HRT and Dementia

March 5, 2024

Reminiscent of fear-provoking headlines in concert with the Women’s Health Initiative (WHI) study, recent 2023 fear-provoking news headlines on major news sources were:

As we have seen time and time again, the media is consistently putting out scientific information in an unscientific way.  These headlines instill fear and disseminate misinformation and myths.  After fear-provoking news headlines of the WHI, many women stopped their hormones leading them to experience needless withdrawal symptoms and suffering.  Now, women are asking whether they should stop their hormones due to the recent fear-provoking headlines.

HRT and Dementia Study

The study was published June 28, 2023, in the BMJ journal entitled, “Menopausal hormone therapy and dementia: nationwide, nested case-control study.”  This retrospective study aimed to assess the association between menopausal hormone therapy and the development of dementia by investigating national registry data for 55,890 Danish women aged 50-60 years old, excluding women with hysterectomies, between 2000-2018.

Women who used HRT continuously and briefly were compared to women who had not used HRT.   The focused hormone treatment investigated was combined estrogen and progestin, a (synthetic progesterone),  with oral route the most common.  In combination with estrogen, norethisterone was the most common progestin used followed by medroxyprogesterone and levonorgestrel.  It was not stated whether estrogen used was natural 17- OH estradiol or synthetic estrogen such as Premarin.  Since the word estrogen was used, not 17-OH estradiol, it is assumed synthetic estrogen is the estrogen to which they are referring.

The authors concluded, “Menopausal hormone therapy was positively associated with development of all cause dementia and Alzheimer’s disease, even in women who received treatment at the age of 55 years or younger…Further studies are warranted to determine whether these findings represent an actual effect of menopausal hormone therapy on dementia risk, or whether they reflect an underlying predisposition in women in need of these treatments.”

The authors stated even short-term use of HRT under a year increased HRT association with dementia.  However, NO association was found between progestin only therapy or vaginal estrogen only therapy and all cause dementia, late onset dementia and Alzheimer’s.

Issues With Study Validity

This is a retrospective study and only associations can be seen, not cause and effect.

The studied hormones focused on were synthetic estrogen plus progestin.  They did not have information on bioidentical progesterone versus synthetic progestin, or 17-OH estradiol, a bioidentical estrogen.

When looking at estrogen only therapy or progestin only therapy, there was no association with dementia.  Why when these 2 were combined was there a difference?

Given many women seek HRT treatment due to cognitive and memory decline, hot flashes and sleep issues, there is bias as these women are more likely to seek HRT treatment than women not experiencing these symptoms.  Therefore, women seeking treatment may be at an increased risk of dementia when they start HRT.

As previously mentioned, the authors found HRT use under a year led to dementia.  This is biologically implausible as various experts have stated in light of this study.

Interestingly, the authors compare their findings to those of the highly flawed Women’s Health Initiative Memory Study (WHIMS) and used that to support their findings.

What Happened in the WHIMS?

The WHI investigators published results of the WHIMS in 2003, concluding estrogen plus progestin almost doubled the relative risk (RR) for dementia in women 65 years and older.  Due to the WHI HRT study’s conclusions, this being one of them, millions of women were denied HRT.

Many studies use relative risk (RR) to make the conclusion sound more significant.  To truly determine results to aid in decision making, absolute risk (AR) needs to be calculated.  When looking at the AR, the “doubled risk” disappeared. The absolute risk was 1% for placebo and 1.8% for HRT.

The WHIMS was designed to include 8,300 women 65 years and older from the original WHI sample, as more than 8,000 would allow a statistically reliable conclusion.  Being 65 and older is not a good representation of the general population and this particular population had predisposing factors for cognitive impairment as 70% of the women were overweight or obese, many had hypertension and half were smokers.

The study design failed as the WHI HRT trial ended early due to the misleading conclusion of increased breast cancer risk with HRT.  At that time, only 4,532 women were enrolled in the WHIMS, not nearly close to the 8,000 needed for a statistically reliable conclusion.  Based off this sample,  researchers stated in their memory study both synthetic estrogen replacement therapy and synthetic estrogen plus synthetic progestin therapy “were associated with an increased incidence of dementia compared to placebo, although the association did not reach statistical significance in the smaller, but longer, estrogen-alone trial.”  This sentence contradicts itself – both groups increased the incidence of dementia but estrogen-alone therapy did not reach significance?  If ERT didn’t increase the incidence of dementia significantly, it didn’t increase dementia.

As concluded within the Danish study, investigators stated the risk of dementia appeared during the first year of women taking HRT which is biologically implausible and suggests the women already had cognitive decline upon starting the study.

Lastly, the WHIMS investigators originally concluded there was no increased incidence of mental cognitive impairment (MCI) between HRT and placebo groups.  MCI always precedes dementia and Alzheimer’s, so how could hormones cause full-blown dementia and Alzheimer’s but skip over the first stage?

In 2004, WHI researchers re-reviewed the original WHI study statistics and reported both ERT and HRT were associated with cognitive impairment but only among those already cognitively impaired at the start of the study.  This would explain the development of dementia within one year of HRT.  When women who presented with cognitive impairment at the start of the study were excluded, the results were no longer statistically significant.  

To simplify, women with healthy cognition on HRT did not go on to experience cognitive impairment.  

Women already with cognitive impairment at the start of the study carried on to have further cognitive decline.  This voids the results completely.   

HRT and Decreased Risk of Dementia Evidence to Date

By the early 1990s, well documented in the medical literature was 50 years of evidence showing the benefits of estrogen as described in History of Menopause and its Treatments.  Arguably one of the most beneficial advantages of estrogen is its effect on cognitive function and memory.

The studies vary in decreased risk of dementia and Alzheimer’s ranging from 24% to 65%; this is a large range but consistently points to a lower risk with ERT:

  • 1952: Women taking ERT had a marked increase in verbal IQ scores on memory and intelligence tests which decreased to baseline after ERT was stopped
  • 1973: Women taking Premarin (synthetic estrogen) had increased scores on communication, relationships, work activities and ability to take care of oneself compared to decreased scores in the placebo group
  • 1988: Women treated with estrogen after total hysterectomy performed better on cognitive functions and verbal memory vs placebo
  • 1992: Women with total hysterectomy taking ERT either stayed at pre-surgery cognitive level or improved vs placebo group who performed worse on verbal tests
  • 1996: Women on estrogen suppression (Lupron) with resultant cognitive deficits had reversal of cognitive deficits with estrogen add-back therapy
  • 1996: Retirement community women followed for up to 14 years on estrogen had 45% decreased Alzheimer’s risk, USA
  • 1998: Estrogen users had 70% decreased Alzheimer’s risk, Italy
  • 2005: Women taking HRT for 2-3 years had 64% decreased risk of cognitive impairment 5-15 years later compared to hormone never users
  • 2021: Vaginal estradiol was not associated with dementia or AD
  • 2023: Women with APOE4 (gene associated with increased risk of Alzheimer’s) treated with HRT had improved delayed memory and larger brain volumes; this effect was greater the earlier HRT was initiated

Neuroprotection and Neuroplasticity Beneficial Effects of Estrogen  

Estrogen receptors are found throughout the brain, especially in areas involved in memory and learning.  Estrogen exerts protective influence on the following in the brain:

  • Increases choline acetyltransferase, an enzyme responsible for the synthesis of neurotransmitter acetylcholine.  Decrease in this enzyme’s activity has been associated with Alzheimer’s
  • Regenerates axons, decreases nerve-cell death and stimulates nerve cell growth
  • Prevents buildup of calcium protecting nerve cells
  • Elevates brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF), both proteins responsible for protection of healthy neurons and development of new neurons
  • Reduces amyloid plaque buildup and protects against beta amyloid
  • Enhances glial cell action, providing nutrients and support to neurons
  • Provides neuroprotection from traumatic brain injury and stroke, reducing oxidative stress and increasing cerebral blood flow
  • Promotes glucose uptake in the brain

Conclusion

  • The current study being retrospective and associative automatically makes it a poor to impossible study from which to derive any causal relationships between HRT and dementia.
  • Similar to the WHIMS, this study is even more flawed resulted in biologically implausible conclusions.
  • The benefits of estrogen replacement therapy have been established with 50 years of evidence to show estrogen’s role in brain function is crucial, supporting and protecting nerve cells and neurotransmitters. Many women love estrogen replacement therapy as they have a clearer mind and sharper memory.
  • Fear-provoking media headlines concerning medical studies need to be reviewed by critically thinking clinicians and scientists before they are allowed to be printed.

Have an awesome day!  Dr. D and Drew Chernisky PA

 

Posted in Hormone Therapy, HRT