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Influence of Estrogens on Copper Indicators: In Vivo and In Vitro Studies


Classic copper indicators are not sensitive and specific for detecting excess copper exposure when this is higher than customary but not markedly elevated. Serum copper and ceruloplasmin (Cp) are the most commonly used indicators to assess nutritional status of copper. The objective of this paper was to study the influence of estrogens on these indicators and others used to assess early effects of excess copper exposure in humans and the expression of a set of copper related proteins in a hepatic cellular model. For the studies in humans, 107 healthy participants (18–50 years) were allocated as follows: group 1 (n = 39), women assessed on day 7 of their hormonal cycle; group 2 (n = 34), women assessed on day 21 of their hormonal cycle, and group 3 (n = 34, comparison group), healthy men. Participants received 8 mg Cu/day (as copper sulfate) during 6 months. Serum Cp and Cu, Cu–Zn–superoxide dismutase activity, liver function indicators [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyltransferase (GGT)], and serum Fe and Zn concentrations were measured monthly. In addition, the influence of estradiol on intracellular total copper content, hctr1, dmt1 and shbg mRNA abundance and hCTR1, and DMT1 expression was measured in HepG2 cells. Serum Cu, Fe, and Zn and liver aminotransferases but not Cu–Zn–superoxide dismutase varied depending on sex. Fe nutrition indicators, GGT, and ALT activities showed significant differences between the hormonal phases. Cellular experiments showed that estradiol increased cellular Cu concentration and hCTR1 and DMT1 mRNA expression and changed these proteins expression patterns. Estradiols significantly influence the responses to copper at the whole body and the cellular levels, suggesting that they help maintaining copper availability for metabolic needs.

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This investigation conducted in the University of Chile. It was funded by Fondecyt (CONICYT, Chile), grants 1040979 and 1070595. Authors thank Dr. Emilio Fernandez for his advice in defining the levels of estrogens and progesterone to form the study groups. They also thank the skillful work of all those involved in the sampling and samples processing that helped guaranteeing the quality of the field operation and of the data collected.

None have conflicts of interest to declare.

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Correspondence to Magdalena Araya.

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All authors have contributed significantly to the paper.

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Arredondo, M., Núñez, H., López, G. et al. Influence of Estrogens on Copper Indicators: In Vivo and In Vitro Studies. Biol Trace Elem Res 134, 252–264 (2010).

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  • Estrogens
  • Copper indicators
  • Liver aminotransferases
  • Cu–Zn–SOD
  • Uptake and copper transport