LHRH analogues for contraception in women

Abstract

LHRH agonists have been comprehensively studied for their ability to disrupt the reproductive cycle in women and are being used in the treatment of hormone-dependent gynaecological disorders. Selected approaches have been evaluated in clinical trials for possible application to contraception. The LHRH antagonists await full clinical evaluation but preliminary clinical studies together with observations from non-human primate investigations allow their potential to be assessed. Despite the different mechanism of action of LHRH analogues and steroids for contraception, many of the issues of acceptability are common to both. The pattern of bleeding, the risk/benefit ratios in relation to cancers of the secondary organs, effects on the cardiovascular system and bone metabolism are major isssues which must be considered with any form of hormonal contraception. LHRH agonists LHRH agonists have been investigated for contraceptive application in a remarkable number of different regimens based on their ability to desensitise the pituitary gonadotroph with subsquent interference with follicular maturation, luteal function or early pregnancy. Approaches based upon intermittent administration at specific stages of the cycle remained as phase I trials (1,2 for reviews) as they seemed to be impractical. The continuous administration of LHRH agonist has been extensively evaluated using either buserelin (200-600 @day) or nafarelin (125-1000 &day) administered by nasal spray for periods of 6-24 months. Dose response studies demonstrated that a problem lay in the variation in estrogen production between individuals. A marked suppression of estrogen produced hot flushes and amenorrhea. Loss of bone mineral would also be predicted. Less suppression of follicular development caused fluctuating blood estrogen concentrations which stimulated the endometrium. Although subsequent bleeding is generally at monthly intervals and of light intensity there are concerns about long-term consequences of exposure of the endometrium to unopposed estrogen. To overcome this problem the agonist has been combined with a progestational agent in a cyclic regimen (3) but application has been limited. LHRH agonists for post-partum contraception During lactation there is a need for a reliable, acceptable and easily administered method of contraception which has no biological effect upon the infant and does not interfere with milk production. An adequate inter-birth interval is of major importance because it enables the mother to recover her physical status and emotional well-being between pregnancies, and confers advantages of improved health and development upon the child. These factors are of particular importance in developing countries. Although the process of lactation has a suppressive effect