Athyreotic Endocrine Instability Syndrome (AEIS): Characterizing Rapid TSH Variability in Response to Micro-Dose Levothyroxine Adjustments

Abstract

Background: Levothyroxine (LT4) replacement is generally viewed as a stable and predictable therapy, yet some patients without residual thyroid tissue show striking biochemical instability despite good adherence and apparently appropriate dosing. In daily practice, a subset of athyreotic patients develop disproportionately large changes in thyroid-stimulating hormone (TSH) after very small LT4 dose adjustments, suggesting loss of physiological buffering and altered feedback sensitivity. We introduce the term Athyreotic Endocrine Instability Syndrome (AEIS) to describe this pattern.

Methods: We conducted a retrospective observational study of adult athyreotic patients receiving long-term LT4 monotherapy in a specialized endocrine clinic between 2021 and 2025. Eligible patients had complete absence of functional thyroid tissue, stable LT4 therapy for at least 12 months, and serial thyroid function tests with at least one documented micro-dose adjustment (12.5–25 μg/day or equivalent weekly change). Clinical, biochemical, and pharmacodynamic data were collected. AEIS was defined using prespecified criteria that included recurrent dose changes, exaggerated TSH shifts, overshoot beyond target range, oscillatory biochemical patterns, and exclusion of identifiable confounders.

Results: Of 142 eligible patients, 49 (34.5%) met criteria for AEIS. Overall, 58.5% had at least one clinically significant TSH fluctuation >2.5mIU/L, and 71.1% showed amplified biochemical responses after micro-dose LT4 changes. The median dose–response amplification index was 2.9 (IQR 1.6–5.4). Compared with non-AEIS patients, those with AEIS had greater TSH variability, more frequent annual dose modifications, and longer time to biochemical equilibrium (9.3 ± 2.1 vs 6.4 ± 1.8 weeks).

Conclusions: AEIS may represent a distinct endocrine phenotype marked by nonlinear, delayed, and amplified TSH responses to small LT4 dose changes in athyreotic patients. Recognizing this syndrome could support more individualized dosing strategies and help avoid unnecessary therapeutic cycling during long-term thyroid hormone replacement.