Is Magnesium Deficiency Driving Multi-System Dysfunction in Midlife Women?

Magnesium is one of the most clinically overlooked nutrients in midlife women - despite being essential for energy, hormone metabolism, neurotransmitter balance, and stress resilience.

It is involved in over 300 enzymatic reactions and is crucial for mitochondrial stability, blood glucose control, oestrogen clearance, and nervous system regulation. Yet, symptoms of magnesium deficiency are often dismissed or misattributed to anxiety, burnout, ageing, or even depression - particularly in perimenopausal and menopausal women.

The Testing Gap: Why Standard Lab Work Misses Magnesium Deficiency

In clinical practice, most women are told their magnesium levels are “normal” based on serum testing. But serum magnesium represents less than 1% of total body magnesium and does not accurately reflect tissue or intracellular levels where magnesium performs its biological work (Costello et al., 2016).

Many of the women I work with have “normal” serum magnesium yet present with:

• Persistent fatigue despite adequate sleep

• Muscle cramps or twitching

• Heightened sensitivity to stress

• Premenstrual tension or mood swings

• Heart palpitations, especially at night

• Difficulty falling or staying asleep

• Glucose instability and reactive hypoglycaemia

More accurate markers such as red blood cell (RBC) magnesium or ionised magnesium give a better window into intracellular stores and functional sufficiency - especially when these symptoms overlap.

Why Midlife Women Are Especially Vulnerable to Magnesium Depletion

As oestrogen and progesterone levels fluctuate during perimenopause and decline with menopause, magnesium needs often increase - yet absorption and retention decrease. Several converging factors make deficiency more likely in midlife:

Chronic Stress

Cortisol increases renal magnesium excretion, meaning chronic stress creates a continuous drain on magnesium stores (Seelig, 1994). This further sensitises the HPA axis, contributing to anxiety, mood lability, and poor sleep.

Proton Pump Inhibitors (PPIs)

Commonly prescribed for reflux or gastritis, PPIs impair absorption of ionised magnesium in the small intestine (Hess et al., 2012), often silently depleting levels over time.

Insulin Resistance

Insulin resistance increases urinary magnesium loss and reduces magnesium uptake into cells. This forms a vicious cycle: magnesium deficiency worsens insulin signalling and glucose control (Barbagallo et al., 2003), compounding metabolic dysfunction.

Low Vitamin D and Ferritin

Magnesium is a necessary co-factor for vitamin D activation (Rosanoff et al., 2012). Women with low ferritin or poor vitamin D status are often low in magnesium, creating a cluster of fatigue, hormonal fragility, and immune dysregulation.

Oestrogen Detoxification

Magnesium supports phase II liver detoxification pathways such as glucuronidation and sulfation, both essential for the safe metabolism of oestrogens (Nielsen, 2010). Deficiency can contribute to oestrogen dominance symptoms such as breast tenderness, heavy periods, and migraines.

Progesterone and GABA Synthesis

Progesterone supports calm, sleep, and emotional stability, but its synthesis depends on adequate levels of magnesium and vitamin B6, which also influence GABA (gamma-aminobutyric acid) production (Wienecke et al., 2009). Low GABA is linked to anxiety, insomnia, and increased sensory sensitivity.

Thyroid Conversion and Mitochondrial Function

Magnesium stabilises mitochondrial membranes and supports 5′-deiodinase, the enzyme responsible for converting T4 to active T3 thyroid hormone. Without magnesium, mitochondrial energy production and thyroid activation both suffer fueling fatigue, brain fog, and weight gain.

Magnesium Is Not a Co-Factor—It’s the Foundation

In functional medicine, we often talk about nutrient “co-factors,” but in many women, magnesium is not secondary. It is a core regulator of neuroendocrine stability, acting as the biochemical buffer across multiple axes:

• HPA axis: stress and adrenal regulation

• HPG axis: reproductive hormone balance

• HPT axis: thyroid and metabolic output

• Enteric nervous system: digestion and motility

• Mitochondrial axis: cellular energy production

Without enough magnesium, these systems become less responsive, more inflamed, and more prone to compensation.

Restoring Balance: Clinical Considerations

Magnesium repletion is rarely achieved through food alone in depleted individuals- especially where stress, medications, or gut dysfunction are involved. Therapeutic options may include:

• Magnesium glycinate – calming and well-tolerated

• Magnesium taurate – for cardiovascular and neurological support

• Magnesium malate – for mitochondrial support and fibromyalgia-type pain

• Topical magnesium – where digestive tolerance is low

• Co-factors – such as vitamin B6 and taurine to support absorption and utilisation

The Takeaway

For women in their 40s and beyond, magnesium is not optional. It is one of the most foundational, multi-system stabilisers we have - yet one of the most commonly missed. If you’re experiencing fatigue, mood instability, blood sugar swings, sleep disturbance, or perimenopausal symptoms that don’t respond to standard interventions, consider looking deeper at your magnesium status.

Testing beyond serum. Replenishing strategically. Supporting the systems that depend on it.

Magnesium may not fix everything, but for many women, it’s the missing piece.

References:

• Costello RB et al. (2016). Perspective: Serum Magnesium Concentration as an Indicator of Magnesium Status. Adv Nutr, 7(6):977–983.

• Seelig MS. (1994). Consequences of magnesium deficiency on the enhancement of stress reactions; preventive and therapeutic implications (a review). J Am Coll Nutr, 13(5):429–446.

• Hess MW et al. (2012). Severe hypomagnesaemia induced by proton pump inhibitors. Clin Kidney J, 5(4):390–394.

• Barbagallo M, Dominguez LJ. (2003). Magnesium and type 2 diabetes. World J Diabetes, 6(10):1152–1157.

• Rosanoff A, Weaver CM, Rude RK. (2012). Suboptimal magnesium status in the United States: are the health consequences underestimated? Nutr Rev, 70(3):153–164.

• Nielsen FH. (2010). Magnesium, inflammation, and obesity in chronic disease. Nutr Rev, 68(6):333–340.

• Wienecke MV et al. (2009). Progesterone enhances GABA synthesis in rat cerebellar neurons. J Neurochem, 110(3):807–818.