Endocrine Abstracts

In the last years estrogens have emerged as important regulators in male reproductive function. Spermatogenesis depends on the tight control of germ cell apoptosis and several studies indicated estrogens as playing a role in this process. The stem cell factor (SCF), a membrane-bound cytokine, and its receptor (c-kit), and the Fas ligand (FasL)/Fas receptor (FasR) system are powerful mechanisms controlling germ cell proliferation and apoptosis through the direct membrane communication between germ cell and Sertoli cells (SCs). Also, regucalcin (RGN) a calcium-binding protein related with apoptosis may play a role in the control of germ cell death. Although estrogens are able to regulate the expression of SCF, c-kit, FasL, FasR and RGN in several cell types, its effect on the testicular expression of the aforementioned factors is unknown. Ex vivo cultures of rat seminiferous tubules (SeT) and primary SCs cultures were exposed to physiological (0.1 nM) or supraphysiological (100 nM) doses of 17β-estradiol (E₂) for 24 or 48 h. Also, selective agonists (100 nM) for classical and membrane-associated estrogen receptor (ER) subtypes were used. 100 nM E₂ induced a decrease in c-kit expression while increasing FasR, FasL and RGN levels. E₂ modulation of SCF/c-kit, FasL/FasR and RGN expression underpinned diminished proliferation and augmented apoptosis of germ cells, as indicated by Ki67 fluorescent immunohistochemistry, caspase-3 activity and Bax/Bcl-2 (proapoptotic/antiapoptotic) proteins ratio. Our results demonstrated that a supraphysiological dose of E₂ induces germ cell apoptosis by disrupting the survival/death communication between SCs and germ cells due to unbalanced expression of SCF/c-kit and FasL/FasR. Moreover, the use of ER selective agonists allowed suggesting GPER/GPR30 as the main receptor mediating estrogen-induction of apoptosis. Ultimately, these findings helped to clarify the mechanisms underlying male infertility associated with hyperestrogenism.