Effect of HPV Adult Vaccination on Serum Anti-Müllerian Hormone Levels: Paired Measurements in a Retrospective Cohort

Concerns that human papillomavirus (HPV) vaccination may adversely affect ovarian reserve contribute to vaccine hesitancy, yet longitudinal data with paired anti-Müllerian hormone (AMH) measurements are limited. We evaluated whether HPV vaccination was associated with short-term changes in AMH compared with an unvaccinated control group.

In this retrospective cohort, women aged 18-45 years who completed a three-dose 9-valent HPV vaccination (Gardasil 9®, Merck Sharp & Dohme LLC, West Point/Pennsylvania/USA) schedule and had AMH measured before dose 1 and after dose 3 were compared with unvaccinated controls who had two AMH measurements during routine gynecologic evaluation. AMH change was summarized as absolute change (ΔAMH), percent change, and log change. To compare rates of AMH change while accounting for heterogeneous follow-up and confounding, AMH was analyzed on the natural log scale using a linear mixed-effects model with a random intercept for participant and fixed effects for time (years), group, and a time × group interaction, adjusted for age, current smoking, gravidity, and parity. Annual percent change was derived from model coefficients. Prespecified sensitivity analyses repeated the primary model under follow-up restrictions and after restricting baseline AMH to 1.0-5.0 ng/mL.

The cohort included 158 vaccinated and 106 control women. Baseline AMH was similar between groups (median 1.88 vs. 1.94 ng/mL), while the follow-up interval was shorter in vaccinated women (6.7 vs. 8.9 months). Unadjusted AMH decline was smaller in vaccinated women (median ΔAMH -0.13 vs. -0.27 ng/mL; p = 0.015; median percent change -10.9% vs. -20.6%; p = 0.006). In the adjusted mixed-effects model, controls showed an estimated AMH decline of -27.6% per year (95% CI -35.5% to -18.7%; p < 0.001). The time × group interaction was positive (β = 0.170, 95% CI 0.027 to 0.312; p = 0.020), corresponding to a slope ratio of 1.185 (95% CI 1.02-1.366) and an implied annual change of -14.2% per year (95% CI -21.0% to -6.7%) in vaccinated women. Results were broadly consistent in follow-up-restricted sensitivity analyses; however, in the baseline AMH 1.0-5.0 ng/mL restricted cohort (vaccinated n = 82, control n = 67), the interaction was attenuated and not statistically significant (β = 0.082, p = 0.237).

In this retrospective cohort with paired AMH measurements, HPV vaccination was not associated with evidence of clinically meaningful short-term impairment in ovarian reserve as assessed by AMH. Observed differences in AMH alterations were modest and should be interpreted cautiously, given residual confounding, measurement variability, and reduced precision in restricted-cohort analyses.