The kisspeptin analog C6 reverses reproductive dysfunction in a mouse model of hyperprolactinemia

Kisspeptin has been shown to be tightly associated with hyperprolactinemia. This study shows that similar to kisspeptin, its analog C6 produces a reversal of HPRL estrus cycle and ovulation disruption.

HPRL, characterized by elevated prolactin levels, disrupts the hypothalamic-pituitary-gonadal axis, leading to reproductive dysfunctions such as menstrual irregularities, anovulation and infertility. Current treatments rely on dopamine agonists but are limited by side effects and resistance. Kisspeptin (Kp), a key neuropeptide regulating the reproductive function, offers potential as an alternative therapy. However, Kp's short half-life requires impractical administration regimens. To address this, we developed a synthetic Kp analog, C6, with enhanced pharmacokinetics. This study evaluated the effects of C6 compared to Kp in a mouse model of HPRL. Mice received subcutaneous PRL injections for 21 days to induce HPRL, followed by daily or alternate-day intraperitoneal administration of Kp10, C6 or vehicle. Estrous cyclicity, luteinizing hormone (LH) secretion, ovarian histology and hypothalamic gene expression were analyzed. As expected, the HPRL treatment blocked estrous activity, which was restored by both Kp10, the shortest bioactive isoform of Kp, and C6. Histological analysis revealed increased corpora lutea in Kp10- and C6-treated groups, indicating restored ovulation. C6 demonstrated equivalent efficacy to Kp10 in mitigating HPRL-induced reproductive dysfunctions, offering a promising alternative therapy. Future investigations should further explore the mechanistic advantages of C6, particularly its role in LH regulation, to optimize treatment strategies for HPRL-related reproductive disorders.