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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.

Objectives: To develop a condition-specific quality of life (QoL) questionnaire to assess the symptoms of the decline in testosterone that occurs as men age, otherwise known as the andropause. Methods: Two focus groups of patients with low testosterone levels and an expert panel of physicians in the treatment of male testosterone deficiency. Results: The patient focus groups confirmed that men are unlikely to realise they have low testosterone levels until this is diagnosed and that they are unlikely to share their experiences with peers. Both patients and physicians considered decreased energy levels and impaired sexual performance had the greatest adverse impact on well-being. Patients generally felt that testosterone replacement therapy led to improved energy levels and, to a lesser extent, improved libido and erectile function. Evaluation of the responses resulted in the identification of seven key domains (energy, emotional, social, social emotional, mental functioning, physical functioning and sexual functioning) that should be considered when assessing the impact of andropause on QoL. Conclusions: Understanding the impact of low testosterone levels on QoL is critical to diagnosis and effective treatment. The use of an andropause-specific QoL questionnaire will facilitate quantification of patient experiences and may thus improve subsequent therapy.

Low HDL cholesterol increases the risk of coronary heart disease. Treatment of postmenopausal women with tibolone lowers HDL cholesterol. We elucidated the consequences of this unwanted side effect in a randomized, double-blind study, where 12 women received 2.5 mg tibolone per day and 6 women, placebo. Blood samples were collected on days − 1 (i.e. baseline), 28, 56, and 84 for the analysis of various parameters of lipid metabolism and HDL function. Compared to placebo, treatment with tibolone led to statistically significant decreases of HDL cholesterol ( − 22% to − 32%), apoA-I ( − 14% to − 22%), and HDL subclass LpA-I ( −30% to −40%) but to no significant changes in apoA-II and HDL subclass LpA-I,A-II. These changes were not associated with statistically significant changes in the activity of plasma to release 3 H-cholesterol from radiolabeled fibroblasts or in the serum activity of the anti-oxidative enzyme paraoxonase/arylesterase. There were no significant changes in either serum levels of triglycerides, LDL cholesterol, apoB, and leptin, or in LDL size. We conclude that changes in insulin do not contribute to the lowering of HDL cholesterol by tibolone. Despite decreased HDL cholesterol, putatively anti-atherogenic activities of HDL remained unchanged. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

Background: We sought to evaluate the incidence and clinical impact of luteinizing hormone (LH) rises prior to and during gonadotropin-releasing hormone (GnRH) antagonist treatment started on day 5 or 6 of ovarian stimulation with recombinant follicle-stimulating hormone (rFSH). Methods: Pooled data from three trials with the GnRH antagonist ganirelix started on day 5 (n = 961) and from five trials with ganirelix started on day 6 (n = 1135) of ovarian stimulation with rFSH were retrospectively analyzed. Results: The incidence of LH rises (LH ≥ 10.0 IU/L) prior to ganirelix treatment was 2.3% and 6.6% on ganirelix start days 5 and 6, respectively (P < 0.01). During ganirelix treatment this incidence was 1.2% and 2.3%, respectively (P = 0.06). Women with LH rise on day 5o r 6h ad ah igher ovarian response with more oocytes recovered, mean ±S D, 12.9 ±8 .5 versus no LH rise, 10.2 ± 6.4 (P < 0.01). In women with and without LH rise prior to ganirelix treatment the ongoing pregnancy rates were similar (26.0% vs 29.9%; odds ratio [OR], 0.89; 95% confidence interval [CI], 0.55-1.44). Women with LH rise during ganirelix treatment had a lower ovarian response with 7.5 ± 6.7 oocytes recovered versus no LH rise, 10.2 ± 6.4 (P = 0.02) and a tendancy for a lower chance of ongoing pregnancy (16.7% vs 29.9%; OR, 0.52; 95% CI, 0.21-1.26). Conclusions: The incidence of early and late LH rises was low but may be further reduced by initiating ganirelix on stimulation day 5 rather than on day 6. In contrast to women with an early LH rise, women with a late LH rise may have a reduced chance of ongoing pregnancy.

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.