Binding of progestins to the glucocorticoid receptor. Correlation to their glucocorticoid-like effects on in vitro functions of human mononuclear leukocytes.
A number of physiological and synthetic progestins were tested for their ability to compete with [3H]dexamethasone for the binding to the glucocorticoid receptor of human mononuclear leukocytes and their ability to elicit glucocorticoid-like effects on the same cells. As compared to the reference compound dexamethasone (relative receptor binding affinity defined as 100%), two potent synthetic progestins with a pregnane-type structure, megestrol acetate and medroxyprogesterone acetate, were found to display a considerable binding affinity towards the receptor (46 and 42%, respectively). The relative binding affinity of the naturally occurring ligand, cortisol, to the receptor was clearly lower (25%). The effective binding of medroxyprogesterone acetate to the glucocorticoid receptor was confirmed by direct binding studies utilizing a tritiated derivative of this steroid. No evidence for the existence of a specific progesterone receptor in human mononuclear leukocytes was obtained as judged by the results of competition experiments where a progesterone receptor-specific ligand [3H]Org 2058 was used. Medroxyprogesterone acetate and megestrol acetate also induced glucocorticoid-like effects on the lymphocyte functions. These included inhibition of the proliferative responses to the T-cell mitogens concanavalin A and phytohaemagglutinin and an enhanced accumulation of immunoglobulin secreting cells in pokeweed mitogen-stimulated cultures. The progestin effect appears to be mediated through a radiosensitive (suppressor) subpopulation of T lymphocytes. In contrast, the synthetic progestins related structurally to 19-nortestosterone, norethisterone and d-norgestrel, were virtually devoid of binding affinity towards the glucocorticoid receptor nor did they measurably influence the in vitro lymphocyte functions. These studies demonstrate that certain progestins in common clinical use probably possess inherent glucocorticoid activity and suggest that side effects attributable to this character (e.g. suppression of the pituitary-adrenal axis) might be expected when these compounds are used in pharmacological doses.
D004261:DNA Replication / Q000187:drug effects; D003692:Delayed-Action Preparations; D003907:Dexamethasone / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology; D008525:Medroxyprogesterone / Q000031:analogs & derivatives / Q000378:metabolism; D017258:Medroxyprogesterone Acetate; D008934:Mitogens; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D011372:Progestins / Q000378:metabolism* / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism
D003692:Delayed-Action Preparations; D008934:Mitogens; D011372:Progestins; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D003907:Dexamethasone; D017258:Medroxyprogesterone Acetate; D008525:Medroxyprogesterone