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Iron Supplementation for Women with Iron Deficiency: Less May Be More

December 30, 2021

Iron supplements can replete iron stores and increase hemoglobin levels in individuals with an iron deficiency, but it can come with a price in the form of gastric irritation, nausea, epigastric discomfort, and constipation. Iron supplementation also acutely increases the circulating plasma hepcidin level (the key regulator of systemic iron balance in mammals), the magnitude and duration of which has not been characterized in humans.

A recent Blood study conducted by Diego Moretti, PhD, from the Institute of Food Nutrition and Health in Zurich, Switzerland, and colleagues sought to quantify the acute iron-induced increase in hepcidin at different iron doses and to measure the effect of iron supplementation administration on hepcidin, iron absorption, and iron status markers.

"Optimizing the absorption of iron from supplements may allow for more effective supplementation schedules with higher effectiveness," Dr. Moretti told ASH Clinical News. Absorption of iron supplements, he explained, varies widely depending on food consumption and timing.

A total of 54 healthy, non-anemic women 18 to 45 years old with depleted iron stores were included in the study. Subjects had no chronic medication use, no reported chronic disease, not pregnant or lactating, had not provided blood donations in the previous four months, did not smoke, and had a body mass index between 18-25 kg/m2. Study participants also had not taken mineral, vitamin, or herbal supplements within two weeks of the study's start date and during the entire duration of the study.

Dr. Moretti and co-authors actually conducted three separate studies to examine the iron-hepcidin relationship: First, a dose-finding investigation in which iron supplements were administered in four different concentrations (40, 60, 80, 160, and 240 mg) at eight hours fasting on one day (study 1, n=25); second, in which supplements were given on two consecutive days (study 2, n=16); and third, a study giving three 60 mg iron doses (twice-a-day dosing) within 24 hours (study 3, n=13).

In all three studies, participants acted as their own controls. Iron absorption was assessed by measuring the amount of stable isotopic tracers incorporated in red blood cells 14 days post-administration.

Studies 1 and 2 indicated that 24 hours after doses of 60 mg of iron or higher were administered, serum hepcidin was increased, while fractional iron absorption was decreased by 35 to 45 percent (p<0.01 for both). With each increased dose of iron, fractional absorption decreased, while absolute absorption increased (p<0.001 for both). Also, a six-fold increase in iron dose (from 40 mg to 240 mg) resulted in just a three-fold increase in iron absorbed: 6.7 mg to 18.1 mg.

Study 3 found that total iron absorbed from three doses was not significantly greater than the iron absorbed from two morning doses.

"Our data show that fractional absorption in iron-depleted women is highest at low iron doses (40-80 mg) and that acute, consecutive-day dosing results in decreased iron bioavailability," the authors concluded. "Providing 60 mg of iron twice-daily amplified the plasma hepcidin increase and decreased the fractional absorption of both the afternoon dose and the next morning dose, so that total iron absorbed from the three doses [two mornings and one afternoon] was not different to that from two morning doses."

"In the short-term in this population, iron at doses of 60 mg and higher increases hepcidin, which has a detrimental effect on iron absorption of the subsequent dose on the next day," Dr. Moretti said. "In addition, our data suggest that the common practice of splitting doses to the morning and the afternoon does not increase the bioavailability. On the contrary, it appears that concentrating the supplementation to the morning provides additional absorbed iron."

The researchers noted limitations of the study, including the small sample size and the exclusion of patients with anemia. Anemic patients may respond differently to iron supplementation than the iron-depleted non-anemic patients who were included.

Longer-term studies are needed to confirm these results, and to investigate whether alternate-day, low-dose iron can maximize fractional iron absorption, increase dosage efficacy, and ultimately improve tolerance of iron supplements.


Moretti D, Goede JS, Zeder C, et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015 August 19. [Epub ahead of print]


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