Erectile dysfunction (ED) frequently occurs in men with prolactin-secreting pituitary tumors (prolactinomas), even when serum testosterone levels remain normal. The precise mechanisms responsible for this phenomenon are poorly understood. We aimed to explore whether elevated prolactin directly impairs erectile function independently of testosterone, and to identify the underlying molecular pathways involved. Clinical data analysis showed that elevated prolactin levels negatively correlated with erectile function in men with pituitary tumors who maintained normal testosterone levels. Using a prolactinoma rat model induced by diethylstilbestrol, we confirmed that hyperprolactinemia resulted in ED without altering testosterone. Bromocriptine, a dopamine agonist, effectively reduced prolactin levels, restored erectile function, and improved penile endothelial nitric oxide synthase (eNOS) expression without affecting testosterone. Mechanistically, hyperprolactinemia significantly inhibited the phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt)-eNOS signaling pathway in penile tissue. Consistent with animal studies, cultured rat corpus cavernosum endothelial cells exposed to prolactin displayed reduced eNOS expression. Our findings demonstrate that prolactin directly impairs erectile function by suppressing the PI3K-Akt-eNOS pathway independently of testosterone, suggesting new therapeutic targets for treating ED in patients with prolactinoma. Patients with prolactinoma accompanied by normal testosterone levels should be evaluated for erectile dysfunction.
Keywords: Dopamine agonist; Endothelial dysfunction; Erectile dysfunction; Prolactin; Prolactinoma; Testosterone.
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