Nitric oxide and the ovary

ABSTRACT Nitric oxide (NO) is synthesized from L-arginine by NO synthase (NOS), an enzyme with three isoforms. Two of them, neuronal and endothelial (nNOS and eNOS, respectively), are constitutive, whereas the third one, iNOS, is inducible. Nitric oxide is effective in mediating multiple biological effects, in part through the activation of soluble guanylate cyclase. Among these effects are smooth muscle cell tone, platelet aggregation and adhesion, cell growth, apoptosis, and neurotransmission. Because these mechanisms are associated with the pathophysiology of several reproductive processes, it has become clear that NO could play a key role in reproduction. Apart from its effects through the modulation of luteinizing hormone releasing hormone release, NO has been proven to act directly at the ovarian level, where it is produced by the vasculature and neurons, as well as by various cell types, including granulosa, theca, and luteal cells. Nitric oxide production is modulated by several hormones (estradiol 17β, luteinizing hormone, follicle-stimulating hormone, and human chorionic gonadotropin) and cytokines that interfere either with eNOS or iNOS expression and activity. Experiments performed with NO donors and/or NO synthase inhibitors have demonstrated that NO decreases apoptosis and inhibits both estradiol 17β and progesterone production by granulosa cells (at least in part via guanylate cyclase). Nitric oxide is possibly involved in follicle growth; it is a potent mitogen in the presence of basic fibroblast growth factor, it increases the receptors for epidermal growth factor on granulosa cells, and it regulates programmed cell death, which is an important part of folliculogenesis. Gonadotropin-stimulated eNOS and iNOS expression, as well as the inhibition of ovulation by NOS inhibitors, suggest that NO participates in the ovulatory process. After ovulation, iNOS is expressed in luteal cells, but its activity diminishes with corpus luteum development. During the luteolysis phase, NO stimulates PGF_2α synthesis while decreasing progesterone secretion. Overall data provide convincing evidence that NO plays a critical role in ovarian physiology with regard to follicle growth, ovulation, and corpus luteum function, but its clinical implications have not yet been clarified.

Implications

This review provides convincing evidence that nitric oxide is involved in all the ovarian functions and plays a crucial role in reproductive processes, even though most studies have been carried out on rats and humans and very little is known about livestock. Fine-tuning of nitric oxide generation seems to be essential for ovarian physiology; however, the precise mechanisms by which it exerts its effects are not clearly understood and need further investigation. Future studies should also be aimed at verifying whether ovarian dysfunctions are associated with an altered nitric oxide production in order to clarify whether these defects can be corrected by nitric oxide.

Key Words: Corpus Luteum, Nitric Oxide, Ovaries, Ovarian Follicles, Ovulation

© 2003, by the American Society of Animal Science. All rights reserved.

J. Anim. Sci. 2003. 81(E. Suppl. 2):E1-E7