Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial.

STUDY QUESTION: Does an estradiol-based combined oral contraceptive (COC) have a milder effect on the serum proteome than an ethinylestradiol (EE)-based COC or dienogest (DNG) only? SUMMARY ANSWER: The changes in serum proteome were multifold after the use of a synthetic EE-based COC compared to natural estrogen COC or progestin-only preparation. WHAT IS KNOWN ALREADY: EE-based COCs widely affect metabolism, inflammation, hepatic protein synthesis and blood coagulation. Studies comparing serum proteomes after the use of COCs containing EE and natural estrogens are lacking. STUDY DESIGN, SIZE, DURATION: This was a spin-off from a randomized, controlled, two-center clinical trial. Women (n = 59) were randomized to use either EE + DNG, estradiol valerate (EV) + DNG or DNG only continuously for 9 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were healthy, young, white volunteer women. Serum samples were collected before and after 9 weeks of hormonal exposure. Samples from 44 women were available for analysis (EE + DNG n = 14, EV + DNG n = 16 and DNG only n = 14). Serum proteins were analyzed by quantitative, discovery-type label-free proteomics. MAIN RESULTS AND THE ROLE OF CHANCE: Altogether, 446 proteins/protein families with two or more unique peptides were detected and quantified. The number of proteins/families that altered over the 9-week period within the study groups was 121 for EE + DNG and 5 for EV + DNG, while no changes were detected for DNG only. When alterations were compared between the groups, significant differences were detected for 63 proteins/protein families, of which 58 were between the EE + DNG and EV + DNG groups. The most affected functions during the use of EE + DNG were the complement system, acute phase response signaling, metabolism and the coagulation system. The results were validated by fetuin-B and cortisol-binding globulin ELISA and sex hormone-binding globulin immunoassay. LARGE SCALE DATA: Data are available via ProteomeXchange with identifiers PXD033617 (low abundance fraction) and PXD033618 (high abundance fraction). LIMITATIONS, REASONS FOR CAUTION: The power analysis of the trial was not based on the proteomic analysis of this spin-off study. In the future, targeted proteomic analysis with samples from another trial should be carried out in order to confirm the results. WIDER IMPLICATIONS OF THE FINDINGS: The EE-based COC exerted a broader effect on the serum proteome than the EV-based COC or the DNG-only preparation. These results demonstrate that the effects of EE in COCs go far beyond the established endpoint markers of estrogen action, while the EV combination is closer to the progestin-only preparation. The study indicates that EV could provide a preferable option to EE in COCs in the future and signals a need for further studies comparing the clinical health outcomes of COCs containing EE and natural estrogens. STUDY FUNDING/COMPETING INTEREST(S): Funding for this researcher-initiated study was obtained from the Helsinki University Hospital research funds, the Hospital District of Helsinki and Uusimaa, the Sigrid Juselius Foundation, the Academy of Finland, the Finnish Medical Association, the University of Oulu Graduate School, the Emil Aaltonen Foundation, the Swedish Cultural Foundation in Finland, the Novo Nordisk Foundation, Orion Research Foundation and the Northern Ostrobothnia Regional Fund. The funders had no role in study design, data collection and analysis, publishing decisions or manuscript preparation. T.P. has received honoraria for lectures, consultations and research grants from Exeltis, Gedeon Richter, MSD, Merck, Pfizer, Roche, Stragen and Mithra Pharmaceuticals. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02352090. TRIAL REGISTRATION DATE: 27 January 2015. DATE OF FIRST PATIENT'S ENROLMENT: 1 April 2015.

Health-related quality of life after a drowning incident as a child.

AIM OF THE STUDY: To describe health-related quality of life (HRQoL), quality-adjusted life years (QALYs) gained and school performance in subjects having received either bystander or emergency medical service personnel initiated cardiopulmonary resuscitation (CPR) after a drowning incident in childhood. MATERIALS AND METHODS: 64 children admitted to pediatric intensive care (PICU) after successful CPR between 1985 and 2007. Eleven died in the PICU, 9 other within 6 months. In 2009 all long-term survivors, except for two, lived at home. Of the 40 patients eligible for the study, 29 (73%) responded to a questionnaire. HRQoL was assessed with the generic 15D, or its versions for adolescents (16D) or children (17D), and compared to that of general population. These HRQoL scores, age-specific survival probabilities, and HRQoL scores of the general population were used in a Markov model to estimate the number of QALYs gained. RESULTS: Median age of the respondents was 17.3 (range: 3.0-28.4) years and 62% were male. At the time of drowning their median age had been 3.0 (range: 1.2-15.7) years. The drowning incident was associated with a significant loss in HRQoL in the oldest age group (total HRQoL total score 0.881 compared to 0.971 in the general population, P<0.01) but not in children (HRQoL score 0.944 vs. 0.938). When submersion time exceeded 10min mean HRQoL score was significantly lower than in patients with a shorter submersion (0.844 vs. 0.938, P=0.032). The mean undiscounted and discounted (at 3%) number of QALYs gained by treatment were 40.8 and 17.0, respectively. CONCLUSIONS: A good HRQoL will be achieved in the majority of patients surviving long-term after a drowning incident in childhood, although HRQoL is affected by the submersion time.