Background-Euthyroid women experience dramatic changes in the demand for thyroid hormone production as early as the first trimester of pregnancy. These changes are important for fetal neurodevelopment and organ development as well as maternal health and succesful full term pregnancy. Therefore, gestation-specific reference intervals assist in appropriate clinical management of thyroid disease in pregnancy to ensure maternal and fetal health.

Serum thyrotropin (TSH) is considered the single most sensitive and specific measure of thyroid function in the general population owing to its negative logarithmic association with free triiodothyronine and free thyroxine concentrations. It is therefore often the test of choice for screening, diagnosis, and monitoring of primary hypothyroidism. Serum TSH concentrations can be analyzed quantitatively using third-generation immunoassays, whereas its bioactivity can be measured by TSH activity assays in cell culture. Theoretically, if serum TSH concentrations are directly related to TSH activity, the two tests should yield comparable results. However, on occasion, the results are discordant, with serum concentrations being higher than TSH biological activity. This review focuses on the dissociation between the clinical state and serum TSH concentrations and addresses clinically important aspects of TSH analysis. Thyrotropin SynthesisT hyrotropin (TSH) is a heterodimeric 28-kDa-glycoprotein hormone released from the anteromedial pituitary and is a regulator of thyroid function. Its synthesis is controlled by the hypothalamic neuropeptide TSH-releasing hormone (TRH). The two peptide subunits of TSH are noncovalently linked and cotranslationally glycosylated with mannose-rich oligosaccharides (1). Posttranslationally, the two subunits are combined and the attached oligosaccharides are further processed. Synthesis of a mature TSH molecule requires the excision of signal peptides from both TSH a-and b-subunits, followed by trimming of mannose and further addition of fucose, galactose, and sialic acids (2). Thus, mature TSH molecules are asparagine-(N)-linked [Asp(N)-linked] complex carbohydrate structures capped with sulfate and/or sialic acid molecules (3,4) (Fig. 1). TSH oligosaccharide structures vary according to the source of TSH: human pituitaryderived TSH comprises fucosylated biantennary glycans with terminal N-acetylgalactosamine sulfate and low sialic acid content (5-7), while recombinant human TSH (rhTSH), synthesized in Chinese hamster ovary cells, specifically terminates in a2,3-linked sialic acid (8-11) and rhTSH formed in yeast lacks sialic acid residues altogether (12). Glycosylation Patterns and TSH BioactivityAppropriate glycosylation is necessary to maintain normal TSH bioactivity (13). Indeed, both a-and b-subunits of TSH have functionally important domains associated with TSH receptor (TSHR) binding and activation. The a-subunit has two Asp(N)-linked oligosaccharide chains with a typical biantennary structure, while TSH b-subunit has only one chain (Fig. 2). The transcriptional and posttranscriptional mechanisms involved in TSH glycosylation result in folding of these subunits, leading to their heterodimerization. These mechanisms also qualitatively regulate TSH secretion, prevent intracellular degradation, and influence TSH clearance rate from the circulation (14,15). A three-dimensional TSH structure has been proposed in the 1990s based on crystallographic studies and comparisons with other glyco...

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