The role(s) of HE4 and other WAP factors for sperm functions and male urogenital diseases.

Abstract

HE4 (human epididymis protein 4) is a secretory glycoprotein with protease inhibitor activity. HE4 is constitutively expressed in the epididymis, testis, prostate, and other male urogenital organs. By its overexpression in the lesion and serum of cancer patients, HE4 is used as a biomarker for patient triage prognosis and recurrent surveillance of gynecologic malignancies. Elevated seminal plasma levels of HE4 have been correlated to oligoasthenozoospermia, and genetic overexpression of HE4 gene in mice led to the development of small testis, Leydig cell hyperplasia, structural anomalies of seminiferous tubules, elevated serum testosterone level, and decreased male fecundity. Since proteases and their endogenous inhibitors are deeply involved in semen liquefaction and sperm maturation/capacitation, motility, acrosomal reaction and fertilization, HE4 and other WAP domain protease inhibitors may participate in the regulation of various sperm functions and male fertility. In addition, increasing data have implicated HE4 and other WAP domain factors such as SLPI in innate immunity and inflammation, and these factors may play a role(s) in male urogenital inflammatory disorders such as epididymitis, testitis and prostatitis. This review summarizes relevant observations from in vitro, in vivo and clinical studies, and analyzes the potential role(s) of HE4 in male infertility and other urogenital diseases. Critical issues concerning HE4 physiopathological functions, mechanisms as well as the current/future research efforts, are raised and discussed.