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Abstract: This study assessed the feasibility of testis tissue cryopreservation (TTC) for fertility preservation in prepubescent boys with cryptorchidism. From January 2014 to December 2022, the University Hospital of Copenhagen (Rigshospitalet, Copenhagen, Denmark) implemented TTC for 56 boys with cryptorchidism to preserve their reproductive potential. Testis tissue samples were collected during orchiopexy (32 cases) or at subsequent follow-up procedures (24 cases), necessitated by an increased risk of infertility as indicated by hormonal assessments and/or findings from initial surgical biopsies. Testis samples were procured for TTC and pathological analysis. The cohort had an average age of 1.3 (range: 0.3-3.8) years at the time of orchiopexy, with 91.1% presenting bilateral cryptorchidism. The study revealed a median germ cell count of 0.39 (range: 0-2.88) per seminiferous tubule, with germ cells detected in 98.0% of the bilateral biopsies and 100% of the unilateral, indicating a substantial potential for fertility in these immature tissues. A dark spermatogonia (Ad) was detected in 37 out of 56 patients evaluated, with a median Ad spermatogonia count of 0.027 (range: 0.002-0.158) per seminiferous tubule. A total of 30.2% of the samples lacked Ad spermatogonia, indicative of potential gonadotrophin insufficiency. The median hormone levels measured were as follows: follicle-stimulating hormone (FSH) at 0.69 (range: 0.16-2.5) U l -1 , luteinizing hormone (LH) at 0.21 (range: 0.05-3.86) U l -1 , and inhibin B at 126 (range: 17-300) pg ml -1 . Despite early orchiopexy, 20%-25% of boys with cryptorchidism remain at risk for future infertility, substantiating the necessity of TTC as a precaution. The study highlights the need for refined predictive techniques to identify boys at higher risk of future infertility., (Copyright © 2024 Copyright: ©The Author(s)(2024).)

Study Question: Do different boys with different types of cryptorchidism exhibit different anogenital distances (AGDs)?, Summary Answer: Length of AGD seemed to differ in different groups of patients with cryptorchidism., What Is Known Already: AGD, which is used as an indicator of prenatal androgen action, tends to be shorter in boys with cryptorchidism compared to unaffected boys. Shorter AGDs have also been reported in boys with hypospadias, in men with poor semen quality, and in men with testicular cancer., Study Design, Size, Duration: A prospective descriptive cohort study was performed using data from consecutively selected boys with cryptorchidism (n = 169) operated in a single center over a period of 3 years (September 2019 to October 2022)., Participants/materials, Setting, Methods: AGD was measured in 169 infant boys, at 3 to 26 months of age, during anesthesia with a vernier caliper measuring the distance from the anus to the base of the scrotum (AGDAS) and from the anus to the anterior base of the penis (AGDAP) in two body positions according to the methods by 'The Infant Development and the Environment Study' (TIDES) and 'Cambridge Baby Growth Study', resulting in four mean values per patient (TIDES AGDAS/AP and Cambridge AGDAS/AP). Normal values for AGD by age were set by our hospital Department of Growth and Reproduction based on a large cohort of healthy infant boys (n = 1940). Testicular biopsies were performed at orchidopexy as a clinical routine. The germ cell number (G/T) and type Ad spermatogonia number (AdS/T) per cross-sectional tubule of at least 100 and 250 tubules, respectively were measured and related to normal samples. Blood samples were obtained by venipuncture for measuring serum LH, FSH, and inhibin B. They were analyzed in our hospital Department of Growth and Reproduction where the normal reference was also established. Correlations between the four mean AGD measurements for each boy were evaluated by Spearman rank correlation analyses. The AGD measurement of every boy was transferred to the multiple of the median (MoM) of the normal AGD for age and named MoM AGD., Main Results and the Role of Chance: There were 104 boysoperated for unilateral, and 47 boys operated for bilateral, undescended testes, whereas 18 boys had vanished testis including one boy with bilateral vanished testes. Only 6% of cases with vanished testes had a MoM AGD higher than the normal median compared to 32% with undescended testes (P < 0.05). MoM AGD increased with the age at surgery for boys with vanished testis (Spearman r = 0.44), but not for boys with undescended testes (Spearman r = 0.14). Boys with bilateral cryptorchidism had longer AGDs and more often had hypogonadotropic hypogonadism than boys with unilateral cryptorchidism (P < 0.005) and (P < 0.000001)., Limitations, Reasons for Caution: Although being the largest published material of AGD measurements of infant boys with cryptorchidism, one limitation of this study covers the quite small number of patients in the different groups, which may decrease the statistical power. Another limitation involves the sparse normal reference material on G/T and AdS/T. Finally, there are currently no longitudinal studies evaluating AGD from birth to adulthood and evaluating childhood AGD in relation to fertility outcome. Our study is hypothesis generating and therefore the interpretation of the results should be regarded as exploratory rather than reaching definite conclusions., Wider Implications of the Findings: The study findings are in agreement with literature as the total included group of boys with cryptorchidism exhibited shorter than normal AGDs. However, new insights were demonstrated. Boys with vanished testis had shorter AGDs compared to unaffected boys and to boys with undescended testes. This finding challenges the current concept of AGD being determined in 'the masculinization programming window' in Week 8 to 14 of gestation. Furthermore, boys with bilateral cryptorchidism had longer AGDs and more often had hypogonadotropic hypogonadism than boys with unilateral cryptorchidism, suggesting that the lack of fetal androgen in hypogonadotropic hypogonadism is not that significant., Study Funding/competing Interest(s): No external funding was used and no competing interests are declared., Trial Registration Number: The trial was not registered in an ICMJE-recognized trial registry., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Cryptorchidism in males constitutes a notable risk factor for both infertility and testicular cancer. Infertility in adulthood is closely linked to the germ cell status in childhood. Furthermore, the significance of germ cell status is important as more than 95% of all reported testicular malignancies are germ cell tumors. The review aims to elucidate the pathogenesis of germ cells in cryptorchid testes concerning their association with infertility and testicular malignancies. Impaired germ cell numbers are evident in cryptorchid testes even during antenatal and neonatal stages. In cryptorchidism there is a rapid decline in germ cell number within the first year of life, partially attributed to physiologic gonocyte apoptosis. Additionally, germ cells fail to differentiate normally during mini-puberty leading to reduced germ cell proliferation and delayed clearance of gonocytes from the seminiferous epithelium. Absence of germ cells in testicular biopsies occurs already 10 months of age and germ cell deterioration progressively worsens with approximately 50% of persisting cryptorchid testes lacking germ cells during puberty. The deficient germ cell maturation and proliferation leads to later infertility. Elevated temperature in the cryptorchid testes and also hormonal deficiency contribute to this phenomenon. Germ cell neoplasia in situ (GCNIS) originating during fetal development may manifest in rare cases associated with disorders of sexual development, chromosomal abnormalities in boys, specific syndromes, and teratomas that include cryptorchidism. In adults, the presence of GCNIS predominantly represents a new histology pattern before invasive germ cell cancer is demonstrated and is neither congenital nor related to abnormal gonocyte transformation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Thorup, Hildorf, Hildorf, Baastrup, Mamsen, Andersen, Olsen and Cortes.)