Aims The aim of this study was to establish the pharmacokinetic profile of serum oestriol (E 3 ) concentrations over 24 h following application of vaginal E 3 in chronic users (>12 weeks of E 3 use). The interindividual and intraindividual differences before and after E 3 were examined. Methods Ten women participated. Vaginal cream was omitted for ≥36 h prior to the study days. Blood sampling was performed for E 3 , oestradiol and oestrone concentrations prior to cream application and at 1, 2, 3, 5, 8, 10, 12 and 24 h afterwards. In five women, all samples were repeated on a separate day. Results E 3 was absorbed rapidly in most women. Peak serum E 3 concentration occurred around 2 h (range 1–5 h). The decline in E 3 concentrations was also rapid: falling <100 pmol L −1 in six out of ten women within 8 h and returning to ≤ 10 pmol L −1 at 24 h in nine out of the ten patients. Interindividual variability for peak concentrations was considerable (mean 546 pmol L −1 ; 95% CI 349–743). Area under the concentration–time curve (AUC) values over a dosage interval also varied widely: mean 2145 pmol.h L −1 ; 95% CI 1422–3233. However, repeated measurements in the same woman were highly (peaks: ρ = 0.94) or moderately (AUC: P = 0.74) correlated. Conclusions Postmenopausal E 3 concentrations are negligible. Serum E 3 concentrations of chronic users of E 3 cream varied greatly; however, concentrations declined rapidly within 8 h, generally reaching ‘postmenopausal’ levels by 24 h. The basis for the variation between subjects needs further elucidation. Additional research is required to establish the safety of topical E 3 .

OBJECTIVE:Mutations of genes encoding the four subunits of succinate dehydrogenase (SDH) have been associated with pheochromocytoma and paraganglioma (PPGLs), gastrointestinal stromal tumors (GISTs) and renal cell carcinomas (RCCs). These tumors have not been characterized in a way that reflects severity of SDH dysfunction. Mass spectrometric analysis now allows measurement of metabolites extracted from formalin fixed paraffin embedded (FFPE) specimens. We assess whether SDH deficiency in various tumor types characterized by loss of SDHB protein expression correlates with SDH dysfunction as assessed by the ratio of succinate:fumarate in FFPE specimens.PATIENTS AND METHODS:Sections of FFPE tumor specimens from 18 PPGL, 10 GIST and 11 RCC patients with known SDHx mutation status for SDH deficiency were collected for mass spectrometric analysis of succinate and fumarate.RESULTS:FFPE samples showed higher succinate:fumarate ratios in SDH-deficient PPGLs compared to SDH-sufficient PPGLs. Similarly, a higher succinate:fumarate ratio was able to distinguish SDH-deficient GISTs and RCCs from their SDH-sufficient counterparts with great selectivity. Interestingly, the cut-off value of the succinate:fumarate ratio was two-folds greater in RCCs than GISTs.CONCLUSION:Analyzing biochemical imbalances preserved in FFPE specimens with mass spectrometry expands the method and sample type repertoire available for characterisation of multiple neoplasias associated with SDH deficiency.