Introduction The effect of female sex hormones on the natural history of herpes simplex virus (HSV) is poorly understood. Studies suggest that vaginal immunity varies throughout the menstrual cycle, with increased inflammatory cytokines and decreased innate immune factors observed during the luteal (post-ovulatory) phase. Whether HSV shedding or presence of genital lesions vary throughout the menstrual cycle is unknown.

Methods We studied HSV-2 seropositive women enrolled in prospective studies of genital herpes at the University of Washington Virology Research Clinic. Participants were eligible if they had established HSV-2 infection, performed daily genital swabbing for HSV DNA, recorded a menstrual diary, and were not using hormonal contraception. We used Poisson mixed effects models to determine if genital HSV DNA detection or lesion frequency differed throughout the menstrual cycle, categorised into four seven-day phases based on most proximate first day of menstrual bleeding: early and late for each of follicular and luteal.

Results In 189 women aged 19–46 (median age 33) who collected 9307 genital swabs, HSV was detected on 1822 days (20%). The rate of shedding was 21% during the early follicular phase versus 18% during late luteal (RR=1.2, 95% CI 1.0–1.4, p=0.04), 21% during late follicular (RR=1.2 relative to late luteal, 95% CI 1.0–1.5, p=0.06), and 19% during early luteal (RR 1.1 relative to late luteal, 95% CI 0.9–1.3, p=0.53). In sensitivity analyses reducing misclassification of phase by excluding samples>10 days from day 1 of menses, these observations were strengthened. The pattern was similar for genital lesions, present on 13% of days during the follicular phase and 11% during the luteal phase.

Conclusion In women with established HSV infection, genital HSV-2 shedding and lesions were slightly more common during the early follicular phase of the menstrual cycle than in the luteal phase. These cyclic variations may be related to changes in oestrogen and progesterone affecting vaginal immunity.