Reviewed by Dr Chris Armstrong, Director of the Melbourne ME/CFS Collaboration, University of Melbourne.
Hormones rise and fall across the day and across the menstrual cycle. Most research in ME/CFS and Long COVID has not accounted for that, which means a result can depend on when the sample happened to be taken. MELLOW is a study built to measure the rhythm rather than a single point in it, and its protocol is now published in npj Women’s Health.
Key points
- MELLOW will follow 60 women: 20 with ME/CFS, 20 with Long COVID and 20 healthy controls.
- Samples are timed to four points in each menstrual cycle, and again when a participant naturally experiences post-exertional malaise, and 24 and 48 hours later.
- This is the study design, not results. The authors describe what a study of this size can produce as hypothesis-generating rather than confirmatory.
What is MELLOW?
MELLOW stands for ME/CFS + Long COVID Longitudinal Omics and Women’s Health. It is a prospective study of people with menstrual cycles with ME/CFS, with Long COVID, and without either condition, run through the Melbourne ME/CFS Collaboration. The study page is here.
Why does it matter when a sample is taken?
Female sex is a major risk factor for both conditions, and there is early evidence linking sex hormones and other fluctuating hormones, including cortisol, aldosterone and DHEA, to them. The difficulty is that those hormones are never still. Their levels change on a daily cycle, a monthly cycle, and a longer one. The authors of the protocol argue that existing studies have not comprehensively captured those rhythms, so two studies sampling the same patient at different moments can disagree without either being wrong.
What will the study measure?
Several layers at once. Continuous physiological data from wearable devices: heart rate, heart rate variability, temperature, respiratory rate, oxygen saturation, sleep and activity. Daily hormone metabolites from morning urine, read on a point-of-care analyser at home. Symptom severity across fatigue, post-exertional malaise, pain, cognitive difficulty, sleep and autonomic symptoms. And on the blood side, a wide multi-omic panel: genomics, transcriptomics, proteomics, metabolomics, lipidomics, steroidomics, inflammatory markers, and imaging of microclots.
When are the samples collected?
Four “gold days” in each menstrual cycle, chosen to sit at meaningful, standardised hormonal moments rather than at convenient ones: the day after the luteinising hormone surge, seven days after that surge, after two consecutive falls in progesterone, and the first day of the cycle. Each gold day involves a fasted capillary blood sample and a 24-hour urine collection. Separately, when a participant naturally experiences post-exertional malaise, samples are taken at onset and again at 24 and 48 hours.
Who can take part?
Sixty participants in total, twenty in each group, aged 18 to 49, with cycles occurring at least every two months. The study is limited to people with their own hormonal cycles rather than those using hormonal treatments, so that the rhythms being measured are the body’s own.
What will this study not tell us?
Two things, both stated plainly by the authors. It will not speak to men, despite ME/CFS and Long COVID affecting men as well, because it is designed around the menstrual cycle. And with sixty participants across three groups, findings from the multi-omic work are intended to generate hypotheses for larger studies to test, not to settle questions on their own.
Who is running it?
The protocol is first-authored by Dr Natalie Thomas and corresponding-authored by Dr Chris Armstrong, both at the Melbourne ME/CFS Collaboration, with Dr Katherine Huang, A/Prof Elena Schneider-Futschik, Dr David Fineberg and A/Prof Caroline Gurvich, and international collaborators including Beth Pollack and Dr Michal Caspi Tal, Prof Resia Pretorius, and Prof Jonas Bergquist of the Collaborative Center at Uppsala.
Source: Thomas, N., Huang, K., Schneider-Futschik, E.K., Pollack, B., Tal, M.C., Fineberg, D., Gurvich, C., Pretorius, R., Bergquist, J., and Armstrong, C.W. (2026). A chronobiology-based protocol for multi-omic mapping of menstrual cycle and diurnal rhythms in ME/CFS and long COVID. npj Women’s Health, 4(3). Published 14 January 2026. doi:10.1038/s44294-025-00120-9