Apoptosis may be an early event of progestin therapy for endometrial hyperplasia.
OBJECTIVE
The aim of this study was to investigate the role of apoptosis during progestin therapy for the treatment of endometrial hyperplasia.


METHODS
Pre- and posttreatment paraffin-embedded endometrial tissue samples from 19 women with endometrial hyperplasia were examined for changes in glandular cellularity and apoptotic activity related to the administration of progestins. Twelve patients were successfully treated with progestin therapy and 7 patients failed treatment. Glandular cellularity was assessed based on calculating the average number of cells per gland obtained on histologic 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 labeling (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 therapy in both treatment outcome groups. The reduction in cells per gland was significantly greater in the group of successfully treated cases compared to the treatment failures (P = 0.005). However, within the successfully treated group, in situ detection of apoptotic cells using the TUNEL assay showed no statistical difference between pre- and posttreatment endometrial samples. Interestingly, a significant decrease in apoptosis was found in posttreatment samples of the group with persistent hyperplasia. The average number of apoptotic cells detected in 10 hpf was reduced from 7.9 prior to treatment 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, reached 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.
Amezcua
C A
CA
Department of Pathology, Women's and Children's Hospital, Los Angeles, California, 90033, USA.
Lu
J J
JJ
Felix
J C
JC
Stanczyk
F Z
FZ
Zheng
W
W
D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D002452:Cell Count; D004714:Endometrial Hyperplasia / Q000188:drug therapy* / Q000473:pathology*; D004717:Endometrium / Q000473:pathology; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology / Q000627:therapeutic use; D019290:Megestrol Acetate / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D016612:Paraffin Embedding; D045167:Progesterone Congeners / Q000494:pharmacology / Q000627:therapeutic use*; D011372:Progestins / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D045167:Progesterone Congeners; D011372:Progestins; D017258:Medroxyprogesterone Acetate; D019290:Megestrol Acetate