Women have been shown to have a greater lifetime risk for Alzheimer’s disease (AD) relative to men, which may be associated with peri-menopausal and menopausal hormone changes. This is a significant public health concern, considering the proportion of the population aged 65 and older continues to grow. According to the Alzheimer’s Association, between 2000 – 2017 deaths resulting from stroke, heart disease and prostate cancer decreased, whereas reported deaths from AD increased 145%!
The impact of hormone therapy (HT) on age-related Alzheimer’s in women has remained controversial because many large clinical trials have indicated no benefit, whereas observational studies have indicated a protective association. Results from ancillary studies of the big RCT studies WHIMS (WHI), KEEPS-cog and ELITE-cog trials concluded neither beneficial nor harmful effect of HT on cognitive function. Of note, all of these trials were conducted in postmenopausal women without menopausal symptoms who were uniformly treated with one HT formulation, dose, and duration of therapy. Subjects had aged past the “critical window” for hormone therapy to have an estrogenic impact on the brain. Therefore, the impact of hormone therapy intervention on menopausal symptoms when they initially appear, during the menopausal transition, could not be evaluated.
In contrast, multiple observational studies based on prescription records of HT use, have indicated a protective association between HT and cognition. Prescription doses, types and durations were determined by best practices and a physician’s judgement, taking into account hormonal symptoms during the menopausal transition. Dosages and delivery methods could be adjusted based on response. This individualized approach to hormone prescribing is termed “precision hormone therapy.”
A retrospective analysis using One Health Insurance Company’s (Humera) claim records between 2007-2016 evaluated the impact of hormone therapies on neurodegenerative diseases (NDD) in 379,352 women age 45 and older, with an average follow-up time of 5 years. NDDs studied included: Alzheimer’s disease (AD), Parkinson’s disease (PD), dementia, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).
The forms of HT studied were:
- Estrace (estradiol – PO tablet)
- Vivelle/Vivelle Dot, Climara, Estroderm (estradiol - patch)
- Estrogel, Divigel (estradiol - gel)
- Evamist (estradiol - spray)
- Premarin (conjugated equine estrogens - PO or IM injection)
- Enjuvia, Cenestin (synthetic conjugated estrogens – PO tablet)
- Menest (esterified estrogen – PO tablet)
- Delestrogen (estradiol valerate – IM injection)
- Prempro (CEE and medoxyprogesterone – PO tablet)
- Prometrium (bioidentical progesterone – PO capsule)
Note: Vaginal application of hormones was not included in the study.
All 14 types of HT reduced risk for NDDs combined, compared to risk in non-HT users. The magnitude of risk reduction differed by composition. Formulations containing the natural steroids 17B-estradiol and/or progesterone were associated with greater reduction in NDD risk versus non-bioidentical formulations. Comparing progestogens, Prometrium had a lower relative risk ratio than Prempro, suggesting a potentially protective role of bioidentical progesterone compared to synthetic.
Premarin, Estrace, Vivelle Dot, Prempro, and estrogen therapy plus prometrium were further investigated for their effects on the risk of each NDD. Researchers found that a decreased risk of AD, PD and dementia was observed in patients who received one of these five HT’s. The data found that the protective effect of estrogen therapy was only modestly reduced when combined with progestin in HT.
Patient Characteristics: Age was a modifier of NDD risk. Interestingly, in the 60-64 age group, there was no significant difference in the risk of AD, dementia or combined NDDs in the treatment versus control populations. However, in controls, the risk of NDD increased with age; whereas those 65+ on HT had a significant reduction in combined NDDs, AD and dementia.
Mode of Delivery: Oral HT was shown to significantly reduce risk for all NDDs studied. Transdermal HT was also shown to reduce risk for all NDDs with significantly reduced risk in all-cause dementia and MS. The authors noted differences in modes of delivery utilized by age – the majority in the 45 – 64 age group used transdermal preparations, whereas the majority in the 65-79 age group used oral modes of delivery. Because the risk for all studied outcomes increases with age, those in the transdermal category, due to their relative younger age, weren’t exposed to all the same studied outcomes as the older demographic.
Effect of Duration of Therapy on NDD Risk: In the treatment population, 60% received HT for one year or less, 21% for 1-3 years, 14% for 3-6 years, and 5% for longer than 6 years. Increased duration of therapy was associated with greater reduction of risk for all combined NDDs, AD, PD and dementia, with 6+ years offering maximal benefit.
The researchers concluded that all modes of HT delivery were associated with reduced risk of all NDDs including AD and dementia. Even the use of oral estradiol, known to produce inflammatory liver markers, was associated with significantly reduced relative risk compared to non-HT users. Longer duration of therapy (>1 year) was associated with greater protective effect than short-term therapy (<1 year). Formulations that contained the bioidentical hormones 17B-estradiol and/or progesterone (compared to synthetic formulations) were associated with a greater reduction of all NDD risk including Alzheimer’s regardless of route of delivery. The authors highlighted the need for precision HT to increase predictive safety and outcomes.
(It should be noted that women who receive HT are known to be generally healthier, more educated, and socioeconomically advantaged relative to non-users, which could influence outcomes in observational studies.)
Doctor’s Data salivary hormone testing is an easy and effective means of measuring free hormones to monitor the progress of your patients who are already using hormone therapy, or to provide a baseline for those who are considering commencing treatment. Likewise, the Hormone and Urinary Metabolites Assessment Profile (HuMapTM) provides information about hormone metabolism pathways and preferences in order to best support healthy elimination patterns, including methylation.
