The hypothalamus-pituitary-thyroid (HPT)-axis and its role in physiology and pathophysiology of other hypothalamus-pituitary functions

May combine two claims.

A thyroid cell study in primary cultures of human thyrocytes showed a ghrelin-induced decrease in TSH-induced production of thyroglobulin and mRNA expression of thyroperoxidase as well as a trend towards inhibition of TSH-stimulated expression of sodium-iodine symporter and TSH-receptor.

“A thyroid cell study in primary cultures of human thyrocytes showed a ghrelin-induced decrease in the TSH-induced production of thyroglobulin and mRNA expression of thyroperoxidase as well as a trend towards an inhibition of TSH-stimulated expression of the sodium-iodine symporter and the TSH-receptor (Barington et al., 2017).”

• cites Barington et al., 2017 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Ghrelin is a brain-gut peptide with GH-releasing and appetite-inducing activities and is the endogenous ligand of the G protein-coupled GH secretagogue receptor.

“Ghrelin is a brain-gut peptide with growth hormone-releasing and appetite-inducing activities and is the endogenous ligand of the G protein-coupled growth hormone secretagogue receptor (Leontiou et al., 2007).”

• cites Leontiou et al., 2007 sourceNot checked yet

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Feedback of TSH at hypothalamic (short) and pituitary (ultra-short) levels exists.

“Moreover, a feedback of TSH at the hypothalamic (short feedback) and the pituitary (ultra-short feedback) levels exists (Fekete and Lechan, 2013;Prummel et al., 2004).”

• cites Fekete and Lechan, 2013Not checked yet

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• cites Prummel et al., 2004 sourceNot checked yet

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The dynamic interplay between TRH and TSH and feedback effects of circulating thyroid hormones result in a remarkably stable morning concentration of TSH and little alteration in circulating thyroid hormones from day to day and year to year.

“The dynamic interplay between TRH and TSH and the feedback effects of circulating thyroid hormones at the hypothalamic and pituitary levels result in a remarkably stable morning concentration of TSH in the circulation and consequently little alteration in the concentration of circulating thyroid hormones from day to day and year to year (Feldt-Rasmussen et al., 2018;Mariotti and Beck-Peccoz, 2016;”

• cites Feldt-Rasmussen et al., 2018Not checked yet

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• cites Mariotti and Beck-Peccoz, 2016Not checked yet

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• cites Persani and Beck-Peccoz, 2021Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Central hypothyroidism is diagnosed in 1:16,000 to about 1:100,000 of the general adult or neonatal populations and accounts for about 1 of 1000 hypothyroid patients.

“Central hypothyroidism is diagnosed in 1: 16.000 to about 1: 100.000 of the general adult or neonatal populations (Persani et al., 2018) and accounts for about 1 of 1000 hypothyroid patients (Yamada and Mori, 2008).”

• cites Persani et al., 2018 sourceNot checked yet

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• cites Yamada and Mori, 2008 sourceNot checked yet

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The nonthyroidal illness syndrome is characterized by decreased T3, normal measurable T4, increased rT3, and normal or low circulating TSH.

“The alterations in the metabolism of the thyroid hormones during illness consisting of the nonthyroidal illness syndrome is characterized by decreased T3 and normal measurable T4, and increased rT3 concentrations in the presence of normal or even low circulating TSH concentrations (Fig. 3).”

• cites Lechan et al., 2016Not checked yet

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Circulating T4 and T3 influence biosynthesis and secretion of TRH in hypothalamus and TSH in anterior pituitary (long feedback).

“Circulating concentrations of the thyroid hormones (T4 and T3) thus influence the biosynthesis and secretion of TRH in hypothalamus (Fig. 2) and TSH in the anterior pituitary (long feedback) (Lechan et al., 2016).”

• cites Lechan et al., 2016Not checked yet

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Both alpha-MSH and CART induce transcription of the TRH gene in hypophysiotropic neurons, whereas NPY and AGRP are inhibitory.

“Both alpha-melanocyte stimulating hormone (MSH) and CART induce transcription of the TRH gene in hypophysiotropic neurons, whereas the effect of NPY and agouti related peptide are inhibitory (Lechan et al., 2016).”

• cites Lechan et al., 2016Not checked yet

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The several hypothalamus-pituitary-target organ axis systems interact in very sophisticated and complicated ways, and for many the interactive and integrated mechanisms are still not quite clear.

“The several hypothalamus-pituitary-target organ axis systems interact in very sophisticated and complicated ways and for many of them the interactive and integrated mechanisms are still not quite clear.”

• Also stated in: § 1. Introduction · plain

  “The several hypothalamus-pituitary-target organ axis systems interact in very sophisticated and complicated ways and for many of them the interactive and integrated mechanisms are still not quite clear (Santisteban and Costagliola, 2021).”

• cites Santisteban and Costagliola, 2021Not checked yet

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The diagnosis of hypothyroidism in routine clinical setting is based on a TSH screening strategy, but this strategy is useless in central hypothyroidism where an inappropriately low/normal serum TSH concentration is seen.

“The diagnosis of hypothyroidism is in the routine clinical setting based on a TSH screening strategy (Baloch et al., 2003;Feldt-Rasmussen and Klose, 2020), but this strategy is useless in case of central hypothyroidism where an inappropriately low/normal serum TSH concentration is seen (Feldt-Rasmussen et al., 2018;Persani et al., 2018).”

• cites Baloch et al., 2003 sourceNot checked yet

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• cites Feldt-Rasmussen and Klose, 2020Not checked yet

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• cites Feldt-Rasmussen et al., 2018Not checked yet

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TSH stimulates thyroid follicular cells to release T4 (80%) and T3 (20%).

“TSH, in turn, stimulates thyroid follicular cells to release thyroxine (T4) (80%), and triiodothyronine (T3) (20%).”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The most common affection of the HPT system is related to failure of hormone production leading to hypothyroidism.

“The most common affection of the hypothalamus-pituitary-thyroid system is related to failure of the hormone production leading to hypothyroidism.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The half-life of circulating TSH ranges from 50 to 80 min.

“The half-life of circulating TSH ranges from 50 to 80 min.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Contrary to primary hypothyroidism with a clear female predominance, central hypothyroidism affects both sexes equally.

“Contrary to primary hypothyroidism with a clear female predominance, central hypothyroidism affects both sexes equally.”

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The major regulators of TSH production are inhibitory effects of thyroid hormone and stimulatory action of TRH.

“The major regulators of TSH production are thus represented by inhibitory effects of thyroid hormone and the stimulatory action of TRH.”

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During fasting, the normal feedback mechanisms are bypassed, inducing a transient state of central hypothyroidism.

“Thus, during fasting the normal feedback mechanisms are bypassed, inducing a transient state of central hypothyroidism.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The hypothalamus and pituitary gland are in close anatomical proximity, connected by the pituitary stalk to the sella turcica.

“The hypothalamus and the pituitary gland are in close anatomical proximity at the base of the brain and extended through the pituitary stalk to the sella turcica.”

• Also stated in: § 1. Introduction · plain

  “The hypothalamus and the pituitary gland are in close anatomical proximity.The hypothalamus is located at the base of the brain and is connected by the stalk-like infundibulum to the pituitary gland which is located in the sella turcica.”

• cites Lechan et al., 2016Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The hypothalamus-pituitary-thyroid axis is one of several hormone regulatory systems from the hypothalamus to the pituitary and ultimately to the peripheral target organs.

“The hypothalamus-pituitary-thyroid axis is one of several hormone regulatory systems from the hypothalamus to the pituitary and ultimately to the peripheral target organs.”

• Also stated in: § 1. Introduction · plain

  “The hypothalamus-pituitary-thyroid axis is one of several hormone regulatory systems, each of them designated an axis from the hypothalamus to the pituitary and ultimately to the peripheral target organs (Lechan et al., 2016) (Fig. 1).”

• cites Lechan et al., 2016Not checked yet

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Retinoids, mitotane and several drugs modulating the immune system used for antineoplastic purpose may result in hypophysitis and cause clinically significant central hypothyroidism, as may head trauma including sport and blast injuries.

“On the other hand, retinoids, mitotane and several drugs modulating the immune system and used for antineoplastic purpose may result in hypophysitis and cause clinically significant central hypothyroidism (Burch, 2019;Feldt-Rasmussen and Klose 2020;Feldt-Rasmussen and Rasmussen, 2018), as may head trauma including those related to sport and blast injuries (Benvenga et al., 2018).”

• cites Burch, 2019 sourceNot checked yet

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• cites Feldt-Rasmussen and Klose 2020Not checked yet

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• cites Feldt-Rasmussen and Rasmussen, 2018Not checked yet

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When hypopituitarism arises from space occupying lesions in sella turcica or subsequent to irradiation, deficiency of gonadotropin production typically occurs before onset of TSH deficiency; therefore presence of regular menstrual cycles in fertile women and normal potency in men renders central hypothyroidism highly unlikely.

“When hypopituitarism arises from space occupying lesions in the sella turcica or subsequent to irradiation, deficiency of gonadotropin production typically occurs before the onset of TSH deficiency; therefore, the presence of regular menstrual cycles in fertile women and normal potency in men renders central hypothyroidism highly unlikely (Fig. 6) (Feldt-Rasmussen et al., 2018;Persani et al., 2018”

• cites Feldt-Rasmussen et al., 2018Not checked yet

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• cites Persani et al., 2018 sourceNot checked yet

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Immunoreactive serum TSH is often measurable in patients with central thyroid deficiency, a phenomenon resulting from dissociation between biological and immunological TSH activity.

“Yet, immunoreactive serum TSH is often measurable in patients with central thyroid deficiency, a phenomenon resulting from dissociation between biological and immunological TSH activity (Fig. 7) (Oliveira et al., 2001;Feldt-Rasmussen and Klose, 2016;Persani 2000).”

• cites Oliveira et al., 2001Not checked yet

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• cites Feldt-Rasmussen and Klose, 2016 sourceNot checked yet

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• cites Persani 2000Not checked yet

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Classified as probably not a substantial claim.

The diagnosis of central hypothyroidism will in most cases be based on finding of a low (or low in normal range) free T4 estimate combined with an inappropriately low or normal serum TSH, excluding confounders, and in appropriate clinical context.

“So, finally the diagnosis of central hypothyroidism will in most cases be based on the finding of a low (or low in the normal range) free T4 estimate combined with an inappropriately low or normal serum TSH, excluding confounders, and in the appropriate clinical context.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The significance of traumatic brain injury in hypopituitarism is still under debate.

“However, the significance of traumatic brain injury in hypopituitarism is still under debate (Garrahy et al., 2017;Klose and Feldt-Rasmussen, 2017).”

• cites Garrahy et al., 2017 sourceNot checked yet

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• cites Klose and Feldt-Rasmussen, 2017Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The general clinical pattern of central hypothyroidism is dominated by vague clinical symptoms and signs which are usually much milder than those of primary hypothyroidism.

“The general clinical pattern of central hypothyroidism is dominated by vague clinical symptoms and signs which are usually much milder than those of primary hypothyroidism.”

May combine two claims.

Free T4 concentrations and free T4 index in central hypothyroidism are subject to a high individuality index (intra-vs inter-individual variation ~25%), which hampers use of population-based reference intervals for correct diagnosis.

“As in other situations, it should also be acknowledged that free T4 concentrations and free T4 index in central hypothyroidism are subject to a high individuality index (intra-vs inter-individual variation ~25%), which further hampers the use of the population-based reference intervals for correct diagnosis (Andersen et al., 2002;Feldt-Rasmussen et al., 1980).”

• cites Andersen et al., 2002 sourceNot checked yet

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• cites Feldt-Rasmussen et al., 1980Not checked yet

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Pituitary hormone defects often develop in sequential order, with growth hormone and gonadotropin secretions affected first, followed by TSH deficiency, and finally ACTH while prolactin deficiency rarely occurs.

“Pituitary hormone defects often develop in sequential order, with growth hormone and gonadotropin secretions being affected first, followed by occurrence of TSH deficiency, and finally ACTH and while prolactin deficiency rarely occurs (Fig. 6).”

May combine two claims.

Hypothyroidism reduces GH secretion and is correlated with a significant decrease in IGF-1 which normalizes following administration of thyroid hormone in both humans and rodents.

“Hypothyroidism reduces GH secretion and is correlated with a significant decrease in IGF-1 which normalizes following the administration of thyroid hormone in both humans and rodents (Chernausek et al., 1983;Feldt-Rasmussen 2007b;Giustina and Wehrenberg, 1995;Tsai and Samuels, 1974).”

• cites Chernausek et al., 1983 sourceNot checked yet

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• cites Feldt-Rasmussen 2007bNot checked yet

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• cites Giustina and Wehrenberg, 1995Not checked yet

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Anti-CTLA4 antibody treatments may result in occurrence of hypophysitis in up to 10% of treated patients, with central hypothyroidism being the most frequently reported deficiency in the early phase.

“This is of significant clinical importance as the recently developed anti-CTLA4 (cytotoxic T lymphocyte protein 4) antibody treatments may result in the occurrence of hypophysitis in up to 10% of treated patients (Lam et al., 2015) with central hypothyroidism being the most frequently reported deficiency in the early phase (Faje, 2015).”

• cites Lam et al., 2015 sourceNot checked yet

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• cites Faje, 2015 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

This is not the case after irradiation induced tumour shrinkage.

“This is not the case after irradiation induced tumour shrinkage.”

May combine two claims.

Lymphocytic hypophysitis presents commonly with isolated ACTH deficiency, with or without TSH deficiency, while gonadotropins tend to be preserved.

“However, lymphocytic hypophysitis presents commonly with isolated ACTH deficiency, with or without TSH deficiency, while gonadotropins tend to be preserved 3 See Fig. 5. 4 Tumour, hypophysitis, empty sella; pituitary stalk interruption; pituitary infiltrative disease.5 Traumatic brain injury; vascular accident; iron overload or haemochromatosis.(Fukuoka, 2015).”

• cites Fukuoka, 2015 sourceNot checked yet

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Depending on cause, TSH secretion deficiency can be quantitative (reduction in TSH-secreting cell number) or qualitative (impaired bioactivity of secreted TSH).

“Depending on the cause of the disease, TSH secretion deficiency can be quantitative (reduction in TSHsecreting cell number) or qualitative (impaired bioactivity of the secreted TSH) (Beck-Peccoz and Persani, 1994;Persani et al., 2000).”

• cites Beck-Peccoz and Persani, 1994Not checked yet

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• cites Persani et al., 2000Not checked yet

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Radiation-induced hypopituitarism does not commence until 2 years or more after irradiation, continuing probably for more than 10 years.

“Response to direct or indirect irradiation of the hypothalamic-pituitary region is insidious and radiation-induced hypopituitarism does not commence until 2 years or more after the irradiation, continuing probably for more than 10 years (Astradsson et al., 2017;Roug et al., 2010).”

• cites Astradsson et al., 2017 sourceNot checked yet

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• cites Roug et al., 2010 sourceNot checked yet

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Craniopharyngiomas are the leading cause of acquired central hypothyroidism in children, followed by cranial irradiation for other childhood brain tumours.

“Craniopharyngiomas are the leading cause of acquired central hypothyroidism in children, followed by cranial irradiation for other childhood brain tumours such as dysgerminomas or malignant haematological diseases (Gurney et al., 2003;Lando et al., 2001;Schmiegelow et al., 2003).”

• cites Gurney et al., 2003 sourceNot checked yet

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• cites Lando et al., 2001 sourceNot checked yet

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• cites Schmiegelow et al., 2003 sourceNot checked yet

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TSH deficiency occurs in up to 25% of children with craniopharyngiomas, the second pituitary deficit to develop after growth hormone deficiency.

“TSH deficiency occurs in up to 25% of children with craniopharyngiomas, the second pituitary deficit to develop after growth hormone deficiency (Karavitaki et al., 2005).”

• cites Karavitaki et al., 2005 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Traumatic brain injury has been suggested a frequent cause of hypopituitarism at all ages with a prevalence of central hypothyroidism between 5% and 29%.

“Traumatic brain injury has been suggested a frequent cause of hypopituitarism at all ages with a prevalence of central hypothyroidism between 5% and 29% (Fernandez-Rodriguez et al., 2015;Krewer et al., 2016).”

• cites Fernandez-Rodriguez et al., 2015 sourceNot checked yet

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• cites Krewer et al., 2016 sourceNot checked yet

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In females on oral oestrogen and often consequent under-replacement with GH, peripheral conversion of T4 to T3 is diminished, resulting in increased serum-free T4 and reduced free T3.

“in females on oral oestrogen and often consequent under-replacement with GH, the peripheral conversion is diminished resulting in increasing serum-free T4 with a concomitant reduction in the active hormone free T3”

May combine two claims.

Hypopituitary patients without defined TSH deficiency and not on levothyroxine replacement demonstrate a reduction in serum T4 after initiation of GH replacement and decompensate the axis into a hypothyroid state, although serum T3 remained constant or increased.

“Hypopituitary patients without defined TSH deficiency and not on levothyroxine replacement were shown to demonstrate a reduction in the serum T4 concentration after initiation of GH replacement and decompensate the axis into a hypothyroid state, although serum T3 remained constant (Agha et al., 2006;Jørgensen et al., 1992Jørgensen et al., , 1994) ) or increased (Portes et al., 2000).”

• cites Agha et al., 2006Not checked yet

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• cites Jørgensen et al., 1992 sourceNot checked yet

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• cites Portes et al., 2000 sourceNot checked yet

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GH replacement increases conversion of T4 to T3, thereby increasing thyroid-related metabolism.

“-GH replacement increases conversion of T4 to T3, thereby increasing thyroid-related metabolism (Filipsson, and Johannsson, 2009;Jorgensen et al., 1994)”

• cites Filipsson, and Johannsson, 2009 sourceNot checked yet

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• cites Jorgensen et al., 1994Not checked yet

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Introducing levothyroxine replacement increases GH sensitivity, resulting in larger increments in IGF-I and acid-labile subunit, and eventually increases metabolic and growth promoting effects of GH.

“Furthermore, introducing levothyroxine replacement increases GH sensitivity, thus resulting in larger increments in both IGF-I and acid-labile subunit, and eventually increases the metabolic and growth promoting effects of GH (Schmid et al., 2006).”

• cites Schmid et al., 2006 sourceNot checked yet

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In males replaced with androgens and most often adequate GH replacement, serum-free T4 is reduced while free T3 increases due to increased conversion.

“in males replaced with androgens and most often adequate GH replacement, serum-free T4 will be reduced while the active hormone free T3 will increase as a result of increased conversion.”

May combine two claims.

T4 treatment increases IGF-I and ALS, thereby increasing GH metabolic effects.

“-T4 treatment increases IGF-I and ALS thereby increasing GH metabolic effects (Schmid et al., 2006)”

• cites Schmid et al., 2006 sourceNot checked yet

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Testosterone stimulates GH secretion centrally and through aromatization to oestrogen.

“Testosterone stimulates GH secretion centrally and through aromatization to oestrogen, but as opposed to the oestrogen concentration in fertile women, also amplifies GH stimulation of IGF-I by enhancing GH receptor expression (Saggese et al., 1996;Span et al., 2000;Weissberger, 1993;Yu et al., 1996).”

• cites Saggese et al., 1996 sourceNot checked yet

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• cites Span et al., 2000 sourceNot checked yet

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• cites Weissberger, 1993Not checked yet

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Initiation of GH replacement may unmask not only latent central hypothyroidism, but also latent hypoadrenalism.

“Initiation of GH replacement may unmask not only latent central hypothyroidism, but also latent hypoadrenalism”

May combine two claims.

Thyroid hormones increase GH, GHRH receptor and GH secretagogue receptor mRNA levels as well as rate of GH gene transcription.

“Thyroid hormones were also shown to increase GH, GHRH receptor and GH secretagogue receptor mRNA levels as well as the rate of GH gene transcription (Kamegai et al., 2001;Valcavi et al., 1992).”

• cites Kamegai et al., 2001 sourceNot checked yet

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• cites Valcavi et al., 1992 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based).

The diagnosis of central hypothyroidism is mostly based on finding of a low/low normal free T4 estimate combined with an inappropriately low/normal serum TSH concentration.

“The diagnosis of central hypothyroidism is mostly based on finding of a low/low normal free T4 estimate combined with an inappropriately low/normal serum TSH concentration.”

Probably not a substantial claim: may not pass S4 (based).

Central hypothyroidism is most often combined with other hypothalamus-pituitary-hormone axes deficits, depending on the underlying diagnosis.

“Central hypothyroidism is most often combined with other hypothalamuspituitary-hormone axes deficits, depending on the underlying diagnosis.”

May combine two claims.

Dysfunction of other hormone axes interacts with the diagnosis of central hypothyroidism, and treatment of both the central hypothyroidism and the other hypothalamus-pituitary axes influence the function of the others by complex central and peripheral mechanisms.

“Dysfunction of these other hormone axes interacts with the diagnosis of central hypothyroidism and treatment of both the central hypothyroidism and the other hypothalamus-pituitary axes influence the function of the others by complex mechanisms involving both central and peripheral mechanisms.”