RESUMEN
Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography-tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.
Asunto(s)
Neoplasias de la Mama , Mifepristona , Humanos , Ratones , Animales , Femenino , Mifepristona/uso terapéutico , Mifepristona/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Receptores de Progesterona , Antagonistas de Hormonas/uso terapéutico , Antagonistas de Hormonas/farmacología , PronósticoRESUMEN
OBJECTIVE: To investigate whether truncal distribution of fat mass (TDFM) is associated with variations of the hypothalamic-pituitary-adrenocortical (HPA) axis activity in prepubertal obese children. STUDY DESIGN: TDFM, assessed with dual energy X-ray absorptiometry and a comprehensive set of measures of HPA axis activity and reactivity have been studied in 45 prepubertal obese children aged 6 to 11 years (girls) and 6 to 13 years (boys). RESULTS: After adjustment for whole body fat mass (%) (WBFM), TDFM correlated positively with insulin (r = 0.50, 95% CI [0.23; 0.70]) and homeostasis model assessment of insulin resistance (r = 0.52, 95% CI [0.25; 0.71]). When adjusted for WBFM, TDFM correlated positively with morning plasma cortisol (r = 0.38, 95% CI [0.15; 0.64]) in the total population. TDFM correlated negatively with the rise of salivary cortisol after a standard meal (r = -0.43, 95% CI [-0.71; -0.02]), obviously in girls. When adjusted for WBFM and TDFM, morning plasma cortisol correlated positively with total cholesterol (r = 0.41, 95% CI [0.11; 0.65]) and triglyceride (r = 0.44, 95% CI [0.14; 0.67]). The rise of salivary cortisol after a standard meal was negatively (r = -0.56, 95% CI [-0.85; -0.01]) and positively (r = 0.74, 95% CI [0.16; 0.94]) correlated with homeostasis model assessment of insulin resistance in boys and girls, respectively. CONCLUSIONS: Association exists in prepubertal obese children between TDFM and markers of HPA axis activity. These data suggest that HPA axis could be involved early in life in obesity associated with pejorative metabolic profile.