ESPEYB19 6. DSD and Gender Incongruence Co-morbidities associated with DSD (2 abstracts)
6.3. Vascular dysfunction and increased cardiovascular risk in hypospadias
Lucas-Herald AK , Montezano AC , Alves-Lopes R , Haddow L , Alimussina M , O’Toole S , Flett M , Lee B , Amjad SB , Steven M , Brooksbank K , McCallum L , Delles C , Padmanabhan S , Ahmed SF & Touyz RM
Eur Heart J. 2022 Mar 17:ehac112. PMID: 35296881, doi: 10.1093/eurheartj/ehac112.
Brief Summary: This translational study explored the molecular and cellular mechanisms whereby testosterone impacts vascular function. The findings suggest that hypospadias is associated with vascular dysfunction and represents a risk factor for hypertension and cardiovascular disease in adulthood due to impaired Rho kinase- and Nox5/ROS-dependent signalling.
Low circulating testosterone concentration is an independent determinant of endothelial dysfunction in men. Testosterone influences vascular reactivity by regulating vascular smooth muscle cell Ca2+ channel expression and activity, intracellular Ca2+ homeostasis, Nox-derived reactive oxygen species (ROS) generation, nitric oxide (NO) production, Rho kinase activation, and mitogen-activated protein kinase phosphorylation. Hypospadias develops secondary to reduced antenatal androgen exposure in the majority of 46,XY boys. The authors hypothesized that, similar to adults, lack of androgens during the critical masculinization programming period of foetal development coincides with the time of vasculature development. This androgen deficiency could cause endothelial dysfunction and vascular injury early in life and predispose to hypertension and cardiovascular events in adulthood.
To test the hypothesis, this study investigated clinical and ex-vivo markers related to vascular function. Small subcutaneous arteries and vascular smooth muscle cells from penile skin of adolescent boys undergoing hypospadias repair and controls were isolated for functional studies. Vascular smooth muscle cells were used to assess: Rho kinase, reactive oxygen species (ROS), nitric oxide synthase/nitric oxide, and DNA damage. Compared to controls, adolescents with hypospadias had higher systolic blood pressure, pulse pressure, and carotid intima-media thickness increased vasoconstriction and reduced vasorelaxation. Markers for vascular and systemic oxidative stress and Rho kinase activity were increased in adolescents with hypospadias. Based on the data on admission for cardiometabolic diseases in 6797 men with hypospadias compared with 8073 controls, men born with hypospadias were at increased risk of arrhythmia, hypertension, and heart failure.
Overall, the findings of this study demonstrate an important extragonadal function of testosterone in cardiovascular (patho)physiology, and that the adverse effects of testosterone deficiency on the cardiovascular system start in the antenatal period. Hypospadias may be an independent risk factor for cardiovascular disease in males.
Volume 19
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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