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Reproductive Endocrinology |
Patologia Medica III (C.F., A.F., A.G., M.R., A.B.), University of Padova, Padova, Italy; Immunogénétique Humaine (S.B.), Institut Pastuer, Paris, France
Address all correspondence and requests for reprints to: Prof. Carlo Foresta, Patologia Medica III, Via Ospedale 105, 35128 Padova, Italy. E-mail: forestac{at}protec.it
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Abstract |
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By means of a PCR strategy we typed Yq microdeletions in 16 azoospermic and 22 severely oligozoospermic subjects whose testicular cytological picture (assessed by fine needle aspiration) was that of Sertoli cell-only syndrome and severe hypospermatogenesis, respectively.
Microdeletions in AZF were found in 37.5% of azoospermic men and in 22.7% of severely oligozoospermic men, suggesting that very frequently these genetic abnormalities determine a severe quantitative defect in spermatogenesis. Furthermore, DAZ and YRRM do not seem to be the sole genes regulating spermatogenesis, as deletions in these genes were observed in only 6 of the 11 deleted cases. No correlation between the spermatogenic defect and the type of Yq deletion exists.
Intracytoplasmic sperm injection performed using spermatozoa of these Y-deleted patients will invariably pass this defect onto their male offspring. Screening for deletion within AZF or at least an informed consent should, therefore, be obtained in all idiopathic infertile male undergoing a program of intracytoplasmic sperm injection of a spermatozoon into the oocyte.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Recently, a genetic component has been proposed as the pathogenetic mechanism for a fraction of idiopathic severe oligozoospermia and azoospermia (8, 9, 10, 11, 12). This aspect is intriguing because in these cases the fertilization obtained by ICSI could result in transmission to male offspring of the genetic defect that caused the spermatogenic failure (13, 14, 15, 16, 17, 18).
A genetic involvement in the pathogenesis of idiopathic infertility has produced great interest, and various studies in the past several years have focused on the possible role of the Y chromosome. On the basis of the first study by Tiepolo and Zuffardi in 1976 (19), reporting six azoospermic individuals with a grossly deleted Y chromosome, there have been a number of reports (8, 9, 10, 11, 12, 17, 20, 21, 22) confirming the presence of different genes critical for the regulation of male fertility on the long arm of the Y chromosome (Yq), above all within deletion interval 6 (also known as Yq 11.23), defined as the azoospermia factor (AZF). With further refinement in the mapping of the AZF region, genetic studies have demonstrated that de novo deletions in Yq interval 6 are associated with spermatogenic impairment, and it has been postulated that this region contains one or more genes regulating spermatogenesis. To date, submicroscopic deletions in this interval have led to the identification of two genes believed to play a role in male gametogenesis and to be candidate genes for AZF: the Y chromosome ribonucleic acid (RNA) recognition motif (YRRM) gene (9), which encodes proteins with RNA-binding motifs and is localized in subinterval 6B, and the deleted in azoospermia (DAZ) gene (11), localized in subinterval 6D, which also encodes a presumed RNA-binding protein. However, there is evidence suggesting that other genes in this region may be involved in spermatogenesis, as patients with YRRM or DAZ deletions show a wide range of spermatogenic defects and may be detected in both oligozoospermic and azoospermic subjects (11, 17, 20, 22). Furthermore, microdeletions other than these genes seem to determine the same tubular alterations (20, 22). At the moment the real relationship between genotype and phenotype related to Yq microdeletions is not well characterized, as a low number of subjects has been studied, and the testicular structure observed in these patients is not homogeneous or is unknown (11, 17, 20, 21, 22). By means of a testicular fine needle aspiration cytology method (23, 24), we identified among idiopathic infertile men two highly selected groups: a group of azoospermic subjects showing a cytological picture of Sertoli cell-only syndrome (SCOS) and a group of severely oligozoospermic subjects (sperm count, <5 x 106 cells/mL) showing a cytological picture of severe hypospermatogenesis.
To clarify the relationship between genotype and phenotype we typed Yq microdeletions in 38 of these highly selected subjects by means of a PCR analysis. Sixteen idiopathic nonobstructive azoospermic patients showing SCOS and 22 idiopathic severely oligozoospermic subjects showing severe hypospermatogenesis were, therefore, studied and compared to 10 fertile men.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Our study was approved by the hospital ethical committee, and informed consent was obtained from each patient.
We studied 260 adult men referred to our infertility center, who complained of infertility for at least 2 yr. Each man was studied on 2 different occasions, separated by a 3-week interval, following a 3-day period of sexual abstinence; a semen sample was obtained on each occasion. After liquefaction of the ejaculate at room temperature, a complete semen analysis was performed, including semen volume and pH, sperm concentration, motility, morphology, eosin test for viability and swelling test, autoantibody determination by means of the immunobead test and the Sperm-Mar test (Ortho Diagnostic System, Milan, Italy), and chromatin structure analysis evaluated with the aniline blue and the decondensation tests (25). Subjects showing severe oligozoospermia on both occasions (sperm count, <5 x 106 cells/mL) or azoospermia were recruited for this study. Among these, only subjects showing no gonadal abnormalities, varicocele, and plasmatic and seminal antisperm autoantibodies and without a history of cryptorchidism, post-mumps orchitis, or testicular trauma were selected, as in these cases seminal alterations can be considered idiopathic. With these criteria, 25 subjects had idiopathic azoospermia, and 61 had idiopathic severe oligozoospermia.
All patients underwent ultrasound scanning of the testes to evaluate testicular size and rule out subclinical varicocele and parenchimal lesions compatible with neoplasms (if these were present, these patients were excluded from the protocol and referred for further urological examination).
Plasma FSH and LH levels were measured in each subject by RIA using 125I-labeled FSH and LH and a double monoclonal antibody (Ares-Serono, Milan, Italy). Plasma testosterone levels were determined using a double antibody RIA.
Only patients with a normal 46,XY karyotype, as shown by GTG and QFQ banding, were included in this study.
The testicular structure could be analyzed by the classic surgical biopsy; nevertheless, the invasiveness of this procedure has limited its routine use in the assessment of infertile men. Fine needle aspiration has proven to be a less painful and minimally invasive diagnostic procedure in the evaluation of the status of several organs, and in our previous studies (23, 24) the effectiveness of this technique has been verified in the testis of infertile men.
Testicular fine needle aspiration and cytological quantification
Bilateral testicular fine needle aspiration cytology was performed in each subject to evaluate the tubular status related to the seminal pattern. The method has been described in detail previously (23). Briefly, bilateral fine needle aspiration was performed using 23-gauge (0.6 mm) needles and aspiration with a 20-mL syringe. The cellular material was placed on two or more microscope slides for each testis, air-dried for 24 h, stained with May-Grünwald-Giemsa, and examined under a light microscope at x125, x400, and x1250 magnifications. At least 200 cells were counted per smear. The following forms are identified and expressed as percentages: spermatogonia (dark and pale), primary spermatocytes, secondary spermatocytes, early and late spermatids (corresponding to Sa-Sb and Sc-Sd steps of spermatogenesis, respectively), and spermatozoa. Sertoli cells are expressed as the Sertoli index (the number of Sertoli cells per 100 spermatogenic cells) that has been found to be a reliable index of the tubular germ potential. The proportion of spermatozoa is expressed as the spermatic index (the number of spermatozoa per 100 spermatogenic cells).
As described in previous studies (23, 24, 26), cytological analysis in azoo-oligozoospermic subjects permits the identification of five different appearances: 1) SCOS, 2) hypospermatogenesis, 3) spermatogonial or spermatocytic arrest, 4) spermatidic arrest, and 5) normal germ line with increased percentage of mature spermatozoa indicating an obstruction of the efferent ducts. Only patients with SCOS (n = 16) and hypospermatogenesis (n = 22) were included in the study.
Thirty-five age-matched normozoospermic subjects, whose characteristics were reported in our previous study (27), were considered as controls for seminal parameters, hormone levels, and testicular volumes.
The results are given in the text as the mean ± SD. Statistical comparisons between groups were made by ANOVA. P < 0.05 was regarded as statistically significant.
Sequence-tagged site (STS)-PCR and criteria used for defining microdeletions
A set of 15 Y-specific STSs that span the euchromatic region of Yq from centromere to interval 7, with particular interest in interval 6 (AZF region), was tested in each patient. All STSs were previously described (9, 11, 21, 28), and we used the order and the localization of the sequences proposed by Vollrath (28, 29), as reported by Reijo (11). Thus, 1 STS was from subinterval 4B [sY78 (centromere)], 1 from 5F (sY151), 1 from 5I (sY100), 1 from 6A (sY131), 2 from 6B (YRRM1 and 2), 2 from 6C (sY153 and sY152), 4 from 6D [sY155, sY147, sY148, and sY255 (DAZ)], 1 from 6F (sY158), and 2 from 7 (sY159 and sY160). This set of primers, able to screen for the presence or absence of 15 specific DNA sequences, was kindly provided by Prof. M. Fellous (Institute Pasteur, Paris, France).
PCR was carried out on 2 µL (50 ng/µL) of each genomic patient DNA extracted from peripheral blood cells in a 50-µL reaction volume, using 5 µL buffer 10x, 5 µL deoxy-NTP mix (2 mmol/L), 2.5 µL of each primer at 0.1 µg/µL, and 0.4 µL Taq DNA polymerase. Thermocycling consisted of an initial denaturation of 10 min at 94 C and 35 cycles of 1 min at 94 C (melting), 1 min at 55 C (annealing), and 1 min at 72 C (extension). Reaction products were stored at 4 C until they were loaded onto agarose gels for analysis. The PCR reaction products were separated on 2% agarose gels by electrophoresis in Tris-acetic acid-ethylenediamine tetraacetate buffer at room temperature using a voltage gradient of 8 volts/cm for 30–60 min.
Ten healthy normal men of proven fertility and 10 normal women were included in the study as positive and negative controls, respectively. Precautions were taken to keep false negative results to a minimum. We only used PCR assays that gave products of the expected size in the positive control DNA and did not in the negative control DNA. Patients were considered positive for a STS if the PCR product was of the expected size and were considered negative only after three amplification failures.
Fathers or brothers of the deleted patients were investigated under the same conditions.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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shows the typical testicular cytological appearances
observed in normozoospermic subjects, as previously reported (23, 24, 26), and in patients.
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Table 1 summarizes the STS-PCR data of the 11
deleted patients. Seven deletions discovered were of small interstitial
portions on the long arm of the Y chromosome (Yq), whereas 4 deletions
were of terminal portions of the Yq euchromatin. The absent STSs are
clustered in Yq intervals 6 and 7, although these microdeletions are
interspersed throughout this region, and frequently PCR analysis failed
to amplify only 1 or a few STSs. Eight of 11 patients (72.7%) have
deletions that overlap with the DAZ gene, and 4 of 11 (36.4%) have
deletions including the YRRM gene. Two patients (18.2%) have deletions
outside both DAZ and YRRM. Four patients have noncontiguous deletions
inside the AZF region.
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are summarized the clinical, hormonal, and
cytological characteristics of the 11 deleted patients. In azoospermic
SCOS patients as well as in severe oligozoospermic hypospermatogenetic
patients, a reduction of testicular volume and an increase in plasma
FSH levels were evident (P < 0.05 vs.
controls). No differences in plasma LH and testosterone levels were
observed in all subjects vs. controls. These data are
consistent with a primary testicular defect in spermatogenic
function.
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are shown typical
STS-PCR amplification results obtained in this study.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fertile controls and, above all, the father or brothers of patients showing STS missing did not show any abnormality, allowing us to exclude a genetic polymorphism. Therefore, the microdeletions found in these patients may be considered new deletions, probably arising in the spermatogenetic cells of the father, and may be the cause of oligoazoospermia.
The prevalence of Yq microdeletions observed in this study in both azoospermic and oligozoospermic subjects is very high compared to that reported by others (11, 17, 20, 21, 22). The reason for this discrepancy may be related to the different approach used in our study in recruiting the patients. The patients were selected by means of history and clinical, hormonal, and, above all, testicular cytological aspects; the Y chromosome analysis was, therefore, performed in specific and well characterized testiculopathies. These patients present a complete lack or a severe depopulation of germ cells. Idiopathic infertile patients showing azoospermia or oligozoospermia related to qualitative alterations of spermatogenesis, such as maturative disturbances at different levels, have been excluded from the study. These greater selection criteria may explain the reason for our higher prevalence.
All azoospermic men considered in this study showed a testicular cytological pattern of SCOS, high plasma FSH levels, and reduced testicular volume. In severely oligozoospermic subjects, the cytological picture was characterized by a great number of Sertoli cells and a reduced number of spermatogenic cells with rare spermatids and mature spermatozoa (severe hypospermatogenesis). Also in these subjects, testicular volume was reduced and plasma FSH levels were high. In all patients, testicular endocrine function was normal on the basis of plasma LH and testosterone levels.
In all studies to date the recruitment of idiopathic infertile patients was performed above all on the basis of the seminal picture; the tubular status has not been considered to be fundamental in the selection of patients, and it was not defined in all patients.
Nevertheless, azoospermia or severe oligozoospermia may be associated with a variety of abnormal tubular status ranging from the complete lack of germ cells to maturative disturbances at different levels, with few or no spermatids or mature spermatozoa. Therefore, the knowledge of testicular defects is of great interest to obtain a correlation between the localization or the size of microdeletions of Yq and the clinical phenotype.
The high prevalence of Yq microdeletions observed in our patients suggests that very frequently these genetic abnormalities determine a severe quantitative defect in spermatogenesis. However, our results do not allow us to conclude that AZF regulates spermatogonial differentiation, and environmental factors influence the maturational process, as proposed by Reijo et al. (11, 17), as identification of the gene product and their biological actions is necessary.
A considerable aspect of our findings is the high incidence of Yq microdeletions found in extreme oligozoospermic subjects. At the moment, the relationship between Yq microdeletion and oligozoospermia is not clear, and very few cases have been reported. Recently, Rejo et al. (17) investigated the AZF region in 35 oligozoospermic subjects reporting deletions in 2 cases. This prevalence (5.7%) is much lower than that observed in the present paper. However, in that study the tubular status was not defined, and this may account for the different prevalence.
The high incidence of de novo deletions found in our patients may be underestimated indeed, as microdeletions not discovered by this set of probes or point mutations not detectable by the PCR technique might be expected.
The PCR technique used in this study is able to screen the Y chromosome for the presence or absence of 15 Y DNA loci, focusing the analysis on the AZF region. PCR strategy in detecting microdeletions is a simple, powerful, and fast tool, ideal for the screening of idiopathic infertile males (28, 30). Furthermore, if used with rigorous procedures, it is very sensitive, reaching the accuracy of other sophisticated techniques, such as Southern blot (20).
In four patients PCR analysis showed the presence of noncontiguous microdeletions within the AZF region. This aspect could be explained by different hypotheses. 1) These deletions are really separated microdeletions involving one or two STSs. 2) The order of these STSs may be incorrect, as discrepancies in the reported deletion maps do exist. 3) Some STSs may be from repetitive sequences, and PCR product may reflect amplification from different site. 4) A complex rearrangement may be the cause. By now it is not possible to exclude any of this hypothesis to explain noncontiguous deletions in the AZF region.
In our study a deletion overlapping the DAZ gene was present in 8 of the 11 deleted patients (72.7%) and a deletion overlapping the YRRM gene in 4 of the 11 (36.4%), whereas in 2 of 11 patients (18.2%), the microdeletions were outside both DAZ and YRRM. These data suggest that DAZ and YRRM are not the only genes implicated in severe spermatogenic impairment, and other genes in Yq deletion intervals 6 and 7 may be associated with male infertility. The pattern of microdeletions in our patients suggests the presence of other hot spots, further supporting the hypothesis of a gene family distributed throughout intervals 6 and 7.
Our data show that no correlation between the severity of the spermatogenic defect (azoospermia with SCOS, oligozoospermia with hypospermatogenesis) and the localization and extent of Yq deletion exists. In fact, patients with different patterns of deletions may display the same tubular alteration; on the contrary, different testicular damage was associated with the same genetic alteration. Oligozoospermic men may, therefore, present a deletion as large or even larger than that observed in azoospermic men with SCOS. According to previous suggestions (17, 20), our data support the hypothesis that this aspect may be explained by considering that other genes outside the AZF or, alternatively, environmental factors may modulate the effects of AZF deletions. On this basis, severe oligozoospermia-hypospermatogenesis and azoospermia-SCOS when associated with Yq deletions may not be etiologically distinct, but could represent clinically different manifestations of the same underlying genetic anomaly.
In conclusion, the findings of this study support the hypothesis that idiopathic severe oligozoospermia and azoospermia frequently depend on a deletion in a Y chromosome region controlling spermatogenesis. The relevance of the present study is the higher percentage of deletions with respect to the previous studies, as our analysis has been performed on subjects showing specific testiculopathies characterized by a complete lack or a severe depopulation of germ cells. These results strongly suggest that a deletion in the Yq euchromatin may be tightly related to the presence of the germline population, even if a clear correlation of genotype change and phenotype is missing. A major problem pointed out in this study is that ICSI performed using spermatozoa of these chromosomally normal men will invariably pass this defect on to all male children, whose phenotype of infertility will be identical to that of the father. Screening for deletion within AZF or at least informed consent should, therefore, be obtained in all idiopathic infertile male undergoing an ICSI program.
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Acknowledgments |
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Received August 20, 1996.
Revised October 28, 1996.
Accepted November 8, 1996.
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