Varicocele and nonobstructive azoospermia

Abstract

Approximately 15% of men in the general population have varicoceles, and varicoceles are diagnosed in 40% of men presenting for fertility evaluations. One percent of men in the general population are azoospermic, and 15% of men presenting for fertility evaluations are diagnosed with azoospermia. This article aims to review the impact of varicoceles on testicular function in men with azoospermia, the impact of varicocele repair on the semen parameters of azoospermic men, and the impact of varicocele repair on sperm retrieval and pregnancy outcomes when the male partner remains azoospermic after varicocele repair.

INTRODUCTION

In the USA, approximately 15% of couples are considered infertile, after trying for pregnancy for 1 year unsuccessfully with unprotected intercourse. In 20% of infertile couples, the male factor is solely responsible, and it is a contributory factor in conjunction with female infertility factors in an additional 40%, suggesting that in 60% of infertile couples, there is male factor involvement.1 One percent of men in the general population are azoospermic, and approximately 15% of men presenting for infertility evaluations are found to be azoospermic.2,3 Azoospermia is defined as a complete absence of sperm from the ejaculate and diagnosed by at least two semen analyses revealing no sperm in the ejaculate by high-power light microscopy. The diagnosis also requires the additional finding of no sperm in the centrifuged concentrated pellet after centrifugation for 15 min at a speed of at least 3000g or greater.4

There are three main categories of azoospermia: pretesticular, testicular, and posttesticular etiologies. Pretesticular etiologies include various causes of hypogonadotropic hypogonadism. Testicular causes refer to primary testicular dysfunction with impaired spermatogenesis within the testes. Posttesticular etiologies include obstructions of the reproductive tract at the level of epididymides, vasa, or ejaculatory ducts. Most testicular etiologies of azoospermia are not correctable, with the exception of varicoceles. Varicoceles offer a guarded opportunity for men with nonobstructive azoospermia (NOA) to regain sperm in the semen and achieve a pregnancy, either with timed intercourse or with assisted reproductive technology (ART) without the need for surgical sperm retrieval.

This article aims to review the impact of varicoceles on testicular function in men with azoospermia, the impact of varicocele repair on the semen of azoospermic men, and the impact of varicocele repair on sperm retrievals and ART outcomes when the male partner does not have a return of sperm to the ejaculate following varicocele repair (Table 1).

Table 1.

Summary of the studies referenced and outcomes following varicocele repair in men with nonobstructive azoospermia

Study	Study type	Mean age (year)	Varicocele grade	Presence of sperm in postoperative ejaculate, n/total (%)	Mean postoperative sperm count (×106 ml−1)	Mean interval between varicocele repair and sperm in ejaculate (months)	SRR, n/total (%)	Mean postoperative sperm motility (%)	Natural pregnancy, n/total	Presence of sperm according to histopathology results in ejaculate, n/total
Schlegel et al.51	Retrospective	NR	-	7/31 (22.5)	NR	14.7	NR	NR	NR	NR
Cakan and Altug22	Retrospective	29	Grade I: 7.6 Grade II: 30.7 Grade III: 61.5	Grade I: 3/13 (23.1) Grade II: 1/4 (25.0) Grade III: 2/8 (25.0)	Grade I: 0.73 Grade 2: 0.7 Grade 3: 1.2 and 0.3	4.5	NR	26.0	0/3	SCO: 0/5 MA: 1/3 HS: 2/5
Esteves and Glina59	Retrospective	32	NR	6/17 (35.3)	0.8*	5	44.4	NR	1/6	SCO: 0/6 MA: 3/5 HS: 5/6
Pasqualotto et al.44	Prospective	NR	NR	9/27 (33.3)	4.06	NR	NR	37.6	1/9	SCO: 4/10 MA: 3/8 HS: 2/9
Lee et al.25	Prospective	32	Grade I: 10.5 Grade II: 42.1 Grade III: 47.4	7/19 (36.8)	0.24	NR	NR	30.2	1/7	SCO: 1/10 MA: 4/6 HS: 2/3
Cocuzza et al.58	Prospective	29.4	Grade I: 0 Grade II: 40 Grade III: 60	Grade I: 3/10 (30.0) Grade II: 1/4 (25.0) Grade III: 2/6 (33.3)	Grade 2: 0.6 Grade 3: 12.2 and 3.9	NR	NR	36.6	NR	SCO: 0/4 MA: 1/4 HS: 2/2
Abdel-Meguid29	Prospective	34.9	Grade I: 40 Grade II: 34 Grade III: 26	10/31 (32.3)	2.30	19.3	NR	15.3	NR	SCO: 0/10 MA: 3/8 HS: 7/13
Zampieri et al.55	Prospective	33	Grade I: 0 Grade II: 0 Grade III: 100	17/35 (48.6)	0.6	6	57.8	11.0	NR	NR
Aboutaleb et al.35	Prospective	29.9	NR	6/20 (30.0)	2.00	NR	NR	NR	NR	SCO: 0/10 MA: 0/3 HS: 0/7
Sajadi et al.38	Retrospective	33.84	Grade I: 21.1 Grade II: 42.1 Grade III: 36.8	8/57 (14.0)	NR	NR	14/38 (36.8)	NR	1/7	NR

^*Total postoperative motile sperm count. -: no value; NR: not reported; SCO: Sertoli cell-only; MA: maturation arrest; HS: hypospermatogenesis; SRR: sperm retrieval rate

A narrative review was performed after searching the PubMed literature bank for published manuscripts on varicocele and NOA. Negative and positive outcome studies were included. Human and animal studies were included. The studies spanned from 1973 to 2023.

VARICOCELE AND NOA

Varicoceles are abnormally dilated scrotal veins, which are found in approximately 15% of men in the general population and in 40% of men presenting for infertility evaluations, making varicoceles the most common diagnosis made in infertile men.5 There is a fair amount of overlap between men with varicoceles and men with azoospermia, as 1% of men in the general population are azoospermic and 15% of men presenting for infertility are azoospermic.1,5 Multiple hypotheses exist for the mechanisms by which varicoceles may adversely impact spermatogenesis and testicular function which may result in low sperm counts and perhaps azoospermia. The prevailing theory based on most data indicates that varicoceles impact testicular function primarily by increasing intratesticular temperatures. This occurs by varicoceles interrupting the countercurrent heat exchange in the pampiniform plexus with opposing flows in a central arterial system.6,7,8 Varicoceles may induce cellular damage through sperm DNA fragmentation, apoptosis, increasing reactive oxygen species through oxidative stress, intracellular ionic and metabolic changes, and predisposition to sperm aneuploidy.9,10,11,12,13,14,15,16 Men with varicoceles demonstrate higher mean tubular apoptotic indices in comparison to controls.17

A theory of varicoceles causing additional testicular cellular damage due to the retrograde flow of adrenal and renal metabolites was supported by a murine model study.18 A study has revealed that thermal abnormalities and Class IIC meiotic abnormalities may be reversed after varicocele repair in the testes of NOA men in 6 months following varicocele repair.19

Although there is controversy and some conflicting data, there may be a role for the repair of palpable varicoceles in men with NOA. Multiple studies have demonstrated the return of sperm to the ejaculate in 10%–50% of men with NOA following varicocele repair. The return of sperm is more likely when testicular histology shows hypospermatogenesis or late maturation arrest, as opposed to less favorable outcomes after repair in men with Sertoli cell-only or early maturation arrest.20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41 In one small study, 3 in 25 men had a return of sperm 4 months after surgery, and this increased to 5 in 25 by the end of 1 year, suggesting that it may take up to 1 year for some men to respond.37 Although the postoperative counts usually tend to remain low, and intracytoplasmic sperm injection (ICSI) is still needed, the responders benefit by avoiding a microdissection testicular sperm extraction (micro-TESE). There are no identifiable predictors for which men will relapse to azoospermia after having a return of sperm in the ejaculate following varicocele repair; hence, sperm cryopreservation is recommended when sperm returns to the ejaculate following varicocele repair in NOA men.29,35,42,43 Sperm cryopreservation is recommended after the return of sperm to the semen regardless of whether the man underwent surgical varicocele repair or embolization, as there are reported cases of relapse to azoospermia as early as 6 months after demonstrating sperm in the ejaculate.25,32,44

Seminal plasma micro-RNA-192a (miR-192a) levels were reported to be higher in azoospermic men who failed to have a return of sperm to the ejaculate after varicocele repair when compared to those that were successful. MiR-192a induces GC-2 cell apoptosis through the activation of Caspase-3 protein and may be a reliable predictor of response to varicocele repair in NOA men attempting to have sperm return to the ejaculate.45

The presence of a Y-chromosome microdeletion must be evaluated before varicocele repair for severe oligozoospermia or azoospermia since the benefit is unlikely when a Y-chromosome microdeletion is identified.46

In a study of 33 azoospermic men with varicoceles, 12 (34%) had sperm return to the semen within 2–14 months after varicocele repair.47 There have been series with small numbers of patients who have reported pregnancy rates in azoospermic men following varicocele repair without other treatments. A series by Mehan48 demonstrated pregnancies in 2 out of 10 men with baseline azoospermia treated only with varicocele repair. Another small series compared response rates to varicocele repair in men with azoospermia (n = 24) versus virtual azoospermia (n = 14). Sperm was identified in the semen of 5 (21%) of the azoospermic men following varicocele repair with a mean follow-up of 14 months, 3 had testicular histology revealing maturation arrest at the spermatid stage, 1 with Sertoli cell-only pattern with focal spermatogenesis, and 1 with hypospermatogenesis. None of the men with pure Sertoli cell-only or spermatocyte stage maturation arrest patterns had a return of sperm to the ejaculate following varicocele repair. Of the virtually azoospermic men, 12 (85%) had improvement in semen parameters and 4 (28%) achieved a total motile count of greater than 5×10⁶. Following varicocele repair, three (21%) of the virtually azoospermic men were able to conceive spontaneously with the level of semen parameter improvement achieved.49 One study reported on 32 men with azoospermia who were treated with percutaneous embolization and 18 (56%) had sperm return to the semen with a mean sperm concentration of 3.81 × 10⁶ (standard deviation: 1.69 × 10⁶ ml⁻¹) following embolization.50

There is controversy regarding the outcomes of sperm returning to the ejaculate following varicocele repair in men with NOA due to variable results in studies.51

VARICOCELE AND SPERM RETRIEVAL

In men with NOA, having sperm return to the ejaculate following varicocele repair does not necessarily equate to having sufficient sperm for use with ART. In a study of 32 NOA men who underwent varicocele repair, 7 (22%) had sperm present on a postvaricocele repair semen analysis; however, only 3 (9.6%) had adequate motile sperm in the ejaculate for use with in vitro fertilization (IVF)/ICSI.51 Thus, there will be many men with NOA, who undergo varicocele repair, but will still need micro-TESE either because they are still azoospermic or because the sperm in the semen are not enough for ICSI. There are data that suggest that varicocele repair in men with NOA improves sperm retrieval rates at the time of micro-TESE and improves IVF/ICSI outcomes. One study demonstrated a surgical sperm retrieval rate of 60.8% in men who failed to have sperm return to the ejaculate following varicocele repair versus a sperm retrieval rate of 38.5% in NOA men who had varicoceles left intact. The varicocele repair group also had a significantly higher clinical pregnancy rate and live birth rate with IVF/ICSI than the men who did not undergo repair (74.2% vs 52.3% and 64.5% vs 41.5%, respectively).52 Another study compared couples who underwent IVF/ICSI when men underwent varicocele repair versus men who did not have varicoceles repaired. The sperm retrieval rate with micro-TESE was significantly higher in the men who previously had their varicoceles repaired (53% vs 30%). However, there was no significant difference in fertilization rate, rate of high-quality embryo formation, or mean number of transferred embryos. The clinical pregnancy rate was significantly higher in the varicocele repair group in comparison to the group who had varicoceles untreated (31% vs 22%).53 Many studies have shown similar findings of improved sperm retrieval rates, fertilization rates, pregnancy rates, and live birth rates with micro-TESE/IVF/ICSI after varicocele repair in comparison to untreated varicoceles.36,38,40,41,54,55,56 One study demonstrated an improvement in the severity of testicular histology following varicocele repair in NOA men. Testicular biopsy for histology was performed at the time of varicocele repair and again at the time of micro-TESE in men who remained azoospermic following varicocele repair. Fourteen men revealed Sertoli cell-only patterns from the biopsies at the time of varicocele repair and had improvement in the severity of histology to focal spermatogenesis in two of them and late maturation arrest in three of them from the biopsies at the time of micro-TESE.57 A limitation of this study is that there may be baseline heterogeneity in testicular histology in certain testicular units at baseline.

However, there are conflicting data in the literature. A small study of 31 men suggested that varicocele repair only resulted in adequate sperm in the semen in three of these men (9.6%) for use with ART, and varicocele repair did not impact surgical sperm retrieval rates; however, this study was limited by a small sample size.51

SPERM RETRIEVAL/TESTICULAR BIOPSY AT THE TIME OF VARICOCELE REPAIR

The histologic pattern has a significant correlation with the success rate of varicocele repair in patients with NOA and a varicocele.34 Several studies have described the utility of testicular histology as a predictor of sperm appearance in ejaculate after surgery as well as success in ICSI outcomes with retrieved sperm.22,25,29,58,59

Men with primary infertility with NOA and a clinically palpable varicocele should be subjected to physical, hormonal, and genetic evaluation (Y-chromosome microdeletions and karyotyping). After completion of this evaluation, the patient may be offered a testicular biopsy first. If the biopsy reveals hypospermatogenesis or late maturation arrest at the spermatid stage, varicocele repair can be recommended. Since patients with Sertoli cell-only22,25,29,58,59 or early maturation arrest22,29 histopathological patterns have very low chances of regaining the appearance of spermatozoa in the ejaculate following varicocele repair, they should be counseled cautiously despite data suggesting some men with Sertoli cell-only pattern may improve their histopathological status with varicocele repair.57

Men with NOA who have additional symptoms due to varicoceles or those whose testis size, consistency, and hormonal profile are not consistent with Sertoli cell-only pattern histopathology, may undergo varicocele repair and testicular biopsy simultaneously, both through a single subinguinal incision. The biopsy would then help with further prognosis.

In one meta-analysis, the overall appearance of sperm in ejaculate after varicocele repair was 30%;34 therefore, a majority of patients with NOA and a clinical varicocele will need surgical sperm retrieval for ART. It is, therefore, recommended that retrieval of testicular sperm alongside with diagnostic testicular biopsy and cryopreservation of testicular tissue be performed in one setting to avoid exposing such men to several surgical procedures.

COUNSELING THE COUPLE ON ODDS OF PREGNANCY FOLLOWING VARICOCELE REPAIR IN NOA MEN

A meta-analysis estimated that the overall appearance of spermatozoa in the ejaculate following varicocele repair was 34%, when men with NOA with all patterns of testicular histopathology (hypospermatogenesis, maturation arrest, and Sertoli cell-only pattern) were included. When excluding men with Sertoli cell-only pattern, the overall rate of having sperm return to the ejaculate following varicocele repair was 54%.34 The recovery of spermatogenesis after varicocele surgery in NOA cases offers the benefits of avoiding sperm retrieval for ART in a proportion of patients. Live birth with ejaculated sperm after varicocele repair has been reported in three studies.21,54,60 In the meta-analysis by Elzanaty,34 13.6% of couples achieved a spontaneous pregnancy after having sperm return to the ejaculate following varicocele repair.

Studies have reported improvement in clinical pregnancy rates and live birth rates in ART cycles using retrieved testicular sperm after varicocele repair. Inci et al.53 reported that clinical pregnancy rates (31.4% vs 22.4%) and live birth rates (25.7% vs 22.2%) were not statistically different in treated and untreated patients.53 In contrast, both clinical pregnancy rates (74.4% vs 52.3%; P = 0.03) and live birth rates (64.5% vs 41.5%; P = 0.02) were significantly higher in the varicocele-treated group in the series by Haydardedeoglu et al.52 Varicocele repair may increase the subsequent chances of surgical sperm retrieval. Inci et al.53 reported an SRR of 53% in treated patients compared with 30% in untreated patients (odds ratio [OR]: 2.63; 95% confidence interval [CI]: 1.05–6.60; P = 0.036).

PROFESSIONAL GUIDELINE STATEMENTS ON VARICOCELES IN MEN WITH NOA

As per the American Urological Association/American Society for Reproductive Medicine (AUA/ASRM) guideline statement regarding men with NOA and a varicocele, “the couple should be informed of the absence of definitive evidence supporting varicocele repair before assisted reproductive technology.61” The European Association of Urology (EAU) guidelines state that in men with NOA and a varicocele, varicocele repair may allow for the return of sperm to the ejaculate in 20.8%–55% of these men. They also state that varicocele repair is associated with improved surgical sperm retrieval rate in cases where sperm does not return to the ejaculate. The EA statement does caution, however, these data are from observational studies and recommends discussing the risks and benefits of varicocele repair with a man with a clinically palpable varicocele and NOA.62 Yan et al.63 suggest that guidelines should be revised to recommend varicocele repair in men with NOA based on the current level of data available in the medical literature.

EXPERTS’ OPINION ON VARICOCELE REPAIR IN MEN WITH NOA

The data on varicocele repair in men with NOA are controversial and limited. Varicocele repair in men with NOA should only be considered if there is a large, clinically palpable varicocele. Therefore, a man without a detectable varicocele on physical examination should not have an ultrasound obtained for the purpose of trying to identify a varicocele. The clinician and the patient should discuss the risks and benefits for shared decision-making. If sperm returns to the ejaculate after varicocele repair, cryopreservation should be considered as there may be a relapse to azoospermia.29 An option is to perform a diagnostic needle biopsy for histopathology, and for cryopreservation if sperm are present. The resultant histopathology from the biopsy may guide a recommendation for varicocele repair in cases with more favorable cellular patterns (Figure 1). If varicocele repair is pursued without a preoperative diagnostic biopsy, a biopsy may be considered at the time of varicocele repair to establish a histopathologic diagnosis, and if sperm are present, they can be cryopreserved at that time. Demonstrated by the survey by Shah et al.64 controversy still remains about varicocele repair in men with NOA. Fifteen percent of respondents in that study reported they never recommend varicocele repair in men with NOA, and 35% reported advising varicocele repair in less than 10% of their patients with NOA. At present, shared decision-making between the physician and patient is recommended due to the lack of well-controlled studies in this patient population.

Figure 1.

Suggested diagnostic and treatment algorithm for men with nonobstructive azoospermia and a clinical varicocele. FSH: follicle-stimulating hormone; LH: luteinizing hormone; NOA: nonobstructive azoospermia; micro-TESE: microdissection testicular sperm extraction; ICSI: intracytoplasmic sperm injection.

CONCLUSIONS

As 1% of men presenting for primary infertility evaluations will be found to be azoospermia and 40% will be found to have palpable varicoceles, the combination of azoospermia with a clinical varicocele is fairly common in reproductive practices, though this may be causal or coincidental. It is important to discuss options for these men and couples based on the level of data currently available. After a complete reproductive evaluation has been performed ruling out other etiologies of azoospermia, a discussion regarding varicocele repair as an option as the next step is appropriate. Counseling should include a discussion of the potential to improve spermatogenesis to reestablish sperm in the ejaculate. Counseling should also include the possibility to optimize surgical sperm retrieval and pregnancy outcomes in those who remain azoospermic following varicocele repair and require subsequent sperm retrieval. Consideration of the female partner’s ovarian reserve status should be included in the shared decision-making the relevance of time in mind.

AUTHOR CONTRIBUTIONS

PKK carried out the study design, literature search, and manuscript writing. CG carried out the literature search and manuscript writing. RS carried out the critical review and revision. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.