Y chromosome microdeletions in `fertile' males

The confusion about the clinical significance of a Yq deletion is increasing in parallel with reports about the presence of Yq microdeletions in `proven fertile' men. The first alarming paper (Pryor et al., 1997) reported the presence of small or single STS deletions on the Yq in 4/200 fertile males and in the fathers of two infertile sons. Another paper also reported single STS deletions in proven fertile males (Kent-First et al., 1999) suggesting that these markers are polymorphic and should be excluded from routine screening. Finally, further observations of the natural transmission of large AZFc deletions (Vogt et al., 1996; Chang et al., 1999; Saut et al., 2000) did apparently question the pathogenetic role of Y chromosome microdeletions in male infertility, suggesting that the characteristics of men with AZFc deletions `can include normal fertility'. The use of terms as `fertility' and `infertility' can be misleading in the context of Y chromosome microdeletions. Fertility is not a synonym of `normozoospermia'. The fertility potential of a man also depends to a greater or lesser extent on his female partner's fertility potential (Mortimer, 1994). A man presenting with a low sperm count can still be defined as `fertile' in the context of a couple where the female partner has a high fertility status, but he can also be defined as `infertile' in the context of a couple where the female partner is subfertile (Forti and Krausz, 1998). Compensation of male subfertility by female `super' fertility is a well known phenomenon and it must be considered whenever a genetic defect, such as a Y microdeletion is found in a `fertile' male with an unknown sperm count. In two papers sperm analysis of the father with a deletion was available. One father reportedly had low sperm concentration (the exact sperm number was not specified in the paper) and was able to father only one child (Pryor et al., 1996) whereas the father of four infertile sons (severe oligozoospermic and azoospermic) was azoospermic many years later after the natural conception of his sons (Chang et al., 1999). The father of a cryptozoospermic man in the paper of Vogt et al. (1996) was 9 years younger at the time when he fathered his son and he was unable to father further children. These findings indicate that the natural transmission of this genetic defect is likely to be related to a situation where the father had oligozoospermia with progressive decrease of his sperm count over time associated with a high fertility state of the female partner. Consistent with this hypothesis, a progressive decrease of sperm number over time has also been reported in infertile men with AZFc deletions (Girardi et al., 1997; Simoni et al., 1997; Saut et al., 2000). AZFc deletions are known to be associated with a wide range of phenotypes, from moderate oligozoospermia to azoospermia. Environmental effects or different genetic backgrounds may account for these variable or changing phenotypes over a period of time (Chang et al., 1999). For instance, in certain men a compensatory effect for the absence of Yq genes, by autosomal or X linked factors could explain the cases where the father showed a sustained fertility over several years (Saut et al., 2000). On the other hand, even sustained fertility does not necessary mean normal spermatogenesis. Since data is not available about the sperm count of any of the fathers at the time of conception of their children, we do not know if they were normospermic or severely oligospermic at that time. It cannot be excluded that their sperm production was the same as their infertile sons i.e. severe oligozoospermia. In the paper by Chang et al. the father conceived his youngest son (the fourth son) at 38 years old but at the time of the observation he was azoospermic (Chang et al., 1999). On the basis of published cases, an estimate could be made of the maximum expected sperm count in a 38 year old man with an AZFc deletion. For example, his 37 year old son has a relatively high sperm count of 0.1×106/ml. Thus if the father has standard AZFc spermatogenesis he is likely to have been able to conceive with a sperm count of <0.1×106/ml. A natural conception with this sperm count certainly depends on the excellent fertility status of the female partner. Although the concept of `fertility is not a synonym of normozoospermia' is well known to andrologists, the large majority of papers used `proven fertile' men (22 papers) as a control group rather than `normospermic men' (four papers). In 12 patients out of 2295 controls, small deletions outside the DAZ region have been reported. The pathogenetic significance of these small or single STSs deletions cannot be determined without knowing the associated phenotype in terms of sperm count. On the other hand, a total of 392 normospermic men has been tested and no Yq microdeletion have been reported for this category of men (Table I). It is therefore clear that AZFc deletions are specific for spermatogenic failure. The pathogenetic significance of Y chromosome microdeletions is spermatogenic failure and not infertility. AZFc deletions can be associated with oligozoospermia which usually leads to male infertility but it can also be associated with normal couple fertility. For the interpretation of any new observations about the transmission of Yq deletions we should keep in mind that fathering one or more children, is the expression of the fertility status of both members of the couple and it does not necessarily mean normal spermatogenesis or normal fertility in the man. List of papers dealing with Y chromosome microdeletion screening in infertile men (from 1995-2000). Only papers in which control males were also studied are cited. The number of controls, 'proven fertile men' and 'normospermic men' are reported. The number of Yq microdeletions among controls are also indicated. List of papers dealing with Y chromosome microdeletion screening in infertile men (from 1995-2000). Only papers in which control males were also studied are cited. The number of controls, 'proven fertile men' and 'normospermic men' are reported. The number of Yq microdeletions among controls are also indicated. The authors are grateful for the financial support of the Italian Telethon (grant no.281/b).