University of Padova, Department of Medical and Surgical Sciences, Clinica Medica 3, Via Ospedale 105, 35128 Padova, Italy
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Abstract |
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Key words: azoospermia/ICSI/pathogenesis/TESE/Y chromosome deletions
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Introduction |
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Indeed, the term `microdeletion of the Y chromosome' does not represent a well-defined genetic diagnosis at the molecular level. It defines only the abscence of segments of the Y chromosome and it includes many different conditions depending on the localization and the extent of the deletion. Furthermore, microdeletions have to be distinguished from more limited gene deletions and even gene mutations.
A recent review of the literature (Foresta et al., 2001) showed that nearly 5000 infertile men have been analysed for the presence of Y microdeletions and the results published from 1992. Taken together, these data show that the overall prevalence of microdeletions in infertile patients is 8%, but remarkable differences exist among the various studies, ranging from 1% (van der Ven et al.1997
) to 35% (Ferlin et al.1999
). One hypothesis to explain such differences is related to the different patient selection criteria (Foresta et al., 2001
), strengthening the concept that male infertility is not a homogeneous disorder. For example, the prevalence of microdeletions increases with more strict patient selection and the higher percentages are found in patients affected by idiopathic severe oligozoospermia (prevalence of 14%) and in idiopathic non-obstructive azoospermia (16%). Microdeletions most frequently involve the AZFc (azoospermia factor c) region (60%), less frequently the AZFb region (16%) and only rarely the AZFa interval (5%). Larger microdeletions involving two or three AZF regions are diagnosed in 14% of cases. Notably, in the remaining 5% of cases the microdeletions are located in regions not overlapping AZFa, b or c.
The most intriguing data resulting from the analysis of the literature are related to the so-called genotypephenotype relationship. To this regard, it is necessary to outline that the phenotype of patients with Y microdeletions should be defined on the basis of both seminal analysis and diagnostic testis histology. However, for the patient the only phenotypic end-point of importance could be the presence or absence of spermatozoa at TESEICSI. The first question is therefore: is there any relation between the localization or the size of the microdeletion and the seminal pattern? The general impression is that this relationship does not exist (Figure 1)
: only when the entire Yq is deleted (absence of AZFa-c) the seminal phenotype is invariably azoospermic, while all the other type of microdeletions may be associated both with azoospermia and severe oligozoospermia. Deletions in AZFa and b seem to produce azoospermia more frequently than severe oligozoospermia, but it should be noted that AZFb deletions may also rarely be associated with moderate oligozoospermia, above all when the deletion includes only a part of this region (Pryor et al.1997
; Van der Ven et al., 1998; Krausz et al.1999a
). Therefore, it is not possible to predict the seminal pattern in a patient with a defined Y microdeletion, and conversely sperm production cannot be used as a parameter of specific microdeletions.
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Another issue concerning male genetic infertility is the question of who should undergo Y chromosome microdeletion testing. It is now clear that all infertile patients with a severe testiculopathy should be analysed for Y microdeletions, regardless of their clinical presentations (idiopathic versus non-idiopathic infertility), hormonal parameters or testicular volumes (Krausz et al.1999a; Foresta et al.2000a
). For example, we reported a high prevalence of microdeletions in infertile patients affected by unilateral ex-cryptorchidism or left varicocele and presenting with a severe bilateral testiculopathy (Foresta et al.1999
; Foresta et al.2000a
; Moro et al.2000a
). These studies demonstrated that the phenotype associated with a Y chromosome microdeletion might also be linked with cryptorchidism and varicocele, other than idiopathic infertility. The bilateral testicular damage observed in these patients is probably related to the deletion of the Y chromosome and not to the abnormal location of the testis or to varicocele itself, although these conditions may worsen the testicular alteration. These observations clarified that all infertile patients with a sperm count <5x106/ml sustained by a severe bilateral testiculopathy should be screened for microdeletions, despite the presence of other concomitant causes of testicular damage.
Neither the hormonal parameters nor testicular volumes can be used to trace the relationship with Y chromosome microdeletions, and they do not allow us to distinguish between patients at risk for microdeletions. In all patients these parameters indicate a severe testiculopathy involving only the spermatogenic system, since testes are reduced in size, FSH concentrations are high, and LH and testosterone are within the normal ranges. However, one study reported that FSH concentrations in patients with microdeletions, although higher than controls, were lower than in patients with similar tubular alterations but without microdeletions (Kremer et al.1997). Another study showed that Y-deleted patients had normal FSH concentrations (Liow et al.1998
). However, the most important point is that these hormonal parameters do not allow us to distinguish which specific region of the Y chromosome is deleted. This is not surprising considering that the testicular phenotype associated with the different localization of Y microdeletions may be very similar or identical. Furthermore, it is well known, for example, that in azoospermic patients FSH values and testicular volumes do not allow the clinician to distinguish between SCOS and severe hypospermatogenesis, or between spermatid arrest and obstructive forms (Foresta et al.1995
). Again, the only method to distinguish the specific tubular alteration present in azoospermic men is to directly analyse the testicular structure by diagnostic open biopsy or fine needle aspiration.
In conclusion, in our opinion the prognostic value of Y microdeletion analysis is very limited since our current knowledge of this pathology is still partial. In fact, the methods used to diagnose the microdeletions are not yet validated and a prognosis could be possible only when a genotypephenotype relationship can be demonstrated. This, in turn, will be the result of a detailed analysis of the genes contained in the AZF regions. To date, the prognosis as to whether an azoospermic man with Y microdeletion has spermatozoa in the testes that can be used for TESEICSI cannot be made on the basis of the localization of the deletion (apart from cases with deletions of the entire AZFac). The promising prognostic value of AZFa and AZFb deletion still awaits confirmation from the study of a larger number of patients. Furthermore, neither the clinical presentation (idiopathic versus non idiopathic) nor clinical parameters (testicular volumes, hormonal concentrations) support the clinician in his decision.
These data further strengthen the usefulness of a proper diagnosis of male infertility, which should include, at least when the patient is a candidate for TESEICSI, a careful analysis of the testicular alteration underlying the azoospermia. Such modern techniques of assisted reproduction should impose a more accurate management of the infertile man, since a correct diagnosis is essential to avoid unnecessary, expensive and stressful therapies (above all for the female partner) such as those related to multiple follicular growth and oocyte retrieval.
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Acknowledgements |
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References |
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