The endogenous hydrogen sulfide generating system regulates ovulation

Abstract

The generation of free-radicals such as nitric oxide has been implicated in the regulation of ovarian function, including ovulation. Tissues that generate nitric oxide typically generate another free-radical gas, hydrogen sulfide (H₂S), although little is known about the role of H₂S in ovarian function. The hypothesis of this study was that H₂S regulates ovulation. Treatment with luteinizing hormone (LH) increased the levels of mRNA and protein of the H₂S generating enzyme cystathionine γ-lyase (CTH) in granulosa cells of mice and humans in vivo and in vitro. Pharmacological inhibition of H₂S generating enzymes reduced the number of follicles ovulating in mice in vivo and in vitro, and this inhibitory action was reversed by cotreatment with a H₂S donor. Addition of a H₂S donor to cultured mouse granulosa cells increased basal and LH-dependent abundance of mRNA encoding amphiregulin, betacellulin and tumor necrosis alpha induced protein 6, proteins important for cumulus expansion and follicle rupture. Inhibition of CTH activity reduced abundance of mRNA encoding matrix metalloproteinase-2 and -9 and tissue-type plasminogen activator, and cotreatment with the H₂S donor increased the levels of these mRNA above those stimulated by LH alone. We conclude that the H₂S generating system plays an important role in the propagation of the preovulatory cascade and rupture of the follicle at ovulation.

Keywords: Follicle; Granulosa cells; Ovary; Ovulation.