The local regulation of testicular steroidogenesis is essential for male fertility but remains incompletely understood. Here, we identify the testis-enriched protein CCDC117 as a critical, local brake on testicular testosterone production. Ccdc117 knockout mice exhibited a paradoxical phenotype: significant reduced testis size (∼21% reduction in weight) accompanied by diminished seminiferous tubule area, yet displaying fully preserved sperm production and near-normal fertility. Mechanistically, loss of CCDC117 triggers a cell-autonomous, compensatory upregulation of the steroidogenic pathway specifically in Leydig cells, leading to a two-fold increase in serum testosterone without a rise in LH. Consistently, intratesticular testosterone levels were significantly elevated (approximately 1.5-fold), directly confirming enhanced local androgen production. This gonadotropin-independent hyperandrogenemia likely supports the maintenance of normal spermatogenic cell numbers within the compromised tubules, facilitating higher-efficiency spermatogenesis that ultimately preserves male fertility in the context of a smaller testis. Collectively, these findings demonstrate that CCDC117 deficiency releases a constitutive brake on Leydig cell steroidogenesis. The resulting compensatory hyperandrogenemia maintains reproductive function under structural compromise, thus uncovering a previously unrecognized local mechanism that ensures reproductive resilience.
Zang et al. (2026) studied this question.