Unraveling the origin of azoospermia in male cystinosis patients

<p>Study question:Is azoospermia in male cystinosis patients obstructive or nonobstructive
\nin origin?
\n</p> <p>Summary answer: Azoospermia in male cystinosis patients is obstructive in
\norigin.
\n</p> <p>What is known already: Cystinosis is a rare autosomal recessive metabolic
\ndisorder caused by mutations in the lysosomal membrane protein cystinosin
\n(CTNS), which leads to intracellular lysosomal cystine accumulation. Depending
\non the disease severity, three forms are distinguished: infantile (most severe),
\njuvenile (intermediate), and ocular (benign) form. The main clinical presentation
\nin infantile cystinosis is the renal Fanconi syndrome, leading to end stage renal
\ndisease (ESRD) by the age of ten, if the patient is left untreated. Cysteamine, a
\ncystine-depleting agent, beside renal replacement therapy, has improved the life
\nexpectancy of cystinosis patients. In contrast to females, male infantile cystinosis
\npatients suffer from infertility.
\n</p> <p>Study design, size, duration: Three groups were included in a prospective
\ncase control study; adult cystinosis patients (three infantile, two juvenile, and
\none ocular male patients), control group (seven adult fertile male subjects), and
\na positive control group for obstructive azoospermia (ten adult vasectomized
\nmales who underwent vasectomy 4-8 weeks prior to enrollment). In addition,
\nclinical data and testicular sections for five adult infantile male cystinosis patients
\nwere retrospectively included in the study (in total, eight infantile cystinosis
\npatients).
\n</p> <p>Participants/materials, setting,methods:Scrotal ultrasound for screening
\nfor soft biomarkers of obstruction and semen analysis were performed in all
\nprospectively included subjects, while sexual hormonal levels were evaluated
\nonly in the cystinosis patients. In addition, clinical data, semen analysis results,
\npercutaneous epididymal sperm aspiration (PESA) results, sexual hormonal
\nprofile, and testicular sections from the retrospectively included cystinosis
\npatients were analyzed. For the testicular sections, morphological evaluation
\nand immunohistochemistry were performed.
\n</p> <p>Main results and the role of chance:All testicular sections taken from three
\ninfantile cystinosis patients (3/3) showed the presence of testicular sperm and
\nnormal spermatogenesis, with a Johnsen’s score of 7 to 9. Besides, epididymal
\nsperm was present in two other infantile cystinosis patients (2/2), obtained
\nby PESA procedure, which was only performed in those two patients. Hence,
\nall of the five investigated infantile cystinosis patients showed either testicular
\nor epididymal sperm (5/5 or 100%), indicating that testicular function was
\npreserved in those patients. In contrast, seven out of the total eight infantile
\ncystinosis patients underwent semen analysis, and they all presented with
\nazoospermia (7/7 or 100%), including four out of the five patients that showed
\ntesticular or epididymal sperm, while a semen sample from one infantile patient,
\nwho underwent testicular biopsy, could not be retrieved. Meanwhile, the two
\njuvenile cystinosis patients (2/2) showed a reduced sperm count (15.9 and
\n6.4 million/ml), and the ocular cystinosis patient (1/1) showed normal sperm
\ncount (71.6 million/ml). Remarkably, the scrotal ultrasound results revealed a
\nsignificant higher epididymis caput diameter (normalized to the testis volume) in
\ninfantile cystinosis group compared with healthy controls (1.63±0.66 mm/cm3
\nfor infantile cystinosis vs 0.50±0.18 mm/cm3 for controls, p<0.001).
\n</p> <p>Limitations, reasons for caution: The study is performed in a small group
\nof patients; however, the rarity of the disease makes it challenging to recruit
\nmore male cystinosis patients. Moreover, we could not investigate the presence
\nof testicular or epididymal sperm in all included cystinosis patients due to ethical
\nreasons.
\nWider implications of the findings: The results obtained in the study
\nfurther unravel the origin of the observed azoospermia in male infantile-type
\ncystinosis patient by suggesting an obstructive cause. In addition, our research
\nmight provide a better age-dependent treatment to circumvent infertility in
\nthese patients.</p>
\n<p>Trial registration number:Not applicable</p>

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