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Menopausal hormone therapy, migraine history, and headache severity: Results from the Women's Health Initiative Hormone Therapy clinical trials
Journal article   Peer reviewed

Menopausal hormone therapy, migraine history, and headache severity: Results from the Women's Health Initiative Hormone Therapy clinical trials

Holly M Crowe, Tracy E Madsen, Janet W Rich-Edwards, Aladdin H Shadyab, Longjian Liu, Leslie V Farland, Peter F Schnatz, JoAnn E Manson, Kathryn M Rexrode and Marcia L Stefanick
Headache, Forthcoming
08 Jul 2026
DOI: https://doi.org/10.1111/head.70168
PMID: 42419355
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Abstract

migraine headache hormone therapy randomized control trial Epidemiology
The aim of this study was to evaluate the association of oral menopausal hormone therapy (estrogen only [E-only] or estrogen and progestin [E+P]), as compared to placebo on postmenopausal headache severity among females with and without a history of migraine in the Women's Health Initiative Hormone Therapy (WHI-HT) trials. Migraine is three times more common among females than males and is a major source of pain and disability among women throughout the life course. Previous observational research found a positive association between menopausal hormone therapy (MHT) use and migraine prevalence, but the longitudinal association of MHT with postmenopausal migraine severity is unclear. We examined changes in self-reported headache severity between baseline and year 1 in 22,876 females (average age 64 years) across the United States enrolled in the WHI-HT trials between 1993 and 1998. We conducted a secondary, stratified analysis of data of two parallel, randomized, placebo-controlled clinical trials to estimate the association of MHT and headache severity overall and stratified by history of migraine at baseline. Additionally, we assessed the association between MHT and headache trajectory, based on whether headaches worsened over the follow-up period. At baseline, the prevalence of a lifetime migraine diagnosis was 10%. Among participants with a history of migraine, randomization to E-only MHT was not associated with more severe headache at 1 year (adjusted odds ratio [aOR] = 1.14, 95% confidence interval [CI]: 0.90-1.44), or worsening headache trajectory (adjusted risk ratio [aRR] = 0.98, 95% CI: 0.71-1.34) after 1 year. Randomization to E+P MHT was modestly associated with more severe headache, although estimates did not reach statistical significance (aOR = 1.21, 95% CI: 0.98-1.50). E+P MHT was significantly associated with worsening headache trajectory (aRR= 1.53, 95% CI: 1.14-2.03). Among those without a migraine history, E-only MHT was not strongly associated with moderate-to-severe headache severity (aOR: 1.11, 95% CI: 1.01-1.21) or worsening headache trajectory (aRR = 1.08 95% CI: 0.96-1.22) after 1 year. However, E+P MHT was associated with modestly increased odds of moderate-to-severe headache severity (aOR = 1.14, 95% CI: 1.06-1.23) and a higher likelihood of worsening headache trajectory (aRR = 1.18, 95% CI: 1.07-1.30) after 1 year. In this study of MHT in the WHI hormone therapy trial participants, E-only MHT was not associated with increased odds of more severe postmenopausal headache severity. Among those with a history of migraine, E+P MHT was associated with more severe and worsening postmenopausal headache. Further research on the effect of newer MHT formulations on postmenopausal headache is warranted.

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