Yutaro Hayashi

Genetic pathway of external genitalia formation and molecular etiology of hypospadias.

Hypospadias is one of the most common congenital disorders in males. Impaired fetal androgen action interferes with masculinization, including external genitalia formation, and can result in this anomaly; however, the molecular etiology remains unknown. Recent molecular approaches, including gene-targeting approaches in mice and single nucleotide polymorphisms analyses in humans, might provide an opportunity to identify the causative and risk factors of this anomaly. Several genes, such as sonic hedgehog, fibroblast growth factors, bone morphogenetic proteins, homeobox genes, and the Wnt family regulate external genitalia formation. Mastermind-like domain containing 1/chromosome X open reading frame 6 mutation and activating transcription factor 3 variants have been shown to be associated with the incidence of isolated hypospadias. In addition, this anomaly may be associated with a specific haplotype of the gene for estrogen receptor alpha, which mediates the estrogenic effects of environmental endocrine disruptors, and the effects of these disruptors on external genitalia formation might depend on individual genetic susceptibility. These molecular studies will refine our knowledge of the genetic mechanism involved in external genitalia formation, and lead to new strategies for the clinical management of hypospadias.

Long-term physical, hormonal, and sexual outcome of males with disorders of sex development

PURPOSEnWe investigated the long-term physical, hormonal, and sexual outcomes of males with disorders of sex development (DSD) and discussed the necessity of long-term follow-up for these patients after surgery.nnnPATIENTS AND METHODnTwelve DSD patients (average age, 21.0 +/- 3.6 years old) who had been designated as male in childhood (3 ovotesticular DSD, four 45,XO/46,XY mixed gonadal dysgenesis, four 46,XX testicular DSD, and one 46,XY DSD; androgen insensitivity syndrome) were enrolled. For these patients, height, penile length, and testicular volume were evaluated in adulthood. Serum levels of luteinizing hormone, follicle-stimulating hormone, and testosterone were also measured during follow-up. In addition, sexual function and romantic relationships were evaluated.nnnRESULTSnDevelopment of the penis and testes was poor. According to the hormonal study, these patients were diagnosed with hypergonadotropic hypogonadism or normogonadism; 90% patients had experienced penile erection and masturbation at the time of participation, and 70% and 40% patients had experienced ejaculation and sexual intercourse with female partners, respectively. No patients preferred to avoid sexual contact with women.nnnCONCLUSIONnAlthough DSD males had an undeveloped penis and testis and had hypergonadotropic hypogonadism or normogonadism, most had male sexual potential and male sex identity as long as testicular tissues were preserved.

Prepuce: Phimosis, Paraphimosis, and Circumcision

Phimosis is a condition in which the prepuce cannot be retracted over the glans penis. Actually, physiologic phimosis is common in male patients up to 3 years of age, but often extends into older age groups. Balanoposthitisis a common inflammation occurring in 4–11% of uncircumcised boys. Circumcision is generally undertaken for three reasons: first, as an item of religious practice, typically neonatally although occasionally transpubertally, as a rite of passage; second, as a prophylactic measure against future ailments for the reduction in the risk of penile cancer, urinary tract infection, and sexually transmitted infection; and third, for immediate medical indication. Balanitisxeroticaobliterans is an infiltrative skin condition that causes a pathological phimosis and has been considered to be the only absolute indication for circumcision. Various kinds of effective alternatives to circumcision have been described, including manual retraction therapy, topical steroid therapy, and several variations of preputioplasty. All of these treatments have the ability to retract the foreskin as their goal and do not involve the removal of the entire foreskin. Paraphimosis is a condition in which the foreskin is left retracted. When manipulation is not effective, a dorsal slit should be done, which is usually followed by circumcision.

Findings of fat-suppressed T2-weighted and diffusion-weighted magnetic resonance imaging in the diagnosis of non-palpable testes

Study Type – Diagnostic (exploratory cohort)u2028Level of Evidenceu20032b

Identification of Novel Low-Dose Bisphenol A Targets in Human Foreskin Fibroblast Cells Derived from Hypospadias Patients

Background/Purpose The effect of low-dose bisphenol A (BPA) exposure on human reproductive health is still controversial. To better understand the molecular basis of the effect of BPA on human reproductive health, a genome-wide screen was performed using human foreskin fibroblast cells (hFFCs) derived from child hypospadias (HS) patients to identify novel targets of low-dose BPA exposure. Methodology/Principal Findings Gene expression profiles of hFFCs were measured after exposure to 10 nM BPA, 0.01 nM 17β-estradiol (E2) or 1 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 24 h. Differentially expressed genes were identified using an unpaired Students t test with P value cut off at 0.05 and fold change of more than 1.2. These genes were selected for network generation and pathway analysis using Ingenuity Pathways Analysis, Pathway Express and KegArray. Seventy-one genes (42 downregulated and 29 upregulated) were identified as significantly differentially expressed in response to BPA, among which 43 genes were found to be affected exclusively by BPA compared with E2 and TCDD. Of particular interest, real-time PCR analysis revealed that the expression of matrix metallopeptidase 11 (MMP11), a well-known effector of development and normal physiology, was found to be inhibited by BPA (0.47-fold and 0.37-fold at 10 nM and 100 nM, respectively). Furthermore, study of hFFCs derived from HS and cryptorchidism (CO) patients (nu200a=u200a23 and 11, respectively) indicated that MMP11 expression was significantly lower in the HS group than in the CO group (0.25-fold, Pu200a=u200a0.0027). Conclusions/Significance This present study suggests that an involvement of BPA in the etiology of HS might be associated with the downregulation of MMP11. Further study to elucidate the function of the novel target genes identified in this study during genital tubercle development might increase our knowledge of the effects of low-dose BPA exposure on human reproductive health.

Association of variants in genes involved in environmental chemical metabolism and risk of cryptorchidism and hypospadias

We hypothesized that single-nucleotide polymorphisms (SNPs) of genes involved in environmental endocrine disruptors (EEDs) metabolism might influence the risk of male genital malformations. In this study, we explored for association between 384 SNPs in 15 genes (AHR, AHRR, ARNT, ARNT2, NR1I2, RXRA, RXRB, RXRG, CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP3A4, CYP17A1 and CYP19A1) and risk of cryptorchidism (CO) and hypospadias (HS) in 334 Japanese (JPN) males (141 controls, 95 CO and 98 HS) and 187 Italian (ITA) males (129 controls and 58 CO). In the JPN study group, five SNPs from ARNT2 (rs2278705 and rs5000770), CYP1A2 (rs2069521), CYP17A1 (rs4919686) and NR1I2 (rs2472680) were significantly associated at both allelic and genotypic levels with risk of at least one genital malformation phenotype. In the ITA study group, two SNPs in AHR (rs3757824) and ARNT2 (rs1020397) were significantly associated with risk of CO. Interaction analysis of the positive SNPs using multifactor dimensionality reduction demonstrated that synergistic interaction between rs2472680, rs4919686 and rs5000770 had 62.81% prediction accuracy for CO (P=0.011) and that between rs2069521 and rs2278705 had 69.98% prediction accuracy for HS (P=0.001) in JPN population. In a combined analysis of JPN and ITA population, the most significant multi-locus association was observed between rs5000770 and rs3757824, which had 65.70% prediction accuracy for CO (P=0.055). Our findings indicate that genetic polymorphisms in genes involved in EED metabolism are associated with risk of CO and HS.

Advances in Molecular Genetics of Cryptorchidism

Cryptorchidism is the most common congenital disorder in boys; one major complication of this disorder is male infertility. Androgens are key hormones to complete testicular descent; therefore, impaired fetal androgen action can result in this anomaly; its molecular etiology, however, remains unknown. Recent molecular approaches might provide an opportunity to identify not only candidate genes but also several predictive markers of future fertility. The purpose of this review is to summarize the recent insight into the genetic pathway of testicular descent and the molecular etiology of isolated cryptorchidism, and discuss the prospects of treatment to achieve future fertility in such patients.

Optimal Cutoff Value of Contralateral Testicular Size for Prediction of Absent Testis in Japanese Boys With Nonpalpable Testis

OBJECTIVESnTo investigate the accuracy of contralateral testicular hypertrophy in Japanese boys with a nonpalpable testis and to determine the optimal cutoff value of the contralateral testicular size to predict the absence of the testis.nnnMETHODSnFrom December 2003 to November 2009, we evaluated 55 boys <60 months old (mean age 19.4) with a unilateral nonpalpable testis and compared their findings with those of a control group. The control group included 20 age-matched boys with 40 testes. The nonpalpable status of the testes was diagnosed by physical examination, and the contralateral testis was measured with calipers before surgery. A sensitivity and specificity analysis were performed using computer software.nnnRESULTSnAt surgery, the testis was found in 22 of the 55 boys and was absent in 33. Of the 33 boys with an absent testis, 4 had a blind-ending vessel and 29 had an atrophic cord and testicular nubbin in the canal or scrotum. The mean contralateral testicular length and volume in the boys with an absent testis was 22.4 mm and 2.20 cm(3) compared with 16.6 mm and 1.10 cm(3) in the boys with the testis present and 16.6 mm and 1.18 cm(3) in the controls, respectively (P < .01). The predictive accuracy, sensitivity, and specificity for an absent testis was 87.3%, 81.8%, and 95.5% for the length and 85.5%, 84.8%, and 86.4% for the volume, respectively, at the optimal cutoff value of 21 mm in length and 1.6 cm(3) in volume.nnnCONCLUSIONSnOur data have shown that contralateral testicular hypertrophy strongly indicates an absent testis in Japanese boys. The optimal cutoff for contralateral testicular hypertrophy with calipers was 21 mm and 1.6 cm(3). This result has provided valuable information for preoperative counseling and treatment planning.

Intratesticular pressure after testicular torsion as a predictor of subsequent spermatogenesis: a rat model

What’s known on the subject? and What does the study add?

Laparoscopic Management for Fibroepithelial Polyp Causing Ureteropelvic Junction Obstruction in a Child

An 11-year-old boy with episodes of intermittent gross hematuria and recurrent left flank pain was referred to our institute with left ureteropelvic junction (UPJ) obstruction. (99m)Tc diethylenetriamine pentaacetic acid (DTPA) renography revealed an obstructive pattern in the left kidney, and the existence of a crossing vessel at the UPJ was suspected with excretory urography. Laparoscopic surgery was performed, and intraoperatively no aberrant vessels were found. Upon opening the ureter, a solitary round polyp was found. The segment of the UPJ area containing the polyp was completely removed, followed by laparoscopic dismembered pyeloplasty. Pathologic findings demonstrated a benign fibroepithelial polyp.