By Risa Kerslake, RN, BSN

Restless legs syndrome (RLS), a sensorimotor sleep disorder, affects women more often than men. Pregnancy is a common precipitating event. Researchers don’t know the exact cause of RLS, but the discovery of potential sex differences can shed insight into clinical presentation, treatment modalities, and provide an overall better understanding of RLS to improve the sleep quality of patients. 

Sensory Versus Motor Symptoms

A retrospective analysis of 42 women and 42 men suggests women report mostly sensory symptoms, and men report more motor symptoms. Sensory symptoms of RLS are subjective feelings that scales such as the RLS-6 and the International Restless Legs Study Group Severity Rating Scale attempt to quantify with questions about the severity of the discomfort, the need to move for relief, and whether moving eases the uncomfortable feelings. Motor symptoms refer to the periodic limb movements tallied when the patient is asleep.¹

The study’s senior author Ambra Stefani, MD, PhD, says that when women have fewer leg movements, it could make clinicians assume their symptoms are less severe. But because the study links higher subjective severity measurements to women, perhaps the same RLS symptom burden is felt differently in women and men. Or maybe women are more aware of RLS symptoms compared with men.  

In general, Stefani, a neurologist at the Medical University of Innsbruck in Austria, recommends clinicians consider a sleep study to exclude other causes when sleep disturbances are severe “and to perform a sleep study when this does not seem to be explained enough by reported sensations.”

Research has not clearly proven that periodic leg movements actually disrupt sleep, says neurologist-sleep specialist Andy Berkowski, MD, who practices at ReLACS Health and was not involved in the study. These symptom differences could indicate separate RLS conditions, types, or variations. 

“What this is suggesting, which I’ve seen clinically, is men may develop the limb movements first, and then if their condition gets more severe, they’ll have the RLS sensations later on,” he says. But the clinical implications are still unknown.  

Is There a Connection to Reproductive Hormones?

One of the more obvious sex-specific features of RLS is its frequency in pregnancy. What’s less understood is why. Knowing this can lead to a better clinical approach to women during pregnancy, according to Mauro Manconi, MD, PhD, head of the Sleep Medicine Unit at the Neurocenter of Southern Switzerland. 

Manconi’s research looks at predicting early in pregnancy which women will develop RLS in later trimesters—a genetic predisposition. A phenomenon he’s studying is the rise in reproductive hormones around the second trimester that coincides with increasing severity of RLS symptoms. Manconi discovered these hormones decreased sharply within days of delivery and around childbirth, “the hormones disappear immediately—just on and off.”

It’s known that women with a family history of RLS are more likely to have RLS themselves in pregnancy. Women with RLS in pregnancy likely have experienced RLS prior to becoming pregnant. RLS during pregnancy has a greater chance of a woman developing an idiopathic form in the future. 

“To be able to explain to women that they may have these symptoms, which may even be severe, and that treatment is available can alleviate fears,” says Manconi. Better understanding of genetic predispositions can also prompt clinicians to keep a watchful eye on laboratory values and take a more pragmatic approach to iron needs, vitamin B12, and folate, as well as physical activity, nutrition, and sleep hygiene, says Manconi. 

The role of hormones in RLS has continued to perplex experts. Reproductive hormones like estrogen and progesterone are likely involved in RLS, but it may have more to do with changes in these hormones, rather than the hormones themselves. When RLS symptoms can be at their most severe in the latter half of pregnancy, estrogen and progesterone levels are higher. “But in comparing women with and without RLS and comparing the value of estrogen and progesterone during pregnancy, we couldn’t find any major difference,” says Manconi.

But it doesn’t mean hormones aren’t involved. There’s evidence demonstrating that women with RLS during pregnancy are already genetically predisposed.² “Estrogen and progesterone may act as a trigger of symptoms during the second trimester. The reason for having RLS in some women and not in others might be because of the genetic predisposition in having RLS under hormonal influence,” Manconi says.

Mark Buchfuhrer, MD, a clinical associate professor at Stanford Medicine, says he hasn’t seen differences in how men and women present with symptoms, but it doesn’t mean there aren’t any. “RLS is difficult to describe. Every time I get a new patient, I ask them to describe what their symptoms feel like. They say, ‘All I can tell you is, I’ve got to move.’ I hear that from men and women equally.”

Buchfuhrer has seen RLS symptoms both improve and worsen with hormonal birth control pills as well as with the start of menopause or beginning hormone replacement therapy. “Menopause could be one year or 15 years, and women have different hormonal levels, so you’d have to do huge studies to see what’s going on,” Buchfuhrer says.

At the moment, there’s no clear data to suggest women withdraw or avoid hormone replacement therapy because of RLS, according to Manconi.

Understanding Iron Levels

Genetic and environmental factors could potentially predispose some pregnant women to RLS. “We don’t understand this as well as we would like, but we do know that one of the best and safest treatments for pregnant women is an iron infusion,” says Buchfuhrer.

Lower iron levels are a risk factor for RLS in both men and women. Ferritin and iron levels in the blood are the best measures available for what clinicians think is in the brain. Indication criteria for iron infusion is at or below 100 μg/l for intravenous iron. But this can be patient-specific. Some patients need iron if their levels drop to below 120—others who are 250, explains Buchfuhrer. “What’s in the blood may not correlate to what’s in the brain,” he says.

A concern with getting an accurate picture of someone’s iron levels has to do with the nature of ferritin. Ferritin is an acute-phase reactant, which can rise during inflammatory events and be falsely high as a representation of iron stores. Since women are at higher risk for autoimmune conditions, they can frequently present with ferritin out of proportion, says Buchfuhrer. Iron saturation below 20% may be a more reliable indicator of iron deficiency if that’s the case, though iron saturation can also be falsely elevated due to recent intake of food or iron supplements in proximity to the blood testing.  

Future Biomarkers Within Cerebrospinal Fluid

One way to study brain biological processes and how they relate to neurological disorders is to look at cerebrospinal fluid (CSF). Exploring sex differences in cerebrospinal fluid composition in RLS, says Maria Paola Mogavero, MD, a neurologist at Vita Salute San Raffaele University in Italy, will hopefully pave the way for a better understanding.

Mogavero, in collaboration with Brian Koo, MD (Yale University, where the study was conducted) and Raffaele Ferri, MD (IRCCS Oasi Troina, Italy), looked at proteins in the cerebrospinal fluid of 22 people with RLS and compared them to 18 people without RLS. The published study describes the proteomic composition of cerebrospinal fluid in RLS patients compared to controls, focusing on sex differences, and assessed over 7,000 peptides. Cerebrospinal fluid analysis revealed more pronounced proteomic alterations in males than females, 68 compared to 17, respectively.³

It indicates the sex difference in RLS, starting from puberty, may be rooted in biological causes, according to Mogavero, in particular, related to a possible role of estrogens, as suggested by clinical, neurophysiological, and transcriptomic studies on RLS, published by this research group in the past three years. “This hypothesis led to our study on sex-related differences in the CSF in RLS, considering that estrogens may modulate the different protein composition in the CSF. Indeed, we found a significantly higher number of differentially abundant proteins in males compared to females,” says Mogavero. “The inflammatory processes, as well as vascular mechanisms, associated with the disorder may be more involved in women than in men.” 

Mogavero says the study results also suggest males with RLS could be more susceptible to changes in clinical presentation in response to gene regulation and epigenetic influences (for example, environmental variation such as infections, diet, stress, pollution, physical activity, and seasonal changes). “This finding could be important for therapeutic outcomes, particularly in males, considering that epigenetic factors are modifiable and that we demonstrated in a previous study that the therapeutic response may differ between the two sexes,” he says.

As research continues to uncover the biological underpinnings through cerebrospinal fluid analysis and proteomic studies, clinicians must recognize that RLS may not be a single uniform condition but rather a spectrum of disorders with distinct presentations based on sex. Moving forward, the development of targeted treatments that account for these sex-specific differences, combined with improved biomarkers and individualized iron management strategies, could enhance the quality of sleep for patients affected by this condition.

References

1. Holzknecht E, Hochleitner M, Wenning GK, et al. Gender differences in clinical, laboratory and polysomnographic features of restless legs syndrome. J Sleep Res. 2020 Jun;29(3):e12875.

2. Schormair B, Zhao C, Bell S, et al. Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction. Nat Genet. 2024 Jun;56(6):1090-99.

3. Mogavero MP, Peng G, Marchese G, et al. Sex differences in cerebrospinal fluid proteomics of patients with restless legs syndrome. Sleep. 2025 Apr 26:zsaf112.

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