Investigating the paradox of hypothyroidism and increased serum thyrotropin (TSH) levels in Sheehan's syndrome: Characterization of TSH carbohydrate content and bioactivity

Serum TSH levels are often paradoxically elevated in patients with hypothyr oidism due to Sheehan's syndrome. To investigate this apparent discrepancy, the biological activity and glycosylation of serum TSH were studied in 9 u ntreated patients with Sheehan's syndrome and 11 normal controls. TSH bioas say was based on cAMP generation, measured by RIA, in a culture system of C HO cells transfected with recombinant human TSH receptor. The oligosacchari de branching of TSH was studied by Con A lectin affinity chromatography, wh ich discriminates TSH isoforms according to their mannose content, and the sialic acid content of TSH was studied by Ricinus communis affinity chromat ography in combination with enzymatic removal of sialic acid with neuramini dase treatment. TSH bioactivity was expressed as the ratio between biologic al and immunofluorometric assays (B/I). Bioactive TSH concentrations were c alculated by multiplying serum TSH intrinsic bioactivity by serum immunorea ctive TSH concentration (B/I x I). Serum free T-4 (FT4) levels were lower i n patients than in controls (3.7 +/- 0.4 us. 14.0 +/- 0.9 pmol/L, respectiv ely; P < 0.0001). Circulating immunoreactive TSH was higher in patients wit h Sheehan's syndrome than in controls (3.8 +/- 0.8 vs. 1.8 +/- 0.2 mU/L, re spectively; P = 0.01). In contrast, TSH B/I was significantly decreased in Sheehan's patients compared with controls (0.6 +/- 0.4 us. 1.7 +/- 0.8, res pectively; P = 0.003). However, the resultant bioactive TSH concentrations in serum of Sheehan's patients were not significantly different from contro l values (2.1 +/- 0.6 us. 3.0 +/- 0.4; P = 0.25). A significant correlation was found between the bioactive TSH concentrations and serum FT, levels in patients with Sheehan's syndrome (r = 0.66; P = 0.05), but not between ser um immunoreactive TSH and FT, levels (r = 0.21; P = 0.59) or between intrin sic TSH bioactivity and FT, levels (r = 0.56; P = 0.12). The Con A chromato graphy of serum TSH showed a similar distribution (0.3 < P < 0.5) of unboun d, weakly bound, and firmly bound TSH in Sheehan's patients (16%, 38%, and 47%, respectively) and controls (15%, 34%, and 52%, respectively). The rici n 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). T hese results show that circulating TSH in Sheehan's syndrome, albeit increa sed, has decreased biological activity. The relevance of this finding is su pported by the direct correlation between bioactive serum TSH concentration s and circulating FT4. The reduced intrinsic TSH bioactivity in pituitary h ypothyroidism of Sheehan's syndrome results from increased sialylation of T SH.