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• November, 2009 •

Post hoc MRI’s cannot justify the conclusions of WHIMS

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Frederick Naftolin, MD PhD, New York University School of Medicine, New York, NY
Jennifer King, BS University of Miami School of Medicine, MIAMI,
and John H. Morrison, PhD Mount Sinai School of Medicine, New York, NY.

The Women’s Health Initiative Memory Study (WHIMS) and WHIMS-MRI trials address the clinical effects of MHT begun in largely asymptomatic postmenopausal women at ages 65 and older (1-3). Contrary to to meta-analysis of observational studies on peri-menopausal women given MHT,4 both WHIMS reports indicate that estrogen and progestin have no preventive role in mild cognitive impairment and may in fact increase risk for dementia (1-3). It is not stressed that the WHIMS population was older and had many characteristics that would discourage MHT.

In fact, the use of CEE and MPA in these trials does not reflect their use in current clinical practice and the outcomes in the WHI are not sufficiently well designed or documented to justify WHIMS’ conclusions that may be drawn from remote post-treatment clinical or MRI studies (5). The Women’s Health Initiative Memory Study (WHIMS) examined whether postmenopausal conjugated equine estrogen with and without medroxyprogesterone acetate would reduce risk of mild cognitive impairment or dementia. The original trialists had been randomized to treatment, but only after the Women’s Health Iniative (WHI) exclusion criteria had ensured that there was not a representative initial subject population(5). Nonetheless, based on their findings, WHIMS reported that estrogen alone or combined therapy did not prevent mild cognitive impairment and stated there was an increased risk for probable dementia in postmenopausal women aged 65 years or older receiving hormone therapy (1-2). This work was followed by the WHIMS-MRI study, in which a subset of women aged 71-89 years who had participated in WHIMS trials received a post-study brain MRI. Scans demonstrated decreased frontal lobe and hippocampal volume in those women receiving hormone therapy when compared to placebo (3). Both brain areas are involved in cognitive function and memory, with decreased hippocampal volume as a potential risk factor for dementia. However, before any conclusion can be drawn about whether the risks of estrogen plus progestin therapy outweigh the benefits, some issues needed to be addressed that in light of the exclusion criteria of the WHI could not be addressed. First, the randomization process had no neurological exam, no brain imaging, no apolipoprotein E4 levels, and no assessment of family history of dementia. The only distinguishing factor between subjects was age. Second, as they were taken from the main WHI study, the WHIMS study participants were not reflective of the usual women in which hormone therapy is initiated (5). Finally, whether or not the results of the MRI study are interpretable may be contested but their clinical inapplicability is not in question; asymptomatic women who are aged 65 or older should never be given MHT at the usual clinical doses reserved for symptomatic women who are still in the first years of the menopause. Extension of conclusions from the WHIMS or the WHIMS-MRI study to clinical decisions regarding the use of MHT in treatment of symptomatic menopausal women is even further afield. The interpretation of this series of studies is further complicated by the agents and regimens utilized: the hormones administered were conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) in constant doses (1-3). While CEE have not been shown to be responsible for neuronal damage in in vitro experiments, the type of progestin used may play an important role in risk (6-8). This seems especially important in the case of MPA since it is known to have potent androgenic effects, including effects on lipoprotein and carbohydrate metabolism, which may play a role in vascular disease (7-8). Finally, MRI was used to assess total volume of the hippocampus and the frontal lobe and decreased volume was indicated to represent neurodegeneration (3). However, because no pretreatment MRI scans were obtained there is no possibility of comparison to baseline brain volumes; at age 65 or older there may have already been significant brain destruction present. Moreover, for interpretation further studies should be done using functional MRI to rule out the possibility that the decreased volume is not secondary to pruning of non-eloquent brain. While hormone treatment may have adverse effects on an already diseased brain when it is administered long after menopause, further investigation is warranted before an opinion can be made regarding the neurotoxicity of estrogen and progestin in the WHI or WHIMS.

References

  1. 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;289:2651-62.
  2. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004;291:2947-58.
  3. Resnick SM, Epeland MA, Jamarillo SA, et al. Postmenopausal hormone therapy and regional brain volumes: The WHIMS-MRI Study. Neurology 2009;72:135-42.
  4. Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA 1998;279:688-95.
  5. Tan O, Harman SM, Naftolin F. What can we learn from design faults in the Women’s Health Initiative randomized clinical trial? Bull NYU Hosp Jt Dis. 2009;67(2):226-9.
  6. Nilsen J, Deng J, Brinton RD. Impact of clinically relevant progestins on the neural effects of estradiol and the signaling pathways involved. Drug News Perspect. 2005 Nov;18(9):545-53.
  7. Ansbacher R. The pharmacokinetics and efficacy of different estrogens are not equivalent. Am J Obstet Gynecol 2001;184(3):255-63.
  8. Darney PD.The androgenicity of progestins. Am J Med 1995;98(1A):104S-10S.

Three questions to the editorial’s Author

  1. What type of study does WHIMS fit into?

    WHIMS was a sub-analysis of subjects randomized for the WHI. It was not a prospective randomized trial.

  2. Why is randomization for one study permissible for use in another study?

    It would not be permissible to refer to such a study as a randomized clinical trial. The subjects in WHIMS were not representative of the WHI, they were only representative of the over-65 year-old subjects in the WHI.

  3. What is the correct conclusion for WHIMS?The possibility that menopausal hormone treatment in women over 65 is associated with Alzheimer Dementia is not resolved by WHIMS.. In any case, treatment of asymptomatic women who are 20 years or more past the menopause with hormonal compounds developed for menopausal symptoms is not appropriate.

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