Cause Of Spermatogenic Failure Research Articles

DAZ family proteins exist throughout male germ cell development and transit from nucleus to cytoplasm at meiosis in humans and mice.

The human DAZ gene family is expressed in germ cells and consists of a cluster of nearly identical DAZ (deleted in azoospermia) genes on the Y chromosome and an autosomal homolog, DAZL (DAZ-like). Only the autosomal gene is found in mice. Y-chromosome deletions that encompass the DAZ genes are a common cause of spermatogenic failure in men, and autosomal homologs of DAZ are essential for testicular germ cell development in mice and Drosophila. Previous studies have reported that mouse DAZL protein is strictly cytoplasmic and that human DAZ protein is restricted to postmeiotic cells. By contrast, we report here that human DAZ and human and mouse DAZL proteins are present in both the nuclei and cytoplasm of fetal gonocytes and in spermatogonial nuclei. The proteins relocate to the cytoplasm during male meiosis. Further observations using human tissues indicate that, unlike DAZ, human DAZL protein persists in spermatids and even spermatozoa. These results, combined with findings in diverse species, suggest that DAZ family proteins function in multiple cellular compartments at multiple points in male germ cell development. They may act during meiosis and much earlier, when spermatogonial stem cell populations are established.

Four DAZ Genes in Two Clusters Found in the AZFc Region of the Human Y Chromosome

The DAZ genes are candidate fertility factors that lie within the human Y chromosome's AZFc region, whose deletion is a common cause of spermatogenic failure. The number of DAZ genes has been difficult to determine, in part because the nucleotide sequences of the DAZ genes are nearly identical. Here, fluorescence in situ hybridization and characterization of BAC clones revealed four full-length DAZ genes on the human Y chromosome. They exist in two clusters, each comprising an inverted pair of DAZ genes (3′ ← 5′::5′ → 3′). Analysis of genomic sequences and testicular transcripts suggested that three or four DAZ genes are translated. Each gene contains at least seven tandem copies of a previously described, 2.4-kb repeat unit that encodes 24 amino acids. In addition, two DAZ genes contain tandem copies of a 10.8-kb repeat unit that encodes the RNA-binding domain, which appears to be multimerized in some DAZ proteins. Combining our present results with previous studies, we can reconstruct several steps in the evolution of the DAZ genes on the Y chromosome. In the ancestral Y-chromosomal DAZ gene, amplification of both intragenic repeats began before the human and cynomolgus (Old World) monkey lineages diverged. During subsequent evolution, an inverted duplication of this modified gene occurred. Finally, the resulting two-gene cluster was duplicated, generating the two-cluster/four-gene arrangement found on modern human Y chromosomes.

Molecular and cytogenetic analysis of Y;1 familial translocation

A balanced reciprocal translocation t(Y;1)(q12;q21) was found in an azoospermic male. Using the testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI), the patient had a boy who was found to have the same translocation. They were revealed to have a balanced reciprocal translocation by G-, C-, R- and high resolution banding. Fluorescence in situ hybridiation (FISH) with the probe chromosome Yq heterochromatin and C-banding were confirmed that the breakpoint is in Yq12 heterochromatic region. It was known that deletion of the AZF region of the Y chromosome is most frequent molecularly defined cause of spermatogenic failure. Especially the DAZ (deleted in azoospermia) gene is expressed exclusively in the human male germ line, and is frequently microdeleted in azoospermic men. To detect the small deletion in AZF gene, we studied on seven loci (sY84, 129, 134, 156, 254, 255, 269) including 3 DAZ regions. Also three loci (SRY, DYZ3. DYZ1) on the short arm, centromere and long arm respectively were amplified. Microdeletion of 10 loci was not detected in infertile male and his son. The results indicate that the infertility of this patient could be due to alteration of the sequence order of Y chromosme or to a disturbance of X chromosome inactivation as a result of the proximity to the autosomal portion.

Men With Infertility Caused by AZFc Deletion Can Produce Sons by Intracytoplasmic Sperm Injection, but Are Likely to Transmit the Deletion and Infertility

The most commonly defined cause of spermatogenic failure in male-factor infertility is a deletion of the AZFc region of the Y chromosome, a finding reported in 2 to 21 percent of men with nonobstructive azoospermia or severe oligospermia. The most frequent management is intracytoplasmic sperm injection (ICSI), but there is concern that infertility might be transmitted to sons in this way. This study focused on three unrelated men from couples who had been primarily infertile for 2 to 3 years. All the men had nonobstructive azoospermia with maturation arrest; there were normal-appearing spermatogonia and spermatocytes but virtually no spermatids. All three men were found on polymerase chain reaction testing to lack the DAZ gene cluster and other markers of the AZFc region in the Y chromosome. All four sons born as a result of ICSI had inherited the Y deletions. The Y chromosome appeared to be intact in the paternal grandfathers, suggesting a de novo deletion in the infertile fathers. The deletions could have arisen either in germ cells of the paternal grandfathers or zygotically or postzygotically in the ICSI fathers. These findings provide a rationale for alerting couples to the likelihood that a Y chromosome deletion conferring male infertility will be transmitted to male offspring by ICSI. Hum Reprod 1999;14:1722–1726

Men with infertility caused by AZFc deletion can produce sons by intracytoplasmic sperm injection, but are likely to transmit the deletion and infertility

Deletion of the AZFc region of the Y chromosome is the most frequent molecularly defined cause of spermatogenic failure. We report three unrelated men in whom azoospermia or severe oligozoospermia was caused by de-novo AZFc deletions, and who produced sons by intracytoplasmic sperm injection (ICSI). We employed polymerase chain reaction (PCR) assays to examine the Y chromosomes of their four infant sons. All four sons were found to have inherited the Y chromosome deletions. Such sons are likely to be infertile as adults. This likelihood should be taken into account when counselling couples considering ICSI to circumvent infertility due to severe oligozoospermia or non-obstructive azoospermia.

Serum levels of inhibin B in men with different causes of spermatogenic failure

Inhibin B appears to be the physiological feedback signal for FSH. Herein the determination of serum levels of inhibin B, FSH, LH and testosterone in 148 infertile patients and their association with clinical findings and seminal parameters are reported. A significant negative correlation of FSH and inhibin B (r = -0.60) was found. LH levels showed a significant inverse correlation (r = 0.37), but a weak regression (c0 = 0.01). No correlation with testosterone levels occurred. A significantly positive correlation was observed between testis volume and inhibin levels (r = 0.39) as well as between sperm count and inhibin levels (r = 0.39). To evaluate whether the secretion of inhibin B depends on the nature of damage to the Sertoli cells, inhibin levels in 23 patients with varicocele; eight after cryptorchidism, and 16 after hemiorchiectomy were compared to those of other patients without these diseases, but identical sperm count. No significant differences were found. In 20 men undergoing testicular biopsy, inhibin levels were compared to histology. Although the men with Sertoli-cell-only syndrome had significantly lower levels ((15.83 +/- 12.2) pg ml-1) than those with normal spermatogenesis ((183.8 +/- 112.3) pg ml-1), a distinction between patients with hypospermatogenesis from those with normal spermatogenesis was not possible on the basis of inhibin levels. Between these groups, the distinction was better achieved by the FSH levels (sensitivity of 85%). We conclude that inhibin B levels are a serum marker of Sertoli cell function, but the prediction of the quality of spermatogenesis is not superior to that of FSH levels.

Serum levels of inhibin B in men with different causes of spermatogenic failure

Serum levels of inhibin B in men with different causes of spermatogenic failure

Altered pulsatile pattern of luteinizing hormone in men with idiopathic normogonadotropic oligospermia

Gonadotropin serum levels and pulsatile secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) are regulated by sexual steroids and perhaps inhibin, but the relative rates of LH and follicle-stimulating hormone (FSH) secretion are modulated by the frequency of GnRH pulses. This study evaluated LH pulsatility in patients with idiopathic normogonadotropic oligospermia (INO) and normal men before and after clomiphene citrate (CC) administration. INO patients evidenced a lower mean LH levels (P less than 0.001), a higher mean pulse frequency (P less than 0.05) and similar pulse amplitude than normal men. CC induced in normal men a higher LH and testosterone (T) increments and increased pulse amplitude only in normal men. Estradiol (E2) showed no difference in either group. Patients with INO might evidence a hypothalamic disorder that may alter pulsatile GnRH secretion. A different response to CC in patients with INO seems to lend support to a primary hypothalamic lesion. A probable gonadotropin imbalance might alter intratesticular concentrations of T and E2 and be the cause of spermatogenic failure.