Type II Gonadotropin-Releasing Hormone Receptor and Gonadtropin-Releasing Hormone - III from Lamprey

Inventors at the University of New Hampshire have cloned GnRH-III and a type II GnRH Receptor from lamprey (an eel-like fish model organism).Lamprey GnRH-III stimulates release of FSH, but not LH, which makes it a useful tool for studying and developing novel GnRH analogs that can modulate the reproductive cycle (and sex hormone synthesis).

Gonadotropin Releasing Hormone (GnRH) analogs are a billion dollar industry, with individual drugs reaching blockbuster status. For example, sales of Lupron Depot® (AbbVie) in 2015 were over $800 million. These analogs are used therapeutically for the treatment of hormone-responsive cancers like prostate cancer, and for uterine diseases like endometriosis. They are also used to regulate conception (primarily for timed ovulation during in vitro fertilization) for humans and livestock.

The GnRH sequence (a ten amino acid peptide) was determined in 1971 and has been the object of continued intense study. Binding of GnRH to its cognate receptors in the pituitary stimulates release of lutenizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn travel through the bloodstream to the gonads, where they stimulate gametogeneis. There are two isoforms of GnRH: GnRH-I is present in the hypothalamus and acts on the pituitary, while GnRH-II is outside the hypothalamus and might not be involved with gonadotropin regulation at all. The two isoforms differ slightly in their amino acid sequence. Over the years, experimental substitutions of each amino acid position has not only helped define the peptide/receptor binding interaction, but also has led to the development of analogs with increased potency and half-life, and are currently high volume drugs. The GnRH-Receptor is a GPCR with two isoforms itself. The Type II form has a highly conserved intracellular tail that is vital for G-protein coupling, while the Type I form is tail-less. The difference between the two could help explain (and modulate) undesirable side effects of GnRH analogs. Existing GnRH analogshave been useful enough to generate billions of dollars in sales, but are far from optimal. As peptides, they are not orally available and need to be injected. Side effects can also be extreme, such as the testosterone and estrogen depleting effects of leuprolide, one of the most popular GnRH agonists.

Dr. Sower has spent her academic lifetime studying endocrinology. She received her Bachelor’s degree in Biology from the University of Utah and her Ph.D. in Fisheries Endocrinology from Oregon State. She has been a Professor in the departments of Biochemistry, and Molecular, Cellular and Biomedical Sciences since her arrival at UNH in 1983 and Director of the Center for Molecular and Comparative Endocrinology since it was founded in 2008. She was named an AAAS Fellow in 2012.