Kisspeptin, Neurokinin B and New Players in Reproduction

Waljit S. Dhillo, MD

The survival of our species relies on reproduction. As such understanding how reproduction is controlled is important and could lead to new therapies for patients with reproductive disorders.

Kisspeptin was discovered in 2003 to be a novel crucial regulator of puberty—mutations in its receptor were found to cause a failure of puberty.[1] [2] This was associated with a hormonal profile of hypogonadotropic hypogonadism and we now know that the major action of kisspeptin to stimulate the reproductive axis is via potent stimulation of GnRH secretion. Kisspeptin is known to co-localize with neurokinin B in the hypothalamus. While studies had been conducted into the role on neurokinin B for some years, it was in 2009 when it was shown that patients with mutations in the neurokinin B gene or its receptor also have a failure of puberty and hypogonadotropic hypogonadism[3] that the physiological role of neurokinin B as another important mediator of the reproductive axis was confirmed.

Since these seminal discoveries, there has been huge scientific interest in understanding the biology of the kisspeptin/neurokinin B systems on the control of the reproductive axis in numerous animal models as well as in humans. Indeed in the space of 16 years, there are now more than 2,300 articles published on the topic of kisspeptin alone and numerous reviews of the area have been published.

While much is now understood about how these hormones regulate the reproductive axis, there still remain many unanswered questions. In addition while the initial focus of researchers investigating kisspeptin and neurokinin B was predominantly their actions on the reproductive axis via GnRH, recent evidence has implicated both hormones to have wider roles in human physiology. As such in putting together this series of reviews, the goal for Prof. Legro and I was to engage leading investigators around the world in their field and ask them to review their particular area but also give their own thoughts on what we know and what questions remain unanswered in the field. In addition, we have several reviews which review the non-GnRH aspects of kisspeptin and neurokinin B biology as well as some “new players” in the reproductive arena which seem to have actions which involve the kisspeptin and neurokinin B system. We were also keen that this series was a “state-of-the-art” review of the field and as such had a rapid review process which means that all of the articles published are up to date for the reader. Prof. Legro and I are very grateful to all of the authors who have risen to the challenge and made this Seminar Series surpass our high expectations. We hope readers will enjoy the thoughtful reviews and they will stimulate further work in this area which continues to move at pace. This is a very exciting field which is already beginning to deliver new therapies for patients with reproductive disorders.

• References

• 1 de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 2003; 100 (19) 10972-10976
• 2 Seminara SB, Messager S, Chatzidaki EE. , et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349 (17) 1614-1627
• 3 Topaloglu AK, Reimann F, Guclu M. , et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 2009; 41 (03) 354-358