Background Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain. Methods In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of −2.5 or less at the hip or spine or a T score of −2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels. Results During a median of 34 months of treatment, the tibolone group, as compared wit h the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P = 0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P = 0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P = 0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups. Conclusions Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. (ClinicalTrials. gov number, NCT00519857.)

After separation by means of preparative isoelectrofocusing, the isohormones of a Chinese hamster ovary (CHO)-derived recombinant follicle stimulating hormone (rFSH, Puregon) were characterized with respect to structural and functional features. A carbohydrate analysis revealed that rFSH isohormones with a low isoelectric point (pl) have a high sialic acid/galactose ratio and are rich in tri- and tetra-antennary N-linked carbohydrate chains in comparison with the high pl isohormones. The relative basic isohormones exhibit receptor binding activity and intrinsic bioactivity 2-3-fold higher than the relative acidic isohormones. However, due to their lower clearance rate these acidic isohormones displayed a 20-fold higher in-vivo bioactivity in the rat. A comparison of the isohormone profile of rFSH and urinary FSH (Metrodin) revealed that rFSH contains about 2-fold more basic isohormones with pl > or = 4.7 and 2-fold less acidic isohormones with pl < 4.1. In-vitro studies showed that the receptor binding affinity and intrinsic bioactivity of both FSH preparations are similar. Also the in-vivo efficacy and the pharmacokinetic behaviour of rFSH and urinary FSH in the rat were similar, which is not surprising since both preparations were compared in terms of in-vivo bioactivity calibrated in the rat Steelman-Pohley assay. However, in dogs the bioavailability of rFSH was lower than that of urinary FSH, which is in agreement with the higher percentage of relative basic isohormones in rFSH. This suggests that the pharmacokinetic behaviour of FSH in rats and dogs is different, which is supported by the much longer elimination half-life of rFSH and urinary FSH in dogs (27.9 and 30.4 h respectively) compared with rats (11.4 and 10.4 h respectively) for rFSH and urinary FSH respectively. The observed differences in pharmacokinetic behaviour in dogs and rats indicate that the rat Steelman-Pohley assay might not be a valid model for the prediction of the FSH bioactivity in species other than rat.

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10519 Background: Large recent studies have shown increased mammographic density, breast pain and a marginally increased risk of breast cancer in women treated with continuous combined estrogen/progestogen (ccEPT), while tibolone has a minimal effect. A placebo-controled clinical trial (STEM), approved by several ethical comities, has been initiated to assess effect and potential mechanism of action of tibolone on breast tumor. We present the results on 12 angiogenesis-related parameters. Methods: 102 women with breast cancer who had to undergo a mastectomy were treated for 2 weeks with tibolone 2.5 mg/day or placebo. RNA was extracted from tumor snap-frozen biopsies (paired before and after treatments) and reverse-transcripted into 2 cDNA batches on which 6 distinct PCRs were performed in duplicate per parameter/sample. A vascular density (VD) index was determined on CD31 specifically stained tumor sections by counting 10 fields per section on 5 distinct sections per biopsy. Results: The validity of the VD evaluation is highlighted by the high correlation coefficient (r = 0.81) between the data within the placebo group at a 2 week interval. In the tumor samples, no change of the VD index was seen. Since it could be argued that VD index could not correctly reflect a modulation of angiogenesis after only 14 days of treatment, we looked at a potential change of the expression of a large array of angiogenesis-related factors (VEGFs, VEGFRs, PAI-1). No modification of the expression in any of these factors was observed. Conclusions: Our data lead to conclude that, in this study, tibolone displays a neutral effect on angiogenesis in breast tumor. [Table: see text]