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.

Cite this article as: Weiten R, Brandenstein M, Huerta M, et al. Altered endothelin receptor expression in idiopathic male infertility: A potential therapeutic target. Urol Res Pract. 2025;51(1):27-32.