EFFECTS OF PROGESTIN ADMINISTRATION ON THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND GLUCOSE-HOMEOSTASIS IN DOGS

The effects of medroxyprogesterone acetate (MPA) and proligestone (PRO L) on the hypothalamic-pituitary-adrenocortical axis and glucose homeo stasis were studied in two groups of eight ovariohysterectomized beagl e bitches. In addition, the binding characteristics of MPA and PROL fo r the progesterone and glucocorticoid receptor were investigated The a dministration of both progestins resulted in suppression of the hypoth alamic-pituitary-adrenal axis. Whereas basal plasma concentrations of adrenocorticotrophic hormone (ACTH) were only moderately affected the basal plasma concentrations of cortisol and the cortisol:creatinine ra tio in urine were significantly decreased after the first administrati on of both progestins. In the group given MPA the increase of ACTH aft er stimulation with corticotrophin-releasing hormone (CRH) remained no rmal but it was suppressed in the group treated with PROL. In both tre atment groups the increase of cortisol after stimulation with CRH was lower. After cessation of progestin administration both basal and stim ulated plasma ACTH concentrations returned to pretreatment concentrati ons within a few weeks. In contrast, it took 6 month to restore the ba sal plasma cortisol concentrations and cortisol:creatinine ratios in u rine. Paradoxically the stimulated cortisol concentrations returned to normal shortly after the cessation. Histological examinations reveale d a severe atrophy of the zona fasciculata and reticularis of the adre nal gland in all treated dogs and a steroid-induced hepatopathy in 50% of them. During the first half of the progestin treatment, glucose ho meostasis was maintained by increased plasma concentrations of insulin in both groups. After prolonged treatment the response to a glucose l oad became impaired. None of these parameters improved during the 6 mo nth recovery period. Histological changes in the pancreas, characteris tic of diabetes mellitus, were found in two dogs of each group. Most p robably the glucocorticoid action of the progestins is not the sole ex planation for the insulin resistance since progestin treatment resulte d in a concomitant increase in plasma concentrations of growth hormone which has diabetogenic properties. Experiments in vitro confirmed the strong glucocorticoid component of MPA and PROL. The inhibition const ants (Ki) of PROL for both the progesterone receptor (PR) and the gluc ocorticoid receptor (GR) were approximately ten times higher than thos e of MPA. Nonetheless, the ratios of the K-i for the GR and PR indicat ed that the specificity of MPA and PROL was only slightly different bu t considerably smaller than that of progesterone. It is concluded that both MPA and PROL act as glucocorticoid agonists and that long-term t reatment with high doses of these progestins may result in a iatrogeni c Cushing's syndrome and diabetes mellitus.