Introduction: Clomiphene citrate (CC) is a selective estrogen receptor modulator (SERM). Empirical off-label use of CC in men with infertility has existed for almost 50 years, yet there is not enough evidence to support its use in non-obstructive azoospermia (NOA) patients. This study aims to evaluate the efficacy of CC in sperm production in NOA, and determine the predictors for success. Methods: A prospective study was conducted on patients who presented with idiopathic NOA from 2015-2022. Patients were evaluated with history, physical examination, karyotyping, scrotal ultrasound, semen and hormonal assessment pre and at least 3 months post treatment. Patients were treated with CC. Patients with abnormal karyotype, positive Y micro-deletion or history of testosterone use were excluded. Patients with cryptospermia were included but analyzed separately. Differences in pre-treatment characteristics by response status were evaluated using Mann-Whitney U tests. ROC analysis was conducted to select the optimal cut-offs for predicting response. 60 patients met the inclusion criteria; 48 azoospermic patients (group A), 12 cryptospmic patients (group B). Response is defined as presence of any sperm in the ejaculate for (group A) and as sperm concentration =10000 sperm/ml for (group B). Results: 8/48 (16.6%) in group A had sperm in the ejaculate with CC (concentration mean 0.51 x106/mL: sd 0.77 x106 /mL: range 0.02 – 2.14). 8/12 (66.6%) in group B had =10000 sperm/mL (mean 1.4 x106 /mL: sd 1.83 x106/mL: range 0.1-5.90). Of the 8 responders in group A: 3 responded within 3 months, 3 responded at 3-6 months 2 responded at 6-9 months. Median time to response was 3.6 months (IQR: 2.8-6.0, range: 0.7-6.8 months). Among all pre-treatment factors analyzed, only testosterone level trended towards statistical significance (p-value: 0.08). The optimal cut-off levels are shown in table1. Conclusions: Approximately 1 in 6 patients with idiopathic NOA treated with CC showed sperm in the ejaculate. Those patients could potentially avoid surgical sperm extraction for in vitro fertilization (IVF). Pre-treatment hormonal levels seem to be the best indicator for response with the optimal levels shown in this study. The duration of response may vary where some patients require more than 3-6 months of treatment. Future studies should focus on the success of IVF results in men with NOA on CC. SOURCE OF Funding: none
