Thymus Involution across the Human Menstrual Cycle

Structured Abstract Importance Thymic involution in humans has traditionally been conceptualized as a linear, age-associated process. Animal studies suggest transient hormone-dependent fluctuations in thymus size during reproductive transitions, including across the estrous cycle, but translational evidence in humans remains limited. Objective To determine whether thymus size changes across the menstrual cycle in healthy women and whether these changes are associated with fluctuations in estradiol and progesterone levels. Design Observational repeated-measures study using quantitative computed tomography (qCT). Data were collected as part of an imaging study examining menstrual cycle–related physiological variation. Participants underwent assessments during menses and the early luteal phase within the same menstrual cycle. Mixed-effects models with robust variance estimation evaluated associations between cycle phase, hormonal contraception, reproductive hormone levels, and thymus size. Thymus segmentation was independently conducted by 2 blinded raters. Setting Single-center university-based imaging study conducted at the University of Iowa. Participants Thirty-one non-smoking women with regular menstrual cycles were included, of whom n = 16 used oral hormonal birth control and n = 15 did not use hormonal contraception. Exclusion criteria included pregnancy, breastfeeding, postmenopausal status, diabetes, body mass index greater than 30 kg/m 2 , hysterectomy, or use of long-term noncyclic hormonal contraception. Participants tracked menstrual cycles using temperature monitoring and ovulation kits before completing visits during menses and the early luteal phase. All participants provided informed consent before study participation. Main Outcomes and Measures Primary outcome was thymus size measured in mm 3 using ultra-low-dose qCT imaging. Secondary outcomes included serum estradiol and progesterone levels. Results Estradiol levels increased from menses to the early luteal phase independent of hormonal contraceptive status. Progesterone levels were significantly lower among women using hormonal birth control. Thymus size differed significantly by hormonal contraceptive group, with larger thymus volumes observed among women not using hormonal birth control. Among women not using hormonal contraception, 66.7% demonstrated thymic involution from menses to the early luteal phase, compared with 37.5% of women using hormonal contraception. Estradiol and progesterone significantly interacted in predicting thymus size. Conclusions and Relevance These findings provide first-in-human evidence suggesting that thymus involution demonstrates short-term dynamics across the menstrual cycle and may be influenced by reproductive hormones and hormonal contraception. Key Points Question Does thymus size change dynamically across the human menstrual cycle in association with fluctuations in reproductive hormones and hormonal contraception use? Findings In this repeated-measures quantitative computed tomography study of n = 31 healthy women, thymus size demonstrated within-person variation across the menstrual cycle. Greater thymic involution was associated with larger increases in estradiol, whereas increases in thymus size were associated with larger increases in progesterone; thymus size also differed significantly by hormonal contraceptive status. Meaning These findings suggest that thymic involution in humans may demonstrate short-term hormone-dependent dynamics beyond age-related atrophy, with potential implications for sex differences in immune regulation and inflammatory disease.