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Current and future applications of GnRH, kisspeptin and neurokinin B analogues

Nature Reviews Endocrinology volume 9, pages 451–466 (2013)Cite this article

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Abstract

Reproductive hormones affect all stages of life from gamete production, fertilization, fetal development and parturition, neonatal development and puberty through to adulthood and senescence. The reproductive hormone cascade has, therefore, been the target for the development of numerous drugs that modulate its activity at many levels. As the central regulator of the cascade, gonadotropin-releasing hormone (GnRH) agonists and antagonists have found extensive applications in treating a wide range of hormone-dependent diseases, such as precocious puberty, prostate cancer, benign prostatic hyperplasia, endometriosis and uterine fibroids, as well as being an essential component of in vitro fertilization protocols. The neuroendocrine peptides that regulate GnRH neurons, kisspeptin and neurokinin B, have also been identified as therapeutic targets, and novel agonists and antagonists are being developed as modulators of the cascade upstream of GnRH. Here, we review the development and applications of analogues of the major neuroendocrine peptide regulators of the reproductive hormone cascade: GnRH, kisspeptin and neurokinin B.

Key Points

  • The reproductive hormone cascade from the brain to the pituitary, gonads and peripheral tissues provides numerous target points for therapeutic intervention in diseases

  • Hormones in the cascade include the neuropeptides kisspeptin and neurokinin B, which regulate hypothalamic gonadotropin-releasing hormone (GnRH); in turn, GnRH stimulates gonadotropins and downstream sex steroid hormones that affect most tissues

  • Modulation of sex steroid hormone levels in contraception, infertility and hormone-dependent diseases (for example, prostate cancer, endometriosis, uterine fibroids and polycystic ovary syndrome) is achieved through steroid hormone and GnRH analogues

  • Novel, orally active GnRH analogues are providing a new dimension in dose regulation for patients who require partial inhibition of sex steroids

  • Kisspeptin and neurokinin B represent new therapeutic targets; analogues have been developed that herald a new era of subtle regulation of the reproductive hormone cascade

  • The enlarged armamentarium of molecules regulating reproductive hormone levels promises to deliver improved control of reproduction and treatment of diseases that impinge on all stages of the human life span

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Figure 1: The reproductive hormone cascade and therapeutic analogues that target the cascade.
Figure 2: The 3D structure of GnRH.
Figure 3: GnRH agonist and antagonist peptide analogues in clinical practice or in clinical development.
Figure 4: Nonpeptide GnRH antagonists.
Figure 5: Docking of the NMR GnRH structure to the human GnRH-R, in which only the essential elements are shown, to reveal the interactions of GnRH in a folded conformation with the receptor.
Figure 6: Kisspeptin analogues.
Figure 7: Neurokinin B analogues.

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Acknowledgements

The authors acknowledge support from the Medical Research Council (South Africa), the National Research Foundation, the University of Pretoria and the University of Cape Town. C. L. Newton is a Claude Leon Foundation Postdoctoral Research Fellow.

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  1. Department of Zoology and Entomology, Mammal Research Institute, Faculty of Natural and Agricultural Sciences, University of Pretoria, Lynnwood Road, Hatfield, 0028, Pretoria, South Africa

    Robert P. Millar

  2. Institute of Infectious Diseases and Molecular Medicine and Division of Medical Biochemistry, UCT/MRC Receptor Biology Research Unit, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, 7925, Cape Town, South Africa

    Robert P. Millar & Claire L. Newton

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Robert P. Millar declares associations with the following companies: Euroscreen (consultant), Ferring (consultant). Claire L. Newton declares no competing interests.

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Millar, R., Newton, C. Current and future applications of GnRH, kisspeptin and neurokinin B analogues. Nat Rev Endocrinol 9, 451–466 (2013). https://doi.org/10.1038/nrendo.2013.120

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