HE4 overexpression in mice leads to leydig cell hyperplasia and spermatogensis impairment: Pathological implications for oligospermia.

Previous studies have shown that HE4 cancer biomarker promoted cancer cell proliferation and tumor growth in mouse xenograft models. Interestingly, HE4 levels are significantly increased in the seminal plasma of oligoasthenospermia patients, raising a question on HE4 role(s) in spermatogenesis. We constructed an HE4 overexpression mouse model (HE4-OE), and observed that HE4-OE male adult mice had small testes, low sperm counts, and elevated serum/testis testosterone levels. These mice exhibited disorganized seminiferous tubules and impaired spermatogenesis. HE4 overexpression concentrated in Leydig cells, and these cells had hyperplasia and increased testosterone biosynthesis. Mechanistic studies indicated that the impaired spermatogenesis was likely caused by a local and direct action of HE4 in the testis rather than by a hypothalamus/pituitary-initiated dysregulation. The new findings reveal a novel HE4 function in male reproductive system, and suggest the existence of a subtype of primary oligoasthenospermia characterized by HE4 overexpression, Leydig cell hyperplasia, and elevated testosterone levels.