Kisspeptin and early pregnancy: Insights from animal models into hormonal regulation and miscarriage

Miscarriage, defined as spontaneous pregnancy loss before 20 weeks of gestation, affects 10-15% of pregnancies in women under 30, rising to over 50% in women over 45. Implantation failure and early placental dysfunction are major contributors, yet the precise mechanisms remain incompletely understood. Kisspeptin, encoded by KISS1, is a critical regulator of the reproductive axis and is highly expressed in the placenta, where it modulates trophoblast proliferation, migration, invasion, and vascular remodelling. Human studies indicate that reduced placental kisspeptin is associated with recurrent pregnancy loss, while circulating kisspeptin levels increase dramatically throughout gestation and may serve as a biomarker for pregnancy viability. Mouse models, including CBA/J × DBA/2 matings and Kiss1/Kiss1r knockout lines, have provided mechanistic insights, showing that loss of kisspeptin signalling impairs decidualization, trophoblast invasion, and embryo implantation. These studies also highlight kisspeptin's role in modulating maternal immune responses and in coordinating hormonal cues, including progesterone, oestrogen, and prolactin, necessary for uterine receptivity. Despite shared features of placentation signal and endocrine regulation, significant species-specific differences exist (e.g. mice lack hCG, exhibit embryo-dependent decidualization, have less invasive trophoblasts) limiting direct extrapolation to human pregnancy. This review synthesizes current evidence on kisspeptin's paracrine and endocrine roles during early gestation, emphasizing the insights gained from murine models while highlighting the translational challenges in applying these findings to human miscarriage research.