Altered Endothelin Receptor Expression in Idiopathic Male Infertility: A Potential Therapeutic Target.

Objective: Idiopathic male infertility is frequently associated with impaired semen quality, particularly in men diagnosed with oligo-astheno-teratozoospermia (OAT) syn- drome. Recent studies suggest a potential role of the endothelin (ET) system, particu- larly ET receptors A (ETAR) and B (ETBR), in male reproductive physiology. Moreover, antiestrogens such as tamoxifen and clomiphene, which are commonly used empiri- cally in this context, may influence ET signaling pathways. However, the relationship between ET receptor expression and specific subtypes of male infertility remains poorly understood. Methods: Semen samples were collected from 56 men: 15 fertile controls with normo- zoospermia and 41 infertile men with abnormal semen parameters, including 22 with OAT syndrome and 19 with isolated teratozoospermia. Men with identifiable female- factor infertility were excluded. Seminal ETAR and ETBR expression were analyzed using immunofluorescence microscopy, Western blotting, enzyme-linked immunosor- bent assay (ELISA), and flow cytometry. Results: The ETAR expression was significantly reduced in infertile men compared to fertile controls (P < .05). The ETBR was undetectable in all samples from patients with OAT syndrome. Notably, 2 distinct ETAR expression profiles were observed within the OAT group: one subgroup with ETAR levels comparable to controls and another with markedly diminished expression, indicating potential phenotypic heterogeneity within OAT syndrome. Conclusion: Altered ETAR expression and the absence of ETBR in men with idiopathic infertility, particularly those with OAT syndrome, highlight a potential role for ET sig- naling in male reproductive dysfunction. Stratification based on ETAR expression may support individualized therapeutic strategies, including ET-targeted or antiestrogen- based therapies, to improve fertility outcomes in this population.