the standard normal range [5]. A population found to be generally healthy without heart disease or cancer had TSH values of 0.4 or less [23]. Many individuals report being healthy with TSH values of 0.1 or even lower [24].

"I look at TSH as one of the pro-inflammatory pituitary hormones that is best when it's minimal." [24]

Animals lacking pituitaries (and therefore TSH) in W.D. Denckla's experiments showed remarkable longevity, and naturally pituitary-deficient dwarf mice that lack TSH, prolactin, and growth hormone live about a year longer than normal mice [25][26].

Side/Adverse effects

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Direct effects of elevated TSH

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When TSH is very low (suppressed)

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The main medical concern regarding suppressed TSH is osteoporosis. However, this argument is based on the same flawed reasoning used to promote estrogen for bone health: reduced bone turnover indicators were equated with bone protection, when in fact the substances that reduce turnover (TSH and estrogen) are associated with calcium being moved from bones into soft tissues [17].

Until there is evidence that very low TSH is somehow harmful, there is no basis for setting a lower limit to the normal range [28].

References

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  1. ↑ Ray Peat, "Thyroid: Therapies, Confusion, and Fraud," Ray Peat Collected Works.
  2. ↑ Ray Peat, "Hypothyroidism," raypeat.com.
  3. ↑ Ray Peat, "Thyroid," raypeat.com.
  4. ↑ Ray Peat, "Hypothyroidism," raypeat.com.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Danny Roddy, "Male Pattern Baldness: A Survival Guide."
  6. ↑ Ray Peat, "Hypothyroidism," raypeat.com.
  7. ↑ PubMed, "Central regulation of hypothalamic-pituitary-thyroid axis."
  8. ↑ Danny Roddy, "Q&A with Georgi Dinkov," Generative Energy podcast.
  9. ↑ Danny Roddy, "If Free T3 Looks Good, Why Is TSH Still a Little High?"
  10. ↑ 10.0 10.1 10.2 Ray Peat, "Hypothyroidism," raypeat.com.
  11. ↑ Whetsell, et al., 1999.
  12. ↑ Ray Peat, interview, "Serotonin and Endotoxin," 2011.
  13. ↑ "Hypothyroidism", raypeat.com.
  14. ↑ 14.0 14.1 14.2 Ray Peat, interview, One Radio Network, 2020.
  15. ↑ 15.0 15.1 15.2 15.3 Ray Peat, "One Radio Network: Vitamin D, Thyroid, Evolving Consciously", One Radio Network, 36:03
  16. ↑ 16.0 16.1 Ray Peat, interview, "Serotonin Raises TSH."
  17. ↑ 17.0 17.1 17.2 17.3 17.4 Ray Peat, interview, "The Thyroid."
  18. ↑ 18.0 18.1 Ray Peat, "Q&A: PUFAs, fructose, weight loss."
  19. ↑ Ray Peat, "Hypothyroidism," raypeat.com.
  20. ↑ Ray Peat, "Hypothyroidism," raypeat.com.
  21. ↑ Ray Peat, interview, "Blood Pressure Regulation," KMUD.
  22. ↑ Ray Peat, "Hypothyroidism," raypeat.com.
  23. ↑ Ray Peat, interview, KMUD.
  24. ↑ 24.0 24.1 Ray Peat, interview, "Peat Ray," 2021-11-15.
  25. ↑ Ray Peat, "Hypothyroidism," raypeat.com.
  26. ↑ Heiman, et al., 2003.
  27. ↑ Wheatley and Edwards, 1983.
  28. ↑ Ray Peat, "Hypothyroidism," raypeat.com.