Chapter 22. Luteinizing Hormone Releasing Hormone Analogs in Control of Fertility and Gonadal Hormone Dependent Disease

Abstract

This chapter discusses the luteinizing hormone releasing hormone (LHRH) developments since 1984, with additional material for perspective. LHRH has diagnostic and profertility applications, but the preponsderance of therapeutic uses for LHRH analogs depends on gonadal suppression. The releasing hormone is released in a pulsatile manner from the hypothalamus and stimulates the secretion of luteinizing hormone and follicle stimulating hormone from the pituitary. The LHRH agonists in clinical development have a relatively hydrophobic, D-amino acid in position 6 and (usually) a further substitution in position 10. Polypeptide hormones may bind to the phospholipid membrane prior to the occupation of membrane-bound receptors and more hydrophobic analogs might do so more readily. The most potent LHRH analogs are also the most hydrophobic. These analogs are more potent in vivo than predicted from in vitro data due in part to a prolonged t1/2 attributed to “hydrophobic depoting” in the body. Amino acids with charged side chains were introduced into position 6 for increased water solubility. Surprisingly, with a positively charged side chain replacing the very hydrophobic, aromatic side chain typically seen at this position, had high potency and a prolonged duration of action. Continual treatment with potent LHRH agonists elicits a decreasing stimulatory response and results within four weeks in complete tachyphylaxis to production of biologically active gonadotropins. While the initial stimulatory phase is frequently unimportant, in metastatic cancer the associated “flare” may restrict agonist use. Pre-pubertal treatment causes no symptomatic stimulation and puberty may be postponed indefinitely. LHRH antagonistic analogs compete with endogenous LHRH for its receptor, and therefore must be constantly present to successfully block gonadotrope function. They do not exhibit a stimulatory phase and do not cause receptor down-regulation. Lowering gonadal steroid output with LHRH antagonists may increase endogenous LHRH secretion. The minimal effective single dose for 24 hours suppression, thus, may not suppress chronically. LHRH agonists are available for the treatment of prostatic cancer in several countries and approval for endometriosis, precocious puberty, and uterine leiomyomata is expected over the next few years.