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Review
. 2023 Jul 20;24(14):11699.
doi: 10.3390/ijms241411699.

Pars Distalis and Pars Tuberalis Thyroid-Stimulating Hormones and Their Roles in Macro-Thyroid-Stimulating Hormone Formation

Eleonore Fröhlich  1 , Richard Wahl  2
Affiliations
Review

Pars Distalis and Pars Tuberalis Thyroid-Stimulating Hormones and Their Roles in Macro-Thyroid-Stimulating Hormone Formation

Eleonore Fröhlich et al. Int J Mol Sci. .

Abstract

Thyroid-stimulating hormone (TSH) and thyroid hormone levels are standard parameters in blood analysis. However, the immunoassays employed may lead to false-positive or false-negative results when the sample contains certain materials that interfere with the assay. Macro-TSH, a complex of TSH with immunoglobulin or albumin, may cause apparently increased TSH concentrations. TSH is produced in the pars tuberalis (PT) of the pituitary gland and by thyrotrophs of the pars distalis (PD). It was found that variable glycosylation can render the molecule more strongly bound to antibodies or albumin in the blood, leading to the hypothesis that macro-TSH consists mainly of PT-TSH. Although less known than PD-TSH, PT-TSH plays an important role in the central regulation of thyroid metabolism. The present review summarizes the physiological function of human PT-TSH and its role in macro-TSH formation. The prevalence of macro-hyperthyrotropinemia, the structure of PT-TSH and macro-TSH, problems in the measurement of TSH, and the action of PT-TSH in animals with seasonal breeding are discussed. Despite the absence of a specific function of macro-TSH in the organism, the identification of macro-TSH is important for avoiding unnecessary treatment based on a falsified readout of increased TSH concentrations as numerous individual case reports describe.

Keywords: circadian changes; immunoassay; macro-hormones; pars distalis TSH; pars tuberalis TSH; seasonal changes; thyroid-stimulating hormone; ultradian changes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Regulation of TSH secretion. Hypothalamic neurons end with terminal buttons at the median eminence (ME) in the upper region of the infundibulum and secrete thyrotropin-releasing hormone (TRH) into the portal system of the pituitary gland. Via this portal system at the ME, TRH is transported to the pars distalis of the anterior pituitary gland (PD) and induces production and secretion of TSH. Pars tuberalis (PT), the source of PT-TSH, represents a thin sheath at the pituitary stalk. In rats, an independent mode of action on thyrotrophs of the PT was found. Melatonin directly inhibits TSH production from these thyrotrophs. This action reduces both the binding of PT-TSH to its receptor on tanycytes lining the 3rd ventricle (V) and the conversion of thyroxine (T4) to triiodothyronine (T3) by intracellular deiodinase type 2 (DiO2). In the systemic circulation PT-TSH is detectable as macro-TSH. PT-TSH and PD-TSH molecules differ in their glycosylation pattern. PD-TSH has biantennary sulfonated glycans, whereas macro-TSH has multi-branched, sialylated N-glycans. Abbreviations: PI, pars intermedia; PP, posterior pituitary lobe; Sial, sialylated glycans; S, sulfonated glycans.
Figure 2
Figure 2
PT-TSH secretion in birds (e.g., Japanese quails, sparrow) is directly regulated by light via activating a receptor in the deep brain. Long daylight induces PT-TSH, increases deiodinase type 2 (DiO2) activity and generates-bioactive T3. Activation of DiO3 by short daylight leads to preferential conversion of T4 to the inactive metabolite reverse T3 (rT3). In mammals (e.g., sheep, goat, hamster, ground squirrel, common vole, Fisher 344 rats), retinal photoreceptors act on the suprachiasmatic nucleus, where long daylight induces short pineal melatonin secretion and increased PT-TSH levels.
Figure 3
Figure 3
In the sandwich immunoassay, the sample is added to the capture antibody (Ab) and the binding is detected by addition of the labelled Ab. Interferences may occur due to Abs that bridge the capture and the labeled Ab (1), by Abs against Fab fragments of the capture Ab (2), by Ab against the analyte (3), and by excess concentrations of analytes, which saturate all binding sites of capture and labeled Ab (Hook effect, 4).
Figure 4
Figure 4
General types of N-Glycosylation in glycoproteins and differences in glycosylation of pars distalis TSH (PD-TSH) and pars tuberalis TSH (PT-TSH).
Figure 5
Figure 5
Algorithm for the identification of macro-TSH (content according to [61]). Findings are written in red, reasons in orange and measures in green boxes. Ruthenium (Ru) was used for automated detection of TSH in the Elecsys® TSH assay (Roche Diagnostics; https://labogids.sintmaria.be/sites/default/files/files/tsh_2018-05_v24.pdf (accessed on 14 May 2023)). Abbreviation: α-Ru, anti-ruthenium; α-TH; anti-thyroid hormone; SCH, subclinical hypothyroidism.
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