Objective. The aim of this study was to investigate the role of apoptosis d
uring progestin therapy for the treatment of endometrial hyperplasia.
Methods. Pre- and posttreatment paraffin-embedded endometrial tissue sample
s from 19 women with endometrial hyperplasia were examined for changes in g
landular cellularity and apoptotic activity related to the administration o
f progestins. Twelve patients were successfully treated with progestin ther
apy and 7 patients failed treatment. Glandular cellularity was assessed bas
ed on calculating the average number of cells per gland obtained on histolo
gic examination of hematoxylin and eosin stained tissue sections. Apoptotic
activity was assessed on the same tissue sections by counting the average
number of apoptotic cells per 10 high power fields (hpf) using the terminal
deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end l
abeling (TUNEL) assay. The effects of progesterone on apoptotic activity in
a low-grade endometrial adenocarcinoma cell line (Ishikawa cells) was also
examined using an ELISA cell death detection kit.
Results. Glandular cellularity significantly decreased with progestin thera
py in both treatment outcome groups. The reduction in cells per gland was s
ignificantly greater in the group of successfully treated cases compared to
the treatment failures (P = 0.005). However, within the successfully treat
ed group, in situ detection of apoptotic cells using the TUNEL assay showed
no statistical difference between pre- and posttreatment endometrial sampl
es. Interestingly, a significant decrease in apoptosis was found in posttre
atment samples of the group with persistent hyperplasia. The average number
of apoptotic cells detected in 10 hpf was reduced from 7.9 prior to treatm
ent to 3.1 after progestin therapy (P = 0.03). In the progesterone-treated
Ishikawa cell line, an increase in apoptotic activity started at 24 h, reac
hed a peak at 48 h, and continued up to 72 h of hormone treatment. At 48 h,
apoptotic activity was 42.6% greater than in the untreated control (P = 0.
04). By 72 h of progesterone treatment, apoptosis was 37.2% greater in the
treated cells compared to the noninoculated cells (P = 0.04).
Conclusions. Progestin-induced apoptosis may occur during the early period
of treatment for endometrial hyperplasia. Compared to the fully responsive
group, persistent endometrial hyperplasia may have intrinsically different
molecular mechanisms in response to progestin therapy. (C) 2000 Academic Pr
ess.