{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:04:56Z","timestamp":1790701496524,"version":"4.1.0"},"reference-count":98,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>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: 17\u03b2-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.<\/jats:p>","DOI":"10.31083\/fbl54404","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:21:51Z","timestamp":1790698911000},"source":"Crossref","is-referenced-by-count":0,"title":["Cyclical Iron Homeostasis: The Role of Sex Hormones in Female Iron Regulation"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0607-7630","authenticated-orcid":true,"given":"Darsiha","family":"Balakirishnan","sequence":"first","affiliation":[{"name":"School of Medicine, University of Western Australia, Perth, WA 6100, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6211-4030","authenticated-orcid":true,"given":"Fanija","family":"Dukovski","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Western Australia, Perth, WA 6100, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8071-9616","authenticated-orcid":true,"given":"Heather","family":"Bytheway","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Western Australia, Perth, WA 6100, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5546-3465","authenticated-orcid":true,"given":"Cory","family":"Dugan","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Western Australia, Perth, WA 6100, Australia"},{"name":"Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA"},{"name":"School of Population Health, Curtin University, Perth, WA 6100, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Beard JL. 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