DEVELOPMENT AND APPLICATIONS OF LUTEINIZING-HORMONE-RELEASING HORMONEANTAGONISTS IN THE TREATMENT OF INFERTILITY - AN OVERVIEW

Luteinizing hormone-releasing hormone (LHRH) plays a crucial role in c ontrolling the ovarian cycle in women. By modification of the molecula r structure of this decapeptide, analogues were synthesized with agoni stic or antagonistic effects on the gonadotrophic cells of the anterio r pituitary gland. The agonists, after an initial stimulatory effect ( 'flare up'), lead to desensitization of the gonadotrophic cells and a reduction in the number of LHRH receptors on the cell membrane ('down- regulation'), while the antagonists produce an immediate effect by com petitive blockade of the LHRH receptors. After administration of LHRH antagonists, the serum levels of FSH and LH decrease within hours. Nev ertheless, the adenohypophysis maintains its responsiveness to an LHRH stimulus ('pituitary response') after pretreatment with an antagonist . This different pharmacological mechanism of LHRH antagonists makes p ossible new approaches to ovarian stimulation and to the therapy of se x steroid dependent diseases. The premature LH surge, the main cause o f cancellation during induction of superovulation in assisted reproduc tion technology (ART) programmes, can be abolished by short term appli cation of an LHRH antagonist associated with a reduced human menopausa l gonadotrophin (HMG) requirement for ovarian stimulation. A future ap proach to ART might be based on the combination of pretreatment with a n LHRH antagonist and ovulation induction by native LHRH or an agonist . The severe side effects encountered with early LHRH antagonists, suc h as anaphylactoid reactions due to histamine release, are almost comp letely eliminated in modern antagonists, especially Cetrorelix which i s presently used clinically in controlled phase II clinical studies.