A systemic review and meta-analysis exploring the predictors of sperm retrieval in patients with non-obstructive azoospermia and chromosomal abnormalities.

CAPSULE

Contributors: Vilvapathy Senguttuvan Karthikeyan, MD (India), and Sanjay Prakash Jayaprakash, MD (India)

This review collates available evidence from 53 articles and includes 2965 patients undergoing surgical sperm retrieval (SSR) for non-obstructive azoospermia (NOA) with chromosomal abnormalities. The review tries to identify predictors for a successful SSR.

Observations:

1. Klinefelter Syndrome (KS) was the most prevalent (75.5%) chromosomal disorder with a positive SSR rate of 38.63%

• In KS patients, lower age, lower FSH & LH levels, higher testosterone levels were analyzed to be positive predictors of successful SSR (mean FSH: 36.8 IU/L). The mean testicular volume in men with KS was 3.4 ml. A larger testis size significantly predicted the overall success of SSR [OR 1.433, 95% CI 1.036– 1.983, p = 0.030) with no observable heterogeneity]. Age did not affect SSR outcome.

   2. Y chromosome microdeletion was seen in 18.6%.

• Men with AZFc microdeletion had a positive SSR of 41.95% and partial AZFc microdeletions had a SSR rate of 55.56% (Mean FSH: 17 IU/L; Mean testis volume 10.4 ml).
• There were not enough predictors identified for SSR outcome in AZFc patients.

  3. There have been successful SSR (33-100%) in men with chromosomal translocations and inversions; however, there were no consensus on the predictors of success.

Comments:

1. Contribution of KS (3-4%) and AZF mutations (7%) in infertile men is around 10%.; Incidence of KS (8-12%) and AZF (15%) put together, in men with NOA is around 25-27%.
2. The additional contribution of data from this SRMA gives an idea as to what proportion of men with NOA could have KS and AZF mutations. A plethora of genetic defects exist in men who test negative for these chromosomal abnormalities.
3. In men with NOA, there is a role for preimplantation genetic testing. In countries where genetic testing and gender selection are prohibited, given the low yield of men with chromosomal abnormalities, this also raises the need to routinely perform these two tests.
4. There has been a growing interest in genomic fertility analysis; these have diagnostic and therapeutic implications. It is too premature to discuss these newer panels due to cost and also the too little data available to support or refute its use. There is at least 50% more of additional information required to prognosticate the success rates of SSR, outcome of ICSI, clinical pregnancy rates and live birth rates.
5. In essence, this review adds little to existing knowledge of KS and AZF mutations in NOA. Though this manuscript shows prediction rates of SSR, it clearly does not give an idea of SSR in men in whom these panels are negative. In clinical practice, most men now have normal karyotype and AZF mutations leaving a big void in the understanding of genetics in NOA.

Limitations:

• Most studies focused on SSR outcomes rather than prediction of success.
• The analysis did not clearly mention the exact cut off FSH values or testis volume beyond which SSR had a predominantly negative outcome because this could be an important factor in counselling the patients.
• SSR rates in both mosaic and non-mosaic variants of KS are different and could have been another component in this data.

Conclusions:

Results of this meta-analysis can guide clinicians to counsel NOA patients undergoing SSR based on clinical and laboratory parameters. Further evidence addressing the limitations and the role of additional genetic tests could be more useful in the future.