Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Ferlin A et al., 2007 · The Journal of clinical endocrinology and metabolism
An explosive growth in Y chromosome long arm (Yq) microdeletion testing demand for male infertility occurred in the past few years. However, despite the progresses in the biology of this chromosome, a number of molecular and clinical concerns are not supported by definitive data.
The objective was to provide information on the type and prevalence of microdeletions in infertile males, indication for testing, genotype-phenotype correlation, sperm aneuploidies, and genetic counseling.
We performed a prospective study from January 1996 to December 2005 in an academic clinic.
We studied 3073 consecutive infertile men, of which 625 were affected by nonobstructive azoospermia and 1372 were affected by severe oligozoospermia. Ninety-nine patients with microdeletions are described here.
Yq microdeletions, seminal analysis, reproductive hormones, testicular cytology/histology, and sperm sex chromosomes aneuploidies were used as outcome measures.
The prevalence of microdeletions was 3.2% in unselected infertile men, 8.3% in men with nonobstructive azoospermia, and 5.5% in men with severe oligozoospermia. Only 2 of 99 deletions were found in men with more than 2 million sperm/ml. No clinical data are useful to identify a priori patients with higher risk of Yq microdeletions. Most deletions are of the AZFc-b2/b4 subtype and are associated with variable spermatogenic phenotype, with sperm present in 72% of the cases. Complete AZFa and AZFb (P5/Proximal P1) deletions are associated with Sertoli cell-only syndrome and alterations in spermatocyte maturation, respectively, whereas partial deletions in these regions are associated with milder phenotype and frequent presence of sperm. Men with AZFc-b2/b4 deletions produce a higher percentage of sperm with nullisomy for the sex chromosomes and XY-disomy.
This extensive clinical research expands the knowledge on genotype-phenotype relationships and confirms that the identification of Yq microdeletions has significant diagnostic and prognostic value, adding useful information for genetic counseling in these patients.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Moro E et al., 2000 · Molecular and cellular endocrinology
The pathogenic mechanisms by which varicocele disrupt spermatogenesis are not clearly understood and it is possible that when varicocele is associated with a severe bilateral testiculopathy, other causes may represent the actual aetiological factor. Since microdeletions in the Y chromosome long arm (Yq) have become in last years a major cause of male infertility, we perform a Yq microdeletion screening in infertile men with varicocele. We selected 40 patients with severe oligozoospermia (sperm count<5x10(6)/ml, group 1) and 80 with varicocele and mild oligozoospermia (sperm count 10-20x10(6)/ml, group 2). Deletions of Yq was observed in seven out of 40 patients (17.5%) of group 1, while no deletions were found in patients of group 2, suggesting that the bilateral testicular damage observed in patients of group 1 is due to the underlying genetic anomaly, and not to varicocele itself. The finding of a genetic aetiology in infertile men with varicocele suggests that in such patients a Yq microdeletion screening should be performed, both for a proper diagnosis and to avoid unnecessary treatments that will probably not improve the sperm count.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Foresta C et al., 2001 · Endocrine reviews
Three different spermatogenesis loci have been mapped on the Y chromosome and named "azoospermia factors" (AZFa, b, and c). Deletions in these regions remove one or more of the candidate genes (DAZ, RBMY, USP9Y, and DBY) and cause severe testiculopathy leading to male infertility. We have reviewed the literature and the most recent advances in Y chromosome mapping, focusing our attention on the correlation between Y chromosome microdeletions and alterations of spermatogenesis. More than 4,800 infertile patients were screened for Y microdeletions and published. Such deletions determine azoospermia more frequently than severe oligozoospermia and involve especially the AZFc region including the DAZ gene family. Overall, the prevalence of Y chromosome microdeletions is 4% in oligozoospermic patients, 14% in idiopathic severely oligozoospermic men, 11% in azoospermic men, and 18% in idiopathic azoospermic subjects. Patient selection criteria appear to substantially influence the prevalence of microdeletions. No clear correlation exists between the size and localization of the deletions and the testicular phenotype. However, it is clear that larger deletions are associated with the most severe testicular damage. Patients with Y chromosome deletions frequently have sperm either in the ejaculate or within the testis and are therefore suitable candidates for assisted reproduction techniques. This possibility raises a number of medical and ethical concerns, since the use of spermatozoa carrying Y chromosome deletions may produce pregnancies, but in such cases the genetic anomaly will invariably be passed on to male offspring.
Reproductive Genetics · Chromosomal Abnormalities
Foresta C et al., 1999 · Annali italiani di medicina interna : organo ufficiale della Societa italiana di medicina interna
We investigated the possible role of Y chromosome microdeletions in regions previously shown to be important for male germ cell development in unilateral ex-cryptorchid subjects manifesting important bilateral testiculopathy, in order to clarify whether cryptorchidism could be the expression of an intrinsic congenital testicular abnormality. Microdeletion analysis of the Y chromosome long arm was performed by polymerase chain reaction and confirmed by Southern blot in 40 selected unilateral ex-cryptorchid patients with azoospermia or severe oligozoospermia sustained by severe bilateral testiculopathy (Sertoli cell-only syndrome and severe hypospermatogenesis, respectively), 20 unilateral ex-cryptorchid men with moderate oligozoospermia and normal function of the descended testis, 110 patients affected by severe idiopathic primary testiculopathies, 20 patients affected by moderate idiopathic testiculopathy and, as controls, 50 patients affected by known causes of testiculopathy and 50 fertile controls. Eleven out of the 40 (27.5%) unilateral ex-cryptorchid patients affected by bilateral testiculopathy and 28 out of 110 (25.4%) patients affected by severe idiopathic primary testiculopathy showed microdeletions in the Y chromosome long arm, while all other subjects were normal. Male relatives of patients with deletions were also normal. Microdeletions were distributed in different regions of the Y chromosome long arm, including known regions involved in spermatogenesis (DAZ and RBM genes, AZFa, b and c regions) and other still poorly defined loci. No difference in localization of deletions was evident between ex-cryptorchid and idiopathic patients. Microdeletions in the Y chromosome may be responsible for bilateral severe testicular damage: the clinical consequence, other than idiopathic azoospermia and severe oligozoospermia, may also be unilateral cryptorchidism, probably due to altered testicular responses to mechanisms regulating testicular descent.
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