Sperm Retrieval Rates in Non-obstructive Azoospermic Men Subjected to Gonadotropin Therapy

Study Overview
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Brief Summary
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Azoospermia is defined as the complete absence of spermatozoa in the ejaculate. Two-thirds of azoospermic patients have non-obstructive azoospermia (NOA); the latter comprises up to 10% of infertile men overall. NOA is an untreatable testicular disorder associated with spermatogenic failure and is the most severe male infertility phenotype. Among the available surgical sperm retrieval techniques, microdissection testicular sperm extraction (micro-TESE) is the procedure of choice due to its high sperm retrieval success rates (SRR), minimal tissue extraction, and low complication rates. Even with the use of micro-TESE, the likelihood of retrieving sperm in patients with NOA remain suboptimal (40% to 60%). Hypogonadism is detected in approximately half of the patients with NOA. Given the role of intratesticular testosterone (ITT) levels for spermatogenesis, some studies have explored the clinical utility of testosterone optimization by medical therapy before sperm retrieval. Moreover, some investigators have hypothesized that the follicle-stimulating hormone (FSH) reset might increase the expression of FSH receptors and improve Sertoli cell function. Hormonal therapy with human chorionic gonadotropin (hCG) has been shown to improve ITT production and decrease FSH levels in patients with NOA. The investigators, therefore, designed an observational cohort study aiming to evaluate whether hormone stimulation with gonadotropins (e.g., hCG alone or combined with FSH) previous to micro-TESE increases sperm retrieval rates in hypogonadal infertile men with NOA, candidates for sperm retrieval. The investigators hypothesize that optimizing ITT production and resetting FSH levels may improve spermatogenesis and successful sperm recovery.

Detailed Description
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A single-center cohort study was conducted based on prospectively collected data inputted in an electronic medical record database, subsequently extracted and analyzed. The diagnosis of NOA was based on medical history, physical examination, semen analysis, reproductive hormone measurements, genetic and imaging studies, and confirmed by histopathology. Hypogonadism was defined based on total testosterone levels equal to or below 350 ng/dL, measured on a peripheric blood specimen taken in the morning (8:00 to 10:00 am). Sample size calculation: Based on existing evidence concerning SRR in patients subjected to micro-TESE with and without medical treatment to boost testosterone production, the investigators estimated a sample size of 464 participants (232 per group) to have an 80% chance of detecting, as significant at the 5% level, an increase in the primary outcome measure from 41% in the control group to 55% in the experimental group. Statistical Analysis: Demographic data will include patient age, BMI, infertility cause, testicular volume, reproductive hormone levels, histopathology findings, infertility duration, presence of clinical varicocele, and history of varicocele repair. Treatment variables will include type, dose, and duration of gonadotropin administration, change in reproductive hormone levels pre- vs. post-treatment, and sperm retrieval outcomes. Continuous data will be presented as median and 25-75% interquartile range. Categorical data will be described by the number of cases and percentages. As appropriate, categorical and continuous data will be analyzed using the Pearson Chi-square and Kruskal-Wallis or Wilcoxon test. Logistic regression analyses will be conducted to examine the association between demographic and treatment covariates and the binary response 'sperm retrieval success' (yes/no). Computations will be carried out using JMP® PRO 13 and SAS 9.3 (SAS Institute, Cary, North Carolina, USA).

Official Title
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Sperm Retrieval Rates by Microdissection Testicular Sperm Extraction in Non-obstructive Azoospermic Men Subjected to Gonadotropin Therapy

Conditions
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Non-obstructive Azoospermia, Hormone Deficiency, Hypogonadism, Male, Male Infertility

Intervention / Treatment
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* Drug: Hormonal Therapy Agent


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consecutive NOA patients with a baseline total testosterone level equal to or below 350 ng/dL who had a sperm retrieval procedure by microdissection testicular sperm extraction (micro-TESE) during the study period. Only patients with histopathology-confirmed NOA, absence of Y-chromosome microdeletion in the azoospermia factor 'a' (AZFa) and/or azoospermia factor 'b' (AZFB) region, and with a complete data record for analysis of primary and secondary outcomes were included. Exclusion Criteria: Patients subjected to sperm retrieval using percutaneous or non-microsurgical testicular biopsies and those with a history of a previous sperm retrieval attempt. Patients who had used any medication with known potential gonadotoxic effects six months before enrollment and patients under gonadotropin treatment who lost follow-up. Patients with NOA due to hypogonadotropic hypogonadism. Patients who had any number of sperm detected in the ejaculate by routine semen analysis with centrifugation before micro-TESE, including the analysis carried out on the surgery day. The latter relates to the fact that our study is designed to include only patients with NOA confirmed by histopathology, from a specimen obtained during micro-TESE. NOA patients with baseline total testosterone levels above 350 ng/dL.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| NOA_Treated<br>Hypogonadal patients with non-obstructive azoospermia who received gonadotropin therapy before sperm retrieval | Drug: Hormonal Therapy Agent<br>* Consecutive patients with NOA and hypogonadism (defined by baseline total testosterone levels equal or below 350 ng/dL) subjected to microdissection testicular sperm extraction who received or not pre-sperm retrieval gonadotropin therapy.<br>* Other names: recombinant FSH;|
| NOA_Untreated<br>Hypogonadal patients with non-obstructive azoospermia who did not receive gonadotropin therapy before sperm retrieval | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sperm retrieval rates | Sperm retrieval success rates by micro-TESE in men with non-obstructive azoospermia subjected or not to pre-operative hormonal stimulation | At least 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sperm retrieval rates according to hypogonadism status | Sperm retrieval success rates by micro-TESE in men with non-obstructive azoospermia subjected or not to pre-operative hormonal stimulation, according to hypogonadism categories based on baseline total testosterone levels | At least 3 months | 
| Sperm retrieval rates according to histopathology findings | Sperm retrieval success rates by micro-TESE in men with non-obstructive azoospermia subjected or not to pre-operative hormonal stimulation, according to testis biopsy histopathology findings | At least 3 months | 
| Predictive factors for sperm retrieval success | Assessment of independent co-variables affecting the binary response sperm retrieval (yes/no) | At least 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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microdissection testicular sperm extraction, human chorionic gonadotropin, sperm retrieval rates, follicle-stimulating hormone, azoospermia, spermatogenic failure