Infertility is a medical condition affecting couples worldwide. Currently, infertility is described as the inability of a heterosexual couple, after 12 months of regular and unprotected intercourse, to conceive a child. Nearly 15.0% to 20.0% or 1:6 of all couples worldwide meet this criterion for infertility.1 Infertility continues to be a very challenging reality for both males and females.2 The inability to conceive an offspring can be related to female factor, male factor, or a combination of both. Male factor infertility is estimated to affect 30.0%–50.0% of all infertile couples and is becoming more common as sperm counts continue to decline worldwide.3,4 In addition, male factor infertility has been associated with reduced life expectancy and heavy financial burden, potentially causing excessive strain within personal relationships of those who suffer from the condition.5–7
In male patients who undergo a complete male factor workup, nonobstructive azoospermia (NOA) is found to be the diagnosis in about 10.0% of cases.8 The development of intracytoplasmic sperm injection (ICSI) technique in 1992 was a significant advance in reproductive technology and allowed men with NOA to have a chance at genetic offspring. Testicular sperm aspiration (TESA) was originally developed and used by practitioners for men with NOA to obtain sperm directly from the seminiferous tubules to allow the cells to be utilized for fertilization. Multiple techniques have since been developed and refined to obtain the sperm directly from the testicle for the ICSI procedure.9,10 The most common technique is conventional testicular sperm extraction (cTESE) due to its more straightforward approach and lower cost. Microdissection testicular sperm extraction (mTESE) was further developed in 1999 as a more targeted way of retrieving sperm from the testicle and causing less microvascular damage.11,12 The reported sperm retrieval (SR) rates (SRRs) in studies comparing mTESE to cTESE vary; however, on average, SRRs are shown to be 30.0%–35.0% and 43.0%–57.0% for cTESE and mTESE, respectively.13–15
There is much debate over deciding the appropriate SR technique. In general, mTESE is more successful in obtaining enhanced SRR over cTESE but also comes with added costs, increased operative time, additional embryology staff, as well as specialized training on the part of the practitioner. Numerous articles have attempted to describe correlations between multiple variables and chances of success for successful SR when using these techniques such as follicle-stimulating hormone (FSH) levels, mean testicular volume (TV), and testosterone (T) levels.16–18 In this comprehensive systematic literature review and meta-analysis, there was an emphasis placed on the development of an improved understanding of the different successes of SRR for cTESE vs mTESE with respect to a patient’s unique hormonal profile. This effort is designed to help guide clinicians in offering patients the most efficacious SR procedure while reducing unnecessary costs and degree of invasiveness.
MATERIALS AND METHODS
Articles published in the English language that compared cTESE with mTESE regarding their SRRs in patients with NOA were sought after. Papers published between January 2000 and December 2018 were searched electronically via search engines such as PubMed, Google Scholar, and ScienceDirect by the two authors (NM and KRE). The computer-based search terms are demonstrated in Table 1.
The study included articles for consideration if they pertained to SRR in men with NOA, compared the performance of at least one other SR method to mTESE, and reported patient-related variables concerning their SR method. For the purpose of this study, NOA was defined as the lack of sperm in the ejaculate due to the failure of spermatogenesis. Studies that did not include mTESE, NOA, and SRR and did not compare different SR methods to mTESE were not included. Similar articles that reduplicated studies on the same populations were limited, and only the most recent articles were selected. Other studies that were excluded pertained to those listing SRR from men with obstructive azoospermia that could not be separated from the SRR of men with NOA, as well as those studies that serially employed the use of multiple comparative techniques that were dependent upon one another. Studies were analyzed for bias using the Newcastle–Ottawa scale and were preferentially selected if they were found to be of “good quality”. After a review of the abstracts of 43 articles, 29 articles were selected for employment within this meta-analysis.12–15,17–41 Of the 29 studies, 9 studies contributed data on 1227 patients who received cTESE12,13,15,17,19,22,24,30,32 and 20 studies contributed a total of 4760 patients who received mTESE14,18,20,21,23,25–29,31,33–41 (Figure 1).
The information used in this meta-analysis and systematic review was independently extracted by the same two authors using a standardized methodology to collect points of data. These categories included publication year, sample size, mean patient age during the time of surgery, demographics, SRR, mean TV, T, FSH, LH, estradiol, inhibin b, and histopathology. While articles that produced data for each of the above categories were sought after, the selected articles that did not have all the categories were not excluded from the analysis. The availability of extractable values for FSH, T, and TV was limited. Of note, SRR was defined as the success rate of procurement of at least a single viable sperm cell to be preserved or used in ICSI or in vitro fertilization.
Studies that were included in this paper were analyzed for the values of the variables listed above and compared with each other. To perform statistical analysis and table creation, SPSS (version 21, SPSS Statistics, Chicago, IL, USA) and Microsoft Excel (Microsoft, Redmond, WA, USA) were employed. Clinical values that were extracted from employed articles were scrutinized as arithmetic means weighted by study sample size. A random effects model was employed to perform the meta-analysis, and a weighted linear regression model was used to describe the association between collected data values. This paper described statistical significance as a two-tailed P < 0.05.
The criterion for article inclusion in this meta-analysis was applied to all 43 papers under review, in which 29 were retained. Nine of these studies contributed data on 1227 patients undergoing cTESE, while 20 studies provided data from 4760 patients who received mTESE. Certain characteristics of interest were queried from within each study, including patient demographics, SRRs, and study averages for T (in ng dl−1), TV (in ml), FSH (in mIU ml−1), and LH (in mIU ml−1), as shown in Table 2. A weighted-means average was calculated for all 29 studies to reveal an average participant number of 338 with an average age of 34.8 years. The analysis also found a mean TV of 10.5 ml, T level of 398.2 ng dl−1, FSH level of 21.0 mIU ml−1, and LH level of 9.2 mIU ml−1.
Weighted-means analysis comparing mTESE to cTESE was performed for each study’s average SRR, FSH (in mIU ml−1), T (in ng ml−1), and TV (in ml). cTESE was found to be less effective than mTESE with an SRR of 40.1% (95% confidence interval [CI]: 34.8%–45.5%) compared to 51.9% (95% CI: 46.1%–57.7%), respectively. Table 3 demonstrates direct comparisons between mTESE and cTESE with respect to average FSH, T, and TV.
Weighted linear regression models were then used to describe the association between SRR and type of extraction, FSH level, T level, and TV. The number of available records was insufficient to identify statistically significant differences for some of the variables, including T level and TV. The analysis showed that using mTESE as compared to cTESE may be expected to add 11.8% to the SRR (P < 0.05). In addition, it was demonstrated that for each 1.19-point increase in the mean FSH across a population, the SRR may be expected to decrease by 1.0%, regardless of the retrieval technique utilized (P < 0.05).
To define a more clinically useful model, FSH was divided into three distinct ranges with SRR calculated for each. The ranges were normal (FSH levels <10 mIU ml−1), moderate elevation (FSH levels: 10–19 mIU ml−1), and significant elevation (FSH levels >20 mIU ml−1). The model demonstrated that for a patient undergoing cTESE, SRRs would be 57.1%, 44.3%, and 31.2% for values of FSH categorized as normal, moderately elevated, and significantly elevated, respectively (P < 0.05; Table 4). A similar model for mTESE was unable to be constructed due to insufficient data.
Azoospermia has been observed in 1.0% of the entire population and is shown to be the underlying etiology of 10.0%–12.0% of all cases of infertility. Nearly 60.0% of men with azoospermia have NOA, but with improvements in assisted reproductive technology (ART), fertility has been made possible. Achieving fertility has also been assisted by the development of multiple SR techniques, including cTESE and mTESE.2 The increasing rates of male factor infertility thus require fertility specialists to be equipped not only with an advanced skill set but also with the knowledge of SRR using different techniques given a patient’s hormonal makeup.
This comprehensive systematic review and meta-analysis is one of the largest of its kind and was designed to create a model to evaluate the preoperative hormonal profile of a patient before undergoing cTESE or mTESE based on pooled data from previously published literature. We also created a clinically useful predictive model for SRR success based upon FSH levels. After compiling 29 studies that met our inclusion criteria, we were able to determine that some variables, such as FSH and SR technique, could be predictive of SRR. Other variables, such as T and mean TV, were unable to be assessed for their predictivity of SRR due to lack of data across examined studies. With the increased usage of ICSI, there has also been an associated increase in usage of SR techniques. This underscores the need for examination of unique patient factors as a means for a more cost-effective solution to SR.42
Using weighted-means values, it was found that mTESE outperformed cTESE with an average SRR of 51.9% vs 40.1%, respectively. This was an expected outcome and has been previously established in the literature and other studies. While SRR is higher when using mTESE, so are other factors such as additional staff, equipment, operative time, and specialized training, which all need to be factored into the clinical decision-making process.12 Weighted linear regression was then utilized to describe associations between SRR, type of procedure, FSH, T, and mean TV. The weighted linear regression demonstrated that FSH can be used as a predictor of SRR. The model found that for each increase of FSH by 1.19 mIU ml−1, there would be a decrease in SRR of 1.0%, but this would be difficult to apply in a clinical setting. We simplified the modeling by dividing FSH values into clinically meaningful categories to help better predict SRR. The model was only computed for cTESE due to limited data regarding average FSH levels and other hormonal values reported in studies examining mTESE. FSH was categorized as three clinically meaningful categories: normal (FSH levels <10 mIU ml−1), moderate elevation (FSH levels: 10–19 IU ml−1), and significant elevation (FSH levels >20 mIU ml−1). The analysis demonstrated that in men with NOA who had a normal FSH, their chance of SR success would be 57.1%. Similar men with moderate FSH elevations would have a 44.3% chance, and those with the highest elevations would only have a 31.2% SRR. These findings have been understudied, yet have the potential to be beneficial in helping to counsel patients appropriately before undergoing a costly SR procedure. By continuing to understand the hormonal influence of positive SRR data, appropriate and realistic expectations can be offered to patients for enhanced shared decision-making.
This review is unique in that the different type of analysis and modeling employed strives to provide a clinically relevant framework to assist physicians in better counseling patients who are weighing the value of undergoing a cTESE vs mTESE. This study is the largest identifiable analysis of the hormonal impact to successful cTESE and mTESE procedures, which is often limited due to its retrospective nature. The data sets that were included were often incomplete and/or insufficient for a thorough analysis to help complete the model that was attempted to be created. Due to the small number of studies included in this meta-analysis, results may be subject to selection bias as well as aggregation bias due to the use of the mean population values in the descriptive models. In addition, the FSH model could only be created for cTESE due to limited data.
Due to the multiple pathologies associated with patients undergoing both cTESE and/or mTESE, there exists the potential for increased heterogeneity within this study, possibly a limiting factor. Future studies would ideally prospectively collect data to compare FSH levels and success with mTESE or cTESE to construct improved predictive models. Preferably, a multicenter study should be enlisted to help obtain significant numbers to better guide practitioners in counseling their patients.
This meta-analysis found mTESE to have a statistically significant higher SRR as compared to cTESE. Performing mTESE on a patient is shown to have an 11.8% increase in SRR over a predicted SRR from cTESE in the same patient. Data analysis also suggested an inverse relationship between FSH levels and SRR when performing either SR technique. Further investigation found that by classifying a patient’s FSH levels alone can be predictive of SRR with cTESE; therefore, this information can be used to help educate patients on possible outcomes to avoid unnecessary costs and hardships.
MR was involved in project development and formed the hypothesis that drove this study. NM drafted the manuscript and helped craft overall study design and coordination. NM and KRE screened articles and performed data collection. NM, KRE, and MR were involved in data analysis, as well as manuscript editing. KS was involved in data analysis with statistical software. All authors read and approved the final manuscript.
All authors declare no competing interests.
1. Ishikawa T. Surgical recovery of sperm in non-obstructive azoospermia. Asian J Androl 2012;14:109–15.
2. Yang Q, Huang YP, Wang HX, Hu K, Wang YX, et al. Follicle-stimulating hormone as a predictor for sperm retrieval rate in patients with nonobstructive azoospermia: a systematic review and meta-analysis. Asian J Androl 2015;17:281–4.
3. Deruyver Y, Vanderschueren D, Van der Aa F. Outcome of microdissection TESE compared with conventional TESE in non-obstructive azoospermia: a systematic review. Andrology 2014;2:20–4.
4. Sciarra J. Infertility: an international health problem. Int J Gynaecol Obstet 1994;46:155–63.
5. Winters BR, Walsh TJ. The epidemiology of male infertility. Urol Clin North Am 2014;41:195–204.
6. Barratt CL, Bjorndahl L, De Jonge CJ, Lamb DJ, Osorio Martini F, et al. The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance-challenges and future research opportunities. Hum Reprod Update 2017;23:660–80.
7. Ko JK, Chai J, Lee VC, Li RH, Lau E, et al. Sperm retrieval rate and pregnancy rate in infertile couples undergoing in-vitro
fertilisation and testicular sperm extraction for non-obstructive azoospermia in Hong Kong. Hong Kong Med J 2016;22:556–62.
8. Jarow JP, Espeland MA, Lipshultz LI. Evaluation of the azoospermic patient. J Urol 1989;142:62–5.
9. Boitrelle F, Robin G, Marcelli F, Albert M, Leroy-Martin B, et al. A predictive score for testicular sperm extraction quality and surgical ICSI outcome in non-obstructive azoospermia: a retrospective study. Hum Reprod 2011;26:3215–21.
10. Carlsen E, Giwercman A, Keiding N, Skakkebaek NE. Evidence for decreasing quality of semen during past 50 years. BMJ 1992;305:609–13.
11. Schlegel PN. Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision. Hum Reprod 1999;14:131–5.
12. Salehi P, Derakhshan-Horeh M, Nadeali Z, Hosseinzadeh M, Sadeghi E, et al. Factors influencing sperm retrieval following testicular sperm extraction in nonobstructive azoospermia patients. Clin Exp Reprod Med 2017;44:22–7.
13. Ramasamy R, Yagan N, Schlegel PN. Structural and functional changes to the testis after conventional versus microdissection testicular sperm extraction. Urology 2005;65:1190–4.
14. Ramasamy R, Lin K, Gosden LV, Rosenwaks Z, Palermo GD, et al. High serum FSH levels in men with nonobstructive azoospermia does not affect success of microdissection testicular sperm extraction. Fertil Steril 2009;92:590–3.
15. Tsujimura A, Miyagawa Y, Takao T, Takada S, Koga M, et al. Salvage microdissection testicular sperm extraction after failed conventional testicular sperm extraction in patients with nonobstructive azoospermia. J Urol 2006;175:1446–9.
16. Jarvi K, Lo K, Fischer A, Grantmyre J, Zini A, et al. CUA guideline: the workup of azoospermic males. Can Urol Assoc J 2010;4:163–7.
17. Bernie AM, Mata DA, Ramasamy R, Schlegel PN. Comparison of microdissection testicular sperm extraction, conventional testicular sperm extraction, and testicular sperm aspiration for nonobstructive azoospermia: a systematic review and meta-analysis. Fertil Steril 2015;104:1099–103.e1–3.
18. Binsaleh S, Alhajeri D, Madbouly K. Microdissection testicular sperm extraction in men with nonobstructive azoospermia: experience of King Saud University Medical City, Riyadh, Saudi Arabia. Urol Ann 2017;9:136–40.
19. Spahovic H, Goktolga U, Junuzovic D, Goktas C, Rama A. Evaluation of prognostic factors and determinants in surgical sperm retrieval procedures in azoospermic patients. Med Arch 2017;71:243–5.
20. Eken A, Gulec F. Microdissection testicular sperm extraction (micro-TESE): predictive value of preoperative hormonal levels and pathology in non-obstructive azoospermia. Kaohsiung J Med Sci 2018;34:103–8.
21. Hussein A, Ozgok Y, Ross L, Rao P, Niederberger C. Optimization of spermatogenesis-regulating hormones in patients with non-obstructive azoospermia and its impact on sperm retrieval: a multicentre study. BJU Int 2013;111:E110–4.
22. Sacca A, Pastore AL, Roscigno M, Naspro R, Pellucchi F, et al. Conventional testicular sperm extraction (TESE) and non-obstructive azoospermia: is there still a chance in the era of microdissection TESE?Results from a single non-academic community hospital. Andrology 2016;4:425–9.
23. Kalsi JS, Shah P, Thum Y, Muneer A, Ralph DJ, et al. Salvage micro-dissection testicular sperm extraction;outcome in men with non-obstructive azoospermia with previous failed sperm retrievals. BJU Int 2015;116:460–5.
24. Ghalayini IF, Al-Ghazo MA, Hani OB, Al-Azab R, Bani-Hani I, et al. Clinical comparison of conventional testicular sperm extraction and microdissection techniques for non-obstructive azoospermia. J Clin Med Res 2011;3:124–31.
25. Yildirim ME, Koc A, Kaygusuz IC, Badem H, Karatas OF, et al. The association between serum follicle-stimulating hormone levels and the success of microdissection testicular sperm extraction in patients with azoospermia. Urol J 2014;11:1825–8.
26. Enatsu N, Miyake H, Chiba K, Fujisawa M. Predictive factors of successful sperm retrieval on microdissection testicular sperm extraction in Japanese men. Reprod Med Biol 2016;15:29–33.
27. Alfano M, Ventimiglia E, Locatelli I, Capogrosso P, Cazzaniga W, et al. Anti-mullerian hormone-to-testosterone ratio is predictive of positive sperm retrieval in men with idiopathic non-obstructive azoospermia. Sci Rep 2017;7:17638.
28. Xu T, Peng L, Lin X, Li J, Xu W. Predictors for successful sperm retrieval of salvage microdissection testicular sperm extraction (TESE) following failed TESE in nonobstructive azoospermia patients. Andrologia 2017;49:e12642.
29. Ozer C, Caglar Aytac P, Goren MR, Toksoz S, Gul U, et al. Sperm retrieval by microdissection testicular sperm extraction and intracytoplasmic sperm injection outcomes in nonobstructive azoospermic patients with klinefelter syndrome. Andrologia 2018;50:e12983.
30. Caroppo E, Colpi EM, Gazzano G, Vaccalluzzo L, Scroppo FI, et al. Testicular histology may predict the successful sperm retrieval in patients with non-obstructive azoospermia undergoing conventional TESE: a diagnostic accuracy study. J Assist Reprod Genet 2017;34:149–54.
31. Cissen M, Meijerink AM, D'Hauwers KW, Meissner A, van der Weide N, et al. Prediction model for obtaining spermatozoa with testicular sperm extraction in men with non-obstructive azoospermia. Hum Reprod 2016;31:1934–41.
32. Okada H, Dobashi M, Yamazaki T, Hara I, Fujisawa M, et al. Conventional versus microdissection testicular sperm extraction for nonobstructive azoospermia. J Urol 2002;168:1063–7.
33. Turunc T, Gul U, Haydardedeoglu B, Bal N, Kuzgunbay B, et al. Conventional testicular sperm extraction combined with the microdissection technique in nonobstructive azoospermic patients: a prospective comparative study. Fertil Steril 2010;94:2157–60.
34. Ando M, Yamaguchi K, Chiba K, Miyake H, Fujisawa M. Outcome of microdissection testicular sperm extraction in azoospermic patients with Klinefelter syndrome and other sex-chromosomal anomalies. Syst Biol Reprod Med 2013;59:210–3.
35. Schwarzer JU, Steinfatt H, Schleyer M, Kohn FM, Fiedler K, et al. No relationship between biopsy sites near the main testicular vessels or rete testis and successful sperm retrieval using conventional or microdissection biopsies in 220 non-obstructive azoospermic men. Asian J Androl 2013;15:795–8.
36. Bryson CF, Ramasamy R, Sheehan M, Palermo GD, Rosenwaks Z, et al. Severe testicular atrophy does not affect the success of microdissection testicular sperm extraction. J Urol 2014;191:175–8.
37. Aydin T, Sofikerim M, Yucel B, Karadag M, Tokat F. Effects of testicular histopathology on sperm retrieval rates and ICSI results in non-obstructive azoospermia. J Obstet Gynaecol 2015;35:829–31.
38. Ramasamy R, Schlegel PN. Microdissection testicular sperm extraction: effect of prior biopsy on success of sperm retrieval. J Urol 2007;177:1447–9.
39. Ravizzini P, Carizza C, Abdelmassih V, Abdelmassih S, Azevedo M, et al. Microdissection testicular sperm extraction and IVF-ICSI outcome in nonobstructive azoospermia. Andrologia 2008;40:219–26.
40. El-Haggar S, Mostafa T, Abdel Nasser T, Hany R, Abdel Hadi A. Fine needle aspiration vs. mTESE in non-obstructive azoospermia. Int J Androl 2008;31:595–601.
41. Colpi GM, Colpi EM, Piediferro G, Giacchetta D, Gazzano G, et al. Microsurgical TESE versus conventional TESE for ICSI in non-obstructive azoospermia: a randomized controlled study. Reprod Biomed Online 2009;18:315–9.
42. Boulet SL, Mehta A, Kissin DM, Warner L, Kawwass JF, et al. Trends in use of and reproductive outcomes associated with intracytoplasmic sperm injection. JAMA 2015;313:255–63.