Nonobstructive azoospermia (NOA) affects 5%-15% of men undergoing infertility evaluation, accounting for nearly 60% of azoospermia cases. Nonobstructive azoospermia can arise from various factors, such as genetic abnormalities, congenital diseases, gonadotoxic exposure, orchitis, and testicular trauma; nevertheless, many cases are idiopathic. Varying degrees of leydig cell insufficiency can coexist with spermatogenic failure in patients with NOA, leading to a reduction in intratesticular testosterone (T) production. Decreased T levels may exacerbate spermatogenesis impairment in the testis of patients with NOA. This is because T levels play a crucial role in spermatogenesis, synergistically interacting with follicle-stimulating hormone (FSH) on sertoli cells to support germ cell development.

For men with NOA seeking fertility, microdissection testicular sperm extraction (micro-TESE) is often recommended for its higher sperm retrieval (SR) rate (SRR) than other methods. However, even with micro-TESE, hypogonadal patients may face lower success rates than eugonadal patients. Although hypogonadism is common among men with NOA, research on factors affecting SR success in this group remains limited. Furthermore, there is little data on the effectiveness of using gonadotropins for hormonal stimulation in hypogonadal men with NOA. This study examined the factors influencing successful micro-TESE in hypogonadal men with NOA using real-world data, particularly focusing on the impact of pre-SR hormonal stimulation with gonadotropins.
A total of 616 consecutive patients with NOA and hypogonadism (total testosterone [T] levels<350 ng/dL) underwent micro-TESE between 2014 and 2021. All patients had no prior sperm retrieval (SR) history. Patients aged 23–55 years underwent comprehensive clinical, laboratory, and histopathological diagnostic evaluation for NOA and were further categorized into two cohorts on the basis of pre-SR hormonal stimulation.

A multivariable logistic regression analysis explored the associations between patient variables and micro-TESE success, defined as the presence of viable spermatozoa in extracted specimens. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were computed to assess the relationship between SR success and relevant predictors. Sperm retrieval rates were compared between patients receiving or not hormonal stimulation, and logistic regression analysis evaluated the effect of baseline follicle-stimulating hormone levels (i.e., normogonadotropic vs. hypergonadotropic classes) on SR success.
The overall micro-TESE success rate was 56.6%. Baseline follicle-stimulating hormone levels (aOR, 0.97; 95% CI, 0.94–0.99), pre-SR hormonal stimulation (aOR, 2.54; 95% CI, 1.64–3.93), presence of clinical varicocele (aOR, 0.05; 95% CI, 0.01–0.51), history of previous varicocelectomy (aOR, 2.55; 95% CI, 1.26–5.16), and testicular histopathology were independent predictors of SR success. Among hormone-pretreated patients, pre-micro-TESE T levels and delta T (an absolute increase in T levels from baseline) were associated with SR success. A pre-micro-TESE T level of 418.5 ng/dL (area under the curve value: 0.78) and a delta T of 258 ng/dL (area under the value: 0.76) distinguished patients with positive and negative SR outcomes. Subgroup analysis showed that pre-SR hormonal stimulation yielded a greater benefit for normogonadotropic patients than for those who were hypergonadotropic.
In this large cohort of hypogonadal men with NOA undergoing micro-TESE, authors found that lower baseline FSH levels and a history of varicocelectomy were associated with increased odds of successful SR. In contrast, the presence of clinical varicocele decreased these odds. A higher proportion of patients with successful SR exhibited either hypospermatogenesis or MA on testicular histopathology, whereas those with negative SR often exhibited SCO. Hormonal stimulation was associated with increased SRRs, particularly among normogonadotropic patients. The optimal cut-off values for premicro-TESE T and delta T levels, predicting SR success among hormone-pretreated patients, were 418.5 ng/dL and 258 ng/ dL, respectively. Lastly, the micro-TESE complication rate was 1.9%, while 10.3% of hormone-pretreated patients experienced minor side effects.
Study findings underscore the intricate relationship between clinical factors and micro-TESE success in hypogonadal men with NOA, suggesting potential advantages of interventions before SR, notably hormonal stimulation and varicocele repair. Although results offer promising prospects for improving fertility outcomes in this patient cohort, establishing standardized treatment protocols and assessing reproductive outcomes are crucial areas for further research. Health care providers contemplating interventions before SR must engage in thorough discussions with patients regarding the limited evidence, associated risks, and costs to ensure informed decision-making.
Source: Sandro C. Esteves, M.D., Ph.D.,a,b Arnold P. P. Achermann, M.D.,a,c Ricardo Miyaoka; Fertil Steril® Vol. 122, No. 4, October 2024 https://doi.org/10.1016/j.fertnstert.2024.06.013