Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a neurohormone secreted by the hypothalamus, which plays an important role in regulating the reproduction of vertebrates. Since the first GnRH was isolated from the brains of pigs and sheep in 1971, there are at least 28 types of GnRH in the GnRH family, among which 15 are from vertebrates and 13 are from invertebrates.

The hypothalamus periodically releases GnRH to control the reproductive axis activity. Under the action of GnRH, the pituitary pulsatile releases gonadotropin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) into the blood. These hormones then induce the gonad to produce a variety of hormones, such as estradiol, progesterone, inhibin, and testosterone, which all play important roles in reproductive regulation.

Gonadotropin-releasing hormone (GnRH) is a key factor on the hypothalamic-pituitary-gonad (HPG) axis of vertebrates, which plays an important role in the development and maturation and reproduction of gonads of vertebrates. Using the zebrafish model, the Institute of Hydrobiology, the Chinese Academy of Sciences has for the first time discovered a new function of GnRH3 neuropeptide and its mechanism of action.

Using gene editing technology, Hu Wei, a researcher at the Institute of Hydrology, constructed a zebrafish model with a GnRH3 mutation, and found that zebrafish with GnRH3 knockout had partial male development, and the proportion of adult males increased significantly. Studies have shown that the number of primordial germ cells (PGCs) in early embryos before the sphere period of GnRH3 mutant zebrafish is not significantly different from that of wild type, but the number of mutant PGCs is significantly lower than that of wild type in subsequent developmental stages. Analysis of the proliferation and migration of zebrafish PGCs revealed that after GnRH3 mutation, PGCs could migrate normally, but their proliferation was significantly affected. Further research revealed that GnRH3 regulates the proliferation of early embryonic zebrafish PGCs through MAPK signaling pathways, and at the same time regulates the expression of genes related to female and male glandular cells in the critical period of zebrafish early sex differentiation, and then further affects zebrafish’s sex differentiation. This is the first time that GnRH3 has been found to play an important role in the proliferation and sex differentiation of PGCs in early zebrafish embryonic development.

This is remarkable and the relevant findings were recently published online in Endocrinology.

Gonadotropin Releasing Hormone Analogs

GnRH agonists and antagonists are both synthetic analogs of the GnRH peptide hormone. Through shutting down the GnRH-mediated release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary, castrate testosterone levels can be achieved. In contrast, GnRH antagonists achieve this effect through direct blockade of the GnRH receptor. Simply put it, GnRH agonists function through their interruption of the normal pulsatile signaling of physiologic GnRH. Persistent elevation of GnRH agonist activity leads to downregulation of the GnRH receptor, thereby causing decreased levels of LH, FSH, and testosterone. 1,2 GnRH agonists often cause an initial surge in LH, FSH, and testosterone before this downregulation occurs. In contrast, GnRH antagonists do not cause this androgen surge. Available GnRH agonists include leuprolide, goserelin, and triptorelin. Available GnRH antagonists include abarelix and degarelix.

Reference:

  1. Ke Feng, Xuefan Cui, Yanlong Song, Binbin Tao, Ji Chen, Jing Wang, Shaojun Liu, Yonghua Sun, Zuoyan Zhu, Vance L Trudeau, Wei Hu.(2019). Gnrh3 regulates PGC proliferation and sex differentiation in developing zebrafish. Endocrinology.
  2. BSBrock R.Baker, BSJahan J.Mohiuddin, MD, MPHRonald C.Chen, Prostate Cancer (Second Edition), Science and Clinical Practice 2016, Pages 387-398.