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. 2025 Jul 22;32(9):818-828.
doi: 10.1097/GME.0000000000002562. Online ahead of print.

Long-term effects of 4 years of menopausal hormone therapy on white matter integrity

Laura L Faubion  1 , Elijah Mak  1 , Firat Kara  1 , Nirobul Tosakulwong  2 , Timothy G Lesnick  2 , Angela J Fought  2 , Robert I Reid  1 , Christopher G Schwarz  1 , June Kendall-Thomas  1 , Ekta Kapoor  3 , Julie A Fields  4 , Kent R Bailey  1 , Taryn T James  5 , Rogerio A Lobo  6 , JoAnn E Manson  7 , Lubna Pal  8 , Dustin B Hammers  9 , Eliot A Brinton  9 , Michael Malek-Ahmadi  10 , Marcelle Cedars  11 , Frederick Nicholas Naftolin  12 , Nanette Santoro  13 , Virginia M Miller  14 , Sherman M Harman  15 , N Maritza Dowling  2 , Carey E Gleason  5 , Kejal Kantarci  1
Affiliations

Long-term effects of 4 years of menopausal hormone therapy on white matter integrity

Laura L Faubion et al. Menopause. .

Abstract

Objectives: To assess the long-term effects of 4 years of menopausal hormone therapy (mHT) on the brain's white matter architecture in women who initiated mHT within 3 years of menopause onset.

Methods: The Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, double-blind, randomized, placebo-controlled 4-year mHT trial with treatment arms of oral conjugated equine estrogens (oCEE), transdermal 17β-estradiol (tE2), and placebo in recently postmenopausal women. KEEPS Continuation was an observational follow-up of KEEPS participants. White matter integrity was evaluated in KEEPS Continuation participants 10 years after KEEPS completion using white matter hyperintensity volume, diffusion magnetic resonance imaging (dMRI) techniques, and cerebral infarcts. Linear regression models were fitted for each brain region to evaluate if there were differences in white matter between KEEPS treatment arms.

Results: There was no evidence to suggest the long-term effects of 4 years of mHT on brain white matter in KEEPS Continuation participants [n=266, mean age 67 (58-73)]. No differences in dMRI metrics were found in each of the treatment arms (oCEE n=70; tE2 n=79) when compared to placebo (n=94), following a false discovery rate adjustment for multiple comparisons. There were no statistically significant differences in white matter hyperintensity volume or infarct occurrence when comparing each of the treatment arms to placebo.

Conclusions: We found no evidence of the long-term effect of 4-year mHT on white matter integrity when compared to placebo, consistent with emerging evidence of the safety of short-term use of mHT in recently postmenopausal women.

Keywords: DTI; Diffusion MRI; Hormone therapy; Infarcts; NODDI; White matter hyperintensities..

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Conflict of interest statement

Financial disclosure/conflicts of interest: K.K. served on the data safety monitoring board for Pfizer Inc. and Takeda Global Research & Development Center, Inc. She received research support from Avid Radiopharmaceuticals and Eli Lilly. She consults for Biogen. N.S. is a member of the Scientific Advisory Boards for Astellas, Que Oncology, Amazon (Ember), and Menogenix, Inc. She is a consultant for Ansh Labs, and has received grant support (to her institution) from Menogenix, Inc. She has been paid by Fertility IQ for developing a series of videos on menopause and has stock options (no payments) from Menogenix, Inc. L.P. is a member of the advisory board for Flo Health and has a financial relationship with WinFertility. E.K. is funded in part by the National Institute on Aging (NIA grant U54 AG044170). E.K. has no conflicts of interest directly related to the subject of this manuscript. However, over the past 36 months, she has had the following conflicts of interest: she has been a consultant for Astellas and Mithra Pharmaceuticals, Scynexis, and Womaness. She receives grant support from Mithra Pharmaceuticals. She has received payment for the development of educational content from Med Learning Group and the Academy of Continued Healthcare Learning. She has received honoraria for CME activity from PriMed and OBG Management. A.J.F. received funding from Northwestern University for participating in a DSMB ($500 in the last year). C.G.S. received past funding from Karolinska Institute and Drum Tower Hospital, Nanjing. J.A.F. receives ongoing institutional funding from the National Institute of Health and Mangurian Foundation and receives ongoing personal funding from the University of Pennsylvania and Medtronic Inc. T.T.J. was one of 2 principal investigators on a grant from the Alzheimer’s Clinical Trial Consortium (ACTC). D.B.H. received institutional funding from the NIH and Alzheimer’s Association funding. M.M.-A. received past funding from the Biomedical Research Alliance of New York. The other authors have nothing to disclose.

Figures

FIG. 1
FIG. 1
Flow chart of KEEPS Continuation participants and subsets for the present study. DTI, diffusion tensor imaging; mHT, menopausal hormone therapy; MRI, magnetic resonance imaging of the brain; oCEE, oral conjugated equine estrogens; tE2, transdermal 17β-estradiol; WMH, white matter hyperintensity.
FIG. 2
FIG. 2
dMRI regression results from best model log-transformed values relative to placebo in white matter regions before FDR correction for multiple comparisons. FA, fractional anisotropy; MD, mean diffusivity; ODI, orientation dispersion index; NDI, neurite density index; tNDI: tissue-weighted neurite density index. Higher FA, NDI, and tNDI and lower MD and ODI correspond to increased axonal organization. Brain region abbreviations are as follows: ACR, anterior corona radiata; ALIC, anterior limb of internal capsule; AWM, angular white matter; BCC, body of corpus callosum; CGC, cingulum cingulate gyrus; CGH, cingulum hippocampus; CST, corticospinal tract; EC, external capsule; ENT, entorhinal area; Fx, fornix; Fx_ST, fornix stria terminalis; GCC, genu of corpus callosum; IFO, inferior fronto-occipital fasciculus; IFWM, inferior frontal white matter; IOWM, inferior occipital white matter; ITWM, inferior temporal white matter; LFOWM, lateral fronto-orbital white matter; MFOWM, middle fronto-orbital white matter; MFWM, middle frontal white matter; MOWM, middle occipital white matter; MTWM, middle temporal white matter; PCR, posterior corona radiata; PLIC, posterior limb of the internal capsule; PoCWM, postcentral white matter; PrCWM, precentral white matter; PTR, posterior thalamic radiation; RLIC, retrolenticular part of the internal capsule; RWM, rectus white matter; SCC, splenium of corpus callosum; SCR, superior corona radiata; SFO, superior fronto-occipital fasciculus; SFWM, superior frontal white matter; SLF, superior longitudinal fasciculus; SMWM, supramarginal white matter; SOWM, superior occipital white matter; SPWM, superior parietal white matter; SS, sagittal stratum; STWM, superior temporal white matter; UNC, uncinate fasciculus.
FIG. 3
FIG. 3
Log-transformed white matter hyperintensity volume (95% CI) of treatment arms relative to placebo. oCEE, oral conjugated equine estrogens; tE2, transdermal 17β-estradiol; WMH, white matter hyperintensity
FIG. 4
FIG. 4
(A) Percentage of participants in each treatment arm with ≥1 infarct (subdivided into total infarcts, subcortical, and cortical infarcts) in each treatment arm. (B) Percentages of participants in each treatment arm who have ≥1 infarct (are infarct positive), have one infarct, and have more than two or more infarcts. oCEE, oral conjugated equine estrogens; tE2, transdermal 17β-estradiol.
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