Subclinical Hypothyroidism Shows Distinct Sex-Specific Metabolic Risks and Adipomyokine Imbalance

A systematic review and meta-analysis encompassing ten clinical studies and more than 1,400 adult participants has found that subclinical hypothyroidism is characterized by distinct sex-specific metabolic patterns and complex tissue signaling imbalances rather than a uniform cardiometabolic phenotype. Subclinical hypothyroidism, defined biochemically by elevated serum thyroid-stimulating hormone alongside normal concentrations of circulating free thyroxine, represents a prevalent condition whose therapeutic thresholds remain subject to persistent debate across endocrinology. Synthesizing data collected through comprehensive searches of the PubMed, Scopus, and Web of Science databases from inception through December 2023, the investigation demonstrates that mild thyroid dysfunction is consistently accompanied by pro-atherogenic blood lipid alterations and structural changes in arterial walls. Furthermore, the findings indicate that cardiovascular and metabolic risks manifest along fundamentally divergent trajectories between younger men and perimenopausal women. Rather than supporting blanket treatment thresholds, the synthesized observational and interventional evidence reveals a nuanced clinical landscape requiring personalized evaluation based on individual physiological traits.

Subclinical hypothyroidism affects between 4% and 10% of the adult population worldwide and has long presented a challenging management dilemma regarding whether mild thyroid failure warrants hormone replacement. Historical longitudinal population investigations, including the Whickham Survey and the Rotterdam Study, conclusively established that untreated subclinical thyroid failure increases long-term susceptibility to coronary atherosclerosis and acute myocardial infarction. Nevertheless, determining which patient groups derive measurable therapeutic benefit from levothyroxine substitution remains controversial due to marked variations in patient age, sex, adiposity, and underlying cardiovascular risk profiles. Contemporary clinical consensus guidelines generally recommend initiating levothyroxine when serum thyroid-stimulating hormone persistently equals or surpasses 10 mIU/L, as this degree of elevation correlates with clearer pathological changes. Conversely, in patients presenting with borderline elevations between 4.5 and 10 mIU/L, clinical guidance advises tailored decision-making that accounts for overt symptoms, chronological age, thyroid autoimmunity status, family planning intentions, baseline lipid profiles, frailty, and existing cardiovascular disease risk.

To clarify these divergent clinical outcomes, investigators conducted a rigorous systematic literature review compliant with PRISMA 2020 reporting standards under registered PROSPERO protocol CRD420251011843. The initial electronic database search identified 608 candidate records across Scopus, Web of Science, and PubMed, which was reduced to 581 unique records following the removal of 27 duplicates. Initial screening of titles and abstracts eliminated 426 citations, leaving 155 full-text reports sought for retrieval, of which 85 reports were either not retrieved or lacked sufficient full-text accessibility. Full-text eligibility evaluations were then performed on the remaining 70 published articles, resulting in the exclusion of 60 studies due to non-standardized levothyroxine dosing protocols, missing biomarker measurements, or high methodological risk of bias. Ultimately, ten studies met all eligibility criteria and were incorporated into the final qualitative and quantitative syntheses. Study selection was conducted independently by two reviewers who demonstrated high inter-rater reliability, achieving a Cohen’s kappa coefficient of 0.89, with discrepancies resolved through consensus or third-party adjudication.

The methodological quality and certainty of evidence across the ten included studies were systematically evaluated using validated assessment instruments tailored to specific study designs. For interventional investigations, randomized controlled trials were appraised using the Cochrane Risk of Bias 2 tool across five domains covering randomization procedures, deviations from intended protocols, missing outcome data, outcome measurement validity, and selective reporting. Observational longitudinal cohorts and case-control studies were evaluated using the Newcastle-Ottawa Scale, in which studies earning seven or more stars were classified as having high methodological quality. Across all synthesized publications, approximately 80% were categorized as exhibiting high methodological quality with low to moderate overall risk of bias. Applying the Grading of Recommendations Assessment, Development and Evaluation framework, the authors assigned a moderate certainty rating to evidence concerning low-density lipoprotein cholesterol and vascular thickness reductions. However, evidence regarding emerging circulating adipomyokines was rated as low certainty due to observational designs, small sample sizes, and assay heterogeneity.

A central biological finding highlighted in the review involves qualitative remodeling of circulating lipids, which appears to play a more decisive role in cardiovascular pathogenesis than conventional lipid concentrations alone. Observational evidence showed that patients with subclinical hypothyroidism exhibit a significantly elevated Atherogenic Index of Plasma, a logarithmically transformed ratio of triglycerides to high-density lipoprotein cholesterol, compared with euthyroid controls. Specifically, patients with subclinical thyroid failure demonstrated a mean Atherogenic Index of Plasma of 0.395, whereas healthy euthyroid controls maintained a mean index of 0.111, representing a highly statistically significant divergence. Furthermore, circulating thyroid-stimulating hormone demonstrated a strong positive linear correlation with the Atherogenic Index of Plasma, yielding a correlation coefficient of 0.72. The authors noted that higher hormone concentrations, particularly when exceeding 10 mIU/L, signal an increased abundance of small dense low-density lipoprotein particles, known as Pattern B, which possess enhanced susceptibility to oxidative modification and readily penetrate the inner endothelial lining of arterial walls.

Beyond generalized lipid disruptions, the synthesis revealed pronounced sexual dimorphism in how metabolic complications unfold among patients presenting with subclinical hypothyroidism. Cohort evidence revealed that younger men under 50 years of age with subclinical thyroid failure faced a substantially elevated incidence of metabolic syndrome compared to euthyroid peers, exhibiting a hazard ratio of 1.87 with a 95% confidence interval spanning from 1.21 to 2.90. This heightened metabolic vulnerability in younger men was primarily characterized by visceral adiposity, severe insulin resistance, elevated homeostatic model assessment values, and pronounced hypertriglyceridemia. In sharp contrast, studies involving perimenopausal women demonstrated an atherogenic dyslipidemia phenotype dominated by elevated blood pressure and an atherogenic lipid switch toward small dense low-density lipoprotein particles. Researchers suggested this female-specific lipid presentation may stem from declining endogenous estrogen protection occurring in combination with impaired thyroid hormone action. However, the authors emphasized that these distinct demographic phenotypes remain empirical cohort observations that require prospective validation before altering routine diagnostic protocols.

To determine whether thyroid hormone replacement rectifies circulating lipid abnormalities, the authors conducted a quantitative meta-analysis pooling outcomes from eligible interventional trials using a random-effects model. The pooled weighted mean difference demonstrated a statistically significant reduction in low-density lipoprotein cholesterol of 15.6 milligrams per deciliter among patients assigned to levothyroxine therapy compared with control cohorts. Predefined subgroup evaluations showed that therapeutic reductions in low-density lipoprotein cholesterol were markedly more pronounced among individuals who began treatment with baseline thyroid-stimulating hormone levels at or above 10 mIU/L than among those presenting with milder elevations. Although these interventional findings confirm a directionally consistent improvement in circulating lipids following hormone replacement, the authors advised cautious interpretation of the absolute effect sizes. They noted that the primary clinical trials exhibited notable statistical heterogeneity, relatively small cohort numbers within individual sub-strata, and incomplete variance reporting in several published datasets, underscoring the preliminary nature of the quantitative estimates.

In addition to circulating lipids, the review quantitatively evaluated structural changes in the vascular wall by examining carotid intima-media thickness, an established noninvasive imaging biomarker of subclinical atherosclerosis. Among interventional cohorts where levothyroxine substitution restored biochemical euthyroidism for a sustained follow-up duration of at least six months, patients achieved a statistically significant 11% reduction in carotid intima-media thickness. Absolute structural improvements across the analyzed trials ranged between 0.04 and 0.11 millimeters of wall thinning. Multivariable regression analyses further revealed that reductions in carotid intima-media thickness were independently associated with concurrent declines in both thyroid-stimulating hormone and low-density lipoprotein cholesterol, producing a coefficient of determination of 0.71. Crucially, the review cautioned that carotid wall thickness represents an intermediate structural surrogate rather than a definitive clinical event endpoint. Consequently, structural improvements in the carotid artery cannot be equated with verified reductions in hard cardiovascular outcomes, such as myocardial infarction, ischemic stroke, or cardiovascular-related mortality.

A particularly novel dimension of the systematic review centered on circulating adipomyokines, where marked statistical heterogeneity exceeding 75% necessitated a qualitative synthesis following Synthesis Without Meta-analysis guidelines. The narrative synthesis uncovered what the authors termed an adipomyokine paradox, characterized by divergent regulatory dynamics between the tissue signaling peptides irisin and apelin following thyroid hormone therapy. Patients with subclinical hypothyroidism exhibited hyperirisinemia at baseline, which correlated positively with markers of systemic oxidative stress and was hypothesized to reflect compensatory metabolic stress or skeletal muscle thermogenic defense. Notably, elevated irisin levels failed to normalize even after six months of levothyroxine replacement therapy despite successful biochemical restoration of euthyroidism. The researchers posited that this sustained abnormality might represent an exploratory metabolic imprint within skeletal muscle and adipose tissues. Conversely, concentrations of the vascular-protective peptide apelin were significantly depressed in untreated patients but exhibited rapid recovery, rising significantly within 12 weeks of initiating levothyroxine therapy.

In assessing the overall clinical significance of their findings, the review authors highlighted several critical methodological limitations inherent to the current published literature. The synthesized evidence base relied heavily on observational cohorts and case-control investigations alongside a limited number of small interventional trials, precluding definitive conclusions regarding causal mechanisms. Moreover, adipomyokine evaluations were constrained by small patient cohorts, disparate commercial enzyme-linked immunosorbent assay platforms, differing reporting units, and inconsistent statistical adjustments for baseline adiposity and insulin resistance. Because fewer than ten trials were available for individual quantitative endpoints, formal statistical testing for publication bias using Egger’s regression could not be performed due to inadequate statistical power, restricting bias evaluations to qualitative funnel plot inspections. The investigators concluded that subclinical hypothyroidism should be recognized as a heterogeneous cardiometabolic condition where treatment decisions must incorporate age, sex, visceral adiposity, lipid quality, and baseline hormone severity, rather than relying exclusively on isolated thyroid-stimulating hormone measurements to guide long-term clinical care.

Subject of Research: Sex-specific cardiometabolic profiles and adipomyokine dynamics in subclinical hypothyroidism

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

Article References: Barbind, S., & Chandak, A. (2026). The adipomyokine paradox and sex-specific metabolic divergence in subclinical hypothyroidism: a systematic review and meta-analysis. Cardiovascular Diabetology – Endocrinology Reports, 12(1), Article 42. https://doi.org/10.1186/s40842-026-00314-3

Image Credits: AI Generated

DOI: 10.1186/s40842-026-00314-3

Keywords: Subclinical Hypothyroidism, Cardiovascular Disease, Adipomyokines, Irisin, Apelin, Metabolic Syndrome, Levothyroxine, Carotid Intima-Media Thickness, adipomyokine, paradox, sex-specific, metabolic