Cyclical Iron Homeostasis: The Role of Sex Hormones in Female Iron Regulation

Iron homeostasis in premenopausal women is governed by a dual regulatory architecture that has been incompletely characterized in the clinical literature. The hepcidin-ferroportin axis, established as the master regulator of systemic iron flux, operates within a second-order hormonal framework in females of reproductive age: 17β-estradiol (E2) and progesterone (P4) directly modulate hepatic hepcidin transcription, superimposing a predictable, cycle-dependent oscillation on baseline iron availability. This review summarizes the molecular mechanisms underlying this cyclical regulation. E2 suppresses hepcidin expression through estrogen receptor-dependent regulation of the HAMP gene, mapped in hepatocyte models to an estrogen-responsive element (ERE) half-site. Preclinical evidence also implicates a competing pathway, mediated by the G protein-coupled estrogen receptor 1 (GPR30, also designated GPER1) and bone morphogenetic protein 6 (BMP6), with opposing upregulatory effects on hepcidin. Progesterone has an opposing effect, raising hepcidin in women when administered exogenously, an effect attributed in preclinical models to the progesterone receptor membrane component-1 (PGRMC1). When mapped onto the menstrual cycle, these hormonal actions predict a follicular phase of enhanced iron acquisition and a luteal phase of iron restriction. We distinguish that prediction from the evidence: the predicted late luteal hepcidin maximum is not evident in cohorts sampled serially across the cycle, and circulating interleukin-6 does not rise in the luteal phase, so the cycle-level consequence of the hormonal mechanism remains the central open question. The clinical implications extend to diagnostics and therapeutics: standard iron status biomarkers fluctuate predictably with cycle phase, confounding single-time-point assessments; and the clinical significance of these fluctuations differs mechanistically depending on whether the underlying deficit reflects absolute storage depletion, impaired functional delivery, or erythropoietic cellular restriction. This review proposes a mechanism-oriented biomarker subtyping framework to address this diagnostic gap and discusses cycle-synchronized iron supplementation as a biologically plausible hypothesis that warrants rigorous evaluation in future clinical trials.