GnRH analogs in reproductive medicine

The uses of gonadotropin releasing hormone (GnRH) analogs in in vitro fertilization (IVF), gamete intrafallopian transfer (GIFT) or related assisted reproductive technologies has advanced rapidly since initial efforts in the early 1980's. By making selective amino acid substitutions, often including the 6 and 10 position, the peptide chemists designed the compounds that we call the GnRH agonists of today. GnRH antagonists possess amino substitutions usually involving positions 1,2,3, 6 and 10, although others may be used. Moreover, recent versions are chemically very sophisticated, often having up to 5 D-amino acids (only L-amino acids occur naturally) and a variety of blocking groups that confer metabolic stability and reduced allergic side-effects. The first available formulation of a GnRH agonist product in the USA was an aqueous preparation for sc injection (usually once or twice daily). It has been studied for several years both in the treatment of prostatic carcinoma and for treatment of children presenting with true precocious puberty. More recently, a depo (monthly) preparation, which microencapulates the GnRH agonist in biodegradable microspheres, received registry approval for treatment of prostatic carcinoma. Also, an implant formulation aimed at chronic treatment indications, as well as nasal delivery products (usually applied multiple times daily) are in development. I will leave specific predictions of the future to those bearing higher powers, except to anticipate that when a safe and effective GnRH antagonist product is developed, it is likely to offer special advantages for IVF/GIFT treatment because of three apparent advantages over GnRH agonist products.