Introduction: Hormonal stimulation therapy is commonly administered to men with azoospermia prior to sperm retrieval. Controversy exists regarding the potential benefits and risks of preoperative hormonal therapy. 

Methods: We conducted a systematic review of randomized controlled trials and non-randomized studies that compared hormonal stimulation to none among adult men with azoospermia undergoing sperm retrieval. We searched MEDLINE, EMBASE, CENTRAL, and LILACS databases from inception to June 2021. We performed a pairwise meta-analysis with a random-effects model to calculate a risk ratio (RR) for binary outcomes, including sperm retrieval, pregnancy, and live births. We used the ROBINS-I tool to assess the risk of bias of non-randomized studies and assessed the certainty of evidence using GRADE.

Results: Eighteen non-randomized studies included 1868 azoospermic patients undergoing hormonal stimulation therapy compared to 2428 patients with none prior to sperm retrieval. Gonadotrophins were commonly used, followed by aromatase inhibitors and clomiphene. There is low certainty evidence for a slight increase in sperm retrieval with hormone therapy (RR 1.10, 95% confidence interval [CI] 0.90–1.34), and little to no effect in clinical pregnancy (RR 1.09, 95% CI 0.80–1.50). Few studies measured live births, resulting in very low certainty evidence for a reduction in live births with hormonal therapy (RR 0.86, 95% CI 0.65–1.13). Side effects were measured in three studies: two reported none and one reported similar numbers in each group. Studies did not measure other important outcomes, such as quality of life or mental health. 

Conclusions: The evidence suggests there may be a slight increase in sperm retrieval but little to no effect on pregnancy when providing hormonal stimulation to men with azoospermia prior to sperm retrieval. In addition, the effect on live births is uncertain. Future randomized controlled trials could strengthen the current evidence base.