The role of partial AZFc deletions of the Y chromosome in spermatogenic impairment is currently debated. Recently, it was also reported that duplications of the same region are associated with oligozoospermia in Han-Chinese men. The aims of this study were (1) to evaluate the clinical signiWcance of partial AZFc deletions in a large study population and (2) to deWne if partial AZFc duplications are a risk factor for spermatogenic failure also in a Caucasian population such as the Italian. We screened 556 infertile patients and 487 normozoospermic controls for partial AZFc deletions with a combined method based on STS+/¡ followed by CDY1-DAZ gene dosage and copy analysis. For the second aim, we performed CDY1-DAZ gene dosage in 229 infertile patients and 263 normozoospermic controls. The frequency of gr/gr deletions in patients was signiWcantly diVerent from the controls (3.2 vs. 0.4%, respectively; P < 0.001), with an OR = 7.9 (95% CI 1.8-33.8). b2/b3 deletions were rare in both groups (0.5% in patients, 0.2% in controls). Concerning gr/gr duplications, we observed no signiWcant diVerences in their frequency between cases (2.6%) and controls (3.8%). This is the largest study population in the literature in which all potential methodological and selection biases were carefully avoided to detect the clinical signiWcance of partial AZFc deletions and duplications. Our study provides strong evidence that gr/gr deletion is a risk factor for impaired spermatogenesis, whereas we did not detect a signiWcant eVect of b2/b3 deletions and partial AZFc duplications on spermatogenesis in this Caucasian ethnic group.

Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network. Asian Journal of Andrology (2012) 14, 49-56; doi:10.1038/aja.2011.68; published online 5 December 201

BACKGROUND: A specific haplotype (AGATA) in the estrogen receptor alpha (ER1) gene was recently described as a new risk factor for cryptorchidism in the Japanese population. In this ethnic group, single-nucleotide polymorphism 12 (SNP12) was concluded to be the tag SNP for the AGATA haplotype. MATERIALS AND METHODS: A large group of patients (total number = 335) and controls (total number = 567) of two Caucasian populations were analysed for the AGATA haplotype and SNP12 to verify whether this genetic variant and its tag SNP were associated with cryptorchidism or with severe spermatogenic failure. RESULTS: We confirm that SNP12 is the tag SNP for the AGATA haplotype also in Caucasians. However, in contrast with the Japanese population we found a protective effect for ESR1 SNP12 on cryptorchidism in the Italian population. No association between SNP12 and severe spermatogenic disturbances was observed. CONCLUSIONS: The observed associations (although with opposite effect) with cryptorchidism encourage future studies on independent cases and controls from different ethnic and geographic origins. On the other hand, in contrast with other ESR1 polymorphisms, SNP12 polymorphism is not associated with severe male factor infertility in two independent European population.

Our data indicate that specific allelic combinations of the ERalpha, which confer a stronger estrogen effect, may negatively influence human spermatogenesis.

SUMMARYThe aim of this study was to provide a comprehensive genetic/phenotypic characterization of subjects suffering infertility owing to sperm macrocephaly (n = 3) or globozoospermia (n = 9) and to investigate whether the patients' genetic status was correlated with the alteration of various sperm parameters. AURKC was sequenced in case of sperm macrocephaly while the DPY19L2 status has been analyzed by multiple approaches including a novel qPCR-based copy number assay in case of globozoospermia. Globozoospermic patients were also analyzed for SPACA1, a novel candidate gene herein tested for the first time in humans. The effect of the patients' genetic status was interrogated by implementing the molecular screening with the characterization of several sperm parameters: (i) routine sperm analysis, integrated with transmission electron microscopy; (ii) sperm fluorescent in situ hybridization (FISH) analysis; (iii) sperm DNA fragmentation (DF) analysis. Moreover, for the first time, we performed microsatellite instability analysis as a marker of genome instability in men with sperm macrocephaly and globozoospermia. Finally, artificial reproductive technology (ART) history has been reported for those patients who underwent the treatment. Macrocephalic patients had an AURKC mutation and >89% tetraploid, highly fragmented spermatozoa. DPY19L2 was mutated in all patients with >80% globozoospermia: the two homozygous deleted men and the compound heterozygous showed the severest phenotype (90-100%). The newly developed qPCR method was fully validated and has the potential of detecting also yet undiscovered deletions. DPY19L2 status is unlikely related to FISH anomalies and DF, although globozoospermic men showed a higher disomy rate and DF compared with internal reference values. No patient was mutated for SPACA1. Our data support the general agreement on the negative correlation between macro/ globozoospermia and conventional intracytoplasmic sperm injection outcomes. Microsatellites were stable in all patients analyzed. The comprehensive picture provided on these severe phenotypes causing infertility is of relevance in the management of patients undergoing ART.