Early-Onset Hypogonadism in Adolescents Linked to Early Vascular Aging: Study

A new study published in the Journal of Vascular Research found that adolescents with early-onset hypogonadism show signs of early vascular aging (EVA), along with oxidative stress and epigenetic changes that require further investigation.

This research investigated boys with conditions associated with intrauterine hypogonadism, specifically Klinefelter syndrome (KS) and hypospadias, comparing them with healthy adolescent controls. The findings suggest that hormonal disruption during early development may contribute to measurable vascular changes and increased oxidative stress long before adulthood.

The study included 33 participants, with 11 boys in each group and a median age of 14.5 years. This study used a series of cardiovascular and biochemical assessments, including blood pressure monitoring, carotid intima-media thickness (CIMT), pulse wave velocity (PWV), and flow-mediated dilatation. Blood tests evaluated hormone levels, metabolic markers, oxidative stress indicators, and epigenetic activity.

This study revealed significantly higher systolic blood pressure in boys with both KS and hypospadias when compared to healthy controls. Adolescents with hypospadias also demonstrated increased CIMT and pulse pressure, both recognised indicators of vascular stiffening and early arterial damage. Meanwhile, boys with KS showed elevated mean arterial pressure, which further supported evidence of early cardiovascular strain.

The boys with hypospadias had elevated levels of thiobarbituric acid reactive substances (TBARS), total antioxidant capacity (TAOC), peroxide, and oxidative stress index (OSI), suggesting an imbalance between oxidative damage and the defence mechanisms of the body. Levels of 8-hydroxy-2′-deoxyguanosine (8OHdG) were significantly higher in hypospadias patients than in healthy controls, although lower than levels observed in boys with KS.

In addition to vascular and oxidative abnormalities, this study found increased DNA methyltransferase (DNMT) activity in both KS and hypospadias groups. DNMT plays a crucial role in epigenetic regulation, indicating that early hormonal disturbances may trigger molecular changes capable of influencing long-term cardiovascular and metabolic health.

No significant changes in alpha klotho protein levels, histone H3 modification, or telomerase activity were observed, which suggested that some ageing-related pathways may remain unaffected during adolescence.

Overall, the findings of this study suggest that cardiovascular ageing processes may begin much earlier in life among individuals with developmental hypogonadism. Further large-scale studies are needed to explore whether early interventions, including hormonal or lifestyle therapies, could reduce the progression of vascular ageing in affected adolescents.

Source:

Lucas-Herald, A. K., McNeilly, J. D., & Ahmed, S. F. (2026). Vascular ageing in conditions associated with early onset hypogonadism. Journal of Vascular Research, 1–17. https://doi.org/10.1159/000552685