Abstract
Hypergonadotropic hypogonadism is a major feature of Klinefelter syndrome (KS), assumed to be caused by testicular hormone resistance. It was previously shown that intratesticular testosterone levels in vivo and Leydig cell function in vitro seem to be normal indicating other functional constraints. We hypothesized that impaired testicular vascularization/blood flow could be a co-factor to the observed hypergonadotropic hypogonadism. We evaluated the testicular vascular system by measuring blood vessel sizes during postnatal development and testis blood flow in adult 41,XXY* mice. Proportional distribution and size of blood vessels were analyzed during testicular development (1, 3, 5, 7, 10, 21 dpp, 15 wpp). While ratios of the vessel/testis area were different at 15 wpp only, a lower number of smaller and mid-sized blood vessels were detected in adult KS mice. For testicular blood flow determination we applied contrast enhanced ultrasound. Floating and reperfusion time for testicular blood flow was increased in 41,XXY* mice (floating: XY* 28.8 ± 1.69 s vs XXY* 44.6 ± 5.6 s, p = 0.0192; reperfusion XY* 19.7 ± 2.8 s vs XXY*: 29.9 ± 6.2 s, p = 0.0134), indicating a diminished blood supply. Our data strengthen the concept that an impaired vascularization either in conjunction or as a result of altered KS testicular architecture contributes to hormone resistance.
Highlights
Hypergonadotropic hypogonadism is a major feature of Klinefelter syndrome (KS), assumed to be caused by testicular hormone resistance
Differences in testis area were most prominent at 15 wpp in fully adult mice when full spermatogenesis was ongoing in control mice but lacking in 41,XXY* mice (Fig. 2a)
By using quantitative methods and sophisticated in vivo measurements of the blood flow, this study addresses a mechanism potentially underlying the testicular hormone resistance, which resembles a hallmark of the KS phenotype
Summary
Hypergonadotropic hypogonadism is a major feature of Klinefelter syndrome (KS), assumed to be caused by testicular hormone resistance. We hypothesized that impaired testicular vascularization/blood flow could be a co-factor to the observed hypergonadotropic hypogonadism. We evaluated the testicular vascular system by measuring blood vessel sizes during postnatal development and testis blood flow in adult 41,XXY* mice. Testes of KS patients are phenotypically described as small and firm with volume of approximately 2–2.5 mL vs the healthy normal range above 12 mL per testis[19,20] which is due to a dramatically altered testicular architecture caused by germ cell loss and Leydig cell hyperplasia. The fact that Leydig cell function is seemingly normal and the blood vessel composition is changed led us to speculate whether an impaired testicular vascularization could contribute to the phenotype of hypergonadotropic hypogonadism
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