Estrogen promotes Leydig cell engulfment by macrophages in male infertility

J Clin Invest. 2014 Jun;124(6):2709-21. doi: 10.1172/JCI59901. Epub 2014 Apr 24.


Male infertility accounts for almost half of infertility cases worldwide. A subset of infertile men exhibit reduced testosterone and enhanced levels of estradiol (E2), though it is unclear how increased E2 promotes deterioration of male fertility. Here, we utilized a transgenic mouse strain that overexpresses human CYP19, which encodes aromatase (AROM+ mice), and mice with knockout of Esr1, encoding estrogen receptor α (ERαKO mice), to analyze interactions between viable Leydig cells (LCs) and testicular macrophages that may lead to male infertility. In AROM+ males, enhanced E2 promoted LC hyperplasia and macrophage activation via ERα signaling. E2 stimulated LCs to produce growth arrest-specific 6 (GAS6), which mediates phagocytosis of apoptotic cells by bridging cells with surface exposed phosphatidylserine (PS) to macrophage receptors, including the tyrosine kinases TYRO3, AXL, and MER. Overproduction of E2 increased apoptosis-independent extrusion of PS on LCs, which in turn promoted engulfment by E2/ERα-activated macrophages that was mediated by AXL-GAS6-PS interaction. We further confirmed E2-dependant engulfment of LCs by real-time 3D imaging. Furthermore, evaluation of molecular markers in the testes of patients with nonobstructive azoospermia (NOA) revealed enhanced expression of CYP19, GAS6, and AXL, which suggests that the AROM+ mouse model reflects human infertility. Together, these results suggest that GAS6 has a potential as a clinical biomarker and therapeutic target for male infertility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Aromatase / genetics
  • Aromatase / metabolism
  • Azoospermia / genetics
  • Azoospermia / metabolism
  • Azoospermia / pathology
  • Biomarkers / metabolism
  • Disease Models, Animal
  • Estradiol / metabolism*
  • Estrogen Receptor alpha / deficiency
  • Estrogen Receptor alpha / genetics
  • Humans
  • Infertility, Male / etiology
  • Infertility, Male / metabolism*
  • Infertility, Male / pathology*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Leydig Cells / metabolism*
  • Leydig Cells / pathology*
  • Macrophages / metabolism*
  • Macrophages / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Middle Aged
  • Models, Biological
  • Phagocytosis
  • Phospholipids / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Testis / metabolism
  • Testis / pathology
  • Young Adult


  • Biomarkers
  • Estrogen Receptor alpha
  • Intercellular Signaling Peptides and Proteins
  • Phospholipids
  • Recombinant Proteins
  • growth arrest-specific protein 6
  • Estradiol
  • Aromatase

Supplementary concepts

  • Azoospermia, Nonobstructive