Structural requirements in LHRH for gonadotropin-releasing activity were investigated by comparing the activity of the natural vertebrate LHRH structural variants and synthetic analogues. Substitution of Arg8 results in a loss of activity of LHRH in mammals, whilst a number of amino acid substitutions for Arg8 retain high gonadotropin-releasing activity in the chicken. Thus Arg8 of LHRH comprises an integral part of the binding site of LHRH and/or contributes towards the conformation of the binding site for the mammalian receptor while this does not pertain in the bird. The possibility that relative conformational stabilization of LHRH is important for biological activity in mammals but not birds, was supported by the demonstration that a gamma-lactam conformationally constrained analogue of LHRH was more active than LHRH in the mammalian system but equipotent in the bird. The chicken LHRH receptor is also relatively undiscriminating with regard to amino acid substitutions in positions 5 and 7. A series of LHRH analogues with pure antagonist activity in rats exhibited a spectrum of activities, from pure agonist to mixed activity and pure antagonist, in the chicken. These differences in LHRH structural requirements of the mammalian and avian receptor are reflected by a difference in molecular size of the chicken receptor (67,000) and mammalian receptor (60,000). Nevertheless, like the mammalian pituitary, the chicken pituitary does exhibit "desensitization" on prolonged exposure to LHRH.