A customized long acting formulation of the kisspeptin analog C6 triggers ovulation in anoestrus ewe

The modulation of the kisspeptin system is holding promise to treat human reproductive disorders and manage livestock breeding. The design of analogs has overcome some unfavorable properties of the endogenous ligands. However, for applications requiring a prolongation of drug activity, like ovulation induction in the ewe during the non‐breeding season, additional improvement is required. To this aim we design and tested three formulations containing the kisspeptin analog C6. Two were based on polymeric nanoparticles (NP1 and NP2) and the third on hydrogels composed of a mixture of cyclodextrin polymers and dextran grafted with alkyl side chains (MD/pCD). Only the MD/pCD formulation prolonged C6 activity, as shown by monitoring LH plasma concentration (elevation duration 23.4±6.1, 13.7±4.7, and 12.0±2.4 hours for MD/pCD, NP1 and NP2 respectively). When compared to the free C6 (15 nmol/ewe) the formulated (MD/pCD) doses of 10, 15 and 30 nmol/ewe, but not the 90 nmol/ewe dose, provided a more gradual release of C6 as shown by an attenuated LH release during the first 6 hours post‐treatment. When tested during the non‐breeding season without progestogen priming only the formulated 30 nmol/ewe dose triggered ovulation (50% of ewes). Hence, we showed that a formulation with an adapted action time would improve the efficacy of C6 in inducing ovulation during the non‐breeding season. This result suggests that formulations containing a kisspeptin analog might find applications in the management of livestock reproduction but also point to the possibility of their use for the treatment of some human reproductive pathologies.

DOI : 10.1111/jne.13121