Hypogonadism, adipose tissue inflammation, and adipose tissue circadian clock disruption independently promote metabolic dysfunction in Klinefelter syndrome - genomic underpinnings and testosterone treatment effects

Claus H. Gravholt; Jesper Just; Emma Hasselholm; Anne Skakkebaek; Simon Chang

doi:10.1530/endoabs.118.PO1

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Endocrine Abstracts (2026) 118 PO1 | DOI: 10.1530/endoabs.118.PO1

IDSD2026 Poster Abstracts Poster Abstracts (93 abstracts)

Hypogonadism, adipose tissue inflammation, and adipose tissue circadian clock disruption independently promote metabolic dysfunction in Klinefelter syndrome – genomic underpinnings and testosterone treatment effects

Claus H. Gravholt ^1,2,3 , Jesper Just ^1,3 , Emma Hasselholm ^1,3 , Anne Skakkebæk ^1,3,4 & Simon Chang ^1,2,3

Author affiliations

¹Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; ²Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark; ³Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; ⁴Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark

Background: Klinefelter syndrome (KS; 47,XXY) features early hypogonadism, adiposity and insulin resistance. The metabolic impact of testosterone replacement therapy (TRT) or X-chromosome dosage is not clear.

Methods: We assessed numerous markers of metabolic function longitudinally among 149 men with KS and 178 controls, stratifying KS by TRT at each visit. We applied mixed models to estimate TRT-associated changes in body composition, insulin sensitivity, and adipokines. Adipose tissue biopsies underwent transcriptomic and DNA methylation profiling; factor analysis identified latent programs, and circadian integrity was assessed with TimeTeller and clock-gene co-expression.

Results: TRT reduced body fat by 4.4 percentage points (15%), and increased lean mass by 2.6 kg, but body fat remained higher and normalized fat-free mass lower in both KS groups vs controls. TRT lowered HDL, reduced leptin (43%) and adiponectin (21%), but did not improve HOMA2-derived insulin resistance. From multi-omics factor analysis, we identified an adiposity-linked inflammatory factor associated with insulin resistance in all participants, whereas a KS-specific factor associated with insulin resistance independent of body fat was enriched for downregulated insulin/circadian regulators and corresponded to circadian disruption with adipose epigenetic age acceleration among KS males. Here, we observed significant disruption of circadian rhythmicity in KS compared with controls, and epigenetic age acceleration was also significantly increased in adipose tissue from KS compared with controls. Commonly applied metrics for prediction of body fat perform poorly in KS. We provide XGBoost models using anthropometrics (± testosterone) predicting KS body fat accurately (training R²=0.83; external RMSE 3–4%).

Conclusions: KS metabolic dysfunction is only partially responsive to TRT and likely involves disrupted adipose genomic and circadian mechanisms, supporting monitoring of body fat and therapies beyond hormone replacement.