A link between MHT and Cognition?

Following on from Dr Stevenson’s presentation on MHT and CHD, Pauline Maki took to the stage to discuss the Critical Window Hypothesis and the link between menopause and cognition.

As we saw in data for CHD, the critical window hypothesis suggests that the beneficial effects of hormone therapy depend on timing of initiation in relation to the menopause and/or age, with expectation that therapy initiated early in menopausal transition would result in greater benefit.

When it comes to cognition, menopausal transition is where women experience the biggest change. As a person ages, their brain compensates; in youth, women use their left hippocampus but as a woman reaches their menopausal transition period they rely more on the right hippocampus. This compensation is related to circulating levels of estradiol. As a result, a study from the Penn Ovarian Study (Epperson et al.) showed that menopause has a significant impact on verbal memory with decline peaking during late transition and then improving post-menopause.

Three randomised clinical trials have looked at the effect early use of MHT has on cognitive function in early post—menopause. WHIMSY (Espeland et al.), Keeps (Gleason et al.)  and ELITE (Henderson et al.) have all shown that the early use of MHT has a neutral effect on cognitive function. Maki et al. have also shown that in the long-term, women who initiate MHT in the perimenopause period show better memory and hippocampal function, resulting in a better delayed verbal recognition memory.

Whilst there can be some positive impact with early use, late use of MHT has a varied impact depending on the regimen used. There is strong evidence that the combination of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) increase the risk of dementia when women initiated treatment after age 65 as demonstrated by the WHI study (Resnick et al.). However the ELITE study which used E2 in a similar study population demonstrated neutral cognitive effect.

With women twice as likely to get Alzheimer’s disease (AD) after 60 as breast cancer, distinguishing any link between AD and MHT is imperative. Three prospective studies have examined timing of initiation of MHT in relation to risk of AD incidence and all match the critical window hypothesis that initiation early in menopausal transition would lead to the best results.  New Finnish data from Mikkola et al. has also shown that women on MHT have a lower risk of death due to vascular dementia or Alzheimer’s regardless of age.

Although initial data is available more clinical data needs to be collected in order to decide if MHT should be indicated for the prevention or treatment of cognitive problems. For now there are still many unanswered questions including:

  1. Does MHT affect cognition in the correct population i.e., in women with moderate to severe VMS?
  2. Does use of MHT or oral contraceptives in the perimenopause enhance cognition?
  3. Does early use of MHT have effects on Alzheimer’s disease risk and the neuropathology underlying that risk?

In order to progress with evaluation of MHT and cognition, clinical trials are needed as we just don’t have the data we need yet.

From open questions to answered ones, stay tune for part 3 of the symposium that looks at study data for MHT and Breast Cancer!



1.       Epperson CN et al. 2013, J Clin Endocrinol Metab.

2.       Espeland et al. 2014, JAMA Intern Med.

3.       Gleason et al. 2015, Plos Med.

4.       Henderson et al. 2016, Neurology.

5.       Maki et al.2011, Brain Research

6.       Resnick S et al. 2006. J Clin Endocrinol Metab.

7.       Mikkola TS et al. 2016. J Clin Endocrinol Metab.