Polycystic ovary syndrome (PCOS) represents a significant health concern for women of reproductive age, manifesting as a complex endocrine disorder with diverse clinical presentations. Characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology, PCOS affects 5% to 20% of women and stands as a leading cause of anovulatory infertility. The pathophysiology of PCOS involves abnormal folliculogenesis, resulting in arrested follicular development and the accumulation of small antral follicles. This follicular arrest is accompanied by mitochondrial dysfunction and oxidative stress, contributing to poor oocyte quality and developmental potential. Recent research has highlighted the potential role of neurotensin (NTS), a gut-brain peptide, in the regulation of ovulation and its dysfunction in PCOS.
NTS, a 13-amino-acid peptide, is primarily involved in thermoregulation, food intake regulation, and pain modulation. It exerts its biological effects primarily through the neurotensin receptor 1 (NTSR1), a G protein-coupled receptor. NTS has been implicated in various physiological processes, including the regulation of ovulation, where it acts as a paracrine mediator. Previous studies have shown that NTS expression increases in ovarian granulosa cells following gonadotropin stimulation, suggesting its importance in the ovulatory process. However, the specific role of NTS and its receptor in PCOS-related ovulatory dysfunction remains unclear.
This study investigates the expression and functional role of NTS in PCOS, utilizing both clinical samples and animal models. The researchers found significantly reduced NTS levels in ovarian granulosa cells and follicular fluid from PCOS patients compared to controls. This decrease in NTS expression was correlated with elevated levels of androgens and other hormonal markers characteristic of PCOS. The study further explored the temporal expression pattern of NTS during ovulation using a mouse superovulation model, demonstrating that NTS expression peaks 6 hours after human chorionic gonadotropin (hCG) administration and returns to baseline levels within 12 hours. This ovulation-dependent expression pattern suggests a critical role for NTS in the coordination of follicular maturation and ovulation.
To elucidate the functional significance of NTS in ovulation, the researchers employed the NTSR1-specific antagonist SR48692 in both in vitro and in vivo settings. Treatment with SR48692 dose-dependently inhibited cumulus expansion and oocyte maturation, key processes in ovulation. This inhibition was associated with disrupted metabolic cooperation between oocytes and cumulus cells, as evidenced by altered expression of genes involved in oxidative phosphorylation, glycolysis, and amino acid metabolism. The antagonist treatment led to mitochondrial dysfunction, increased reactive oxygen species (ROS) production, and decreased adenosine triphosphate (ATP) levels in oocytes and cumulus-oocyte complexes, mirroring the metabolic disturbances observed in PCOS.
The study identified early growth response 1 (EGR1) as a critical downstream mediator of NTS signaling in ovulation. EGR1 expression was significantly reduced in SR48692-treated cells and was found to be essential for oocyte maturation. The ERK1/2 pathway, known to activate EGR1, was inhibited by SR48692 treatment, both in vitro and in vivo. This inhibition of the NTSR1/ERK/EGR1 axis was associated with ovulatory dysfunction, including reduced follicular rupture and oocyte retrieval in mouse models.
In a PCOS-like mouse model induced by dehydroepiandrosterone (DHEA), NTS administration partially ameliorated ovarian abnormalities. NTS treatment improved estrous cyclicity, reduced the number of cystic follicles, and partially restored normal follicular development. These findings suggest that NTS supplementation may offer therapeutic potential for improving ovulatory function in PCOS.
The research provides comprehensive evidence that decreased NTS expression contributes to ovulatory dysfunction in PCOS through the NTSR1/ERK/EGR1 signaling pathway. The study's multi-faceted approach, combining clinical observations, animal models, and molecular mechanistic investigations, strengthens the conclusions about NTS's role in ovulation and its dysfunction in PCOS. Future research directions may include further exploration of NTS receptor subtypes, validation in primate models, and clinical trials to assess the therapeutic potential of NTS-based interventions for PCOS-related infertility.
DOI: 10.1007/s11684-024-1089-z