The adipomyokine paradox and sex-specific metabolic divergence in subclinical hypothyroidism: a systematic review and meta-analysis

BACKGROUND: Subclinical hypothyroidism (SCH) increases CVD risk but the threshold for treatment remains controversial. Sex-based metabolic profiles, novel adipocytokines (Irisin/Apelin), and reversibility of vascular remodeling were examined. METHODS: A PRISMA 2020-compliant systematic review of PubMed/MEDLINE, Scopus, and Web of Science was conducted using the PROSPERO-aligned search window from 1 January 2010 to 31 December 2023. Ten studies met the final eligibility criteria and were synthesized according to outcome comparability. Study quality was assessed using RoB 2 and the Newcastle-Ottawa Scale, and certainty of evidence was considered using GRADE principles. RESULTS: SCH was associated with a pro-atherogenic phenotype, including higher Atherogenic Index of Plasma (AIP) in observational evidence. Sex-specific patterns were observed: cohort evidence suggested increased incident metabolic syndrome among younger men with SCH (HR 1.87; 95% CI: 1.21-2.90), whereas studies in perimenopausal women showed a more lipid-dominant atherogenic profile. Narrative synthesis suggested divergent adipomyokine behavior, with persistent irisin abnormalities despite biochemical euthyroidism and more rapid apelin change in limited interventional evidence. Levothyroxine therapy was associated with modest improvement in selected lipid parameters and CIMT in some interventional studies; however, these findings should not be extrapolated to hard cardiovascular outcomes. CONCLUSION: SCH appears to be associated with heterogeneous cardiometabolic risk patterns across sex, age, adiposity, lipid phenotype, and baseline TSH. The available evidence supports individualized risk assessment but remains insufficient to mandate phenotype-specific treatment thresholds or to infer long-term cardiovascular-risk reduction without further prospective validation.