Role of kisspeptins in the control of the hypothalamic-pituitary-ovarian axis: old dogmas and new challenges

In humans and other mammals, a hallmark of female reproductive function is the capacity to episodically release fertilizable oocytes under the precise control of a cascade of hormonal regulators that interplay in a cyclic manner within the hypothalamic-pituitary-ovarian (HPO) axis. Although the basic elements of this neurohormonal system were disclosed several decades before, a major breakthrough in our understanding of how the HPO axis is controlled during the lifespan came in the first decade of the 21st century, when the reproductive dimension of kisspeptins was disclosed by seminal studies documenting that genetic inactivation of the kisspeptin pathway is linked to central hypogonadism and infertility. Kisspeptins are a family of peptides, encoded by the Kiss1 gene, that operate via the surface receptor, Gpr54 (also called Kiss1r), to regulate virtually all aspects of reproduction in both sexes. The primary site of action of kisspeptins is the hypothalamus, where Kiss1 neurons engage in the precise control of the pulsatile release of GnRH to modulate gonadotropin secretion and, thereby, ovarian function. Nonetheless, additional sites of action of kisspeptins within the HPO axis, including the pituitary and the ovary, have been proposed; yet, the physiologic relevance of such extrahypothalamic actions of kisspeptins is still a matter of debate. In this review, we summarize the current consensus knowledge and open questions on the sites of action, physiologic roles, and eventual therapeutic implications of kisspeptins in the control of the female reproductive axis.