Pj. Selman et al., EFFECTS OF PROGESTIN ADMINISTRATION ON THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND GLUCOSE-HOMEOSTASIS IN DOGS, Journal of Reproduction and Fertility, 1997, pp. 345-354
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.