nafarelin and detirelix

Prospects for the use of LHRH analogs for human fertility control have been reviewed with particular reference to two highly potent representatives. Nafarelin acetate, the LHRH agonist, has a potency about 200 X that of LHRH and is consistently effective in suppressing gonadal function in females through a desensitization of LHRH receptors in the pituitary. Such agents show promise as ovulation inhibitors for women although concern has been expressed over the dangers of unopposed estrogen or alternatively hypoestrogenemia. Although early studies indicated luteolysis in women and interceptive action in baboons it is now clear that the LHRH agonists will not be useful clinically to terminate pregnancy. Wide species differences in the male response to LHRH agonists exist. Unfortunately azoospermia has not been achieved in men. The LHRH antagonists, typified by [N-Ac-D-Nal(2)1, D-pCl-Phe2, D-Trp3, D-hArg(Et2)6, D-Ala10]LHRH, require high doses to competitively inhibit responses to endogenous LHRH. Their advantages include a rapid induction of the hypogonadal state with apparently little species or sexual variation in response. Based on animal studies, preferable utility of the antagonists would lie in male contraception and pregnancy interception.. This review of luteinizing hormone-releasing hormone (LHRH) analogs suggests that both LHRH agonists and antagonists have potential utility in fertility control. Very potent agonistic analogs of LHRH are now under intensive investigation for treatment of gonadal hormone- dependent syndromes and for antifertility effects. Such analog, nafarelin acetate, has a potency 200 times that of LHRH and is consistently effective in suppressing gonadal function in females through a desensitization of LHRH receptors in the pituitary. Some dispute remains, however, as to whether daily doses of LHRH agonists can be titrated to avoid the dangers of both unopposed estrogen and endometrial hyperplasia as well as the effects of estrogen deprivation. For females, it is now clear that neither menstrual induction nor pregnancy termination will be achieved with LHRH agonists. Wide species differences in response to LHRH agonists have been noted in males. Consistent induction of azoospermia has not been achieved; when it is, controlled release formulations for the LHRH agonist and possibly testosterone supplementation will be required. Although evaluation of LHRH antagonists is in the early stages, interspecies variation has not been recorded. Azoospermia and aspermatogenesis have been consistently obtained in male rats, dogs, and macaque monkeys. There is rapid induction of the hypogonadal state, although high doses are required to competitively inhibit responses to endogenous LHRH. Animal studies suggest that the most effective potential uses of LHRH antagonists are in male contraception and pregnancy interception. Although ovulation suppression most likely can be achieved with LHRH antagonists, use of LHRH agonists is considered more advantageous.

Topics: Abortion, Induced; Animals; Contraception; Corpus Luteum; Delayed-Action Preparations; Dogs; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Macaca fascicularis; Macaca mulatta; Male; Nafarelin; Ovulation; Papio; Pituitary Gland; Rats; Receptors, Cell Surface; Receptors, LHRH; Species Specificity; Sperm Count; Testosterone

Gonadotropin-releasing hormone agonists and antagonists have initial divergent effects on the pituitary secretion of intact biologically active gonadotropins and long-term divergent effects on the secretion of free alpha-subunit. The antagonists appear to function as true competitive inhibitors, blocking the stimulatory effects of endogenous GnRH without evoking any known postreceptor activity. The agonists, in contrast, initially stimulate pituitary secretion and then incompletely desensitize the gonadotrope, resulting in suppression of intact gonadotropin, but not free alpha-subunit, secretion. The mechanisms by which GnRH-a produce this incomplete gonadotrope desensitization and facilitate limited postreceptor activity remain to be elucidated.

Topics: Adult; Estradiol; Female; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Nafarelin; Osmolar Concentration

The degradation of native LHRH in aqueous buffers of pH approximately 1-10 obeyed the rate equation, kobs = kH + alpha H+ + ko + kHO-(alpha HO-)x, where x at 60-100 degrees C was approximately 0.64 and temperature independent. Extrapolation to 25 degrees C using the Arrhenius equation and secondary rate constants showed that native LHRH is reasonably stable at pH 5.4, giving a shelf life (t90) of approximately 5 years. Regarding physical properties, hydrophobic LHRH analogues nafarelin and detirelix were found to be surface active as demonstrated by a decrease in apparent surface tension with increased peptide concentration. The CMC for detirelix at pH 7.4 was determined to be 5.3 x 10(-4) M (0.88 mg/ml), and that for nafarelin, greater than 2 mg/ml. At higher concentrations (approximately 4-8 mg/ml), nafarelin and detirelix formed nematic liquid crystals of undulose extinction (birefringence, less than 0.001). The thermodynamic stability of these peptide liquid crystals was probed by determining their melting points (Tcm) in the presence of propylene glycol, a solvent which proved to be efficacious at suppressing gelation and at destabilizing liquid crystals as measured by a reduction in Tcm.

Topics: Chemical Phenomena; Chemistry, Physical; Crystallization; Drug Stability; Gonadotropin-Releasing Hormone; Hydrogen-Ion Concentration; Kinetics; Nafarelin; Solutions; Surface Properties; Surface-Active Agents; Temperature