Abstract. The effect of two synthetic injectable progestins, norethisterone oenanthate3 (NET-e) and medroxyprogesterone acetate (MPA) upon the hypothalamic pituitary unit was evaluated in post-menopausal women (PMW) and in castrated individuals with androgen un-responsiveness in order to gain insight into their mechanism of gonadotrophin inhibition. Continuous administration of natural progesterone (P4) to PMW by medicated vaginal rings was used as the experimental control. Elevated base line levels of serum immunoreactive gonadotrophins and normal pituitary LRH responses were found in PMW and pseudohermaphrodites. Progesterone did not affect circulating gonadotrophin levels or the pituitary LRH response in PMW. Administration of MPA 150 mg induced a clear decrease in serum gonadotrophins and a significant decrease in LRH pituitary responsiveness in a post-menopausal woman whereas no effect was observed on serum gonadotrophins and pituitary response to LRH in a patient with androgen unresponsiveness. Administration of NET-e 200 mg resulted in a significant decrease in circulating gonadotrophins in PMW and pseudohermaphrodites, while LRH pituitary sensitivity was diminished in all subjects except one post-menopausal woman. These results demonstrated that two structurally different synthetic progestins (NET-e and MPA) had a potent gonadotrophin inhibitory activity in PMW while natural progesterone did not, thus indicating a different mode of action. Furthermore their differing effect on individuals with complete androgen unresponsiveness suggested that antigonadotrophic activity of NET-e is mediated by its oestrogenic-progestational effect, while MPA acts through its androgenic potency and therefore requires the presence of androgen receptors.