Adeline Angeli (1), Fabrice Lainé (1), Bruno Laviolle (1), Emmanuelle Comets (1,2)
(1) INSERM CIC 1414, Rennes, France; Université Rennes-1, Rennes, France (2) INSERM, IAME UMR 1137, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, Paris, France
Objectives: Iron is a key element for the organism, involved in many biological processes.Serum iron levels are regulated through digestive absorption from food and sophisticated storage mechanisms Hepcidin is a peptidic hormone regulating iron storage and release. It is synthesised by the hepatocytes, and interacts with ferroportin, a cellular iron-exporter located on macrophages, hepatocytes and intestinal cells, to prevent iron from being released from these cells into the general circulation . A recent analytical method developed to measure hepcidin allows its use in the diagnostic of iron-related pathologies such as iron overload or anaemia. Women lose iron during menstruation, which causes cyclic variations in iron-status variables [1]. The HEPMEN study was designed to follow serum levels of hepcidin and iron during the menstrual cycle.
Methods: Ninety menstruating women between 18 and 45 years of age were recruited in after a screening visit, where demographic covariates were recorded. Six fasting blood samples for determination of iron-status variables were taken in the morning throughout the cycle, starting on the second day of the period. Non-linear mixed effect models were used to describe the evolution of iron and hepcidin, first separately then simultaneously. Parameters were estimated using the Monolix software [2]. Diagnostics included VPC and npde [3].
Results: A general pattern was observed for both hepcidin and iron, consisting of an initial decrease during menstruation, followed by a rebound, and stabilisation during the second half of the cycle. Considerable fluctuations were observed in both iron and hepcidin levels, as well as in individual profiles.
We developed a joint model of iron and hepcidin. Menstruation induced a decrease of both molecules at the beginning of the menses, and the rebound was modelled as an increased input. Iron stimulated the release of hepcidin. Several covariates, including contraception, amount of blood loss and ferritin, were found to influence the parameters of the model. Simulations were then performed to evaluate the fluctuations of both variables during a typical cycle, and to establish recommendations for time of measurement.
Conclusions: Considerable fluctuations of hepcidin occur throughout the menstrual cycle. Hepcidin should be measured during the second half of the cycle, but the residual variability for hepcidin was large, reflecting daily intraindividual variations.
Acknowledgments: This work was funded by a grant from the PHRC inter-régional 2012 (PHRC/12-02)
References:
[1] Kim I, Yetley E, Calvo M. Variations in iron-status measures during the menstrual cycle. Am J Clin Nutr 1993; 58:705-9.
[2] Monolix User Guide, version 4.2.2. Lixoft 2013. http://www.lixoft.eu/wp-content/resources/docs/UsersGuide.pdf[3] Comets E, Brendel K, Mentré F. Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: The npde add-on package for R. Comput Meth Prog Biomed, 2008; 90:154-66.
Reference: PAGE 24 () Abstr 3389 [www.page-meeting.org/?abstract=3389]
Poster: Drug/Disease modeling - Other topics