The potential bidirectional relationship between long COVID and menstruation, 2025, Maybin et al.

[SNT Gatchaman]

The potential bidirectional relationship between long COVID and menstruation

Spoiler: Authors

Maybin, Jacqueline A; Walker, Catherine; Watters, Marianne; Homer, Natalie Zm; Simpson, Joanna P; Robb, Cara; Gibson, Douglas A; Jeanjean, Luna; Critchley, Hilary O D; Kountourides, Gabriella; Olszewska, Zuzanna; Alvergne, Alexandra

Women have reported menstrual changes following SARS-CoV-2 infection and variation in long COVID symptoms across the menstrual cycle. We examined (i) whether COVID is linked to abnormal uterine bleeding (AUB), (ii) if long COVID symptoms vary with the menstrual cycle, and (iii) potential underlying mechanisms.

Here we show long COVID was associated with AUB in a UK population. When compared to those never infected (n = 9423), long COVID participants (n = 1048) reported increased menstrual volume, duration and intermenstrual bleeding, while those who recovered from acute COVID (n = 1,716) reported minimal menstrual disruption.

Long COVID symptoms examined in 54 women across the menstrual cycle revealed that severity was highest during the perimenstrual and proliferative phases. Serum and endometrial analysis revealed higher serum 5α-dihydrotestosterone and lower endometrial androgen receptors in long COVID versus no COVID. Other ovarian hormones showed no significant differences. Serum cytokine profiling indicated increased menstrual inflammation with long COVID and immune cell aggregates were observed in menstrual endometrium.

In conclusion, long COVID was associated with AUB but not impaired ovarian function. Differences in peripheral and endometrial inflammation may contribute to AUB and long COVID symptom severity. We anticipate our findings will instigate exploration of new therapeutic strategies for women with long COVID.

Web | PDF | Nature Communications | Open Access

 

[Dolphin]

Press release:

Menstrual cycle and long COVID: a relation confirmed

www.cnrs.fr

1. Home
2. Press Area

Menstrual cycle and long COVID: a relation confirmed​

September 18, 2025
Health

Women suffering from long COVID have a greater risk1 of experiencing abnormal uterine bleeding2 . The symptoms of the illness intensify during the perimenstrual and proliferative phases of the menstrual cycle, notably fatigue, headaches, and muscle pain. This bidirectional relationship between long COVID and menstrual disorders has been revealed by a French-British research team co-led by a CNRS researcher3 . An inflammatory reaction is suspected of being behind this connection, after the discovery of an immune cell cluster in the endometrium of the patients receiving treatment. No abnormalities were detected in relation to ovarian hormones.

These conclusions, which were just published in Nature Communications, are based on a combination of three approaches: a study conducted among 12,187 British women; follow-up care for 54 women suffering from long COVID for three months; and analysis of blood and endometrial samples.

As long COVID affects 3-7% of the world’s population4 , and is twice as prevalent among women than men, this novel study paves the way for new therapeutic prospects. It also underscores the importance of considering the menstrual cycle in long COVID biomarkers, as well as the need to develop therapies specifically adapted to women.

Long COVID is associated with abnormal uterine bleeding among women suffering from the illness, with its symptoms intensifying during certain phases of the menstrual cycle. © AdobeStock / Anastassiya

Bibliography

The potential bidirectional relationship between long COVID and menstruation.
Jacqueline A Maybin, Catherine Walker, Marianne Watters, Natalie ZM Homer, Joanna P Simpson, Cara Robb, Douglas A. Gibson, Luna Jeanjean, Hilary O.D. Critchley, Gabriella Kountourides, Zuzanna Olszewska and Alexandra Alvergne. Nature communications, 16 September 2025.
DOI : https://doi.org/10.1038/s41467-025-62965-7

​

Notes​

1. Outside of a long COVID context, “abnormal” uterine bleeding already affects one in three people worldwide, causing anaemia and major socioeconomic impact.
2. Compared to a control group, long COVID is associated with reporting more abundant and longer periods, in addition to bleeding between cycles, contrary to acute COVID.
3. From the Montpellier Institute of Evolutionary Sciences (CNRS/IRD/Université de Montpellier).
4. Approximately 400 million people are or have been affected by long COVID worldwide. In France, 4% of the population is concerned, or 2.7 million people.

 

[SNT Gatchaman]

From the introduction —

AUB is abnormal uterine bleeding

The underlying cause(s) of AUB may be classified as structural or non-structural […] Structural causes are those that can usually be detected […] and include Polyps, Adenomyosis, Leiomyomas (fibroids) or Malignancy (PALM). Non-structural causes are not detected on imaging and include Coagulopathies, Ovulatory disorders, primary Endometrial disorders, Iatrogenic causes and those that are Not otherwise classified (COEIN).

The rapid onset of menstrual disturbance described with SARS-CoV-2 infection favours a non-structural cause such as an ovulatory or endometrial disorder. Development and shedding of the endometrium at menstruation is controlled by the ovarian hormones. […] Those with AUB due to endometrial disorders have previously been shown to have excessive endometrial inflammation at the time of menstruation.

we hypothesised (i) that long COVID is associated with increased reports of AUB, (ii) women with long COVID experience increased number and severity of their long COVID symptoms prior to and during menstruation, (iii) that those with long COVID have altered ovarian sex hormones production or response and/or excessive peripheral or endometrial inflammation.

We tested these hypotheses using three approaches:
(i) a large online UK COVID and reproductive health survey,
(ii) a longitudinal study of long COVID symptoms across the menstrual cycle, and
(iii) collection and analysis of carefully categorised biological samples of serum and endometrium at three phases of the menstrual cycle from those with and without long COVID.

 

[SNT Gatchaman]

Results (survey) —

Out of the 26710 individuals who completed our online survey, “The COVID-19 Pandemic and Women’s Reproductive Health”, we excluded participants who did not have a menstrual bleed in the 12 months preceding the survey, those who were postmenopausal or peri-menopausal, breastfeeding or pregnant, those who did not live in the UK, those enrolled in a clinical trial, and those with unknown vaccine, COVID or long COVID status.

The final sample size was 12187, of which 9423 (77%) had never been diagnosed with COVID (no COVID group), 1716 (14%) of participants reported previous acute COVID and 1048 (9%) had long COVID

Compared to the control group, the prevalence of menstruation lasting longer than 8 days is increased twofold for the long COVID group (PR = 2.26, 95% CI [1.46 to 3.49], FDR p value < 0.001)

a history of COVID-19 increased the risk of more intermenstrual bleeding by 59% for long COVID (RRR = 1.59, 95% CI = [1.29 to 1.97], FDR p value < 0.001), but not for previous acute COVID (RRR = 1.15, 95% CI = [0.97 to 1.36], FDR p value = 0.22)

the prevalence of reported “missed” and/ or “stopped” periods increases by 39% in the long COVID group (PR = 1.39, 95% CI = [1.13 to 1.7], FDR p value = 0.003) but not in the previous acute COVID group (PR = 1.15, 95% CI = [0.97 to 1.37], FDR p value = 0.17

In summary, reported menstrual flow volume, menstrual duration (>8 days), inter-menstrual bleeding and missed episodes of menstruation were significantly increased in those with long COVID versus no COVID. Menstrual frequency and regularity were unchanged. In contrast, in those with previous acute COVID, only menstrual volume was increased, but did not reach statistical significance.

 

[SNT Gatchaman]

Results (longitudinal study of LC symptoms across menstrual cycle) —

A total of 93 individuals with long COVID provided informed consent for our UK-wide app-based prospective survey to examine 29 common long COVID symptoms across the menstrual cycle. Participants were asked to complete a daily survey to record their menstrual bleeding and the number and severity of their COVID symptoms over 3 months.

After excluding participants […] the final sample included 54 participants. […] Half of the participants were overweight or obese, and half reported a healthy BMI.

while some symptoms are reported most days by most individuals (e.g., brain fog, memory issues, post-exertional malaise and fatigue), others appear to be infrequent (e.g., elevated temperature, sore throat

The LS/M [late secretory / menstrual] phase was associated with an increased risk of experiencing chills/sweats (OR = 2.30, 95% CI [1.63 to 3.22]) and vision issues (OR = 2.08, 95% CI [1.37 to 3.17]) as compared to the secretory phase. By contrast, the risk of experiencing breathlessness decreases in the proliferative phase (OR = 0.47, 95% CI [0.27 to 0.81]) as compared to the secretory phase.

the late secretory/menstruation phase is associated with more severe dizziness (OR = 1.94, 95% CI = [1.28 to 2.95], FDRadjusted p value = 0.005), fatigue (OR = 1.79, 95% CI = [1.38 to 2.33], FDR-adjusted p value = 0.000), post-exertional malaise (OR = 1.45, 95% CI = [1.1 to 1.90], FDR-adjusted p value = 0.02), muscles aches (OR = 1.48, 95% CI = [1.06 to 2.053], FDR-adjusted p value = 0.04), headache (OR = 2.106, 95% CI = [1.50 to 2.97], FDR-adjusted p value = 0.000), and tinnitus (OR = 2.35, 95% CI = [1.16 to 4.74], FDR adjusted p value = 0.03).

the proliferative phase is associated with more severe postexertional malaise (OR = 1.63, 95% CI = [1.1 to 2.38], FDR adjusted p value = 0.024), breathing issues (OR = 3.15, 95% CI = [1.36 to 7.26], FDR adjusted p value = 0.015), nausea (OR = 2.25, 95% CI = [1.08 to 4.70], FDR adjusted p value = 0.05) and headache (OR = 2.801, 95% CI = [1.76 to 4.46], FDR adjusted p value = 0.000)

 

[SNT Gatchaman]

Results (serum) —

Given our findings of an association between long COVID and menstrual disturbance and an increase in COVID symptom severity in the peri-menstrual (LS/M) and proliferative phase, we wished to determine if ovarian sex hormone levels were altered in regularly cycling women experiencing long COVID.

Our group of women who had recovered fully from acute COVID were significantly younger than no COVID controls and those with long COVID and were therefore not included in ovarian hormone analyses.

A significantly higher level of serum 5α-dihydrotestosterone, the most active androgen, was observed in women with long COVID versus those with no COVID during the secretory phase (p = 0.0138, 95% CR = [−0.06732 to −0.007898], DF 75) […] no significant differences in 17 β -estradiol or progesterone between the two groups.

we analysed a subset of our control cohort who had provided paired samples from the secretory and menstrual phases (n = 14) and compared these with paired samples from the long COVID group (n = 7). This did not reveal any clear differences in how ovarian hormone levels changed from secretory to menstrual phase in those with long COVID versus controls

We found no differences in serum cortisol, cortisone or cortisol/cortisone ratio when comparing those with long COVID and these two control groups at any phase of the menstrual cycle

we observed higher levels of serum cytokines in those with long COVID during the menstrual phase, and lower levels during the proliferative phase, when compared to those with no COVID or those who had recovered from acute COVID. Serum TNF was significantly higher during the menstrual phase in those with long COVID versus no COVID controls (p = 0.0002, 95% CI = [−5.650 to −1.509], DF 102) and compared to women who had recovered from COVID (p = 0.0177, 95% CI = [0.4016–5.182], DF 102).

Those with long COVID had lower serum TNF during the proliferative phase of the cycle vs those who had never had COVID (p = 0.0197, 95% CI = [0.3139; 4.454], DF 102). Serum IL8 protein was also significantly lower in those with long COVID versus no COVID controls during the proliferative phase of the menstrual cycle (p = 0.0016, 95% CI = [5.127; 25.81]).

There were no significant differences detected in serum IFNG, IL10, or IL6 between the groups at any menstrual cycle stage. A similar non-significant trend was observed for serum IL6 protein, with higher menstrual and lower proliferative levels in those with long COVID. […] Our subset analysis of paired serum samples from the secretory and menstrual phases showed significant increases in IL8 and TNF on transit into active menstruation in both no COVID and long COVID groups, but IL10 and IL6 serum levels were significantly increased during menstruation in the group with long COVID

 

[SNT Gatchaman]

Results (endometrial biopsies) —

We then examined ovarian sex hormones in endometrial tissue from the subset of women who provided endometrial biopsies, as levels in the local endometrial environment are often different to circulating hormone levels due to peripheral tissue metabolism. There were no significant differences in endometrial levels of estradiol, estrone, estrone/17 β-estradiol (E1/E2) ratio, progesterone, testosterone or 5α-dihydrotestosterone between those with long COVID and controls at any cycle stage.

For endometrial testosterone, there were significant differences between menstrual and proliferative phases (p = 0.0084) in the control group, which were not demonstrated in the long COVID group.

Progesterone receptor mRNA (PGR) was lower in those with long COVID versus controls during the proliferative phase of the menstrual cycle (p = 0.0096 95% CI = [0.1671; 1.136], DF 42).

Comparison of endometrial AR staining in those with and without long COVID revealed a significantly lower percentage of positive cells in those with long COVID during the menstrual phase

We then examined glucocorticoid levels in endometrial tissue. It was not possible to obtain endometrial biopsies from our ‘healthy’ COVID recovered group. There were no differences in endometrial glucocorticoids between those with long COVID and controls at any cycle stage. However, the cortisol/cortisone ratio was significantly higher at menstruation versus other cycle stages in controls (menstrual v proliferative p = 0.0036, menstrual v secretory p = 0.0033) but did not reach statistical significance in those with long COVID.

we also examined endometrial tissue cytokine mRNA concentrations

Significantly lower menstrual endometrial IL10 and TNF was detected in women with long COVID versus controls (p = 0.0121, 95% CI = [1.033; 7.929], DF 42 and p = 0.0406, 95% CI = [0.8572; 37.38], DF 42 respectively)

Given the importance of endometrial immune cells at menstruation43,44 , we then localised endometrial neutrophils and macrophages in menstrual endometrium

menstrual endometrial neutrophil number was not significantly different in those with and without long COVID, but neutrophil aggregates were visible within endometrial glands in those with long COVID and were not visible in endometrium from those who had never had COVID).

menstrual endometrial macrophage number was not significantly different in endometrium from those with and without long COVID, but there was evidence of accumulation within endometrial glands in endometrium from those with long COVID.

 

[SNT Gatchaman]

Discussion —

a small group of well-characterised patients revealed that serum 5α-dihydrotestosterone was higher in the secretory phase and endometrial AR staining appeared less intense in the menstrual and proliferative phases in those with long COVID versus controls. Serum menstrual TNF was found to be increased in those with long COVID, with blood serum cytokine expression tending to be increased in those with long COVID versus controls during the menstrual phase and decreased in the proliferative phase.

Collectively, these findings indicate a bidirectional relationship between long COVID and abnormal uterine bleeding, potentially mediated by disruptions in androgen regulation and the inflammatory response within the endometrium.

Consistent with the normal 17β -estradiol and progesterone serum levels we observed in those with long COVID, serum testosterone levels were also similar between the groups. However, 5α-dihydrotestosterone, the most active androgen, had higher levels in those with long COVID during the secretory phase.

our finding of increased serum 5αdihydrotestosterone in the secretory phase of those with long COVID provides a potential mechanism that could alter endometrial function during menstruation and result in prolonged, heavy menstrual bleeding. 5α-reductase drives peripheral conversion of testosterone to 5α-dihydrotestosterone. Therefore, our findings are consistent with more active 5α-reductase in women with long COVID. It remains to be determined if long COVID causes this increase in activity or if those with more active 5α-reductase are more susceptible to developing long COVID, e.g., those with polycystic ovary syndrome. All participants in our study had regular menstrual cycles, and none had a confirmed diagnosis of PCOS, but undiagnosed PCOS cannot be excluded.

We revealed an altered serum cytokine profile in those with long COVID that varied across the menstrual cycle, with higher cytokine levels during menses and lower levels during the proliferative phase. This was not observed in those who had recovered from acute COVID.

Cortisol is also known to impact the immune response and has recently emerged as a potential biomarker for long COVID, with lower levels in long COVID patients versus controls. Our smaller study here did not detect any such differences, consistent with findings by Fleischer et al. In fact, those with long COVID had a higher cortisol/cortisone ratio during the menstrual phase. However, this may reflect increased adrenal hormone production with age, with participants who had recovered from COVID being younger than the long COVID/ No COVID age-matched participants. Of note, our study was not designed to analyse cortisol levels, and these single samples were not consistent for time since waking

found that the endometria from those with long COVID lacked the significant increase in cortisol/ cortisone ratio that was observed in controls at menstruation.

we found that endometrial tissue from those with long COVID had lower levels of TNF when compared to controls. However, the immunosuppressive cytokine IL10 was also lower during menstruation in those with long COVID.

we examined endometrial neutrophil and macrophages and found their number appeared similar between the groups, but neutrophil aggregates were visualised in endometrial epithelial glands from those with long COVID. It remains to be determined if these are neutrophil extracellular traps

In conclusion, this study provides evidence of an association between long COVID and AUB that may be the result of increased androgens and an altered endometrial inflammatory response at menstruation, warranting further investigation. Reassuringly, ovarian function appears to be maintained in this group of regularly cycling women with long COVID. We also reveal an association of increased severity of long COVID symptoms with the late secretory/menstrual phase of the menstrual cycle, when progesterone levels rapidly decline. This may be explained by increased cytokine production during the menstrual phase, which was greater in those with long COVID than in controls.