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

Abstract

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.

Ceruloplasmin and Heart Failure in the Atherosclerosis Risk in Communities Study

“…In addition, we also found that in the Caucasian subgroup in ARIC, higher Cp levels were also associated with incident stroke and incident CVD events. Studies in animals and humans suggest that Cp levels are influenced by hormones 23, 24 . Prior observations in very small numbers of patients found higher mean Cp levels in women compared with men and in women taking HRT compared with those who did not 10 .…”

Update on the clinical management of Wilson's disease

“…Additional important cause of higher ceruloplasmin is elevated estrogen levels, most commonly induced by birth control pills or estrogen replacement therapy 33. Abnormally low ceruloplasmin levels <5 mg/dL are strongly suggestive of WD, but such low values can also be found in conditions with very low copper plasma values, especially with copper deficiency and aceruloplasminemia, which is a rare cause and an autosomal recessive condition caused by mutations in the ceruloplasmin gene 34,35.…”

Human copper homeostasis: a network of interconnected pathways

“…Larger amounts of CTR1 protein (and an increase in copper uptake) are observed in macrophages in response to hypoxia [9 •• ] or treatment with gamma-interferon [10 • ], both of which increase the flow of copper towards the secretory pathway. The physiologic signals such as 17-β estradiol may also modulate the response of CTR1 to changes in copper levels [11]. The complex kinetics and tissue specificity of CTR1 regulation is well illustrated by recent studies in fish [12].…”