Long COVID and menstruation: bidirectional associations and potential mechanisms.

Women have reported both menstrual disruption following SARS-CoV-2 infection and that long COVID symptoms change across the menstrual cycle. Yet there is a lack of female-specific research on COVID and menstruation. We aimed to determine if (i) acute/long COVID is associated with abnormal uterine bleeding (AUB), (ii) long COVID symptoms vary across the menstrual cycle and (iii) the mechanisms underpinning any such associations. We reveal that long COVID was significantly associated with AUB in a UK population, with menstrual flow volume, duration, and intermenstrual bleeding reported as significantly increased (n=1048) compared to those who had never had COVID (n=9433). With acute COVID (n=2017), only menstrual volume was increased. Examination of long COVID symptoms in 54 women across the menstrual cycle revealed that symptom severity was increased during the peri-menstrual and proliferative phases. To determine the impact of long COVID on ovarian and endometrial function, we analysed blood serum and endometrial tissue from ten women with long COVID at three points of their menstrual cycle and age-matched samples collected pre-pandemic. Higher secretory phase serum 5α-dihydrotestosterone and lower menstrual and proliferative phase endometrial androgen receptor levels were found in those with long COVID versus controls. No other significant differences in ovarian sex steroid hormone levels were detected. Serum Anti-Mullerian Hormone levels were also comparable, consistent with no significant impact of long COVID on ovarian reserve. Serum cytokine profiling indicated more menstrual phase inflammation in those with long COVID versus controls and less inflammation during the proliferative phase. We detected menstrual endometrial immune cell aggregates in those with long COVID that may contribute to altered tissue inflammation and AUB. In conclusion, whilst long COVID was associated with menstrual disturbance, it reassuringly does not appear to significantly impact ovarian function. Differences in peripheral and endometrial inflammation may contribute to AUB and increase long COVID symptom severity at menstruation. We anticipate that these data from across the menstrual cycle will decrease the gender health gap in long COVID biomarker development and instigate further exploration of new therapeutic strategies for long COVID symptoms in women.