Non-obstructive azoospermia (NOA) represents the most severe form of male infertility. Hypogonadism is common in NOA patients, and normal testosterone (T) levels are considered essential for spermatogenesis. Fertility-preserving hormonal therapy (FpHT) has been proposed to optimize hormonal milieu and improve sperm retrieval rates (SRR) at microdissection testicular sperm extraction (mTESE), although evidence remains controversial and meta-analyses have not shown consistent benefit.
To determine whether FpHT improves SRR in hypogonadal men with NOA undergoing mTESE.
We retrospectively evaluated 1256 selected men with NOA (601 Klinefelter syndrome [KS], 655 normal karyotype) from a cohort of 3086 men who underwent mTESE at our tertiary andrology center between 2010 and 2024. Patients with obstructive azoospermia, prior gonadotoxic exposure, or hypogonadotropic hypogonadism were excluded. All participants underwent comprehensive clinical, hormonal, and genetic assessment. Comparisons were performed between eugonadal and hypogonadal patients, and within the hypogonadal group, between those who received FpHT and those who did not.
Hypogonadism was present in 49.9% of patients, predominantly in KS (p < 0.001). FpHT significantly increased serum T levels in both groups (ΔT +3.1 nmol/L in KS; +5.6 nmol/L in 46, XY; p < 0.001). However, despite biochemical normalization, FpHT did not improve SRR in either karyotypic group (overall SRR: 32.4%). Multivariate analysis identified younger age as the sole independent predictor of successful retrieval in KS (p = 0.011).
FpHT restores serum androgen levels but does not improve spermatogenic activity or sperm retrieval rates in men with NOA. These findings support current EAU guidelines and indicate that FpHT should be used to treat symptomatic hypogonadism rather than to enhance fertility outcomes before mTESE.
Andrology. 2026 Jun 25 [Epub ahead of print]
Mattia Anfosso, Maria Schubert, Jann-Frederik Cremers, Sabine Kliesch, Michael Zitzmann, Simone Bier
Department of Andrology, Centre of Reproductive Medicine and Andrology (CeRA), University Hospital of Münster, Münster, Germany.