CORRESPONDENCE

Tamoxifen’s Apoptotic Effect on theEndometrium

To the Editor: We read with great interest the study byMourits et al1 comparing apoptosis in benign and malignantendometrium recovered from tamoxiofen-treated postmeno-pausal breast cancer patients and endometrium resectedfrom controls and from patients not treated with tamoxifen.The authors claim that “no data exist on the extent of apo-ptosis in tamoxifen-exposed endometrium.”

We would like to direct the authors’ attention to ourstudy titled “Tamoxifen modulates apoptotic pathways in pri-mary endometrial cell culture,”2 which they overlooked intheir report.

Mourits et al1 found no difference in the mean apoptoticindex of benign endometrium between tamoxifen users andcontrols, or between tamoxifen-exposed and nonexposed en-dometrial cancer patients. However, the ratio of the apoptoticand proliferation indexes was lower in benign endometriumfrom tamoxifen users than in controls. The authors con-cluded that this lower apoptosis/proliferation ratio indicated

that the tamoxifen-induced higher proliferation was not com-pensated for by increased apoptosis, and that the imbalancein the apoptosis/proliferation equilibrium might contributeto the increased endometrial cancer risk in postmenopausaltamoxifen users.1

Our study was conducted on primary endometrial cellcultures. In a simulation of postmenopausal hormonal envi-ronment, we maintained cell cultures in steroid hormone–devoid media and compared these cultures to the same cellsmaintained in steroid hormone–containing media. We eval-uated tamoxifen’s apoptotic effect on the cultured endome-trial cells demonstrated in the proportions of pre-G1 popula-tions. A significant (P � 0.03) reduction in the pre-G1 peak,equivalent to an antiapoptotic response, was observed in 6 of13 (46%) cell cultures maintained in steroid-deficient envi-ronment. This effect is consistent with the clinically knownestrogenic-like agonistic effect of tamoxifen in the low-estro-gen environment of menopause.2

We concluded that tamoxifen modulates apoptotic path-ways. Moreover, we established that the hormonal environ-ment of the endometrial cells indeed influences tamoxifen’s

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apoptotic effect and determines the propensity for a cell toundergo apoptosis or, in contrast, to resist apoptotic death inresponse to tamoxifen treatment. Our results, based on thepre-G1 cell population, reflect the final equilibrium in apopulation of cells on tamoxifen exposure, thereby reflectingthe balance between cell proliferation and cell death. Mouritset al implemented a direct measurement of proliferation,thus enabling a differentiation between the 2 trends.1 Thiseffect may explain why a relatively high percentage (25% to35%) of postmenopausal tamoxifen-treated patients developdifferent benign and malignant endometrial pathologies.2

ILAN COHEN, MDRODIKA STACKIEVICZ, MDSHAI YARKONI, MD, PHDLIAT DRUCKER, PHDDepartment of Obstetrics and Gynecology, and

Oncogenetics LaboratorySapir Medical Center, Kfar-Saba,

Affiliated with Sackler Faculty of Medicine,Tel Aviv University

Tel Aviv, Israel.

1. Mourits MJE, Hollema H, De Vries EGE, et al: Apoptosis and apoptosis-associated parameters in relation to tamoxifen exposure in postmenopausalendometrium. HUM PATHOL 33:341-346, 2002

2. Stackievicz R, Drukcer L, Radnay J, et al: Tamoxifen modulates apopto-tic pathways in primary endometrial cell cultures. Clin Cancer Res 7:415-420,2001

doi:10.1053/hupa.2003.38

Reply

To the Editor—We appreciate the comments of Cohen etal regarding our paper in HUMAN PATHOLOGY1 in which wedemonstrated that the tamoxifen-induced endometrial pro-liferation is not compensated for by increased apoptosis inpostmenopausal women. We concluded that an imbalance inthe proliferation/apoptosis equilibrium might contribute tothe increased endometrial cancer risk in postmenopausallong-term tamoxifen users.

We did not mention the study of Stackievitz et al becausethis was an ex vivo study with a different outline. Theseauthors described an interesting experiment in which pri-mary endometrial cell cultures were incubated with tamox-ifen in the presence or absence of steroid hormones.2 In thecell cultures in steroid-devoid media, simulating a postmeno-pausal situation, the authors observed 2 opposing (proapop-totic and apoptotic) trends. In 6 of the 13 endometrial cellcultures, an antiapoptotic effect was observed as a reductionin the pre-G1 peak, whereas in the other 7 the opposite, anelevation of the pre-G1 peak, was found, suggesting an apo-ptotic effect. Although these are ex vivo experiments withshort-term (24 hours) tamoxifen exposure, in small numbers

of endometrial samples, under well-defined but artificial con-ditions, the findings are interesting. Clinical findings in post-menopausal tamoxifen users show a ultrasonographic endo-metrial thickening in at least 50% of the patients, whereas theendometrial lining in the others remain thin.3 An explana-tion for these diverse clinical findings of the postmenopausalendometrium observed in long-term tamoxifen users is stilllacking.

Katzenellenbogen et al4 studied the pharmacologic basisfor the cell- and promoter-specific action of steroid hor-mones. They referred to the cell and tissue selectivity thatsteroid hormones display as part of a tripartite system com-prising ligand, receptor, and effector. Their results showedthat coactivators and corepressors within the cell nucleusinteract with the ligand–estrogen receptor complex and thusmodify the transcriptional response to the ligand. The find-ings of Stackietitz et al2 in which 50% of the cell culturesunder estrogen-deprived conditions showed proapoptotic af-fects and the other 50% showed antiapoptotic effects, mightlay in the interaction of the steroid receptor–tamoxifen com-plex with these coactivators or corepressors.5 However, a com-parison between their and our findings is difficult, because wecompared apoptotic parameters in the endometrium of long-term tamoxifen users with nonusers, whereas Stackievitz et alcompared tamoxifen effects on the pre-G1 peak in endome-trial cell cultures in an artificial situation. We agree with theauthors that a better understanding of the effects of tamox-ifen on the endometrium is needed, and basic research in thisfield should be encouraged to unravel the mechanism ofaction of tamoxifen and other SERMs on the human endo-metrium.

M. J. E. MOURITS, MD, PHDE. G. E. DE VRIES, MD, PHDP. H. B. WILLEMSE, MDA. G. J. VAN DER ZEE, MD, PHDH. HOLLEMA, MD, PHDDepartment of Gynaecologic OncologyUniversity Hospital GroningenGroningen, The Netherlands

1. Mourits MJ, Hollema H, de Vries EG, et al: Apoptosis and apoptotisassociated parameters in relation to tamoxifen exposure in postmenopausalendometrium. HUM PATHOL 33:341-346, 2002

2. Stackievitz R, Drucker L, Radnay J, et al: Tamoxifen modulates apopto-tic pathways in primary endometrial cell cultures. Clin Cancer Res 7:415-420,2001

3. Mourits MJ, van der Zee AG, Willemse PH, et al: Discrepancy betweenultrasonography and hysteroscopy and histology of endometrium in postmeno-pausal breast cancer patients using tamoxifen. Gynecol Oncol 73:21-26, 1999

4. Katzenellenbogen JA, O’Mailley BW, Katzenellenbogen BS: Tripartitesteroid receptor hormone receptor pharmacology: Interaction with multipleeffector sites as a basis for the cell-and promotor-specific action of thesehormones. Mol Endocrinol 10:119-131, 1996

5. Shang Y, Brown M: Molecular determinants for the tissue specificity ofSERMs. Science 295:2465-2468, 2002

doi:10.1053/hupa.2003.39

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