Ccdc117 deficiency triggers hyperandrogenemia, maintaining normal sperm production despite reduced testis size.

Local testosterone regulation is critical for male fertility but poorly understood. We show that loss of CCDC117 triggers testosterone elevation despite lower luteinizing hormone levels, revealing a gonadotropin-independent compensatory mechanism that preserves fertility in smaller testes. AbstractThe 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 2-fold increase in serum testosterone without a rise in luteinizing hormone. Consistently, intratesticular testosterone levels were significantly elevated (∼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.