Polycystic ovary syndrome (PCOS) represents a major well being concern for ladies of reproductive age, manifesting as a posh endocrine dysfunction with various medical shows. Characterised by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology, PCOS impacts 5% to twenty% of ladies and stands as a number one reason for anovulatory infertility. The pathophysiology of PCOS includes irregular folliculogenesis, leading to arrested follicular growth and the buildup of small antral follicles. This follicular arrest is accompanied by mitochondrial dysfunction and oxidative stress, contributing to poor oocyte high quality and developmental potential. Current analysis has highlighted the potential position of neurotensin (NTS), a gut-brain peptide, within the regulation of ovulation and its dysfunction in PCOS.
NTS, a 13-amino-acid peptide, is primarily concerned in thermoregulation, meals consumption regulation, and ache modulation. It exerts its organic results primarily via the neurotensin receptor 1 (NTSR1), a G protein-coupled receptor. NTS has been implicated in numerous physiological processes, together with the regulation of ovulation, the place it acts as a paracrine mediator. Earlier research have proven that NTS expression will increase in ovarian granulosa cells following gonadotropin stimulation, suggesting its significance within the ovulatory course of. Nonetheless, the particular position of NTS and its receptor in PCOS-related ovulatory dysfunction stays unclear.
This research investigates the expression and useful position of NTS in PCOS, using each medical samples and animal fashions. The researchers discovered considerably diminished NTS ranges in ovarian granulosa cells and follicular fluid from PCOS sufferers in comparison with controls. This lower in NTS expression was correlated with elevated ranges of androgens and different hormonal markers attribute of PCOS. The research additional explored the temporal expression sample of NTS throughout ovulation utilizing a mouse superovulation mannequin, demonstrating that NTS expression peaks 6 hours after human chorionic gonadotropin (hCG) administration and returns to baseline ranges inside 12 hours. This ovulation-dependent expression sample suggests a vital position for NTS within the coordination of follicular maturation and ovulation.
To elucidate the useful significance of NTS in ovulation, the researchers employed the NTSR1-specific antagonist SR48692 in each in vitro and in vivo settings. Remedy with SR48692 dose-dependently inhibited cumulus growth and oocyte maturation, key processes in ovulation. This inhibition was related to disrupted metabolic cooperation between oocytes and cumulus cells, as evidenced by altered expression of genes concerned in oxidative phosphorylation, glycolysis, and amino acid metabolism. The antagonist therapy led to mitochondrial dysfunction, elevated reactive oxygen species (ROS) manufacturing, and decreased adenosine triphosphate (ATP) ranges in oocytes and cumulus-oocyte complexes, mirroring the metabolic disturbances noticed in PCOS.
The research recognized early development response 1 (EGR1) as a vital downstream mediator of NTS signaling in ovulation. EGR1 expression was considerably diminished in SR48692-treated cells and was discovered to be important for oocyte maturation. The ERK1/2 pathway, identified to activate EGR1, was inhibited by SR48692 therapy, each in vitro and in vivo. This inhibition of the NTSR1/ERK/EGR1 axis was related to ovulatory dysfunction, together with diminished follicular rupture and oocyte retrieval in mouse fashions.
In a PCOS-like mouse mannequin induced by dehydroepiandrosterone (DHEA), NTS administration partially ameliorated ovarian abnormalities. NTS therapy improved estrous cyclicity, diminished the variety of cystic follicles, and partially restored regular follicular growth. These findings recommend that NTS supplementation could provide therapeutic potential for bettering ovulatory perform in PCOS.
The analysis supplies complete proof that decreased NTS expression contributes to ovulatory dysfunction in PCOS via the NTSR1/ERK/EGR1 signaling pathway. The research’s multi-faceted strategy, combining medical observations, animal fashions, and molecular mechanistic investigations, strengthens the conclusions about NTS’s position in ovulation and its dysfunction in PCOS. Future analysis instructions could embody additional exploration of NTS receptor subtypes, validation in primate fashions, and medical trials to evaluate the therapeutic potential of NTS-based interventions for PCOS-related infertility.
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Journal reference:
Wang, D., et al. (2024). Decreased neurotensin induces ovulatory dysfunction by way of the NTSR1/ERK/EGR1 axis in polycystic ovary syndrome. Frontiers of Medication. doi.org/10.1007/s11684-024-1089-z.
