Iron deficiency impairs the health and wellbeing of women worldwide. Beyond anaemia, iron deficiency has a broad canvas of effects on the various tissues, organs and systems in the body,¹ affecting quality of life for many.

Natural health practitioners are ideally placed to assess nutritional status and identify women with or at risk of iron deficiency, with a clinical focus on prevention and treatment where indicated.

The Spectrum of Iron Deficiency

Iron deficiency occurs as a spectrum beginning with depleted ferritin (tissue iron stores) and minimal clinical symptoms. This can progress to exhaustion of iron stores, interference with iron-dependant biochemical reactions, impaired erythropoiesis (e.g. increased microcytes) and increasing severity of anaemia.^1,2

Iron deficiency anaemia (IDA) is the most common nutritional deficiency in the world and the leading cause of anaemia in both developed and developing countries. Its prevalence is greatest in menstruating women of reproductive age and preschool children.² Infants, children, pregnant and post-partum women, vegetarians and vegans, female endurance athletes and blood donors may also be at increased risk of iron deficiency.³

Iron Homeostasis

Iron is an essential element required for haemoglobin synthesis, cell growth and differentiation, neurotransmission, immunity and cardiopulmonary function.³ It also plays key roles in energy metabolism and gene expression.^1,2 These functions are so basic for survival that iron deficiency has the potential to impact every organ system.^1,2

Systemic iron homeostasis is controlled by the peptide hormone hepcidin. Hepcidin blocks dietary iron absorption and iron recycling; it is increased in response to inflammation and high levels of circulating iron, and decreased in iron deficiency, hypoxia and during blood loss.³

A Myriad of Causes

The aetiology of iron deficiency is multifactorial and may result from reduced intake, decreased absorption, increased requirements, chronic blood loss and other causes (see Figure 1).³

Figure 1. Causes of iron deficiency anaemia.³

[PPI, proton pump inhibitors; H2RA, H2 receptor antagonists; IRIDA, iron-refractory iron-deficiency anaemia; NSAIDs, non-steroidal anti-inflammatory drugs.]

A Common Clinical Presentation

A study investigating iron deficiency in women of reproductive age found 85.3% reported non-haematological symptoms, many of which are overlooked if patients are not directly questioned about them.²

Common signs of iron deficiency include fatigue, impaired physical and cognitive performance, poor concentration (brain fog), impaired immunity, aching and restless legs, and mood changes (anxiety or depression). ^2,3

When assessing patients’ iron status, look out for these clinical signs associated with deficiency: pale skin, conjunctiva and nail beds, breathlessness on exertion, cold intolerance, angular stomatitis, glossitis, ridged/brittle nails (or ‘spoon nails’), alopecia, fainting, vertigo, pica (ice cravings), headaches and tachycardia. ^2,3,4

Iron is Critical for Pregnancy and Childhood Development

Women have greater requirements for iron during pregnancy to support the increase in maternal red blood cells, maintain placental and foetal growth, and allow for potential loss during delivery.³

Iron deficiency and IDA during pregnancy are associated with adverse maternal and foetal outcomes, including an increased risk of postpartum haemorrhage (in the mother), and learning and memory impairments in children born to iron-deficient mothers.³ Postpartum anaemia is associated with depression, high levels of fatigue, poor cognition, and difficulties breastfeeding,³ commonly seen in woman after childbirth.

With around 45% of women entering pregnancy with low or absent iron stores,⁵ optimising iron status during preconception and pregnancy is critical for the health and wellbeing of female patients and their children.

Neuronal Networks

Appropriate levels of brain iron are necessary for optimal brain development and functioning in infancy and beyond. Diminished attention span and reduced performance in school have been reported in IDA. Depression, sleep disturbances, and reduced mental alertness also occur.¹ Alterations in GABA metabolism and downregulation of dopamine receptors in low iron states may contribute to deficits in learning, memory, and behaviour.^1,6

Iron plays a crucial role in maintaining neuronal activity and networks.² In subjects with iron deficiency, iron administration resulted in improvements in attention and working memory tests.² Iron concentrates in different parts of the nervous system and is involved in production of neurotransmitters such as serotonin, noradrenaline, and dopamine.⁶

Thyroid Dysfunction – Is Iron Deficiency Implicated?

A growing body of evidence suggests that iron deficiency may play a role in the pathogenesis of thyroid dysfunction, however further evidence is required.⁷ A 2023 systematic review and meta-analysis of 10 studies found that thyroid levels (FT3 and FT4) were lower in patients with iron deficiency, particularly in pregnant women.⁷

Iron deficiency can affect the hypothalamic-pituitary-thyroid axis, leading to altered thyroid hormone levels and a decreased response to thyroid-stimulating hormone. Iron is also essential for the activity of thyroid peroxidase, the enzyme that catalyses the iodination of tyrosine into thyroglobulin, a precursor for thyroid hormone synthesis.⁷

Blood Building with Iron Bisglycinate and Nutritional Cofactors

Iron supplementation may be effective to prevent IDA in those at risk or to treat patients with symptoms and pathology indicating iron deficiency.³

Iron bisglycinate is a well-tolerated form of iron that helps maintain normal iron levels. Iron bisglycinate has been shown to have superior bioavailability and tolerability compared to other iron salts.^8,9 Other supportive nutrients include ascorbic acid for enhanced non-haem iron absorption,^10,11 and thiamine (vitamin B1) which promotes iron absorption.¹²

Active vitamin B2 (riboflavin sodium phosphate) participates in the mobilisation of iron from ferritin stores,^13,14 energy production¹⁵ and methylation,¹⁶ while active folate (5-methyltetrahydrofolate) is essential for erythropoiesis.¹⁷ Together, these nutrients help to maintain iron homeostasis and support normal red blood cell production.

Updates in Iron Dosing

Recent research suggests oral iron should be limited to a single dose administered daily in the morning to maximise iron absorption.^18,19 Plasma hepcidin follows a circadian rhythm and typically increases over the day (gradually limiting absorption), so ideally iron doses should not be given in the afternoon or evening following a morning dose.¹⁸ Taking elemental iron in doses higher than 60 to 120 mg/day or every other day are unlikely to offer significant benefit in terms of iron repletion and may cause unintended side effects.¹⁹

Clinical Management and Prevention

Iron deficiency and iron deficiency anaemia are highly prevalent in women, compromising quality of life. Iron is responsible for a wide range of important physiological functions, with deficiency impacting every organ system.

This highlights the importance of screening patients for deficiency. When indicated, prescribing iron bisglycinate with blood building nutrients may assist in the clinical management of iron deficiency and aid prevention.

References

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2. Fernandez-Jimenez MC, Moreno G, Wright I, Shih PC, Vaquero MP, Remacha AF. Iron deficiency in menstruating adult women: much more than anemia. Womens Health Rep (New Rochelle). 2020 Jan 29;1(1):26-35. doi: 10.1089/whr.2019.0011.
3. Benson CS, Shah A, Stanworth SJ, Frise CJ, Spiby H, Lax SJ, et al. The effect of iron deficiency and anaemia on women's health. Anaesthesia. 2021 Apr;76 Suppl 4:84-95. doi: 10.1111/anae.15405.
4. Hechtman L. Clinical naturopathic medicine. 2nd ed. Chatswood NSW: Elsevier Australia; 2019. p. 173-5.
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6. Shah HE, Bhawnani N, Ethirajulu A, Alkasabera A, Onyali CB, Anim-Koranteng C, Mostafa JA. Iron deficiency-induced changes in the hippocampus, corpus striatum, and monoamines levels that lead to anxiety, depression, sleep disorders, and psychotic disorders. Cureus. 2021 Sep 20;13(9):e18138. doi: 10.7759/cureus.18138. 
7. Garofalo V, Condorelli RA, Cannarella R, Aversa A, Calogero AE, La Vignera S. Relationship between iron deficiency and thyroid function: a systematic review and meta-analysis. Nutrients. 2023 Nov 15;15(22):4790. doi: 10.3390/nu15224790. 
8. Fischer JAJ, Cherian AM, Bone JN, Karakochuk CD. The effects of oral ferrous bisglycinate supplementation on hemoglobin and ferritin concentrations in adults and children: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2023 Feb;nuac106. DOI: 10.1093/nutrit/nuac106
9. Abbas AM, Abdelbadee SA, Alanwar A, Mostafa S. Efficacy of ferrous bis-glycinate versus ferrous glycine sulfate in the treatment of iron deficiency anemia with pregnancy: a randomized double-blind clinical trial. J Matern Fetal Neonatal Med. 2019 Dec;32(24):4139-4145. DOI: 10.1080/14767058.2018.1482871
10. Lane DJR, Merlot AM, Huang MLH, Bae DH, Jansson PJ, Sahni S, et al. Cellular iron uptake, trafficking and metabolism: key molecules and mechanisms and their roles in disease. Biochim Biophys Acta. 2015 May;1853(5):1130-1144. DOI: 10.1016/j.bbamcr.2015.01.021
11. Sharma DC, Mathur R. Correction of anemia and iron deficiency in vegetarians by administration of ascorbic acid. Indian J Physiol Pharmacol. 1995 Oct;39(4):403-406.
12. Jacobs A, Owen GM. Effect of gastric juice on iron absorption in patients with gastric atrophy. Gut. 1969 Jun;10(6):488-490. DOI: 10.1136/gut.10.6.488
13. Funk F, Lenders JP, Crichton RR, Schneider W. Reductive mobilisation of ferritin iron. Eur J Biochem. 1985 Oct;152(1):167-172. DOI: 10.1111/j.1432-1033.1985.tb09177.x
14. Sirivech S, Driskell J, Frieden E. NADH-FMN oxidoreductase activity and iron content of organs from riboflavin and iron-deficient rats. J Nutr. 1977 May;107(5):739-745. DOI: 10.1093/jn/107.5.739
15. Haddad A, Mohiuddin SS. Biochemistry, citric acid cycle [Internet]. StatPearls: Treasure Island; 2022 [cited 2023 Feb 24]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541072/
16. Wan L, Li Y, Zhang Z, Sun Z, He Y, Li R. Methylenetetrahydrofolate reductase and psychiatric diseases. Transl Psychiatry. 2018 Nov;8(1):242. DOI: 10.1038/s41398-018-0276-6
17. Koury MJ, Ponka P. New insights into erythropoiesis: the roles of folate, vitamin B12, and iron. Annu Rev Nutr. 2004;24:105-131. DOI: 10.1146/annurev.nutr.24.012003.132306
18. Stoffel NU, von Siebenthal HK, Moretti D, Zimmermann MB. Oral iron supplementation in iron-deficient women: How much and how often? Mol Aspects Med. 2020 Oct;75:100865. doi: 10.1016/j.mam.2020.100865
19. Lo JO, Benson AE, Martens KL, Hedges MA, McMurry HS, DeLoughery T, et al. The role of oral iron in the treatment of adults with iron deficiency. Eur J Haematol. 2023;110(2):123-130. DOI: 10.1111/ejh.13892