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Becoming a phenotypic male is ultimately determined by androgen-induced masculinization. Disorders of fetal masculinization, resulting in hypospadias or cryptorchidism, are common, but their cause remains unclear. Together with the adult-onset disorders low sperm count and testicular cancer, they can constitute a testicular dysgenesis syndrome (TDS). Although masculinization is well studied, no unifying concept explains normal male reproductive development and its abnormalities, including TDS. We exposed rat fetuses to either anti-androgens or androgens and showed that masculinization of all reproductive tract tissues was programmed by androgen action during a common fetal programming window. This preceded morphological differentiation, when androgen action was, surprisingly, unnecessary. Only within the programming window did blocking androgen action induce hypospadias and cryptorchidism and altered penile length in male rats, all of which correlated with anogenital distance (AGD). Androgen-driven masculinization of females was also confined to the same programming window. This work has identified in rats a common programming window in which androgen action is essential for normal reproductive tract masculinization and has highlighted that measuring AGD in neonatal humans could provide a noninvasive method to predict neonatal and adult reproductive disorders. Based on the timings in rats, we believe the programming window in humans is likely to be 8-14 weeks of gestation.

Background Cryptorchidism is one of the most common reproductive abnormalities in rams, which seriously harms the reproductive capacity of rams and causes significant economic losses to the sheep industry. However, there are few studies elucidating its hereditary predisposition in sheep. Results In the present study, the transcriptome and proteome of the cryptic (CT) and contralateral (CLT) testis from four unilaterally cryptorchid rams, and the normal testis (NT) from four healthy rams were analyzed using RNA-seq and TMT-based proteomics, respectively. A total of 10,357, 10,175, and 132 differentially expressed genes (DEGs) were identified between CT vs. CLT, CT vs. NT, and CLT vs. NT. Venn diagram showed that 9744 DEGs (5499 up-regulated and 4245 down-regulated) shared in CT vs. CLT and CT vs. NT. Functional enrichment analysis revealed that 5499 up-regulated DEGs were mainly involved in regulation of programmed cell death and metabolic process, while 4245 down-regulated DEGs were closely related to reproductive process, such as spermatogenesis, sexual reproduction, reproduction and male gamete generation. Furthermore, 325 overlapped genes (114 up-regulated and 211 down-regulated) between DEGs and DAPs that shared the same regulatory status were identified by combining transcriptomics and proteomics. Ten genes, including AKAP4 , AKAP3 , FSIP2 , HSPA1L , HSPA4L , TUBB , TXNRD2 , CDC42 , PGK1 and HSPA1A , were identified as candidate key genes related to unilateral cryptorchidism. Conclusion Our results revealed that both gene and protein expression in the cryptic testis of unilateral cryptorchid rams is massively altered. Bioinformatics analysis unveiled several candidate genes and signaling pathways potentially involved in unilateral cryptorchidism. These findings provide new insights into the molecular mechanism underlying spermatogenesis failure caused by cryptorchidism.

Cryptorchidism, a prevalent congenital defect in pigs, raises animal welfare and economic concerns in the breeding industry. This study utilized a genome-wide transcriptome analysis, examining samples from the pituitary gland, cremaster muscle and testis of one-week-old piglets. In the cremaster muscle of cryptorchid piglets,1225 genes exhibited significant differential expression (log2FoldChange = |2.0|, p-adjusted value ≤ 0.01). Downregulated genes were linked to biological processes like muscle tissue development and actin cytoskeleton organization. Pathway analysis further revealed the suppression of metabolic pathways including ‘Oxidative phosphorylation’, ‘TCA cycle’ and ‘Motor Proteins’. Notably, several genes integral to the motor protein pathway were significantly downregulated. Additionally, crucial genes in the noncanonical Wnt signalling pathway that regulates tissue morphogenesis and repair during the embryonic stage, were also suppressed. Our results indicate that a disruption in the normal testicular descent is accompanied by the suppression of major genes in the motor protein pathway, potentially hampering the presumed role of the cremaster muscle in testicular descent. However, we propose this to be a consequence of the down regulation of key genes in the noncanonical Wnt signalling pathway. Based on our findings, future research might be able to uncover causal mutations related to the expression of these genes.

ABSTRACT Cryptorchidism is one of the most common congenital malformations in the paediatric genitourinary tract. Data analysis of cryptorchidism‐related datasets in the GEO database and gene sequencing results from our institution, along with bioinformatic analysis of the merged mitochondrial gene datasets, revealed that COX5B is differentially expressed in the testes of children with cryptorchidism. Its encoded protein has attracted our attention as a key component of the mitochondrial respiratory chain complex IV. This study aims to explore the COX5B gene expression changes and related mitochondrial issues in cryptorchid rats. For this purpose, we established a cryptorchid rat model by surgery and used molecular biology and biochemistry techniques to detect and analyse the expression level of the COX5B gene and mitochondrial function indexes. The results indicated a significant decrease in COX5B gene expression in the affected testis of cryptorchid rats. The knockdown of COX5B expression in TM3 cells could be observed as the aggravation of cellular senescence, which led to the reduction of proliferation, as well as accompanied by the obvious disorders of mitochondrial function, including the increase of ROS and the decrease of ATP, in which MMP was significantly reduced. This suggests that the COX5B gene may play an important role in cryptorchid testis‐induced reproductive system damage and may be a new target for small molecule‐targeted therapy.

Giant pandas are an endangered species with low reproductive rates. Cryptorchidism, which can negatively affect reproduction, is also often found in pandas. Seminal plasma plays a crucial role in sperm–environment interactions, and its properties are closely linked to conception potential in both natural and assisted reproduction. The research sought to identify seminal fluid protein content variations between normal and cryptorchid giant pandas. Methods: Using a label-free MS-based method, the semen proteomes of one panda with cryptorchidism and three normal pandas were studied, and the identified proteins were compared and functionally analyzed. Results: Mass spectrometry identified 2059 seminal plasma proteins, with 361 differentially expressed proteins (DEPs). Gene ontology (GO) analysis revealed that these DEPs are mainly involved in the phosphate-containing compound metabolic, hydrolase activity, and kinase activity areas (p ≤ 0.05). The KEGG functional enrichment analysis revealed that the top 20 pathways were notably concentrated in the adipocyte lipolysis and insulin metabolism pathway, with a significance level of p ≤ 0.05. Further analysis through a protein–protein interaction (PPI) network identified nine key proteins that may play crucial roles, including D2GXH8 (hexokinase Fragment), D2HSQ6 (protein tyrosine phosphatase), and G1LHZ6 (Calmodulin 2). Conclusions: We suspect that the high abundance of D2HSQ6 in cryptorchid individuals is associated with metabolic pathways, especially the insulin signal pathway, as a typical proteomic feature related to its pathological features. These findings offer insight into the ex situ breeding conditions of this threatened species.

Abstract Disclosure: S.P. Martin Benitez: None. E. Monteverde: None. R. Grinspon: None. R.A. Rey: None. Background: Cryptorchidism is a frequent complaint in boys. The choice between surgical and hormonal treatments may vary according to the etiology. The efficacy of human chorionic gonadotropin (hCG) therapy varies from <10% to >50% between different series. The aim of this study was to detect factors associated with therapeutic success of hCG to bring testes down to the scrotum in prepubertal boys. The primary hypothesis was that impaired testicular function at baseline, defined as serum AMH <3rd centile for age, is a risk factor for unsuccessful treatment, defined as testes not reaching the scrotum after 1 weekly injection of hCG 1000 IU im or sc for 5 weeks. Methods: We performed a retrospective case-control study in a single center between 2000 and 2020. Based on a pilot study, considering that the incidence of treatment success is 10% in boys with impaired testicular function, and establishing a confidence level of 99% and a power of 90% for an odds ratio (OR) of 3, the estimated sample size was 112 for each group. Results: A total of 260 boys with cryptorchidism were analyzed: 136 with successful (controls) and 124 with unsuccessful (cases) hCG treatment. Median ages (IQR) were 4.7 (3.1-7.2) years and 4.4 (2.8-7.0) years (p=0.45), respectively. Baseline serum AMH was 698 (520-931) and 248 (169-579) pmol/L (p<0.001). The relative prevalence of impaired testicular function was 5.9% and 56.5% (p<0.001), with an OR (95% CI) of 25.5 (11.2-65.1). The relative prevalence of high inguinal position of the testes before hCG was 8.1% and 54.0% (p<0.001), with an OR of 16.7 (7.8-39.0). No differences between the groups were found in baseline FSH or in the relative prevalences of congenital or acquired cryptorchidism, being born small for gestational age or the existence of inguinal hernia. A multivariate analysis did not detect a statistically significant interaction between impaired testicular function and inguinal position of the testes. Conclusion: Low serum AMH and high inguinal testicular position were independent predictors of unsuccessful hCG treatment for cryptorchidism in prepubertal boys, allowing clinicians to consider each factor separately when assessing treatment prognosis. These findings also highlight serum AMH as a key marker for pretreatment assessment, as it reflects the functionality of Sertoli cells and the ability of the testes to respond to hCG stimulation. Presentation: Sunday, July 13, 2025

Abstract Disclosure: F. Otsuka: None. Y. Soejima: None. N. Iwata: None. K. Yamamoto: None. A. Suyama: None. Y. Nakano: None. Kallmann syndrome (KS) is a congenital developmental disorder characterized by hypogonadotropic hypogonadism and anosmia, which results from incomplete embryonic migration of gonadotropin-releasing hormone (GnRH)-synthesizing neurons and olfactory neurons. KS is often accompanied by cryptorchidism, testicular atrophy, micropenis, orofacial clefts and/or tooth agenesis, renal anomalies, bimanual synkinesis, and hearing loss. KS exhibits different inheritance patterns and genetic heterogeneity including X-linked recessive, ANOS1; autosomal recessive, PROK2 and PROKR2; and autosomal dominant, FGFR1, FGF8, and CHD7. Fibroblast growth factor receptor 1 (FGFR1) was the first gene to be identified as an autosomal dominant form of KS, and more than 140 FGFR1 variants have so far been reported. FGFR1, also known as KAL2, is a tyrosine kinase receptor for FGF and it regulates cell proliferation, differentiation and migration. FGFR1 gene is expressed mainly in Rathke’s pouch and the ventral diencephalon during the embryonic period. It has been reported that variants of FGFR1 cause KS and variants have been detected in 10% of KS cases. We here report an adult case of KS with a novel variant of FGFR1. A middle-aged male was refereed for a compression fracture of a lumbar vertebra. It was shown that he had severe osteoporosis, anosmia, gynecomastia, and a past history of operations for cryptorchidism. Endocrine workup by pituitary and gonadal stimulation tests revealed the presence of both primary and central hypogonadism. Genetic testing revealed a novel variant of FGFR1 (c.2197_2199dup, p.Met733dup). To identify the pathogenicity of the novel variant and the clinical significance for the gonads, we investigated the effects of the FGFR1 variant on downstream signaling of FGFR1 and gonadal steroidogenesis by using human steroidogenic granulosa KGN cells. It was revealed that transfection of the variant gene significantly impaired FGFR1 signaling, detected by downregulation of SPRY2, compared with that in the case of forced expression of wild-type FGFR1, and that the forced expression of the variant gene apparently altered the expression levels of key steroidogenic factors including StAR and aromatase in the gonad. Collectively, the results suggested that the novel variant of FGFR1 detected in a patient with KS was linked to impairment of FGFR1 signaling as well as alteration of gonadal steroidogenesis, leading to the pathogenesis of latent primary hypogonadism. Presentation: Saturday, July 12, 2025

Cryptorchidism is a common cause of male infertility, often necessitating microdissection testicular sperm extraction (m-TESE) for sperm retrieval post-surgery. However, uncertainties persist regarding m-TESE outcomes and influencing factors following cryptorchidism surgery. A systematic review and meta-analysis were conducted to evaluate sperm retrieval rates (SRR) among patients undergoing m-TESE after cryptorchidism surgery. Factors including age at orchidopexy, age at m-TESE, type of cryptorchidism, serum hormone levels, testicular volume, and interval from surgery to m-TESE were analyzed for their impact on SRR.Nine studies encompassing 935 patients were included. The overall SRR was 57% (95% confidence interval [CI] 51% to 63%). Compared to patients with negative sperm retrieval (SR-), patients with positive sperm retrieval (SR+) underwent m-TESE at an older age (1.81 years; 95% CI 1.17 to 2.45) and orchidopexy at a younger age (-3.35 years; 95% CI -6.34 to -0.36). Different types of cryptorchidism (including high scrotal, inguinal canal, intra-abdominal) significantly influenced SRR (P<0.05). Serum testosterone, follicle-stimulating hormone, luteinizing hormone levels and testicular volume showed no significant correlation with SRR (P>0.05). Furthermore, SR- patients typically experienced shorter intervals from orchidopexy to m-TESE compared to SR+ patients (34.09 months; 95% CI 0.40 to 67.77). Earlier orchidopexy and much later m-TESE procedures, as well as undescended testis closer to the scrotum, increase the likelihood of successful sperm retrieval. Orchidopexy for cryptorchidism should be done as early as possible, whether it is performed before 18 months of age or detected at a much older age. In patients with undetected cryptorchidism and azoospermia after puberty, m-TESE should not be performed immediately after orchidopexy, the optimal interval from orchidopexy to m-TESE still requires further study.