New mouse studies suggest potential sex and gender differences in narcolepsy symptoms, but will the dissimilarities extend to humans?
By Lisa Spear
What, if anything, do sex and gender have to do with a patient’s narcolepsy journey? Biological and societal differences between men and women can influence how diseases manifest, so why are there still many more questions than answers around how narcolepsy impacts different genders?
A handful of recent animal studies, published in SLEEP, offer new clues but fall far short of firm answers. One mouse model found that female mice exhibit cataplexy earlier than male mice, but that symptom difference evened out a few weeks later.1 Another found biologically-driven sex-related differences exist in the symptomatology of narcolepsy type 1 mice—including increased wake at the expense of sleep during the dark phase and decreased rapid eye movement sleep in females compared to males—which the authors say “calls for including both sexes in future research.”2 A study of orexin knock-out mice found cataplexy occurrence was greatly influenced by estrous cycle.3
And a study published in Frontiers in Neuroscience in 2021 found some minor differences in narcolepsy symptoms (specifically, more cataplexy) in female mice.4
Whether the results will be replicated in humans remains to be seen, but there is some excitement about how these mouse studies could spur future research, says Markus Schmidt, MD, PhD, medical director for sleep medicine at the Sleep-Wake-Epilepsy Center at Inselspital, Bern University Hospital.
“When you see these results in the animal model, you think that maybe there is something that we have missed on the clinical side and we really need to know about it,” says Schmidt, who is also the medical director of the Ohio Sleep Medicine Institute in Columbus, Ohio, and is first author on a perspective article for SLEEP on the recent narcolepsy sex-differences research.5
“It just tells me that there may be some gender differences. It tells me that there might be some specific symptoms that may be different depending on gender that may be important to keep our eyes open about. We don’t know that yet, but we shouldn’t be surprised that perhaps females versus males have different symptomology,” says Schmidt.
Still, several clinicians interviewed by Sleep Review reported they have not detected any differences between the sexes when it comes to narcolepsy symptoms, treatment outcomes, or diagnosis onset.
“There’s really remarkably little research in this area. First, the incidence or prevalence seems to be roughly equal across both sexes, but if anything there seem to be more men who are affected—but it is difficult to know if it is not a bias that a few more men are diagnosed for one reason or another,” says Emmanuel Mignot, MD, PhD, the Craig Reynolds Professor of Sleep Medicine in the Department of Psychiatry and Behavioral Sciences at Stanford University and the director of the Stanford Center for Narcolepsy.
Mignot adds that mouse studies are helpful to test hypotheses but not much can be extrapolated about how these results will translate to humans.
Another study from Yale University found that men and women presented with remarkably similar narcolepsy symptoms, yet women were more likely to see a delay in diagnosis. Eighty-five percent of men were likely to be diagnosed by 16 years after symptom onset, whereas women waited 28 years.6
“I think the study from Yale is interesting, but it is a relatively small sample of patients,” says neurologist-sleep specialist Michael Thorpy, MB, ChB, who was not involved in the research.
Patients, male or female, seem to be very similar in terms of their symptoms, says Thorpy, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center in Bronx, NY.
So though mouse models now offer some potential clues about how the disease might differ across sex and gender, many scientists caution: Mice are not humans and we are far from able to draw any definitive conclusions for clinical practice.
That being said, there are socioeconomic differences between the genders that clinicians would be wise to keep in mind. Women undergo unique changes over their lifetimes, from puberty to pregnancy. Some women report changes in sleepiness closer to their menstrual cycle, says Mignot.
Socioeconomic stressors, such as childcare responsibilities, may also impact women more. “In my opinion, it is more the socioeconomic aspect that has an impact. I see a lot of women: sometimes they are a single mother with narcolepsy. It is much harder. We often ask more of women than men, so in some ways, the brunt of the disease is harder,” says Mignot.
Lisa Spear is associate editor of Sleep Review.
1. Sun Y, Tisdale R, Park S, et al. The development of sleep/wake disruption and cataplexy as hypocretin/orexin neurons degenerate in male vs. female Orexin/tTA; TetO-DTA Mice. Sleep. 2022 Dec 12;45(12):zsac039.
2. Piilgaard L, Rose L, Gylling Hviid C, et al. Sex-related differences within sleep-wake dynamics, cataplexy, and EEG fast-delta power in a narcolepsy mouse model. Sleep. 2022 Jul 11;45(7):zsac058.
3. Arthaud S, Villalba M, Blondet C, et al. Effects of sex and estrous cycle on sleep and cataplexy in narcoleptic mice. Sleep. 2022 Jul 11;45(7):zsac089.
4. Coffey AA, Joyal AA, Yamanaka A, Scammell TE. The impacts of age and sex in a mouse model of childhood narcolepsy. Front Neurosci. 2021 Mar 4;15:644757.
5. Schmidt MH, Bassetti CLA. Gender differences in narcolepsy: What are recent findings telling us? Sleep. 2022 Dec 12;45(12):zsac126.
6. Won C, Mahmoudi M, Qin L, et al. The impact of gender on timeliness of narcolepsy diagnosis. J Clin Sleep Med. 2014 Jan 15;10(1):89-95.