BAG-1 expression in normal and neoplastic endometrium.

OBJECTIVE: BAG-1 has anti-apoptotic actions and is known to bind BCL-2 and steroid receptors. High levels of BAG-1 have been implicated as a prognostic indicator in breast cancer. Whether this observation can be generalized to endometrial cancer remains unknown. METHODS: IRB permission was obtained for use of human discarded tissue. Immunohistochemical analyses were performed on: proliferative endometrium (PEM, 6), secretory endometrium (SEM, 28), "low-grade" neoplastic lesions (complex atypical hyperplasia and grade 1 endometrial adenocarcinomas) (19), and "high-grade" cancers (grade 2 and 3 endometrial adenocarcinomas) (13). The level of total BAG-1 and its isoforms was evaluated by Western blot in lysates from Ishikawa cells (grade 1), MFE 296 cells (grade 2), and SK-UT(2) cells (grade 3). RESULTS: The proportion of "high-grade" cancers with positive cytoplasmic staining for BAG-1 was higher than that of secretory endometrium (P = 0.006). Additionally, the proportion of specimens with positive staining for nuclear BAG-1 expression was significantly higher among high-grade carcinoma specimens compared to secretory specimens (P = 0.009). A high proportion (91%) of all specimens were positive for BCL-2, limiting the ability to subcategorize the other variables analyzed. There was no relationship between positive nuclear BAG-1 expression and either estrogen receptor (ER) or progesterone receptor (PR) expression. BAG-1 was expressed in the three cell lines evaluated and total BAG-1 level was not different among the different cell lines. CONCLUSION: BAG-1 is expressed in the endometrium. High-grade cancers stain more frequently than secretory endometrium for both cytoplasmic and nuclear BAG-1 expression, perhaps indicating an association between expression of BAG-1 and prognosis.

Leptin-induced increase in leukemia inhibitory factor and its receptor by human endometrium is partially mediated by interleukin 1 receptor signaling.

Leptin and leukemia inhibitory factor (LIF) have been implicated as important mediators of implantation. The present study was designed to investigate whether leptin can directly regulate the expression of LIF and its receptor (LIF-R) in human endometrial cells and/or whether leptin-induced effects are linked to, or regulated in part by IL-1 signaling. Primary endometrial cells and endometrial epithelial cell lines (HES and Ishikawa cells) were cultured for 24-48 h in a medium containing insulin (5 microg/ml) and leptin (3, 10, and 62 nm) or IL-1beta (0.6, 3, and 10 nm) in the presence or absence of cytokines and/or receptor antagonists. The endpoints included phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the relative levels of LIF, LIF-R, IL-1beta, IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type I (IL-1R tI) as determined by ELISA or Western blotting techniques. Leptin treatment increases the level of phosphorylated STAT3, LIF-R, and LIF. Leptin also increases the levels of IL-1 ligand, receptor, and antagonist as was previously reported. Blockade of OB-R with antibodies or with a specific OB-R inhibitor (leptin peptide antagonist-2) abrogated leptin-induced effects, suggesting that leptin binding to its receptor activates Janus kinase 2/STAT3 signaling. Treatment of endometrial cells with IL-1beta also results in elevated levels of LIF-R. Interestingly, the inhibition of IL-1R tI with a specific antibody or with IL-1Ra negatively affects both leptin-induced and IL-1-induced effects on LIF-R levels. Abnormal endometrial LIF expression has been associated with human infertility and leptin has profound effects on the levels of LIF, IL-1, and their cognate receptors in vitro. Thus, it is tempting to speculate that leptin's role in vivo could include the regulation of other key cytokines to be fundamental to endometrial receptivity during implantation (i.e. LIF and IL-1).

Laparoscopic oophoropexy and ovarian function in the treatment of Hodgkin disease.

BACKGROUND: Hodgkin disease commonly affects women of reproductive age. Total lymph node irradiation (TNI) typically delivers a dose of 2000-4000 centigray (cGy) to the ovaries, which invariably results in premature ovarian failure (POF) and infertility unless the ovaries are shielded. Transposition of the ovaries at staging laparotomy has had mixed success and may be remote in time from pelvic radiation. METHODS: A laparoscopic technique has been described that allows transposition of the ovaries just prior to pelvic radiation. This is a report of the outcome of 12 patients who underwent laparoscopic oophoropexy at the University of Florida from 1989 to 1995. Two were excluded from analysis, because one died and the other had a second malignancy for which radiation was aborted. RESULTS: At follow-up, five patients had evidence of ovarian function, and the four patients of these five who desired children achieved pregnancies. All five had zero to two courses of chemotherapy. Two patients who subsequently had pregnancies had staging laparotomy with oophoropexy 5 and 6 months, respectively, before laparoscopy. In both cases the ovaries had migrated back to their original positions, and their therapy would have resulted in ovarian failure had the repeat procedure not been performed. Five patients had ovarian failure at follow-up. Four of the five had received multiple courses of chemotherapy; the other had pelvic primary disease and received 3500 cGy to the femoral lymph nodes and pelvis, with little central shielding. CONCLUSIONS: Laparoscopic oophoropexy performed immediately prior to pelvic irradiation is effective in preserving ovarian function in nearly all patients who are to undergo TNI for Hodgkin disease and who receive minimal or no chemotherapy.