OBJECTIVE: Selective estrogen receptor modulators (SERMs) demonstrate tissue specific estrogenic and antiestrogenic effects. SERMs improve bone density having little effect on endometrial and no effect on breast cell proliferation. Combining estrogen with SERM to form a TSEC has been demonstrated to provide an improved blend of tissue specific agonist and antagonist effects. TSECs alleviate vasomotor symptoms, although their action in breast and uterine cells is not completely understood. Proliferating cell nuclear antigen (PCNA) is one of the best characterized markers of proliferation. Here we evaluated the effects of raloxifene (RAL), tamoxifene (TAM), lasofoxifene (LAS) and bazedoxifene (BZA) alone and in combination with E2 on PCNA gene expression in uterine and breast cells.DESIGN: In vitro study in breast and uterine cancer cell lines. MATERIALS AND METHODS: Ishikawa and MCF-7 cells were treated for 24 h with 10nM E2, RAL, TAM, LAS, BZA, or P, either alone or with E2. RNA was extracted, reverse transcribed and RTPCR performed three times in triplicate. PCNA mRNA expression was normalized to b-actin.RESULTS: PCNA mRNA expression was increased in both cell lines treated with E2. In MCF7 cells BZA and LAS alone (p<0.01) but not TAM or RAL significantly decreased PCNA expression. The response to E2 was significantly attenuated by all TSECs (p<0.01) except for RALþE2. In Ishikawa cells SERMs did not induce PCNA expression and all TSECs prevented estrogen induced PCNA expression.CONCLUSIONS: Estrogens induced proliferation of breast and uterine cells. Adding a SERM to estrogen, forming a TSEC, prevented the estrogen induced proliferation of both cell types. While TAM and RAL have shown clinical efficacy in prevention of breast cancer, these data suggest that other SERMs and TSECs have a similar or greater effect on suppressing breast cell proliferation without inducing uterine cell growth. TSECs are a promising menopausal therapy that will treat symptoms while demonstrating protective effects on breast and uterine cells.OBJECTIVE: To determine if the duration of the menopausal transition, as measured by patterns of change in serum E2 and FSH, differs by age at FMP. DESIGN: SWAN is a multi-site, longitudinal, observational cohort study of the menopausal transition conducted in community-based groups of women.MATERIALS AND METHODS: At baseline, 3302 menstruating women aged 42-52 in one of 5 ethnic groups were recruited and followed annually. Serum was obtained on days 2-5 of a spontaneous cycle or visit date þ/-90 days in non-cycling women, and assayed for E2 and FSH. This analysis includes data from 1215 women with a natural FMP and 1þ hormone value from baseline through follow-up 09, providing 9404 observations from FMP þ/-8 years. Data were analyzed using semi-parametric stochastic mixed modeling, first and second order derivatives, and piecewise linear mixed models. Data were stratified by mean age of menopause.RESULTS: Independent of age at FMP, mean E2 was stable until FMP-2, fell rapidly until FMPþ2, then b...