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Objective To investigate the potential drug interaction between tibolone and warfarin in healthy postmenopausal women. Methods and results The study was designed as a double-blind, randomized, placebo-controlled, two-way crossover study in postmenopausal women. After stabilization of the International Normalized Ratio (INR; a standardized prothrombin time, PT) between 1.4 and 2.0 with warfarin, subjects were randomized to receive either tibolone (2.5 mg/day) or placebo for 21 days. After a 7-day wash-out period (during which warfarin treatment was continued) the treatments were crossed over. Primary efficacy parameters were INR and coagulation Factors II, VII, VIIa and X (means of measurements at Days 18 and 20 and Days 46 and 48). Treatment with tibolone induced a statistically significant increase in INR (estimate of mean difference = 0.40; P = 0.002), and a statistically significant decrease in coagulation factors. Treatments were generally well tolerated and no clinically significant adverse events were observed. Conclusions Tibolone enhances warfarin-induced anticoagulation in postmenopausal women, as reflected by increases in INR and decreases in coagulation Factors II, VII, VIIa and X, compared to placebo. It is advisable to monitor for changes in coagulation status during (and after discontinuation of) simultaneous use of tibolone and warfarin.

Objective To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF. Design Phase 3 randomized, double-blind, noninferiority trial. Setting Multicenter trial. Patient(s) A total of 1,390 women aged 35–42 years. Intervention(s) A single injection of 150 μg of corifollitropin alfa or daily 300 IU of recombinant FSH for the first 7 days then daily recombinant FSH until three follicles reach ≥17 mm in size. Ganirelix was started on stimulation day 5 up to and including the day of recombinant hCG administration. If available, two good quality embryos were transferred on day 3. Main Outcome Measure(s) Vital pregnancy rate (PR), number of oocytes, and live birth rate. Result(s) Vital PRs per started cycle were 23.9% in the corifollitropin alfa group and 26.9% in the recombinant FSH group, with an estimated difference (95% confidence interval) of -3.0% (−7.4 to 1.4). The mean (SD) number of recovered oocytes per started cycle was 10.7 (7.2) and 10.3 (6.8) in the corifollitropin alfa and the recombinant FSH groups, respectively, with an estimated difference of 0.5 (−0.2 to 1.2). The live birth rates per started cycle were 21.3% in the corifollitropin alfa group and 23.4% in the recombinant FSH group, with an estimated difference (95% confidence interval) −2.3% (−6.5 to 1.9). The incidence of serious adverse events was 0.4% versus 2.7% in the corifollitropin alfa and recombinant FSH groups, respectively, and of ovarian hyperstimulation syndrome (OHSS; all grades) was 1.7% in both groups. Conclusion(s) Treatment with corifollitropin alfa was proven noninferior to daily recombinant FSH with respect to vital PRs, number of oocytes retrieved, and live birth rates, and was generally well tolerated. Clinical Trial Registration Number NCT01144416.

concentrations with ovarian response among women undergoing OI/IUI. DESIGN: Prospective cohort, 239 OI/IUI cycles, 119 women. MATERIALS AND METHODS: Urinary concentrations of 7 P metabolites [mono(2-ethylhexyl)-P (MEHP), mono(2-ethyl-5-hydroxyhexyl)-P (MEHHP), mono(2-ethyl-5-oxohexyl)-P (MEOHP), mono(2-ethyl-5-carboxypentyl)-P (MECPP), monobenzyl-P (MBzP), monoethyl-P (MEP), and monobutyl-P (MBP)] were measured using solid-phase extraction, high performance liquid chromatography, isotope dilution tandem mass spectrometry. Outcome measures: serum peak estradiol (E2) & follicle count (pre-ovulatory follicles R15mm & medium size:13-15mm). Mixed effect and Poisson regression models were used to evaluate the association of P concentrations with ovarian response adjusting for age, day-3 FSH, BMI, and accounting for multiple cycles. RESULTS: P metabolites were detected in urine from >70% of participating women. MEHP, MEP, and MBP concentrations were positively associated with both pre-ovulatory follicle count and E2 levels. Higher concentrations of all metabolites were associated with higher peak E2 levels. CONCLUSION: There was a significant trend for both a higher pre-ovulatory follicle count and peak E2 levels with higher P levels (mainly DEHP metabolites). These results raise concern that some P may alter endogenous steroid hormone signaling, thus affecting the follicle dynamics and response to gonadotropins. Supported by: NIEHS ES009718 & ES000002.