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Human Reproduction, Vol. 19, No. 4, 788-793, April 2004
© 2004 European Society of Human Reproduction and Embryology

Y chromosome microdeletion screening in infertile men in France:a survey of French practice based on 88 IVF centres

Isabelle Esther Aknin-Seifer1,2, Hervé Lejeune3, Renaud Laurian Touraine2, Rachel Levy1,4 and Under the aegis of the SALF (Societe d’Andrologie de Langue Francaise)

1 Laboratoire de Biologie de la Reproduction, Hôpital Nord, 42055 Saint Etienne, 2 Laboratoire de Génétique Moléculaire, Faculté de Médecine, Saint Etienne and 3 Département de Médecine de la Reproduction, Hôpital Edouard Herriot, Lyon, France

4 To whom correspondence should be addressed. e-mail: rachel.levy{at}chu-st-etienne.fr


   Abstract
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Introduction
 Response rate
 Reasons for not proposing...
 Prescribing centres
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Y chromosome microdeletion screening is advised in cases of severely impaired spermatogenesis. Improvements in molecular biological techniques have made diagnosis more accessible in routine analysis. However, Y chromosome microdeletions are not diagnosed in all IVF centres. The aim of the present study was to determine the regulatory (indications, financing) and performance (methods, invoicing) conditions required for this analysis, in France. Microdeletion detection was found to be spreading fast and consistantly. It therefore seems necessary for a consensus to be reached on indications, with a view to a standardized technique, with a common effort of experts in the field. Financial management by the French Health Insurance bodies (Sécurité Sociale) would be an essential step towards routine adoption. Lastly, the answers to our questionnaire revealed a strong demand for information concerning this analysis.

Key words: France/male infertility/microdeletions/survey/Y chromosome


   Introduction
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The existence of an essential spermatogenesis factor called AZF (azoospermia factor) was suspected as early as 1976, from de novo Yq deletion in azoospermic patients (Tiepolo and Zuffardi, 1976Go). PCR study of anonymous markers called sequence tagged sites (STSs), distributed every ~30 kb (Foote et al., 1992Go; Vollrath et al., 1992Go), enabled detection of small deletions in the AZF region that were undetectable with classical cytogenetic techniques, leading to the identification in Yq11 of three loci carrying genes involved in the control of spermatogenesis, corresponding to three deleted regions: AZFa, AZFb and AZFc (Reijo et al., 1995Go; Vogt et al., 1996Go). Y chromosome microdeletion is the most frequently encountered genetic abnormality in male infertility. The estimated frequency of Yq microdeletion is 10–15% in cases of azoospermia and 5–10% in cases of oligozoospermia. The detection of Y chromosome microdeletions is recommended in cases of severely impaired spermatogenesis, and in particular before ICSI (Krausz et al., 2003Go).

Y chromosome microdeletion screening is of aetiological and prognostic interest. In addition, it can improve genetic counselling.

Improvements in molecular biology techniques have, in theory, made this diagnosis more accessible in routine male infertility analysis. However, not all centres performing IVF have in fact been diagnosing Y chromosome microdeletions.

Our survey sought to establish an overview of French practice with respect to prescribing Yq deletion screening and molecular diagnostic methods, and to answer the following points. (i) How many practitioners and IVF centres request Y chromosome microdeletion screening and what are the prescribing practitioners’ specialities? (ii) What are the indications adopted? (iii) How is the screening financed? (iv) How many molecular genetic diagnosis laboratories screen for microdeletions? (v) How many analyses are performed? (vi) What methods are used? (vii) How is the analysis invoiced?

Our objectives are to give a (technical, financial) overview of Y chromosome microdeletion screening issues.

Two questionnaires were drawn up, one for prescribers and the other for molecular biologists. These questionnaires were sent out in June 2001 via the persons in charge (clinicians and biologists) in the 88 authorized IVF centres in France (according to the French national FIVNAT register). Survey objectives were explained in an accompanying letter. The persons in charge in these centres (clinicians and biologists) were asked to pass on the questionnaires to prescribers/molecular biologists performing this analysis in or for their centre if they did not have sufficient data to reply themselves or if various prescribers were not in agreement. A second copy of the questionnaire was faxed to those centres that had not replied within 6 months. Physicians who had not replied were contacted by telephone 8 months later. CHUs (teaching hospitals), CHGs (general hospitals), non-profit making establishments and Institutes were classified as ‘public’, giving a total of 39 such public centres (44%). Professional establishments, classified as ‘private’, were made up of 47 centres (53%). Two entities were classified as ‘mixed’ as they combined both public (e.g. biology) and private (e.g. gynaecology) activity.

Statistical comparisons were made using the {chi}2-test for qualitative variables.


   Response rate
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Prescribers
Seventy-two of the 88 IVF centres provided their ‘prescriber’ responses, i.e. a response rate of 82% (by return of questionnaire or by telephone). Forty-two out of these 72 centres prescribed Y chromosome microdeletion screening (25 public, 16 private and one mixed centre). Thirty of the 72 centres did not prescribe microdeletion screening (nine public, 20 private and one mixed centre). Response rates were not significantly different between public and private centres. On the other hand, a higher proportion of public centres than private centres prescribed microdeletion screening (74% versus 44%) (P = 0.01).

Molecular biologists
From the IVF centre responses, 30 laboratories performing molecular biology analysis were identified. Twenty-nine of these laboratories (97%) answered our questionnaire.


   Reasons for not proposing Y chromosome microdeletion analysis
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Questions of technique or lack of consensus as to the choice of markers were rarely suggested as reasons for not carrying out microdeletion screening. The main reasons given by 30 IVF centres not prescribing Yq microdeletion screening were that it was not available locally (60%), cost was high (43%), result did not modify therapeutic management of couples (36%) or that genetic counselling was difficult without specialized training (26%).

Questions about usefulness
It is worth recalling that the diagnosis of a Y chromosome microdeletion does, as a matter of fact, affect patient management, because freezing of sperm for preventive purposes has been proposed since 2000 (Krausz et al., 2000Go) on the basis of articles reporting a decreased sperm count in patients with AZFc deletions (Girardi et al., 1997Go; Simoni et al., 1997Go; Chang et al., 1999Go; Saut et al., 2000Go; Dada et al., 2003Go). Moreover, a positive diagnosis of microdeletion is of prognostic value for the indications for testicular biopsy according to the type of microdeletion found (Brandell et al., 1998Go; Silber et al., 1998Go; Krausz et al., 2000Go; Hopps et al., 2003Go), or for possible surgical intervention for varicocele (Cayan et al., 2001Go). In close to one-quarter of responses, the non-prescribers pointed out the difficulty of genetic counselling after the discovery of Y chromosome microdeletion; however, the genetic counselling would be better adapted: the phenotype of a son conceived by ICSI cannot yet be definitively predicted, but the deletion is necessarily transmitted (Kent-First et al., 1996Go; Mulhall et al., 1997Go; Jiang et al., 1999Go; Kamischke et al., 1999Go; Kleiman et al., 1999Go; Cram et al., 2000Go; van Golde et al., 2001Go; Oates et al., 2002Go; Peterlin et al., 2002Go). Furthermore, preventive therapy (sperm cryoconservation for successive assisted reproductive techniques) could be proposed to affected sons, as suggested by previous studies (Krausz and McElreavey, 1999Go; Toth et al., 2001Go; Dada et al., 2003Go).

It should also be mentioned that the detection of nullisomic gametes for the sex chromosomes in patients with microdeletions (Siffroi et al., 2000Go; Jaruzelska et al., 2001Go) may lead to the conception of embryos presenting Turner’s syndrome or sexual ambiguity. The converse has also been demonstrated recently: a Y chromosome microdeletion in AZFc has been reported in 33% of subjects presenting a Turner-like phenotype with sexual ambiguity and a 45,X/46,XY karyotype (Patsalis et al., 2002Go). However, there is no single equivalent case among ICSI children of Y-deleted men. Thus, these theories are still controversial.


   Prescribing centres
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As can be seen in Figure 1, the number of centres prescribing this investigation has been rising steadily over the last 8 years. According to how the multidisciplinary groups are constituted, prescribers are gynaecologists (33% of the total of 78 prescribers for all groups taken together), urologists (26%) or biologists (27%). The majority of centres (50%) had between two and five prescribers.



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  		Figure 1. Number of centres prescribing microdeletion screening.

 
For azoospermia, the main indication adopted was non-obstructive azoospermia (54%) (Figure 2). Azoospermia of whatever origin made up the remaining 38%, except for three centres where Yq microdeletion analysis was not prescribed at all in case of azoospermia. We can only speculate that it may be a reflection of the lack of available treatment in cases of azoospermia.



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  		Figure 2. Indications for Y chromosome microdeletion screening.

 
For oligozoospermia, 38% of prescribers adopted a threshold of 5 x 106 spermatozoa/ml and 38% of practitioners used a threshold of 1 x 106 spermatozoa/ml. Eight centres did not consider oligozoospermia to be an indication. The reason for these limitations is unclear. Another surprising result was that four centres paradoxically considered the notion of familial infertility as a prime indication for this investigation, although microdeletions in point of fact appear de novo in the great majority of cases. In fact, microdeletions are found almost exclusively in patients with <1 x 106 spermatozoa/ml and extremely rarely (~0.7%) above the threshold of 5 x 106 spermatozoa/ml (Simoni et al., 1998Go; Krausz and McElreavey, 1999Go). For oligozoospermia, European recommendations set the threshold for microdeletion testing at <5 x 106 spermatozoa/ml.


   Laboratories performing this analysis
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In parallel with prescribing centres, the number of laboratories carrying out this analysis is steadily increasing (Figure 3). A total of 10 399 analyses have been carried out since the practice began in the 29 laboratories that sent back their questionnaires, with the number of analyses increasing over the years (2617 detections during the year 2000) (Table I). The overall activities of each laboratory since analysis began are shown in Figure 4. Clinical data and semen parameters are provided to laboratories by 76% and 79% of the centres, respectively.



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  		Figure 3. Number of laboratories performing microdeletion investigation.

 

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  		Table I. Activity of laboratories
 


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  		Figure 4. Number of centres participating and analyses carried out since the beginning of each centre’s microdeletion screening programme.

 
Technical aspects
Our survey revealed an extreme diversity of practice: the majority of centres (66%) used a ‘home-made’ technique (i.e. developed in and by the laboratory itself). Two centres preferred a commercial kit (Y Chromosome Deletion Detection System, version 1.1; Promega, Madison, WI, USA) and only eight centres followed European Academy of Andrology (EAA) (Simoni et al., 1999Go) and the Société Française de Génétique Humaine (www.sfgh.net/public/infertilite.asp) recommendations. The majority of laboratories employed multiplex PCR, which is time-saving, even though technical difficulties have been widely described (Henegariu et al., 1997Go; Bor et al., 2001Go; Thornhill et al., 2002Go). Three laboratories analysed their markers by a simplex technique alone. Only one-quarter of the centres followed European recommendations, despite their enabling detection of >95% of symptomatic deletions, as there was no ready-to-use kit meeting these criteria that was commercially available in France (Simoni et al., 1999Go). The only commercially available kit at the time of this study was not fully reliable, very expensive and did not explore the AZFa region correctly (Aknin-Seifer et al., 2003Go).

Fourteen laboratories carried out a preliminary investigation with a limited number of markers and, in a second step, refined the deletion limits and extent with a series of supplementary markers. The number of markers used for first intention screening, and in second intention, to determine the deletion extent, varied greatly from one centre to another (Figure 5). Eight laboratories performed the diagnosis without specifying the extent of the microdeletion detected.



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  		Figure 5. Number of markers used.

 
However, it must be kept in mind that this survey was conducted in 2001, before the refined map of the Y chromosome was published (Skaletsky et al., 2003Go). As far as routine screening is concerned, it is clear that the use of a minimal set of well chosen primers allows detection of >95% of clinically relevant deletions. On the other hand, fine definition of the breakpoints of the AZFa, AZFb and AZFc regions with the introduction of new markers will allow the selection of new second step markers (Saxena et al., 2000Go; Kuroda-Kawaguchi et al., 2001Go; Tilford et al., 2001Go; Repping et al., 2002Go; Ferlin et al., 2003Go).

Control genes used also greatly varied from one centre to another: the SRY gene was used in 22 centres and the ZFY gene in seven centres. One centre used an autosomal gene (not specified) and another used DAZLA. Two centres made use of an X chromosome gene. The extent to which control subjects were used varied greatly from one laboratory to another (Figure 6): using normal male DNA as reactivity control was not systematic (22/28). Two laboratories did not use a negative control (tube without DNA). Furthermore, the use of reaction specificity controls (women’s DNA, or DNA from microdeleted men) varied greatly according to laboratory. Thus, many of the laboratories are not using appropriate negative and positive controls.



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  		Figure 6. Number of centres using controls (28 responses).

 
Although most laboratories were satisfied with their technique, some were interested in making changes regarding the markers used, e.g. increasing their number (11/18), developing the multiplex technique (5/17), or having more informative or better-selected markers (2/17). Fifteen out of 20 laboratories were in favour of an exchange of positive samples (DNA from microdeleted male subject).

In parallel, the idea of quality control was warmly welcomed. Laboratories would agree to participate in an international (17/29), national (16/29) or both national and international (8/29) quality control scheme. As an example of a quality control programme, the External Quality Assessment, under the auspices of the EAA and the European Molecular Quality Network, represents a real effort being made towards an improvement of Y chromosomal microdeletions diagnosis.


   Results
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The total percentage of microdeletions detected in France varied from 1% to 22% from laboratory to laboratory, with a mean of 8% (n = 25 responses), which is in agreement with the literature (Patrat et al., 2001Go). This discrepancy should be interpreted according to the total number of analyses performed by each laboratory since the beginning of microdeletion detection: at the date of the survey, this number ranged from 2 to >500 (Figure 4). Regarding microdeletion frequency, numerous reports are in agreement on the accepted averages: 10–15% in cases of azoospermia, and 5–10% in cases of oligozoospermia (Kostiner et al., 1998Go; Martinez et al., 2000Go; Peterlin et al., 2002Go).

Cost considerations
This analysis is charged to patients at an average rate of 164 euros (range 54–635) (Table II). The high cost of the test (43% of responses), with no national health insurance (Sécurité Sociale) cover, is the second most often stated reason for non-prescription. Apart from in research protocols, which are usually of limited duration, the cost of this analysis was borne by the patient (in the private sector) or the hospital (in the public sector). The great variability in cost rating from one centre to another is the result of the overall problem of inadequate financial cover for molecular biology tests under the French system. For this reason, each centre adopts its own policy. Recognition and cover by the Sécurité Sociale appears to be an essential step towards its adoption in French routine practice. The present survey suggests a double cost rating for this analysis: one for ‘detection’ and one for ‘definition of the extent of Y chromosome microdeletion’.


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  		Table II. Financial aspects
 

   Conclusions
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Y chromosome microdeletion screening, recommended in cases of severe spermatogenetic impairment by numerous societies (Société Française de Génétique Humaine, European Society of Human Reproduction and Embryology, EAA, American Urological Association), has markedly increased in the last few years. For example, since the end of the present survey, four French centres that had been unable to perform this analysis have now set up and launched facilities.

The heterogeneity of the observed protocols calls for standardization, which is an important issue that can be reached only by a joint effort of experts in the field. We call for increased participation of laboratories performing AZF diagnostics in a quality control program, such as the External Quality Assessment.

The current data concerning the French practice should be discussed among experts in this field, who can draw up a consensus concerning screening indications and move towards identifying the most cost effective methods. In France, the current data could also help in the consideration of financial management by health insurance organization (Sécurité Sociale).


   Acknowledgements
 
We would like to thank all the practitioners who took part in collecting the data and who devoted valuable time to completing these questionnaires. Thanks to Iain McGill, Denise Schiffmann and Julie Dawson-Castellon for their contributions to preparing the manuscript.


   References
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Submitted on July 18, 2003; resubmitted on November 25, 2003; accepted on December 3, 2003.


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