Endocrine Abstracts

Background: Klinefelter syndrome (KFS) is the most common chromosomal aberration in men, characterized by an extra-X chromosome (47, XXY). Besides the well-known reproductive defects, KFS is characterized by a 4-fold increase in metabolic syndrome, cardiovascular morbidity and mortality. The exact cause of this constellation remains unclear.

Methods: Data from non-mosaic KFS adults and adolescents, evaluated in the endocrine unit of Lausanne University Hospital between 2015 et 2022, were analyzed. Only men without testosterone replacement therapy (TRT) at the moment of evaluation were included. Metabolic phenotyping consisted of a fasting blood test, an oral glucose tolerance test and body composition assessment using Dual X-ray absorptiometry. A longitudinal analysis was conducted in men with available metabolic data after at least 1 year of TRT intake.

Results: seventy-five men were included of whom 57 at diagnosis (TRT-naïve) and 18 after TRT wash-out. The cohort spanned across a large age range (31.4 ± 11.9 years). As expected, the majority of patients were hypogonadal, defined as clinical and biochemical [morning serum total testosterone (T) < 10.4 nmol/l] signs of testosterone deficiency. Mean TT levels were moderately decreased (9.4 ± 6.1 nmol/l) as opposed to normal estradiol (E) levels (0.09 ± 0.03 nmol/l). Consequently, most participants had relative hyperestrogenism defined as a T/E ratio < 100. Roughly half of participants were overweight (BMI > 25 kg/m²), whereas two third of them were insulin resistant (HOMA-IR > 2.6) and had fat excess defined as a fat mass index (FMI) > 6 kg/m². Hypogonadal men had higher incidence of metabolic syndrome (26% vs 11%), glucose intolerance (33% vs 10%) and hypertension (11% vs 5%) as compared to those with normal TT levels. Linear regression revealed an inverse association of T with several metabolic traits including FMI (r=-0.48, P=0.002) and HOMA-IR (r=-0.33, P=0.03). Interestingly, T/E ratio exhibited even stronger associations (r=-0.66, P<0.0001 and r=-0.46, P=0.002 for FMI and HOMA-IR, respectively). Sustained TRT intake in 20 patients for a mean follow-up of 5 years led to a slight but significant increase in BMI (mean delta + 1.2 kg/m², P=0.02). FMI and HOMA-IR did not significantly improve during TRT.

Conclusions: KFS is characterized by high metabolic risk that is only partially reflected in BMI. Besides hypogonadism, other imbalances such as relative hyperestrogenism may contribute to the metabolic deterioration. The absence of improvement in surrogate metabolic markers by long-term TRT implies the need to evaluate additional therapies for KFS-associated metabolic risk.