Genetic screening in the ASRM’s new guidelines on diagnostic evaluation of the infertile male

18 12 2012

To the Editor:

I read with interest the new ASRM Practice Committee opinion report on diagnostic evaluation of the infertile male (1). Considering the importance of these guidelines for clinical practice, I should draw attention to inaccuracies and outdated information in the section related to genetic screening.

In the section on Y-chromosome microdeletions (YMD), the report states:  “Microdeletions of clinically relevant regions of the Y chromosome have been found in 7% of infertile men with severely impaired spermatogenesis compared with 2% of normal men. However, the percentage of men with Y-chromosome microdeletions increases to 16% in men with azoospermia or severe oligospermia.” This statement referring to Y-chromosome microdeletions in normal men is new in relation to previous ASRM opinions on male infertility and azoospemic males (2). Another section states that “… some Y-chromosome microdeletions are rarely found in fertile or subfertile males who have fathered children.”

The section regarding the normal male references an article in The New England Journal of Medicine (4) that found “Y-chromosome microdeletions” in 4 of 200 (2%) “normal men” (without screening sperm quality in them), but only in 2 Y-chromosome markers; 2 had deletions in  sY207, and 2 had deletions in sY272. The section referring to males with YMD who fathered children references the same article (3) and another (4), the “AZFd” article, which only reported the absence of single markers in 4 of 320 controls in sY269 and in 2 other individuals in sY207 and sY272. The existence of AZFd region in Y chromosome was not confirmed. In addition, these supposed “partial deletions” are not supported by the known mechanism of production of YMD (5) and the practice guidelines for YMD testing (6).

Several years ago this controversy was extensively discussed in Fertility and Sterility (7), warning us of the consequences of methodological mistakes in YMD screening, and most geneticists are aware of these in the practice of genetic testing. The most complete evidence of extensive genetic testing demonstrates that control men with normal sperm characteristics do not have YMD (8, 9), and expert reviews of genetic testing in the infertile male do not support the possibility of finding YMD  in normal males (6, 9).

Although the final recommendation in the ASRM opinion (1): “Men with non-obstructive azoospermia or severe oligospermia (<5 million/mL) are at increased risk for having a definable genetic abnormality and should be offered karyotype and Y-chromosome analysis before performing ICSI using their sperm. Genetic counseling may be offered when a genetic abnormality is suspected in either the male or female partner and should be provided whenever a genetic abnormality is detected” is completely correct, the statements about YMD in normal males and males who fathered children are inadequate, and I recommend they be removed. More importantly, the ASRM’s guidelines (1) should refer to guidelines for YMD testing supported by the European Academy of Andrology and EMQN (6), and ASRM should urgently consider generating a specific practice guideline on YMD laboratory testing to give the current practice the necessary confidence to test results.

The role of new genetic variants, such as mutation genes implicated in sperm biology, copy number variations (4), single nucleotide polymorphisms, and partial YMD, is not mentioned in the ASRM guidelines.  But they are of increasing relevance to male infertility, and the indications for genetic testing can be different from traditional azoospermia or severe oligozoospermia. Taking this into account, I believe that genetic counseling by a clinical geneticist should be provided to any male with primary male infertility, and this should be stated in the ASRM guidelines.

Raul E. Piña-Aguilar
Medical Genetics Department, National Medical Center “20 de Noviembre,” ISSSTE, México DF, México

References

1. The Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril 2012;98:294-301.

2. Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Report on optimal evaluation of the infertile male. Fertil Steril 2006;86(5 Suppl 1):S202-9.

3. Pryor JL, Kent-First M, Muallem A, Van Bergen AH, Nolten WE, Meisner L, et al. Microdeletions in the Y chromosome of infertile men. N Engl J Med 1997;336:534-9.

4. Kent-First M, Muallem A, Shultz J, Pryor J, Roberts K, Nolten W, et al. Defining regions of the Y-chromosome responsible for male infertility and identification of a fourth AZF region (AZFd) by Y-chromosome microdeletion detection. Mol Reprod Dev 1999;53:27-41.

5. Carvalho CM, Zhang F, Lupski JR. Structural variation of the human genome: mechanisms, assays, and role in male infertility. Syst Biol Reprod Med 2011;57:3-16.

6.  Simoni M, Bakker E, Krausz C. EAA/EMQN best practice guidelines for molecular  diagnosis of y-chromosomal microdeletions. State of the art 2004. Int J Androl 2004;27:240-9.

7. Noordam MJ, van der Veen F, Repping S. Techniques and reasons to remain interested in the Y chromosome. Fertil Steril 2006;86:1801-2.

8. Foresta C, Moro E, Ferlin A. Y chromosome microdeletions and alterations of spermatogenesis. Endocr Rev 2001;22:226-39.

9. McLachlan RI, O’Bryan MK. Clinical Review: State of the art for genetic testing of infertile men. J Clin Endocrinol Metab 2010;95:1013-24.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.12.017

The authors respond:

The Practice Committee of the American Society for Reproductive Medicine appreciates the insightful comments of Dr. Piña-Aguilar. The analysis and interpretation of Y-chromosome microdeletion data remain controversial with consensus regarding their clinical significance and prognostic value elusive. The Practice Committee has considered the comments of Dr. Piña-Aguilar and others, carefully weighing the overall strength of the body of evidence. The statement regarding the rarity of some Y-chromosome microdeletions in fertile or subfertile males has been removed from “Diagnostic evaluation of the infertile male: a committee opinion” to minimize ambiguity and misinterpretation. Currently available evidence supports the recommendation that Y-chromosome analysis be offered to men with non-obstructive azoospermia or severe oligozoospermia before considering performing ICSI with their sperm. It is expected that further research will identify the exact roles specific Y-chromosomal genes play in spermatogenesis.

On behalf of the Practice Committee:

Samantha Pfeifer, M.D.
Chair, ASRM Practice Committee

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.12.021

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