Human and animal fertility studies in cystinosis reveal signs of obstructive azoospermia, an altered blood‐testis barrier and a subtherapeutic effect of cysteamine in testis

Abstract

Cystinosis is an inherited metabolic disorder caused by autosomal recessive mutations in the CTNS gene leading to lysosomal cystine accumulation. The disease primarily affects the kidneys followed by extra-renal organ involvement later in life. Azoospermia is one of the unclarified complications which are not improved by cysteamine, which is the only available disease-modifying treatment. We aimed at unraveling the origin of azoospermia in cysteamine-treated cystinosis by confirming or excluding an obstructive factor, and investigating the effect of cysteamine on fertility in the Ctns À/À mouse model compared with Ellen Goossens and Elena Levtchenko contributed equally to this study.

Fertility in Cystinosis

“…Hypogonadism with delayed puberty and delayed bone age was found to be very common, but it was not reported whether the men studied (all of whom had been transplanted) were treated with cysteamine or not. Over the years, primary hypogonadism with increased levels of the gonadotropins LH and FSH was reported very frequently in male cystinosis patients [ 18 , 19 , 20 , 21 ], and also in those investigated in the current era when treatment with cysteamine is started early in life and continued after kidney transplantation [ 19 , 20 , 21 ]. In addition, inhibin B is a hormone secreted by Sertoli cells that has an important role in spermatogenesis [ 22 , 23 ].…”

“…Reduced kidney function or immunosuppressive treatment for kidney transplantation did not seem to be the cause for these hormone disturbances [ 18 , 19 , 20 ]. In fact, in the original study by Chik et al hormone levels in cystinosis patients were compared to a group of men of similar age who underwent a kidney transplant for a disease other than cystinosis, with a comparable renal function and immunosuppressive treatment regimen [ 18 ].…”

“…In fact, in the original study by Chik et al hormone levels in cystinosis patients were compared to a group of men of similar age who underwent a kidney transplant for a disease other than cystinosis, with a comparable renal function and immunosuppressive treatment regimen [ 18 ]. Interestingly, secondary hypogonadism, characterized by reduced FSH and LH levels with normal testicular function [ 18 , 19 ], and even normal sex hormone levels have been reported sporadically as well, the latter being more frequently observed in younger men [ 18 , 19 , 20 , 21 ].…”

“…In the early cohort described by Chik et al, who were likely to be treated with cysteamine less vigorously compared to current practice, testicular volume was reduced in all 10 studied men [ 18 ]. In more recent cohorts, it was strikingly found that testicular volume was generally normal in younger men but tended to decrease with increasing age, indicating progressive testicular atrophy [ 20 , 21 ].…”

“…There are sporadic reports of testicular biopsy samples, the first being a postmortem investigation showing fibrosis, germinal dysplasia and Leydig cell hyperplasia with numerous cystine crystals, but seminiferous tubules were still visible [ 18 ]. Later, histology reports in patients treated with cysteamine confirmed fibrosis, but showed no germinal dysplasia and the Johnson score (a measure for spermatogenesis in the seminiferous tubules [ 26 ]) ranged between 7 and 9, indicating intact spermatogenesis [ 19 , 20 ]. Interestingly, while biopsy samples from the central part of the testes showed intact spermatogenesis, more damage was observed, including spermatogonial arrest on light microscopy and enlarged lysosomes in both Leydig and Sertoli cells on transmission electron microscopy in samples taken from the periphery, indicating that the progressive testicular damage seen in male cystinosis patients starts in the periphery at the end of the arterial blood supply [ 21 ].…”