Lancaster Physician Winter 2020 - 29

WINTER 2020

Research is being done to determine if the
changes that happen as a result of menopause
play a role. Menopause is the cessation of regular
menses for one year. In the U.S., the mean age
of menopause is 51. Physiologically, we know
that decline in estrogen production by the
ovaries characterizes many of the symptoms
associated with menopause. These symptoms
are felt to be neuroendocrine changes modulated by estrogen. Vasomotor symptoms such
as hot flashes, night sweats, genital atrophy, and
associated dyspareunia occur. Estrogen or combined progesterone and estrogen therapy can
improve these symptoms. Other symptoms of
menopause are less reliably treated with estrogen
therapy. Insomnia, loss of libido, memory, and
emotional lability are common but not reliably
improved with estrogen therapy.
There is a growing body of research regarding
the pathophysiology of Alzheimer's. Well known
is the deposition of amyloid protein in the
neurons of those having the disease. Genetics
play a role; the APOE4 genotype is more common in patients with Alzheimer's. The APOE
gene encodes instructions for the production
of lipoproteins, which are important in the
packaging and transport of lipids. Maintaining
normal levels of these proteins is important for
the prevention of cardiovascular disease such
as coronary vascular disease and stroke. There
are three different alleles of the APOE gene:
e2, e3, and e4. The most common allele is the
e3. The presence of the e4 allele increases the
risk that one will develop late onset Alzheimer's
disease (after age 65). Individuals who have
two copies of the e4 allele (homozygous) are
at even greater risk of developing Alzheimer's
disease. Note that the presence of the homoor heterozygous APOE4 genotype does not
mean the disease is inevitable. While it is not
known how the APOE4 genotype results in
Alzheimer's, it is known that the genotype is
associated with greater amyloid deposition in
the brain.
Recently, a study performed at NYU/ Weill
Cornell medical schools attempted to elucidate the role of estrogen metabolism in the
development of Alzheimer's. The hope is that
we can elucidate a mechanism that explains
the observed gender difference in the risk for
Alzheimer's. The results of this study suggest
a cellular mechanism that contributes to the

greater probability that menopausal women
develop Alzheimer's. These and other findings
suggest that estrogen therapy may offer moderation of this risk.
Dr. Lisa Mosconi and her colleagues at NYU/
Weill Cornell medical centers have performed
a longitudinal study over a three-year period,
which looked at neuro-imaging (MRI and
PET) scanning in four groups: premenopausal
women, women transitioning to menopause,
menopausal women, and men. It is important to
note that their subjects did not demonstrate any
cognitive change over the course of the study.
However, they found a consistent progression
of markers of Alzheimer's disease in the peri and
menopausal groups compared to the premenopausal group and men. The changes included
decrease in brain glucose bioenergetics (ATP
mediated), increased deposition of amyloid
protein, and gray matter volume loss.
Estrogen has a regulatory role in the female
brain with respect to glucose transport, aerobic
glycolysis, and mitochondrial function to produce ATP for cell energetics in regions of the
brain responsible for cognitive function. Loss
of this regulatory function by estrogen during
the menopause transition may result in changes
in energy use by neurons and eventual decline
of neuronal activity leading to cell malfunction
or death. These observations open a door for
research for interventions, which might modify
this observed change in neuronal metabolism
during the menopause transition.
None of the subjects in the NYU/Weill Cornell study were taking hormone replacement
therapy, and it is important to note that there
remains no evidence that hormonal therapy
after menopause alters the observed markers
of Alzheimer's disease. It is also important to
note that metabolic changes seem to precede
any cognitive decline, suggesting a "window"
of opportunity for therapeutic intervention.
This begs the question: Can estrogen therapy
prevent Alzheimer's disease in women? Currently, there is no evidence to suggest that this is
the case. However, the evidence indicates that
the markers of Alzheimer's disease appear long
before any cognitive decline is evident. This
suggests that if estrogen can prevent cognitive
decline, its value may be related to the timing of

LANCASTER

29

PHYSICIAN

therapy; earlier is better. This remains conjecture
only at this point. More research is needed to
address this question.
The American College of Obstetrics and
Gynecology does not list cognitive impairment
or prevention of the same as a primary indication for initiation of hormone replacement
therapy - the above information notwithstanding. Recommended indications include
vasomotor symptoms such as hot flashes and
night sweats, vaginal dryness, and improved
bone metabolism.
There is an arm of the Women's Health Initiative study that looked at cognitive decline related
to various HRT regimens including Selective
Estrogen Receptor Modulators (SERM). There
is some evidence that use of HRT in older
women increased the risk of dementia. The
NIH consensus regarding hormone therapy,
dementia, and cognition includes:
* Estrogen-plus-progestin therapy initiated
at age 65 or older increases dementia risk.
* Observational evidence, based largely on
short-term use by younger women close to
the time of menopause, associates hormone
therapy with lower risk of Alzheimer's
disease risk.
* If increased risk from WHIMS is extrapolated to postmenopausal women aged 50
to 59 years, the absolute risk of dementia
from standard dose hormone therapy
would be rare, representing about one
additional case among 1000 women using
hormone therapy for five years.
* For healthy young and old postmenopausal
women, standard dose conjugated equine
estrogen (CEE) / medroxyprogesterone
acetate (MPA) therapy has a small, but significant adverse impact on verbal memory.
* For healthy older postmenopausal
women, standard dose estrogen therapy
does not have a clinically important effect
on cognition.

Continued on page 30



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