Estrogens and Prolactin Do Not Regulate Maternal and Embryo Iron Homeostasis during Pregnancy

Iron is essential for maternal and fetal health but the molecular mechanisms ensuring increased iron availability during pregnancy are not well understood. Hepcidin is the key iron-regulatory hormone and functions by blocking iron absorption, recycling and mobilization from stores, effectively decreasing plasma iron levels. In healthy human and rodent pregnancies, maternal hepcidin decreases starting in the second trimester and is nearly undetectable by late pregnancy. This decrease in hepcidin allows for greater iron availability for transfer to the fetus. If hepcidin is not appropriately suppressed during pregnancy, it results in fetal anemia, intrauterine growth restriction, and even fetal demise in severe cases¹.

Unrelated to pregnancy, hormones estrogen and prolactin have been previously implicated in hepcidin regulation^2,3, although with conflicting results on the direction of hepcidin change^4-6. The levels of both hormones increase dramatically over the course of pregnancy, thus we hypothesized that they may modulate iron homeostasis during pregnancy. Studying the role of estrogens and prolactin during pregnancy is challenging as both hormones are required for pregnancy. Additionally, mice with global knockout (KO) of either estrogen receptor alpha or prolactin receptor are infertile. Thus, to determine the contribution of estrogens and prolactin on maternal hepcidin suppression during pregnancy, we generated liver-specific knockouts of either estrogen receptor alpha (Er-α^f/f;Alb-Cre⁺) or prolactin receptor (Prlr^f/f;Alb-Cre⁺), here abbreviated as ER-α KO and PRLR KO. Female ER-α KO, PRLR KO and WT mice were set up for timed pregnancy, and liver hepcidin mRNA, as well as maternal and embryo iron and hematological parameters were measured at E18.5 . Hepcidin suppression in ER-α KO and PRLR KO dams was not different from that in WT dams, suggesting that estrogens and prolactin are not major mediators of maternal hepcidin suppression. Additionally, maternal and embryo hematological parameters and liver iron concentrations were similar between WT, ER-α KO, PRLR KO pregnancies, further supporting our observation that estrogens and prolactin do not regulate iron homeostasis in pregnancy. The mechanisms by which maternal hepcidin is suppressed during pregnancy remain to be determined.

¹Sangkhae V et al, Blood, 2020

²Yang Q et al, Endocrinology, 2012

³Wang J et al, Nanomedicine: nanotechnology, biology and medicine, 2015

⁴Zhen et al, Hepatology, 2013

⁵Ikeda Y et al, PloS one, 2012

⁶Lehtihet M et al, PloS one, 2016