Restless legs syndrome (RLS) is a neurological condition characterised by an uncomfortable urge to move the legs, typically worst in the evening and at rest, and partially or fully relieved by movement. It is more common in women than men, and its prevalence increases during pregnancy and at menopause, both periods of significant hormonal change. For many perimenopausal women, RLS either begins or worsens at this stage, and clinicians rarely connect it to the hormonal transition.

The connection is mechanistic and it matters: RLS is a significant driver of sleep disruption that compounds every other perimenopausal symptom it accompanies.

What RLS Feels Like

The sensation varies between people. Common descriptions include crawling, creeping, tingling, pulling, or an irresistible itch deep inside the legs that cannot be scratched. In most cases it is not painful in the conventional sense, though severe presentations can be. It is bilateral in most people, though one leg may be more affected. It is consistently worse in the evening and when lying down, which means it directly interferes with sleep onset.

Many women with RLS also experience periodic limb movements of sleep (PLMS): involuntary leg jerks or kicks during sleep that may wake them or their partner. These can occur without the conscious sensation of RLS and are confirmed by polysomnography.

The Dopamine Connection

The primary physiological mechanism of RLS involves dopaminergic pathways in the central nervous system, particularly the A11 diencephalospinal pathway, which projects from the hypothalamus down the spinal cord and regulates sensory and motor thresholds in the limbs.[1]

Dopamine function in this pathway is circadian, peaking in the morning and falling in the evening. This directly explains why RLS is worst at night: dopaminergic inhibition of sensory signals is at its lowest in the evening. When this system is already compromised, by iron deficiency, genetic factors, or hormonal changes, the evening nadir produces symptoms.

Estrogen modulates dopamine synthesis, transport, and receptor sensitivity. Animal studies have shown that estrogen increases dopamine availability in several brain regions, and that estrogen withdrawal reduces dopaminergic function.[2] This provides a plausible mechanism for why RLS onset or worsening correlates with the estrogen fluctuations of perimenopause.

Iron and Its Central Role

Iron deficiency is the most clearly established correctable risk factor for RLS, even without anaemia. Iron is a cofactor for tyrosine hydroxylase, the enzyme that converts tyrosine to L-DOPA in the dopamine synthesis pathway. Low brain iron reduces dopamine synthesis capacity, worsening the dopaminergic deficit that underlies RLS.[3]

The relevant measure is brain iron status, not peripheral iron. The blood-brain barrier creates a compartment in which brain iron can be low while serum ferritin appears normal. Research by Allen et al. has established that a serum ferritin below 75 mcg/L (some guidelines use 50 mcg/L) is associated with RLS even in patients without anaemia, and that iron supplementation in this range produces clinically meaningful improvement in RLS severity.[4]

Standard NHS testing for anaemia uses a threshold of 12–13 mcg/L for ferritin. A result that returns as "normal" by anaemia criteria may still represent iron insufficiency from an RLS perspective. If you have RLS symptoms, ask specifically for ferritin and request the numerical result, not just a "normal/abnormal" interpretation.

Why Perimenopause Raises Risk

Several converging factors explain the peak in RLS prevalence during perimenopause:

Estrogen decline and dopamine. Falling estrogen reduces dopaminergic tone in pathways that modulate sensory processing in the limbs.

Iron status changes. Perimenopausal women may have accumulated iron depletion from years of menstruation. As cycles become irregular and then cease, the ongoing menstrual iron drain stops, but women who enter perimenopause with low-normal ferritin carry that deficit forward. Lower estrogen also reduces gut iron absorption efficiency.[5]

Sleep disruption feedback. Sleep deprivation itself worsens RLS severity, because sleep is the period when dopamine systems restore function. Vasomotor-disrupted sleep in perimenopause creates a cycle in which poor sleep worsens RLS, which further disrupts sleep.

Magnesium deficiency. Magnesium insufficiency, common in midlife women and worsened by estrogen decline, is associated with both muscle cramps and RLS. Magnesium has an inhibitory effect on NMDA receptors that, when absent, may increase excitatory signalling in limb sensory pathways.[6]

Diagnosis

RLS is a clinical diagnosis based on four essential criteria, often abbreviated as URGE: - Urge to move the legs - Rest induced (symptoms are worse at rest) - Gets better with movement - Evening and nighttime predominance

These four criteria, confirmed by history, are sufficient for diagnosis. No imaging or electrophysiology test is required. A GP can diagnose RLS.

Before treating, it is worth excluding secondary causes and correctable contributors: - Full blood count and serum ferritin (with the numerical result) - Kidney function (chronic kidney disease is a strong risk factor for RLS) - Thyroid function (hypothyroidism can cause or worsen RLS) - Glucose (diabetes and peripheral neuropathy can mimic RLS)

Medication review matters too. Several common medications worsen RLS: antihistamines (including those in over-the-counter sleep aids), antiemetics (metoclopramide, prochlorperazine), antidepressants (SSRIs, tricyclics), and antipsychotics. If any of these are being taken, discussing alternatives with the prescriber is worth considering.

What Actually Helps

Iron supplementation is the first step if ferritin is below 75 mcg/L. Oral ferrous sulphate or ferrous fumarate taken on an empty stomach (or with vitamin C, which improves absorption) for 3 to 6 months is standard. Retesting ferritin at 3 months confirms response. RLS symptom improvement often lags the ferritin increase by 4 to 8 weeks.

Magnesium at 300 to 400 mg glycinate or citrate at bedtime has shown benefit in RLS in small trials, with a plausible mechanism and good tolerability. A reasonable adjunct alongside iron correction.[6]

Sleep hygiene targeted at RLS. Keeping legs cool at bedtime (cool room, light bedding), leg stretching or massage before bed, and avoiding triggers such as caffeine, alcohol, and sedating antihistamines, to reduce symptom severity in the vulnerable evening window.

Aerobic exercise during the day (not too close to bedtime) consistently reduces RLS severity in controlled trials, likely through its effects on dopaminergic function and iron utilisation in muscle.[7]

HRT. Several observational studies and case series have found improvement in RLS symptoms in perimenopausal women following initiation of estrogen therapy, consistent with the dopaminergic mechanism.[8] This is not a licensed indication for HRT and the evidence is observational rather than from randomised trials, but it adds to the potential benefits for women considering HRT for other reasons.

Prescription treatment. When lifestyle and iron correction are insufficient, first-line pharmacological treatment for RLS in the UK includes dopamine agonists (pramipexole, ropinirole) at low doses, and pregabalin or gabapentin. These are effective but carry side-effect profiles requiring consideration; dopamine agonists in particular carry augmentation risk (the paradoxical worsening of RLS over time). A GP or neurologist prescribes these; they are not available over the counter.

## References [1] Clemens, S., Rye, D., Hochman, S. (2006). Restless legs syndrome: Revisiting the dopamine hypothesis from the spinal cord perspective. Neurology, 67(1), 125–130. https://doi.org/10.1212/01.wnl.0000223316.53428.c9

[2] Weick, B. G., Bhansali, P., Bhansali, S., Solberg, R. A. (1993). Estrogen effects on dopamine synthesis: Influence on L-DOPA and ergot alkaloid interactions. Journal of Pharmacology and Experimental Therapeutics, 266(2), 767–773.

[3] Connor, J. R., Ponnuru, P., Wang, X. S., Patton, S. M., Allen, R. P., Earley, C. J. (2011). Profile of altered brain iron acquisition in restless legs syndrome. Brain, 134(4), 959–968. https://doi.org/10.1093/brain/awr012

[4] Allen, R. P., Auerbach, S., Bahrain, H., Auerbach, M., Earley, C. J. (2013). The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. American Journal of Hematology, 88(4), 261–264. https://doi.org/10.1002/ajh.23397

[5] Hercberg, S., Preziosi, P., Galan, P. (2001). Iron deficiency in Europe. Public Health Nutrition, 4(2B), 537–545. https://doi.org/10.1079/phn2001139

[6] Hornyak, M., Voderholzer, U., Hohagen, F., Berger, M., Riemann, D. (1998). Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: An open pilot study. Sleep, 21(5), 501–505. https://doi.org/10.1093/sleep/21.5.501

[7] Aukerman, M. M., Aukerman, D., Bayard, M., Tudiver, F., Thorp, L., Bailey, B. (2006). Exercise and restless legs syndrome: A randomized controlled trial. Journal of the American Board of Family Medicine, 19(5), 487–493. https://doi.org/10.3122/jabfm.19.5.487

[8] Dzaja, A., Wehrle, R., Lancel, M., Pollmacher, T. (2009). Elevated estradiol plasma levels in women with restless legs during pregnancy. Sleep, 32(2), 169–174. https://doi.org/10.1093/sleep/32.2.169