Neurology -- Correspondence for Resnick et al., 72 (2) 135-142

Correspondence published:

Postmenopausal hormone therapy and regional brain volumes: The WHIMS-MRI Study: Tom den Heijer, Fedde van der Lijn, Wiro J. Niessen, Monique M.B. Breteler (6 May 2009)

Postmenopausal hormone therapy and regional brain volumes: The WHIMS-MRI Study 6 May 2009

Tom den Heijer,
Erasmus MC
Department of Neurology, H-673, PO Box 2040, 3000 CA Rotterdam, The Netherlands,
Fedde van der Lijn, Wiro J. Niessen, Monique M.B. Breteler
Send Correspondence to journal:
Re: Postmenopausal hormone therapy and regional brain volumes: The WHIMS-MRI Study

t.denheijer{at}erasmusmc.nl Tom den Heijer, et al.

We read the article by Resnick et al. regarding findings from the Women’s Health Initiative Memory (WHIMS)-MRI Study on hormone therapy (HT) and brain volumes on MRI. [1]
The investigators found slightly lower hippocampal volumes on MRI after a three-year follow-up in women assigned to HT compared to placebo. This confirms our previous observation in the Rotterdam Scan Study, a population-based MRI study in non-demented elderly where we found no beneficial effect of high endogenous plasma estradiol levels on manually measured hippocampal volumes on MRI in 210 randomly selected women. [2] If anything, we found that higher estradiol levels were associated with lower hippocampal volumes.
For a portion of this cohort (n=94), follow-up MRIs are now available and were made an average of three years after baseline. Using an automatic segmentation procedure, baseline and follow-up hippocampal volumes were obtained in 94 women not using HT. [3] Baseline total estradiol levels were not significantly associated with baseline hippocampal volumes on MRI. However, women in the lowest tertile of total estradiol at baseline had the largest decline in hippocampal volume. Estradiol levels at baseline were not associated with refusing the second MRI or risk of dying before the second MRI.
The WHIMS investigators previously reported that the use of HT increased the risk of dementia and suggest in their current report that this effect is mediated by increased hippocampal atrophy. [4] HT leads to much higher estradiol levels compared to the range of endogenous levels, for which we found an increased hippocampal atrophy rate in women with the lowest levels of estradiol.
Combined, these findings suggest that either too low or very high level of estrogens could be detrimental to the hippocampus. An animal study has also indicated that estrogens could be neuroprotective except when evident in high doses. [5]
References
1. Resnick SM, Espeland MA, Jaramillo SA, et al. Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI Study. Neurology 2009;72:135-142.
2. den Heijer T, Geerlings MI, Hofman A, et al. Higher estrogen levels are not associated with larger hippocampi and better memory performance. Archives of Neurology 2003;60:213-220.
3. van der Lijn F, den Heijer T, Breteler MM, Niessen WJ. Hippocampus segmentation in MR images using atlas registration, voxel classification, and graph cuts. Neuroimage 2008;43:708-720.
4. Shumaker SA, Legault C, Thal L, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651-2662.
5. Chen S, Nilsen J, Brinton RD. Dose and temporal pattern of estrogen exposure determines neuroprotective outcome in hippocampal neurons: therapeutic implications. Endocrinology 2006;147:5303-5313.
Editor’s Note: The authors of the article were offered the opportunity to respond but declined.
Disclosures:
Dr. T. den Heijer is a post-doctoral fellow and received research support from the non-profit organizations Hersenstichting Nederland and the Internationale Stichting Alzheimer Onderzoek for research on early MRI markers in dementia in the Rotterdam Scan Study. Dr. F. van der Lijn is a PhD student on a project on medical imaging tools for brain imaging which is funded by the Netherlands Organisation for Scientific Research (NWO). Prof.dr. MMB. Breteler is head of the neuro-epidemiology section of the Department of Epidemiology at Erasmus MC, Rotterdam, the Netherlands, and started the Rotterdam Scan Study, a study on age-related brain changes on MRI. She received research support from the Netherlands Organisation for Scientific Research (NWO) and the Dutch Cancer Society. She received funding from Pfizer Pharmaceuticals on a project on biomarkers in Alzheimer disease, which is not related to the current Correspondence.