Since the advent of microTESE for NOA due to primary testicular dysfunction, multiple investigators have assessed predictors such as age, testicular volume and FSH levels of various outcomes [7,8,9,10,11,12,13,14,15,16,17,18,19,20]. Most of this research has been focused on only the first step for the couple: retrieving sperm. Although this is a crucial first step to allow for successful pregnancies and live births downstream, to date there has been a paucity of investigation regarding predictors of the intermediate and conclusive steps, such as fertilization with IVF/ICSI, embryology progression to ET, clinical pregnancy, live birth, and having surplus sperm from the retrieval to allow for multiple IVF/ICSI cycles. To our knowledge, the current study is the most comprehensive assessment of the most numerous predictors for multiple milestones for these couples including the most critical, live birth, while accounting for male and female factors. It is also the only study evaluating predictors of surplus sperm cryopreserved for use beyond the initial IVF/ICSI cycle.
All patients in this cohort underwent varicocele repair if a palpable varicocele was present on their physical examination with reassessment of their semen analysis at 3 to 6 months post varicocele repair prior to undergoing microTESE. Men who had return of sperm to the ejaculate following varicocele repair did not undergo microTESE and were not included in this sample. Varicocele repair was recommended for all men with palpable varicoceles prior to microTESE as a number of studies have revealed return of sperm to the ejaculate in men with NOA who underwent varicocele repair [25,26,27,28]. There is data reporting that varicocele repair in men with NOA improves sperm retrieval rates at the time of microTESE and improves IVF/ICSI outcomes; therefore, the clinical protocol was to repair all palpable varicoceles and repeat semen analyses prior to offering microTESE [29,30,31].
Previously published studies on predictors of microTESE outcomes have primarily focused on sperm retrieval as the sole endpoint for success. In 2004, Tsujimura et al. found FSH, testosterone levels, and inhibin B levels to be the most influential predictive factors for sperm retrieval in a retrospective review of 100 men who underwent microTESE for NOA . Ramasamy et al. published a retrospective study revealing that elevated FSH levels did not decrease the sperm retrieval rate with microTESE . A retrospective review by Bernie et al. revealed that there is no individual clinical characteristic that accurately predicts sperm retrieval with microTESE in men with NOA . A retrospective review by Bryson et al. reported that severely atrophic testicles did not impact the sperm retrieval rate in microTESE . Ramasamy et al. performed a retrospective study which showed that age does not adversely impact sperm retrieval rates at the time of microTESE . A retrospective study by Berookhim et al. demonstrated that men with NOA with Sertoli cell only histologic patterns, testicular volumes of ≥15 mL, and FSH between 10 and 15 mU/mL had poor sperm retrieval rates . A meta-analysis in 2018 by Li et al. demonstrated that FSH, testicular volume, and testicular histopathology had limited predictive value for sperm retrieval . The commonality of these previous studies is that the endpoint assessed for predictors was sperm retrieval at the time of microTESE in NOA men. Although sperm retrieval is a critical first step, downstream goals include fertilization, reaching ET, clinical pregnancy, and ultimately live birth for the couple. Surplus sperm beyond an initial IVF/ICSI cycle may be important for the couple as well.
This current study examined predictors for multiple microTESE/IVF/ICSI outcomes and revealed a hypospermatogenesis histology pattern as being significantly associated with several outcomes, including higher rates of sperm retrieval, clinical pregnancy, live birth, and having surplus sperm retrieved for future IVF/ICSI cycles when compared to maturation arrest or Sertoli cell only patterns. After adjusting for age, volume, and FSH levels, men with hypospermatogenesis patterns had 423% higher odds of having sperm retrieved. Those with maturation arrest histology also had substantially higher odds; however, this study was not powered to allow for detection of this odds ratio as significant. After adjusting for testicular volume, FSH, and histology pattern, each additional year of male age resulted in 11% higher odds of reaching ET. FSH levels trended towards significance with a negative relationship to odds of ET, but did not reach statistical significance. Adjusting for age, testicular volume, and FSH levels; those with hypospermatogenesis patterns had 413% higher odds of achieving a clinical pregnancy, 385% higher odds of live birth, and 650% higher odds of having surplus sperm retrieved for multiple IVF/ICSI cycles. FSH levels had a marginally significant negative relationship to retrieving surplus sperm. Although histopathology is not known in order to counsel couples prior to microTESE, it is useful to be able to counsel couples that the other potential predictors of outcomes should not be a deterrent to proceeding with microTESE/IVF/ICSI, even though they may be assumed to be unfavorable by patients and clinicians, they do not predict unfavorable outcomes.
An unexpected finding of this study was that male partner age was a significant predictor of reaching ET with older men having increased odds. This seems counterintuitive as there are data consistent with semen parameters and sperm DNA fragmentation worsening with increased age. However, the median age of the patient cohort in the current study was 35 years of age and only 15% (11/72) of them were in their forties, 2.8% (2/72) were in their fifties, and 2.8% (2/72) were in their sixties. Most of the men were in their twenties and thirties, so although age is a significant predictor, most men were below ages considered to be advanced paternal age which are typically the age ranges associated with poorer fertility outcomes overall. A previous publication revealed that increased age of men at the time of microTESE did not adversely impact sperm retrieval rates .
A limitation of this study is the sample size, although the statistical methodology utilized was appropriate for the size of the data set. The size of the sample is unique as NOA is present in only 1 % of men in the population. It would, therefore, be quite challenging for a single practicing reproductive urologist to accrue a larger sample of men undergoing microTESE, which would allow for more statistical power. Multi-site collaborations may be important to study this problem further in the future. An additional challenge to the power of the current study is that not all couples with NOA elect to undergo this level of treatment, technology, and expense.
A major strength and the novelty of this study is that all fertility diagnostic categories were included, making it the most comprehensive assessment of the predictors for multiple embryologic and clinical outcomes for these couples, including the most critical outcome, live birth, while accounting for male and female factors. It is also the only study evaluating predictors of surplus sperm cryopreserved for use beyond the initial IVF/ICSI cycle. The rate-limiting factor in the majority of these cases was NOA, based on overall female partner age, and there being no significant difference in mean female partner age between those for whom their cycles resulted in live birth versus those that did not. There was also only a small percentage of female partners in this cohort who were diagnosed with DOR, two of whom underwent donor oocyte cycles excluding oocyte quality as a variable in their outcomes.