LHRH and Its Analogs: Contraceptive and Therapeutic Applications Part 2

Since the discovery of LHRH in 1971, research into the physiology and therapeutics of this compound can be divided into three dis- tinctly different phases. In the first phase, attention was paid chiefly to the natural sequence hormone; efforts were channeled to explore its diagnostic use; and nearly all the clinical investigations were coordinated by a single pharmaceutical company. The successes in this area were quite limited and the interest in the promise of this agent as a diagnostic test has long since waned. This phase of research con- sumed roughly the first seven years of clinical testing after the isolation and characterization of the compound by the two groups involved in the Nobel effort. With the appearance of long-acting LHRH agonists, the second phase of research on LHRH began in the late '70's. LHRH agonists were the only compounds available during this period of research and paradoxical desensitization was the predominant therapeutic basis for the discoveries. An ever-widening number of therapeutic applications using this approach were unearthed. A second theme which emerged during this second 5-7 year period was that the pulsatile administration of the natural sequence LHRH could be used to treat LHRH deficiency in men and women.

Table of Contents:
Section 1 Chemistry.- 1. Development of LHRH antagonists.- 2. LHRH antagonists with low histamine releasing activity.- 3. Specificity of design to achieve antagonists of LHRH of increasing effectiveness in therapeutic activity.- 4. Biosynthesis of LHRH.- 5. Phylogenetic diversity of LHRH.- Section 2 Mechanisms of Action of Hypothalamic LHRH and Analogs.- 6. Molecular mechanism of LHRH action in the gonadotrope.- 7. Mediation of the preovulatory LH surge: LHRH pulsatility and opioid modulation.- Section 3 Extra-Hypothalamic LHRH-Like Materials.- 8. LHRH binding sites in human tissues.- 9. LHRH and “LHRH-like” factors in the male reproductive tract.- 10. Placental LHRH-like activity.- Section 4 Pharmacology of LHRH Antagonists.- 11. In vitro histamine release with LHRH analogs.- 12. Anaphylactoid properties of LHRH analogs.- 13. Reproductive physiology and general pharmacology of LHRH antagonists.- 14. Suppression of plasma gonadotropins, testosterone and sperm production in adult male monkeys by a potent inhibitory analog of LHRH.- 15. LHRH antagonists and female reproductive function.- Section 5 Basic Clinical Studies.- 16. LHRH antagonists in normal men.- 17. Clinical investigations of the contraceptive and therapeutic potential of nafarelin.- 18. LHRH agonists and antagonists: therapeutic possibilities for premenstrual syndrome.- 19. Early clinical studies with LHRH antagonists in women.- 20. Profertility uses of LHRH agonist analogues.- Section 6 Clinical Trials.- 21. Ovulation induction with pulsatile LHRH.- 22. Treatment of endometriosis by nasal administration of nafarelin.- 23. Effects of nafarelin in precocious puberty.- 24. Pharmacokinetics, metabolism and clinical studies with buserelin.- 25. Trials with leuprolide.- 26. Zoladex studies in prostatic andbreast cancer.- 27. Intermittent LHRH agonist sequentially combined with a progestogen as antiovulatory contraception.- 28. LHRH agonists and male contraception.- Section 7 Gonadal Protective Prospects with LHRH Analogs.- 29. Interactions between an LHRH analogue and cancer chemotherapeutic agents at the testicular level in dogs.- 30. Is it possible to conserve the fertility of patients with Hodgkin’s disease treated with cytotoxic chemotherapy?.- Section 8 Diagnostic Applications.- 31. Predicting predisposition to osteoporosis: GnRH antagonist for acute estrogen deficiency.- Section 9 Applications in Animals.- 32. The use of LHRH analogs in aquaculture.- 33. Uses of LHRH and its analogs in cattle.- 34. Clinical uses of LHRH analogs in dogs.- Section 10 Formulation and Metabolism.- 35. Intra-nasal administration of LHRH and its analogs.- 36. The controlled delivery of polypeptides including LHRH analogs.- 37. Pharmacokinetics and metabolism of LHRH analogs.- Epilogue.