Gonadotropin-releasing hormone: incredible 50 years

It has been almost exactly 50 years since the first description of the structure of gonadotropin-releasing hormone (GnRH). Thanks to the pioneering work of Dr. Andrew Schally and Dr. Roger Guillemin, who shared the 1977 Nobel Prize for their work, we now know that GnRH is comprised of only 10 amino acids, yet serves as the conductor of the reproductive system, responsible for all its actions and, arguably, for life itself (1, 2).

The path from the original discovery of the native molecule to the synthesis of its agonists and antagonists moved along relatively quickly, perhaps because it was clear that the modulation of GnRH action would have profound potential effects on all aspects of reproduction. Gonadotropin-releasing hormone activation of its receptor was unusual in that the stimulation had to be pulsatile; continuous stimulation produced a suppression rather than an enhancement of gonadotropin section (3). Early attempts at altering the native structure of GnRH focused on amino acid substitutions that did not change the receptor-binding site but simply extended its half-life by preventing its rapid degradation. This is how the agonists of GnRH came to be the first to be produced and tested. They proved to be very useful (albeit in a physiologically antagonistic role) and are still in common clinical use. In the United States, leuprolide acetate continues to be used for endometriosis, fibroids, in vitro fertilization, and precocious puberty. The synthesis of the antagonists was more challenging because it required modification of the receptor-binding portion of the native molecule (4). Early antagonists produced allergic reactions, which limited their clinical use. Eventually, the currently approved ganirelix and cetrorelix were synthesized and are in common use for the prevention of ovulation during in vitro fertilization stimulation.

Incredibly, orally active GnRH antagonists have now been synthesized and tested successfully. These nonpeptide molecules are able to block the GnRH receptor, thus antagonizing GnRH action, yet can be taken by mouth. The potential of these medications has not been realized fully yet (5). They have the potential to replace all other forms of contraception, in addition to being excellent alternatives to injectable antagonists and agonists. The future is now.

In this special issue, we learn how the fundamental knowledge of the structure of GnRH, elucidated 50 years ago, has been used to manage numerous conditions with agonist and antagonist formulations. These include endometriosis, heavy menstrual bleeding from fibroids, polycystic ovary syndrome, menstrual migraines, and certain cancers. They are also an integral part of infertility treatments. Overall, their impact on the quality of life of millions of patients cannot be overestimated. We also trace the development of the various analogues to document this journey of discovery.

We start our journey with Tony Plant recollecting the early days in the Ernst Knobil laboratory, which discovered that pulsatile GnRH was required for normal pituitary ovarian axis function.

We continue with Richard Fleming’s thoughts on how GnRH analogues became part of the controlled ovarian stimulation protocol that is now the standard of care for assisted reproductive technologies throughout the world.

We also heard from Peter Humaidan and Thor Haahr about the challenges involved in providing appropriate luteal phase support because the field shifted from using human chronic gonadotropin for final oocyte maturation to using a GnRH agonist to trigger the luteinizing hormone required for final oocyte maturation in assisted reproductive technologies.

Next, we hear from Marco Filicori expound on the journey to understand how varying the frequency of pulsatile GnRH affects the reproductive axis.

Nils Lambalk recalls the efforts to understand how one releasing hormone (GnRH) can preferentially stimulate follicle-stimulating hormone vs. luteinizing hormone by varying pulse frequencies. He did this by studying various frequencies of exogenous GnRH in patients lacking endogenous GnRH activity

Kristof Chwalisz details the efforts needed to bring leuprolide acetate depot to the market, Eric Surrey goes on to describe how GnRH agonists are used clinically to manage endometriosis, and Sandra Leveaux, Michal Ciebiera, and Ayman Al-Hendy discuss their usage in the management of uterine fibroids.

Keith Gordon describes the early nonclinical primate studies conducted in the laboratory of Gary Hodgen, which provided proof-of-concept for many of the current uses of GnRH analogues.

There is also an overview of the development and registration processes for the 2 most widely used peptide GnRH antagonists: ganirelix from Bernadette Mannaerts and cetrorelix from Sebastian Findeklee and Klaus Diedrich. Then, we read about the next-generational shift with Kristof Chwalisz. Juan Camillo Arjona Ferreira and Elizabeth Migoya provide overview of the development of elagolix and relugolix, the 2 most widely used nonpeptide GnRH antagonists.

Finally, we have a clinical overview from Farrah Saleh and Hugh Taylor that summarizes the many uses of these compounds in the field of reproductive medicine.

The elucidation of the amino acid sequence of GnRH was one of the most important events in the field of reproductive medicine. We hope that you will enjoy reading about the work required to bring them to the clinic, as we look forward to the next 50 years of discovery.