Development and applications of luteinizing hormone-releasing hormone antagonists in the treatment of infertility: an overview.

Luteinizing hormone-releasing hormone (LHRH) plays a crucial role in controlling the ovarian cycle in women. By modification of the molecular structure of this decapeptide, analogues were synthesized with agonistic or antagonistic effects on the gonadotrophic cells of the anterior 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 competitive blockade of the LHRH receptors. After administration of LHRH antagonists, the serum levels of FSH and LH decrease within hours. Nevertheless, the adenohypophysis maintains its responsiveness to an LHRH stimulus ('pituitary response') after pretreatment with an antagonist. This different pharmacological mechanism of LHRH antagonists makes possible new approaches to ovarian stimulation and to the therapy of sex steroid dependent diseases. The premature LH surge, the main cause of cancellation during induction of superovulation in assisted reproduction technology (ART) programmes, can be abolished by short term application of an LHRH antagonist associated with a reduced human menopausal gonadotrophin (HMG) requirement for ovarian stimulation. A future approach to ART might be based on the combination of pretreatment with an LHRH antagonist and ovulation induction by native LHRH or an agonist. The severe side effects encountered with early LHRH antagonists, such as anaphylactoid reactions due to histamine release, are almost completely eliminated in modern antagonists, especially Cetrorelix which is presently used clinically in controlled phase II clinical studies.