Sridhar, R.

Abstract Introduction While microdeletions in the azoospermia factor (AZF) regions of the Y chromosome are a well-recognized cause of genetic male infertility, reproductive outcomes and broader health profiles among affected men remain poorly characterized. Objective We explore the distribution of AZF deletion subtypes and evaluate comorbidities and fertility management patterns in this unique population. Methods We performed a multi-institutional retrospective cohort study of men diagnosed with AZF deletions following evaluation by a reproductive urologist and genetic testing. The primary exposure variable was the AZF subtype (AZFa, AZFb, AZFc, or multilocus [e.g., AZFabc]).Clinical data were extracted to assess the presence of comorbidities, including hypertension, diabetes mellitus, hyperlipidemia, liver disease, and cardiac disease. Descriptive statistics were used to characterize the distribution of AZF subtypes, comorbidity profile, and outcomes of sperm retrieval procedures within our cohort. Results Among 40 men with confirmed AZF microdeletions across three academic centers, four patients with SRY translocations were excluded. Of the remaining 36, AZFc was the most common subtype (75%), followed by multilocus (16.6%), AZFa (5.5%), and AZFb (2.7%). The median age was 32.8 years (IQR: 29.2–33.6) and median BMI was 28.6 kg/m2 (IQR: 25.6–32.8). Comorbid conditions were identified in 8% of the cohort, with hyperlipidemia (13.9%), hypertension (11%), and diabetes (11%) most commonly reported. Sperm retrieval was attempted in 31% (n=11) of patients, exclusively among those with AZFc (n=10) andAZFb (n=1) deletions. Microscopic testicular sperm extraction (mTESE) was the predominant technique (91%). Sperm was successfully retrieved in 46% of these cases, all within the AZFc subgroup. Conclusions This study advances limited literature on AZF microdeletions by characterizing systemic health profiles and post-diagnosis infertility management. Our results support a broad phenotype associated with genetic causes of male infertility. In this cohort of men with YCMD, AZFc was the most prevalent subtype. Compared to national estimates for similarly aged men, our findings suggest that men with YCMD may have a distinct comorbidity profile compared to the general population, with an elevated prevalence of metabolic disease. Our findings reinforce male infertility as a heterogeneous condition that may serve as an early marker for broader metabolic disease. In addition, nearly all patients who underwent sperm retrieval were within the AZFc group. Fertility management trends favored mTESE, with moderate success rates in sperm retrieval, particularly among AZFc patients. Our results highlight provider preferences in surgical fertility management in patients withYCMD. Our findings underscore the need for a holistic approach to men with YCMD, addressing both surgical fertility management and systemic health risks. Clear patient counseling on sperm retrieval success rates and early identification of comorbidities may redefine outcomes for this unique population. Our results support a broad phenotype associated with genetic causes of male infertility. Disclosure No

Abstract Introduction Male-factor infertility contributes to a substantial portion of infertility cases. Genetic factors are believed to play an important role, with Y chromosome microdeletions commonly identified among men with azoospermia. Due to the relatively high prevalence of these deletions, genetic testing for Y chromosome microdeletions has become a routine component of the diagnostic workup for infertile men. While deletions in the AZF (Azoospermia Factor) region are known to impair spermatogenesis, the hormonal profile in this population remains poorly characterized. Hormonal evaluation plays a key role in guiding treatment decisions, including the use of empirical medical therapy (EMT). However, there is limited data on hormonal profiles and EMT usage in men with AZF deletions. Objective We aimed to characterize preoperative hormonal profiles and evaluate the use and outcomes of EMT in men with AZF microdeletions undergoing surgical sperm retrieval. Methods We conducted a multi-institutional retrospective cohort study of men with genetically confirmed AZF micro-deletions, including AZFa, AZFb, AZFc, and combined deletions. Data were collected on preoperative serum gonadotropin levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), total testosterone (TT), and semen analysis parameters. Additionally, we evaluated patterns of empirical medical therapy (EMT) prescriptions and outcomes of surgical sperm retrieval. Results 40 men with confirmed Y-chromosomal micro-deletions across three academic centers was identified. Patients with SRY translocations (n=4) were excluded from the study. The final cohort included 27 patients with AZFc deletions (75%), 2 with AZFa (6%), 1 with AZFb (3%), and 6 with multilocus deletions (17%). FSH (reference: >7.6 mIU/mL) was elevated in 23 patients (64%), with a median of 19.6 IU/L (IQR: 14.4–25.8). LH (reference: >9 mIU/mL) was elevated in 8 patients (22%), with a median of 14.9 IU/L (IQR: 13.7–20.1). Overall median TT was 243.5 (7.7-379.7). TT was below the lower limit of normal (<300 ng/dL) in 13 patients (36%), with a median of 184 ng/dL (IQR: 133–233). Most patients were azoospermic on semen analysis (86%, n=31/36). Of the seven men treated with EMT, the majority (6/7, 86%) received clomiphene citrate. While there were differences in initial levels of TT, FSH, and LH for those treated with EMT compared to those without EMT, these were not statistically significant (Table 1). Among the 13 patients who underwent surgical sperm retrieval, 6 (46%) had successful outcomes; however, only one had received EMT. Conclusions Men with AZF deletions exhibit varying degrees of hormonal imbalance and rates of empirical medical therapy (EMT) use. Despite EMT, sperm retrieval outcomes were poor, with only 1 out of 7 EMT-treated patients achieving successful sperm retrieval. While hormonal differences were observed between those who received EMT and those who did not, these differences did not reach statistical significance. This is likely due to the limited sample size inherent to this rare patient population. Our findings underscore the variability in hormonal profiles and the unclear efficacy of EMT in promoting spermatogenesis in men with AZF deletions, highlighting the need for further research to inform standardized management strategies. Disclosure No