Evidence that Nitric Oxide Is Critical for LH Surge Generation in Female Sheep

Area of Science:

• Neuroendocrinology
• Reproductive Biology
• Sheep Physiology

Background:

• Estradiol (estrogen) induces a surge in gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH), essential for ovulation.
• Neural systems regulating this surge in sheep are complex, with somatostatin (SST) neurons in the ventral medial nucleus (VMN) identified as potential key players.

Purpose of the Study:

• To investigate the role of SST neurons in the ventral lateral region of the VMN (vlVMN) in mediating estradiol's positive feedback on GnRH and LH secretion.
• To determine if these SST neurons co-produce nitric oxide (NO) and if NO signaling is critical for the LH surge.

Main Methods:

• Assessed SST synaptic input onto GnRH and kisspeptin, neurokinin B, dynorphin (KNDy) neurons during different estrous cycle phases.
• Examined co-localization of SST and neuronal nitric oxide synthase (nNOS) in vlVMN neurons.
• Measured c-Fos expression in SST-nNOS neurons during the LH surge.
• Administered a nitric oxide synthase inhibitor (N(G)-nitro-L-arginine methyl ester) via intracerebroventricular infusion to block the estrogen-induced LH surge.

Main Results:

• SST input to GnRH neurons increased during the LH surge.
• Over 80% of SST neurons in the vlVMN co-expressed nNOS.
• c-Fos expression significantly increased in dual-labeled SST-nNOS neurons during the surge.
• Inhibition of nitric oxide synthase completely blocked the estrogen-induced LH surge.

Conclusions:

• SST-nNOS neurons in the vlVMN are a critical source of NO involved in the positive feedback of estradiol.
• These neurons represent a key site mediating the pre-ovulatory LH surge in sheep.