New app-based research suggests that the menstrual cycle phase may influence COVID-19 vaccine reactogenicity, raising fresh questions about how hormonal fluctuations shape immune responses.
Study: Menstrual cycle phase and its association with COVID-19 vaccine outcomes among period tracking app users. Image Credit: SeventyFour / Shutterstock
In a recent study published in npj Women’s Health, researchers investigated whether the timing of a woman’s COVID-19 vaccination within her menstrual cycle is associated with self-reported side effects and exploratory measures of subsequent infection timing.
The study analyzed data from Clue (a popular period-tracking application), comprising an analytical dataset of 1,474 individuals. The analyses focused on matching logged menstrual data with participants’ self-reported vaccine experiences.
Study findings showed that individuals vaccinated during the estrogen-dominant follicular phase had 35% higher odds of self-reporting any side effects than those vaccinated during the progesterone-dominant luteal phase.
Furthermore, the data showed a longer median self-reported time to breakthrough infection among those vaccinated during the follicular phase, although this finding was exploratory and underpowered.
While these findings remain preliminary, they are among the first to suggest this pattern and may help inform future research on whether menstrual-cycle timing affects vaccine reactogenicity or protection.
Background
Historical scientific beliefs (now considered biases) have often excluded the menstrual cycle from non-reproductive health research. However, the COVID-19 pandemic cast an unexpected spotlight on the previously understudied intersection between immunization and reproductive health.
While previous research predominantly focused on how vaccines might alter menstrual parameters such as cycle length, scientists now question whether the natural endocrine environment at the time of vaccination may influence immune responses, a field that remains severely lacking in empirical evidence.
This hypothesis is informed by the fact that, biologically, sex steroid hormones such as estradiol and progesterone fluctuate significantly throughout a standard menstrual cycle. Decades of research have established that estradiol generally acts as an immune enhancer in a context-dependent manner, whereas progesterone tends to act as a relative immune suppressant.
Because these hormones bind directly to receptors on immune cells, scientists now hypothesize that the estrogen-dominant follicular phase might amplify self-reported vaccine side effects (reactogenicity) and potentially influence vaccine protection (immunogenicity).
About the Study
The present study aimed to test this hypothesis through a collaboration with the popular period tracking application (“app”) Clue. The study specifically analyzed longitudinal, prospectively logged menstrual data from an in-app survey hosted by Clue, which was subsequently matched to participants’ self-reported vaccine experiences.
The study initially reviewed more than 13,000 respondents, of whom only those aged 18-44 years with regular cycle lengths of 24-38 days (based on the International Federation of Gynecology and Obstetrics [FIGO] criteria) were included in the analytical dataset. Furthermore, respondents using hormonal contraceptives or with recent pregnancies were excluded, as were those with irregular cycles or insufficient cycle tracking, resulting in a final sample cohort of 1,474 participants.
Participants were classified based on a calendar estimation of their menstrual phase (at the time of vaccination) into: 1. Follicular-phase vaccinated (n = 760), and 2. Luteal-phase vaccinated (n = 714). Herein, the luteal phase was defined (via FIGO criteria) as the 14 days before a participant’s next documented menstruation.
The study’s primary endpoints were evaluated using multivariable regression models focusing on the presence, severity, and total count of side effects. Regression models were adjusted for participants’ age, body mass index (BMI), smoking status, and presence of pre-existing medical condition(s). Finally, the study calculated the participant-specific time to breakthrough COVID-19 infection over a 67- to 372-day window post-vaccination, using self-reported infection dates.
Study Findings
Study analyses identified an association between vaccination timing and side effects, with 75.9% of participants vaccinated in the follicular phase reporting side effects, compared to 70.3% in the luteal phase.
Most notably, participants in the follicular-phase vaccination group demonstrated 35% higher odds of self-reported side effects than those in the luteal phase (OR = 1.35). Age was also found to play a significant role in observed outcomes. Younger participants (aged 18 to 24) showed a much stronger follicular-phase association (OR: 2.18, 95% CI: 1.24–3.84), likely driven by lower luteal-phase side-effect reporting.
In contrast, the regression models did not identify a statistically significant association between phase timing and side effect severity (OR = 1.21) or between phase timing and variation in the total number of side effects reported across phases (IRR = 1.03).
Finally, the self-reported infection data showed that the median time to breakthrough infection was 35 days longer for the follicular group than the luteal group (200 days vs. 165 days, p = 0.05). However, because only 82 participants reported breakthrough infections, a subsequent Cox proportional hazards model was found to be statistically underpowered at 29% and therefore could not yield definitive inferential conclusions. The authors therefore interpreted the infection finding as descriptive and hypothesis-generating rather than confirmatory.
Conclusions
The present study is among the first to provide preliminary evidence that cyclical hormonal fluctuations may influence vaccine reactogenicity, underscoring the urgent need for additional research in the field and the importance of considering menstrual-cycle phase in future sex-based immunity research.
While the study is limited by its exclusive reliance on calendar-based estimates rather than direct hormonal biomarkers, self-reported vaccine and infection outcomes, possible recall bias, and a self-selected app-user sample, it may serve as a basis for future large-scale investigations aimed at clarifying whether cycle timing affects long-term clinical protection.
Future work will also need to determine whether the side-effect pattern reflects immune activation, differences in pain perception, or misattribution of menstrual-cycle symptoms.
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