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Investigating the Paradox of Hypothyroidism and Increased Serum Thyrotropin (TSH) Levels in Sheehan’s Syndrome: Characterization of TSH Carbohydrate Content and Bioactivity¹

Neuroendocrine Unit, Division of Endocrinology, Hospital Sao Paulo-Universidade Federal de Sao Paulo (J.H.A.O., J.A.), Sao Paulo, Brazil 04039-002; and Institute of Endocrine Sciences, Ospedale Maggiore Istituto di Richerca e Cura a Caratere Scientifico and Istituto Auxologico Italiano, University of Milan (L.P., P.B.-P.), 20145 Milan, Italy

Address all correspondence and requests for reprints to: Julio Abucham, M.D., Division of Endocrinology, Hospital Sao Paulo-Universidade Federal de Sao Paulo, Rua Pedro de Toledo, 910 Sao Paulo, Brazil 04039-002.

Serum TSH levels are often paradoxically elevated in patients with hypothyroidism due to Sheehan’s syndrome. To investigate this apparent discrepancy, the biological activity and glycosylation of serum TSH were studied in 9 untreated patients with Sheehan’s syndrome and 11 normal controls. TSH bioassay was based on cAMP generation, measured by RIA, in a culture system of CHO cells transfected with recombinant human TSH receptor. The oligosaccharide branching of TSH was studied by Con A lectin affinity chromatography, which discriminates TSH isoforms according to their mannose content, and the sialic acid content of TSH was studied by Ricinus communis affinity chromatography in combination with enzymatic removal of sialic acid with neuraminidase treatment. TSH bioactivity was expressed as the ratio between biological and immunofluorometric assays (B/I). Bioactive TSH concentrations were calculated by multiplying serum TSH intrinsic bioactivity by serum immunoreactive TSH concentration (B/I x I). Serum free T₄ (FT₄) levels were lower in patients than in controls (3.7 ± 0.4 vs. 14.0 ± 0.9 pmol/L, respectively; P < 0.0001). Circulating immunoreactive TSH was higher in patients with Sheehan’s syndrome than in controls (3.8 ± 0.8 vs. 1.8 ± 0.2 mU/L, respectively; P = 0.01). In contrast, TSH B/I was significantly decreased in Sheehan’s patients compared with controls (0.6 ± 0.4 vs. 1.7 ± 0.8, respectively; P = 0.003). However, the resultant bioactive TSH concentrations in serum of Sheehan’s patients were not significantly different from control values (2.1 ± 0.6 vs. 3.0 ± 0.4; P = 0.25). A significant correlation was found between the bioactive TSH concentrations and serum FT₄ levels in patients with Sheehan’s syndrome (r = 0.66; P = 0.05), but not between serum immunoreactive TSH and FT₄ levels (r = 0.21; P = 0.59) or between intrinsic TSH bioactivity and FT₄ levels (r = 0.56; P = 0.12). The Con A chromatography of serum TSH showed a similar distribution (0.3 < P < 0.5) of unbound, weakly bound, and firmly bound TSH in Sheehan’s patients (16%, 38%, and 47%, respectively) and controls (15%, 34%, and 52%, respectively). The ricin chromatography of serum TSH showed a higher proportion of sialylated TSH molecules in Sheehan’s patients than in controls (55% vs. 29%; P = 0.02). These results show that circulating TSH in Sheehan’s syndrome, albeit increased, has decreased biological activity. The relevance of this finding is supported by the direct correlation between bioactive serum TSH concentrations and circulating FT₄. The reduced intrinsic TSH bioactivity in pituitary hypothyroidism of Sheehan’s syndrome results from increased sialylation of TSH.

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