Submitted May 31, 2002
Returned for revision June 17, 2002
Accepted December 20, 2002
Mechanisms of Hormone Action
Effects of an Antiprogestin Onapristone on the
Endometrium of Bonnet Monkeys: Morphometric and
Ultrastructural Studies
Kamala Gopalkrishnan ,
R. R. Katkam ,
Geetanjali Sachdeva ,
S. D. Kholkute ,
Varsha Padwal ,
C. P. Puri *
* To whom correspondence should be addressed. E-mail: dirirr{at}vsnl.com.
Abstract
Our previous studies demonstrated the ability of low doses
of antiprogestin ZK 98.299 (onapristone) to inhibit
fertility in bonnet monkeys. In the present study
cumulative effects of low doses of ZK 98.299 on the
endometrial cytoarchitecture of bonnet monkeys were
analyzed. Treatment with either the vehicle (n=3) or
onapristone at 2.5 mg (n=4) or 5.0 mg (n=3) was initiated
on day 5 of the first menstrual cycle and thereafter
repeated every third day for 4 to 7 consecutive cycles.
The last treatment cycles were anovulatory in two animals
treated with 2.5 mg and all animals treated with 5.0 mg.
Endometrial biopsies were collected on day 8 after the
mid-cycle estradiol peak in ovulatory menstrual cycles and
on day 20 in anovulatory menstrual cycles during the last
treatment cycle. Ultrathin sections of the fixed
endometrium were stained with toluidine blue for
morphometric analysis and uranyl acetate and lead citrate
for ultrastructural analysis. The ZK 98.299 treated
animals showed a dose dependent endometrial atrophy as
evident by a decrease in the height and diameter of the
glands and early signs of compaction in the stroma.
Ultrastructural analysis also revealed dose dependent
degenerative changes in the subcellular organelles such as
nucleus, mitochondria, endoplasmic reticulum, lysosomes,
golgi apparatus. This suggests that long term treatment
with low doses of ZK 98.299 leads to the suppression of
estrogen dependent endometrial proliferation. However,
this blockade operates independent of estradiol receptor
(ER) and progesterone receptor (PR) concentrations as the
expressions of these steroid receptors did not show any
significant changes even after prolonged treatment. The
study demonstrated an anti-estrogenic effect of ZK 98.299
on endometrium after prolonged treatment in bonnet
monkeys.
