Second chance in fertility: a comprehensive narrative review of redo micro-TESE outcomes after initial failure

Abstract

When microdissection testicular sperm extraction (micro-TESE) fails, a redo procedure may be the only option for patients who want a biological child. However, there are many gaps of knowledge surrounding the procedure, which need to be addressed to help clinicians and patients make informed decisions. This review explores redo micro-TESE in the context of nonobstructive azoospermia (NOA). Literature was searched using Google Scholar, Medline, and PubMed. Search terms were “NOA” AND “second microdissection testicular sperm extractions” AND “redo microdissection testicles sperm extraction” AND “repeat microdissection testicular sperm extractions” AND “failed microdissection testicular sperm extractions” AND “salvage microdissection testicular sperm extractions”. Only original articles in English were included. A total of nine articles were included, consisting of four retrospective and five prospective studies. The time gap between the first and second micro-TESE varied from 6 months to 24 months. Most of the included studies reported successful surgical sperm retrieval (SSR) in the second micro-TESE in the range of 10%–21%, except in one study where it reached 42%. It has not been presented any definitive information about the use of hormonal treatment or the benefit of varicocelectomy prior to the second micro-TESE. Patients with hypospermatogenesis and Klinefelter syndrome (KS) had the highest chance of success in redo surgery. In conclusion, redo micro-TESE following a negative procedure can lead to sperm recovery in 10%–21%. Patients with hypospermatogenesis and KS have a higher chance of success. There is no enough evidence to conclude which is the best hormonal stimulation if any before a redo surgery.

INTRODUCTION

Nonobstructive azoospermia (NOA) is a complex and often challenging condition characterized by the absence of sperm in the ejaculate following two separate semen analyses. It represents a significant subset of male infertility cases, affecting approximately 10%–15% of all infertile men and approximately 1% of men in the general population.1

NOA, in contrast to obstructive azoospermia, is characterized by sperm production failure. Typically, men with NOA present with elevated levels of follicle-stimulating hormone (FSH; >7.6 IU ml⁻¹), and some may exhibit decreased total testosterone levels and reduced testicular volume.2

The underlying causes of NOA are multifaceted and account for approximately 60%–70% of azoospermic cases. The etiology of NOA can be attributed to various factors such as a medical history of undescended testis (cryptorchidism), testicular torsion or trauma, infection (such as mumps orchitis), exposure to toxins (including chemotherapy and radiotherapy), and genetic abnormalities (e.g., Klinefelter syndrome [KS] and Y chromosome microdeletions). However, it is noteworthy that, in approximately half of the men diagnosed with NOA, the etiology of sperm production failure remains elusive.3 In 1999, microdissection testicular sperm extraction (micro-TESE) was introduced by Schlegel;4 and this technique is considered the gold standard surgical technique for patients with NOA.5

In the literature, the nomenclature for the second micro-TESE following the initial failure differs. While some authors refer to it as “repeat micro-TESE”,6,7 others use “salvage micro-TESE”.8,9 Notably, the term “repeat micro-TESE” is often associated with cases where the initial micro-TESE is successful, and a second procedure is performed. Conversely, “salvage micro-TESE” is commonly used when the first conventional TESE (cTESE) yields no sperm, and a second attempt is made by micro-TESE. We prefer to name the second micro-TESE as “redo micro-TESE following unsuccessful procedure”.

In patients with failed micro-TESE, a redo procedure is the only option to have a biological child before considering the use of donor sperm or adoption. It is crucial to discuss with the patients the success rate and the risks of testicular atrophy and hypogonadism. It is imperative to review all the details of the previous procedure and any patient-modifiable factors such as weight loss,10,11 varicocele,12,13 time of gonadotoxic exposure, and whether he received any treatment.

For patients facing the disappointment of a failed micro-TESE procedure, alternative strategies emerge. Some studies have explored the potential benefits of hormone optimization treatments14 or varicocele repair15 in men with varicocele coexistence.

Despite the promising prospects of redo micro-TESE, gaps of knowledge and controversies exist. These may revolve around patient selection criteria, the timing of repeat procedures, medical and surgical therapy before redo surgery, and ethical considerations. Addressing these gaps of knowledge and controversies is essential to guide clinicians and patients in making informed decisions regarding redo micro-TESE attempts.

This narrative review explores the intricacies surrounding redo micro-TESE procedures in the context of NOA. By delving into the definitions, predictors, options, rationale, and challenges, we aim to provide a comprehensive overview of this evolving field, aiding both clinicians and patients in navigating the complex landscape of male infertility.

We conducted a thorough literature search using Google Scholar, Medline, and PubMed, reliable and user-friendly search engines. Search terms were “NOA” AND “second microdissection testicular sperm extractions” AND “redo microdissection testicles sperm extraction” AND “repeat microdissection testicular sperm extractions” AND “failed microdissection testicular sperm extractions” AND “salvage microdissection testicular sperm extractions”. We looked for studies published in English from the beginning of the micro-TESE procedure in 1999 to December 2023. Only original, retrospective, or prospective studies that discussed repeat micro-TESE after unsuccessful micro-TESE were included. Case reports, systemic reviews, meta-analyses, and articles discussing micro-TESE following unsuccessful cTESE or testicular sperm aspiration (TESA) were excluded. To select the studies, we screened the titles and abstracts of all search results to ensure their relevance to our selection criteria. The author, year of publication, study design, sample size, number of patients, method of surgical sperm retrieval (SSR), site of first and second micro-TESE, number of positive SSR, predictors of positive SSR, histopathology, abnormal genetics including KS, azoospermia factor deletion, procedure, medical treatment before the micro-TESE, and finally intracytoplasmic sperm injection (ICSI) outcomes were recorded in a spreadsheet. The data were divided among two researchers (HE and EB) and further assessed and revised by a reviewer (DK) for accurate results.

A total of nine articles were reviewed, comprising four retrospective and five prospective studies. Among these studies, three of them performed the second micro-TESE at the same site as the first micro-TESE.14,16,17 In contrast, three studies carried out the second micro-TESE at different sites.18,19,20 The remaining studies did not mention the site of the first procedure.21,22,23 The time gap between the first and second micro-TESE varied from 6 months to 24 months, but two studies did not specify the gap.22,23 Three studies excluded patients with abnormal genetics, such as KS and Y chromosome microdeletion,14,16,21 and one study focused solely on KS.22 The remaining five studies included both idiopathic cases and those with abnormal genetics.15,17,18,19,20 Four studies excluded patients with varicocele,14,16,21,23 three discussed the effects of varicocele,17,18,20 and the remaining two studies did not mention varicocele in their cohort.19,22 Most of the included studies reported successful SSR in the second micro-TESE in the range of 10%–21%, except in one study where it reached 42%.17 Only three studies included ICSI outcomes in patients with positive SSR.14,16,18 Table 1 summarizes the included studies.

Table 1.

Summary of the included studies with surgical sperm retrieval and intracytoplasmic sperm injection outcomes

Study	Design	Site of second micro-TESE	Investigation	Time gap after first procedure	Number of patients	Genetics/risks	Varicocele	Success rate, n/total (%) or n (%)	ICSI outcome
Shiraishi et al.16 2012	Prospective	Same	Effects of high doses of hCG on serum T and GnRH levels and on SSR	>6 months Mean: 17–20 months	Total: 48 Received GnRH: 28 With no treatment: 20	Not included	Excluded	6/28 (21)	Not mentioned
Shinjo et al.21 2013	Prospective with control	Not mentioned	ITT before and after hCG Expression of spermatogonial PCNA before and after the hormonal therapy and to compare this expression with ITT levels	>6 months Mean: 13 months	20	Not included	Excluded	3/20 (15) hCG only: 1 Both hCG and rhFSH: 2	Not mentioned
Haliloglu et al.22 2014	Retrospective	Not mentioned	Redo micro-TESE in KS after negative attempt	Not mentioned	18	All KS	Not mentioned	3 (16.7)	One live birth
Shiraishi et al.14 2016	Prospective multi-institution	Same	Efficacy of salvage hormonal therapy before second micro-TESE	>6 months Mean: 20 months	21	Not included	Excluded	2/21 (10)	One positive live birth
Yücel et al.17 2018	Retrospective of 445 patients	Same	Predictor of successful second micro-TESE	>3 months	49 patients divided in to 2 groups according to positive and negative outcome of micro-TESE	1 KS patient and 0 cryptorchidism patient	Included	21 (42.8)	Not mentioned
Jarvis et al.18 2018	Prospective	Different sites	FNA mapping to guide sperm retrieval after failed micro-TESE	>6 months Mean: 2.2 years to FNA mapping; 7.5 months from FNA to sperm retrieval	82	Included but no details	Included and operated but no further information	FNA positive: 24 (29.3) Underwent micro-TESE all positive: 15 (62.5) With additional frozen sperm: 10/15 (66.7)	6 pregnancies resulted in 4 live births, 1 ectopic, and 1 miscarriage
Spahovic et al.23 2020	Retrospective of 33 patients	Not mentioned	Correlation between HP findings and outcomes	Not mentioned	3	AZFc	Excluded	1/3 (33)	Not mentioned
Amer et al.19 2020	Prospective case – control study	Different site	Role of combining GnRH with testosterone downregulation	>6 months	40 Group A: testosterone for 1 month followed by hCG and FSH for 3 months Group B: no treatment	Not mentioned	Not mentioned	Group A: 2/20 (10) Group B: 0/20 (0)	Not mentioned
Özman et al.20 2021	Retrospective of 435 patients	Different site	Redo micro-TESE in NOA patients after negative attempt	>6 months	125 patients divided in to 2 groups according to positive and negative outcome of micro-TESE	14 KS patients, 4 patients with deletion in AZFc, and 1 patient with partial deletion in AZFb	Included	23/125 (18.4) Idiopathic NOA: 12/69 (17.4) KS: 7/14 (50) AZFc deletion: 1/5 (20) Varicocelectomy: 0/13 (0) Varicocele: 1/12 grade 3 (8.3) Orchiopexy: 2/11 (18.2) Testicular cancer: 0/1 (0)	Not mentioned

hCG: human chorionic gonadotropin; ICSI: intracytoplasmic sperm injection; T: testosterone; GnRH: gonadotropin-releasing hormone; SSR: surgical sperm retrieval; ITT: intra-testicular testosterone; PCNA: proliferating cell nuclear antigen; FSH: follicle-stimulating hormone; rhFSH: recombinant FSH; micro-TESE: microsurgical testicular sperm extraction; KS: Klinefelter syndrome; FNA: fine needle aspiration; HP: histopathology; AZFc: azoospermia factor c; AZFb: azoospermia factor b; NOA: nonobstructive azoospermia

REDO MICRO-TESE AND PRIOR HORMONAL STIMULATION

Six studies evaluated the effect of hormonal stimulation prior to redo micro-TESE.14,16,19,20,21,23 Table 2 delineates the hormone regimen, time, laboratory monitoring, and success rates of sperm retrieval. The study of fine needle aspiration (FNA) mapping after failed micro-TESE included 10 of 15 men who were medically optimized with anastrozole, clomiphene citrate, FSH, or human chorionic gonadotropin (hCG), but no specific protocol or laboratory monitoring details were presented.18 Three of the studies used a similar regimen of hCG with additional recombinant follicle-stimulating hormone (rhFSH) if endogenous gonadotropins dropped below prepubertal levels (<2 mIU l⁻¹).14,16,21 In the study by Spahovic et al.,23 hormone stimulation consisted of FSH and menotropins for 3 months. One study administered anastrozole or clomiphene citrate with additional hCG if there was an inadequate response to the former.20 In the study of Amer et al.19 evaluating the effect of using testosterone downregulation for 1 month followed by gonadotropin for 3 months, 2 (10%) patients had sperm retrieval on the subsequent micro-TESE compared to those who did not receive hormonal therapy (P = 0.072). It should be noted that it was unclear from the study design whether all the cases and controls had undergone a cTESE or a micro-TESE first. Shinjo et al.21 found intratesticular testosterone (ITT) levels significantly increased in a linear fashion after hCG-based hormonal therapy in NOA patients (mean ± standard deviation [s.d.]: 273.6 ± 134.4 ng ml⁻¹ to 1348.1 ± 505.4 ng ml⁻¹, P < 0.0001), though there were no significant differences between NOA patients who did or did not have spermatozoa at initial micro-TESE. Additionally, compared to patients with obstructive azoospermia (control group), NOA patients had lower expression of spermatogonial proliferating cell nuclear antigen (PCNA). HCG-based hormonal therapy promoted PCNA expression, especially in men whose spermatozoa were obtained at the second micro-TESE. Additionally, spermatogonial PCNA expression was enhanced in patients with low ITT and using rhFSH in addition to hCG. Finally, histological examination revealed that the men who responded to the hormonal therapy improved from maturation arrest to hypospermatogenesis, whereas those who did not respond showed changes in interstitial tissue with basement membrane thickening and interstitial fibrosis.

Table 2.

Hormone regimen, timing, laboratory monitoring, and success rates of sperm retrieval

Study	Hormonal therapy	Timing after initial micro-TESE	Regimen	Laboratory monitoring	Semen analysis	Success, n/total (%)	ICSI outcome
Shiraishi et al.16 2012	hCG with or without rhFSH	>6 months Mean: 17–20 months	hCG (5000 IU, SC 3 times per week) for 3 months; then if plasma FSH values were still high, maintain hCG treatment for 1–2 months; if FSH dropped <3 mIU l−1, add rhFSH (150 IU, 3 times per week) for additional 2 months	FSH, LH, and T: monthly; E2: just before redo micro-TESE	None	Hormonal therapy: 6/28 (21) No hormonal therapy: 0/20 (0)	Not mentioned
Shinjo et al.21 2013	hCG with or without rhFSH	>6 months Mean: 13 months	hCG (5000 IU, SC 3 times per week) for 3 months; then if plasma FSH values were still high, maintain hCG treatment for 1–2 months; and if high FSH dropped <2 mIU l−1, add rhFSH (150 IU, 3 times per week) for 2 months	FSH, LH, and T: monthly; E2: just before redo micro-TESE; ITT: before and after hCG; expression of spermatogonial PCNA: before and after the hormonal therapy, compared to expression with ITT levels	None	3/20 (15) hCG only: 1 hCG + rhFSH: 2	Not mentioned
Shiraishi et al.14 2016	hCG + rhFSH	>6 months Mean: 20 months	hCG (5000 IU, SC 3 times per week) for 4 weeks; at week 4: add rhFSH (150 IU, 3 times per week) for 12 weeks	Serum T, LH, and FSH: monthly; E2: just prior to redo micro-TESE; Hgb and AST/ALT: monthly	Every 3 months	2/21 (10)	One live birth
Spahovic et al.23 2020	FSH + Menotrophin	Not mentioned	hCG (5000 IU, once per week) + Menotrophin (75 IU, twice per week) for 3 months	Not mentioned	None	1/3 (33)	Not mentioned
Amer et al.19 2020	T then hCG + FSH	>6 months	Testosterone enanthate (250 mg, weekly) for 1 month; then hCG (5000 IU, weekly) and purified urinary FSH (150 IU, 3 times per week) together with testosterone enanthate (250 mg, monthly) for 3 months	FSH, LH, prolactin, total and testosterone: at baseline and 1 month after starting the hormonal treatment; liver enzymes: at baseline and after the end	At the end of treatment	2/20 (10)	Not mentioned
Özman et al.20 2021	Aromatase inhibitor or SERM with or without hCG	>6 months	If total testosterone <300 ng dl−1, anastrozole (1 mg, daily) administered; anastrazole if testosterone/estradiol ratio <10, or clomiphene citrate if LH within normal range; +hCG weekly injections if inadequate response aromatase inhibitors or SERM	Serum T: at the 3rd week; then monthly, aiming to maintain T >300 ng dl−1 and T/E2 ratio >10	Included	23/125 (18.4) Idiopathic NOA: 12/69 (17.4) KS: 7/14 (50) AZFc deletion: 1/5 (20) Varicocelectomy: 0/13 (0) Varicocele: 1/12 grade 3 (8.3) Orchiopexy: 2/11 (18.2) Testicular cancer: 0/1 (0)	Not mentioned

hCG: human chorionic gonadotropin; ICSI: intracytoplasmic sperm injection; SC: subcutaneous self-injections; T: testosterone; GnRH: gonadotropin-releasing hormone; LH: luteinizing hormone; E2: estradiol; Hgb: hemoglobin; AST/ALT: aspartate aminotransferase/alanine aminotransferase; SERM: selective estrogen receptor modulator; ITT: intra-testicular testosterone; PCNA: proliferating cell nuclear antigen; FSH: follicle-stimulating hormone; rhFSH: recombinant FSH; micro-TESE: microsurgical testicular sperm extraction; KS: Klinefelter syndrome; FNA: fine needle aspiration; AZFc: azoospermia factor c; NOA: nonobstructive azoospermia

Overall, these studies reported an SRR ranging from 10% to 21%, and only 1 study14 reported a live birth in 1 patient; ICSI outcomes were not mentioned in other studies. In the retrospective series by Özman et al.,20 42 patients received hormonal optimization to increase total testosterone, and SRR was similar between those who received (11 [26.2%] patients) and those who did not receive hormonal treatment (12 [14.5%] patients; P = 0.11). The lack of a true control group in these studies and different hormonal stimulation protocols are significant limitations to making recommendations that may change clinical practice.

REDO MICRO-TESE WITH ABNORMAL GENETICS

The studies by Shiraishi et al.14,16 and Shinjo et al.21 excluded men with KS due to low testosterone levels and small testes. The genetic analysis and Y chromosome microdeletion of the patients were not mentioned in the studies by Jarvis et al.18 and Amer et al.19

Yücel et al.17 excluded patients with azoospermia factor a (AZFa) and azoospermia factor b (AZFb) deletion from their study. However, they did not mention the outcomes and numbers of participants with azoospermia factor c (AZFc). In their cohort, only one participant had KS that failed the first micro-TESE attempt. Haliloglu et al.22 reported redo micro-TESE on 18 men with KS who had unsuccessful first micro-TESE attempts in a 5-year retrospective study. Three (16.8%) of the men had a successful redo micro-TESE. Özman et al.20 reported 14 men with KS and 5 men with Y chromosome microdeletion in the genetic analysis of the study group. In Y chromosome microdeletion, 4 men had AZFc and 1 man had partial AZFb deletion. Redo micro-TESE was the most successful in the men with KS with a 50% (7/14) success rate. Only one man with AZFc deletion had spermatozoa recovered in the second micro-TESE attempt.

Collectively, patients with abnormal genetics have a chance of sperm retrieval on redo micro-TESE. However, the inclusion criteria varied significantly between studies. Although there is a signal for positive results in patients with KS, a larger well-controlled study is necessary to draw a firm conclusion.

REDO MICRO-TESE AND HISTOPATHOLOGY

The data were difficult to interpret due to differences in pathological classifications between articles. For instance, hypospermatogenesis is interpreted according to different classifications in many articles. One article by Shiraishi et al.16 stated that pathological classification was described by McLachlan et al.24 However, the table classifying the histological patterns stated that there were no late spermatids in any of the 12 hypospermatogenesis cases, which contradicted the McLachlan classification. Moreover, it was unclear whether there were mature spermatozoa in the group of patients diagnosed with hypospermatogenesis. Jarvis et al.18 used Levin’s pathological classification.25 In Levin’s classification, hypospermatogenesis was divided into three categories: mild (a slight generalized reduction in the number of spermatogenic cells that may be seen focally within the seminiferous tubules); moderate (a more uniform, generalized reduction involving many tubules); and severe (an extensive reduction in spermatogenic activity sometimes approaching germinal cell aplasia).

Yücel et al.17 defined hypospermatogenesis based on Johnsen’s score.26 Hypospermatogenesis was defined as arrest at late spermatid stage (mean Johnsen’s score: 8–9). Interestingly, the article included patients with 4 negative micro-TESE with normal spermatogenesis in the first attempt that was positive with the redo micro-TESE procedure. In the study of Özman et al.,20 testicular biopsy was categorized based on the most advanced pattern of spermatogenesis seen in the histologic examination. In this classification, hypospermatogenesis was defined as cases where mature spermatozoa were seen in tubules at a level less than normal spermatogenesis.

Only one study did not describe the histopathological pattern in the cohort.21 Table 3 summarizes the different histopathological patterns of the included studies. The definitions of histopathology vary among the studies. Therefore, it is difficult to conclude the success of the second micro-TESE operation by analyzing the pathological outcomes in the selected articles. It is known that hypospermatogenesis is a favorable pathological finding according to the studies.

Table 3.

Summary of different histopathological patterns of the included studies and sperm retrieval

Study	Study population (n)	Positive SSR, n/total (%) or n (%)	HP definition	Histopathology	Sperm positive HP
Shiraishi et al.16 2012	Total: 48 Received GnRH: 28 With no treatment: 20	6/28 (21)	McLachlan et al.24 2007	Hypospermatogenesis: 12 (25%) Early arrest: 15 (31%) Late arrest: 7 (15%) SCO: 10 (21%) Hyalinization: 4 (8%)	Hypospermatogenesis: 4 Early arrest: 2 All 6 received stimulation
Shinjo et al.21 2013	20	3 (15)	Not specified	Not specified	Hypospermatogenesis and late arrest
Haliloglu et al.22 2014	18	3 (16.7)	Not mentioned	SCO: 12 Leyding cell only: 4 Unknown: 2	All 3 positive are SCO
Shiraishi et al.14 2016	21	2 (10)	McLachlan et al.24 2007	SCO: 13 Maturation arrest: 7 Hypospermatogenesis: 1	Hypospermatogenesis and late maturation arrest
Yücel et al.17 2018	49 patients divided in to 2 groups according to positive and negative outcome of micro-TESE	21 (42.8)	Johnsen26 1970	Hyalinization of tubules: 8 SCO: 11 Maturation arrest: 21 Early maturation arrest: 11 Late maturation arrest: 10 Hypospermatogenesis: 5 Normal spermatogenesis: 4	Hyalinization of tubules: 2 (25%) SCO: 4 (36%) Maturation arrest: 8 (38%) Early maturation arrest: 3 (27%) Late maturation arrest: 5 (50%) Hypospermatogenesis: 3 (60%) Normal spermatogenesis: 4 (100%)
Jarvis et al.18 2018	82	FNA positive: 24 (29.3) micro-TESE: 15/15 (62.5)	Levin25 1979	SCO: 67% Early maturation arrest: 20% Late maturation arrest: 6% Complete spermatogenesis: 6%	There were no significant shifts in associated histology frequencies
Spahovic et al.23 2020	33	1/3 (33.3)	Not mentioned	Hypospermatogenesis: 2 (6%) SCO: 14 (43%) GCMA: 5 (15%) Hyalinization: 5 (15%) Mixed pattern: 7 (21%)	Hypospermatogenesis
Amer et al.19 2020	Total: 40 Group A: T for one month followed by hCG and FSH for 3 months Group B: no treatment	Group A: 2/20 (10) Group B: 0/20 (0)	Not mentioned	Group A CI arrest: 6 (30%) Mixed Sertoli: 2 (10%) SCO: 12 (60%) Group B CI arrest: 3 (15%) Mixed Sertoli: 7 (35%) SCO: 10 (50%)	Not mentioned
Özman et al.20 2021	125 patients divided in to 2 groups according to positive and negative outcome of micro-TESE	23/125 (18.4)	Most advanced pattern	TS and Leyding hyperplasia: 11 SCO: 69 Maturation arrest: 43 Hypospermatogenesis: 2	TS and Leyding hyperplasia: 6 (54.5%) SCO: 7 (10.1%) Maturation arrest: 8 (18.6%) Hypospermatogenesis: 2 (100.0%)

SCO: Sertoli cell only; FNA: fine needle aspiration; micro-TESE: microsurgical testicular sperm extraction; TS: tubular sclerosis; hCG: human chorionic gonadotropin; FSH: follicle-stimulating hormone; GnRH: gonadotropin-releasing hormone; SSR: surgical sperm retrieval; HP: histopathology; GCMA: germ cell maturation arrest

VARICOCELE AND VARICOCELECTOMY PRIOR TO A REDO MICRO-TESE

There were only two studies that discussed the impact of varicocele on SSR. In the first study conducted by Yücel et al.,17 clinical varicocele Grade 1–2 was found in four patients in the positive SSR group and five patients in the negative SSR group. However, the study did not distinguish between the patients who underwent varicocelectomy and the effect it had on the SSR outcome. In the second study conducted by Özman et al.,20 a left varicocele was palpated in 12 patients. Upon grading with genital palpation, one patient had Grade 1, seven patients had Grade 2, and four patients had Grade 3 varicoceles. Thirteen patients had undergone varicocelectomy (four left and nine bilateral) at least 3 months before their first micro-TESE. None of the 13 patients who had undergone varicocelectomy had a successful surgical sperm recovery, except for one patient with a Grade 3 left varicocele who had a sperm recovery with repeat micro-TESE. However, this study did not evaluate patients who had a negative micro-TESE and underwent a varicocelectomy surgery before the second micro-TESE.

Varicocele is found in approximately 5% of men with NOA, but its role in the pathophysiology of azoospermia is not fully established.27 While it is still debatable whether varicocele is coincidental or contributory to spermatogenesis disruption in these men, its surgical treatment has been aimed at improving sperm production. Treatment goals are, therefore, allowing the appearance of small quantities of sperm in the ejaculate, consequently obviating the need for sperm retrieval, or increasing the likelihood of sperm retrieval success.28 According to a study by Elbardisi et al.,13 26.2% (11 of 42) of patients with NOA and clinical Grade 2–3 varicocele had spermatozoa successfully recovered in the ejaculate after a mean follow-up period of 6.7 months postvaricocelectomy. Furthermore, a meta-analysis conducted by Esteves et al.,12 which included 11 retrospectives and 7 prospective studies with a total of 468 men with NOA, showed that the success rate of SSR in the varicocelectomy group was 61% compared to 39%, in the no varicocelectomy group, with an odds ratio (OR) of 2.7 (95% confidence interval [CI]: 1.69–4.14).16 Therefore, treating clinical varicocele in men with NOA is considered a modifiable factor that may improve the success rates of second micro-TESE sperm retrieval.

PREDICTORS OF SUCCESS OF THE REDO MICRO-TESE

Several studies examining the predictors of success for salvage micro-TESE after unsuccessful conventional TESE reported SRR between 30% and 46%. In prior reports of redo micro-TESE, sperm retrieval rates after failed micro-TESE ranged from 10% to 60%.29,30 In our review, 2 studies evaluating predictors of success of redo micro-TESE found that FSH levels significantly correlated with spermatozoa retrieval,17,23 while 4 studies suggested testicular histology may impact success rates.14,16,20,23

Yücel et al.17 found that a lower preoperative FSH level statistically significantly correlates with spermatozoa retrieval in salvage micro-TESE (mean ± s.d.: 20.4 ± 9.7 mIU ml⁻¹ in retrieval vs 31.2 ± 10.4 mIU ml⁻¹ without retrieval, P = 0.013; univariate analysis), and FSH was an independent predictive factor in a multiple logistic regression model including age, FSH, LH, and Johnsen’s score (P = 0.032). Other factors were not statistically significant including age, body mass index (BMI), history of varicocele, duration of infertility, testosterone, LH, estradiol, prolactin, and testicular histopathology results of the first micro-TESE.

There was a similar finding by Spahovic et al.,23 where the mean±s.d. of FSH in NOA patients with spermatozoa on redo micro-TESE was 17.26 ± 3.11 IU l⁻¹ compared to 24.28 ± 4.71 IU l⁻¹ without spermatozoa found (P = 0.038).

Four of 6 (67%) patients who had positive sperm retrieval at redo micro-TESE after hormonal therapy had hypospermatogenesis on histopathology from the first micro-TESE (compared to only 18% in men without sperm found).16 Additionally, out of the 28 men who received hormonal stimulation, 8 (29%) had hypospermatogenesis in their histopathology during the first trial, and 4 patients (50%) had positive SSR in the redo procedure.16 Spahovic et al.23 only performed redo micro-TESE in patients with hypospermatogenesis or mixed pattern hypospermatogenesis/SCO on initial micro-TESE (3/33) and 1 of those patients (33%) had sperm retrieval; interestingly, 2 patients were found to have SCO on final histopathology.

Özman et al.20 found a higher SRR in Leydig cell hyperplasia and tubular sclerosis histopathology (all patients with KS) compared to SCO and maturation arrest (MA; 54.5% vs 10.1% and 18.6%, respectively; both P = 0.001); though 2/2 patients with hypospermatogenesis had spermatozoa retrieval, the sample size was too small for statistical analysis. In this analysis, testicular volume was also found to be significantly lower in men with successful sperm retrieval (mean±s.d.: 8.2 ± 5.4 ml) than those without (mean±s.d.: 11.3 ± 5.3 ml, P = 0.01). On the contrary, another study demonstrated that the mean testicular volumes of 6 patients with sperm retrieval at redo micro-TESE were lower than those of patients without sperm (mean±s.d.: 13 ± 6.5 ml vs 18 ± 9.1 ml), but this was not a statistically significant finding (no P-value reported).16

Taken together, testicular histopathology appears to play a role in the likelihood of sperm retrieval on redo micro-TESE. Although classifications were quite heterogeneous between studies, there is a signal for positive results in patients with hypospermatogenesis. Lower relative levels of FSH may also increase the chances of sperm retrieval, but specific ranges or cut-off values are far from defined. However, given the significant variability, lack of adequate control groups, low overall patient numbers, lack of knowledge of the surgeons’ experience and technique of initial attempt, and conflicting results in the aforementioned studies, it is clear that no single factor predicts the success of a redo micro-TESE. Without further rigorous larger studies controlling for surgeon-dependent factors and using precise definitions and inclusion criteria, it would be difficult to ascertain what clinical characteristics may help counsel patients on their chances of successful sperm retrieval. Even with a positive result on redo micro-TESE, this may not result in pregnancy or live birth; thus, longer follow-up and comprehensive reporting are also necessary.

CONCLUSION

Redo micro-TESE following a negative procedure can lead to sperm recovery in some cases. Patients with hypospermatogenesis and KS have a higher chance of success. There is no enough evidence to conclude which is the best hormonal stimulation if any before a redo surgery. It is worth noting that the majority of the studies conducted on the subject have been of low quality. In addition, the study populations and protocols used have been highly diverse, making it challenging to draw firm conclusions. Given these limitations, it is essential to approach the findings of these studies with caution, and further research is needed to establish more definitive results.

AUTHOR CONTRIBUTIONS

HE conceived and designed the study. HE, EB, WL, and DK contributed to the provision of the study material or results. HE, EB, and WL collected and assembled the data. All authors contributed to the manuscript writing, and read and approved the final manuscript.

COMPETING INTERESTS

All authors declared no competing interests.