Estrogen, Hypothalamus Hormones and Brain Function – Part 2
Hypothalamus Hormones, Estrogen and Alzheimer’s Disease
Demonstratively the main cause of age-related dementia, Alzheimer’s is the reason behind at least 50 percent of dementia cases. It is a complex of declining hypothalamus hormones, cognitive and functional skills beginning in middle age or later and includes behaviors that vary in severity and type.
Both dementia and a clear pattern of changes in the brain are present. Some of these brain changes include atrophy, loss of neurons, extracellular plaques that contain beta-amyloid peptides, intracellular neurofibrillary tangles, and granulovacuolar cytoplasmic changes in several brain regions.
Estrogen plays a significant role in some of these brain regions affected by Alzheimer’s. This suggests the lower levels of estrogen in aging brains in both men and women could play a part in the development of this health condition.
Projections by scientists involved in studying Alzheimer’s are that the number of people who suffer from this condition will increase to 14 million in the U.S. by the middle of this century. A connection has been shown between the effects of menopause in women and Alzheimer’s. The onset of menopause signals a decrease in protection of the brain by hypothalamus hormones and estrogen. Currently, three times more women than men have Alzheimer’s.
Interestingly, research into the relationship of Alzheimer’s and estrogen has shown mixed results. Reasons for this are unclear but may involve different forms of estrogen, different dosages, and different times and ways of administration.
One of the factors that must be taken into consideration when evaluating the effects of estrogen or any other hypothalamus hormones is the bioavailability of the hormone. Bioavailability levels may be much different than total levels of any hypothalamus hormones or estrogen. A hormone that is present but not usable by the body will not have the beneficial effect desired.
A large part of the estrogen circulating in the body is bound to sex hormone binding globulin (SHBG), which is one of the hypothalamus hormones. This estrogen does not cross the blood-brain barrier and thus doesn’t have the beneficial neuroprotective effect of the non-SHBG bound estrogen.
There has been research indicating increased levels of SHBG to be associated with the cognitive decline seen in Alzheimer’s. This connection supports the findings related to estrogen having a positive effect on Alzheimer’s symptoms. Some studies suggest low bioavailable estrogen and high SHBG post-menopause may increase the likelihood of Alzheimer’s developing.
However, other research has either not found similar effects of estrogen on cognitive outcome or found the opposite. Reasons for these discrepancies may involve the different procedures used in measuring hormones or the difficulty in measuring estradiol in the bloodstream of women who have been postmenopausal for many years.
Another possible reason for these apparently conflicting results may have to do with the type of estrogen utilized in the studies. A study conducted at Stanford University examined two groups of women – one of which took estrogen replacement therapy and the other stopped it.
These women, ages 50 to 65, had metabolic activity in specific brain regions involved in memory and executive function studied using PET scans. These are areas of the brain that can show deterioration before signs of Alzheimer’s appear.
The women were also chosen because of their increased risk of developing Alzheimer’s due to having a first-degree relative with the condition or due to having the specific variant of the ApoE gene that has been shown to be associated with Alzheimer’s.
Results of this study showed that women who were taking estradiol as their replacement hormone had better preserved brain function than women taking Premarin, a conjugated equine estrogen. Women who were taking Premarin saw a decline in functioning in the brain areas investigated.
Along with estrogen, some of the women in the study also took progesterone. This is fairly common with hormone replacement therapy due to the increased risk of uterine cancer in women who only take estrogen. In this study, the progesterone cream appeared to significantly decrease the benefits seen with estradiol and increased the deficits seen with Premarin.
There appear to be benefits of taking estradiol as a hormone replacement, but not with progesterone. The benefits were much more significant than any seen with the conjugated equine urine estrogen. Much more study is needed before these benefits can be deemed certain.
Some possible shortcomings of this study include lack of randomization and the use of metabolic changes in some brain areas. The first suggests these same findings might not be seen in a larger, better-controlled study. The second suggests changes in those brain areas are only possible precursors of Alzheimer’s and not a sure sign of the condition.
Another possibly important factor to be considered by women choosing hormone replacement therapy is whether to take progesterone with their estrogen replacement. The findings of this small study are very interesting and, if proven accurate through more research, would suggest the risk of developing Alzheimer’s might be increased with the addition of progesterone to hormone replacement therapy.
Other research has investigated the effect of insulin-degrading enzyme (IDE). This protein degrades beta amyloid, another protein fragment associated with symptoms of Alzheimer’s. A decreased level of estradiol, such as happens during menopause, decreases the effectiveness of IDE. This would lead to more beta amyloid because the brain can’t rid itself of this protein.
Researchers also found the timing of the use of estrogen to be important in its effects. In general, the earlier estradiol is added, the more beneficial its protective function. Beginning estrogen therapy at the beginning of menopause increases the benefits to the woman’s brain and decreases her risk of developing Alzheimer’s later in life. Women who started estrogen replacement in their 60s did not see the benefit seen by women who started it in their 40s or 50s.
In addition to timing, the dosage of the hormones used is important to producing hypothalamus hormones. Using a naturally occurring estradiol brings a better response than using synthetic estrogen. The synthetics are not metabolized properly due to their chemical makeup and thus can be seen as toxins by the woman’s system.
Bioidentical estrogen absorbed through the skin appears to bring better results than a synthetic estrogen taken orally. The same appears to be true of bioidentical progesterone. This type of progesterone serves to protect brain functioning where synthetic progesterone may hamper functioning.
Testosterone’s Protective Functions
Current research has shown men also have a hypothalamic-related hormone that serves a protective function. Testosterone has been studied in applications with players in the National Football League who suffered concussions as well as with wounded warriors from Iraq and Afghanistan.
Concussions typically lead to hypopituitarism, in which the pituitary gland fails to produce sufficient hormones. This leads to a disruption in the HPA axis, a significant part of the body’s response to stressors. Insufficient levels of testosterone can result, leading to deficiencies in cognitive function and hypothalamus hormones.
Studies have shown those who suffer from concussions or other traumatic brain injuries recover cognitive functioning faster and to a greater extent with higher testosterone levels. Bioidentical testosterone replacement appears to be the best choice for this type of remediation.
Increasingly, low levels of testosterone in men have been linked closely with the development of Alzheimer’s. In fact, some research has indicated men have a three times greater risk of Alzheimer’s if their testosterone levels are low.
Testosterone appears to provide the same neuroprotective functions as estrogen. Evidence from research indicates testosterone to improve the axonal regeneration and survival of motor neurons. It has been linked to an increase in neuronal growth, plasticity, and in the development of new synapses in the spine and pelvic regions.
Research into whether androgens like testosterone provide a neuroprotective function have seen interesting results.
One study of the effects of androgens on dopamine neurons under oxidative stress showed pretreating these cells reduced oxidative stress-induced cell death, but using androgens after the oxidative stress actually increased cell death. This suggests using androgens when oxidative stress levels are low is neuroprotective, but the opposite is true under conditions of high oxidative stress.
Because the male brain is very dependent on testosterone to function properly, low levels of these hypothalamus hormones can result in cognitive decline, lessened memory ability, and other dementia-related symptoms. Low testosterone levels have also been associated with increased secretion of beta-amyloid proteins which have been implicated in the development of Alzheimer’s.
Acetylcholine, a neurotransmitter dealing with learning and memory, is dependent on testosterone as well. Low testosterone would lead to lower levels of this neurotransmitter and difficulty with learning and memory. Dopamine, a neurotransmitter that appears to protect the brain against Parkinson’s Disease, is also dependent on testosterone. Low testosterone has been implicated in the development of Parkinson’s.
There are some potential drawbacks of testosterone therapy, also. This hormone has been shown not to have neuroprotective functions in either the methamphetamine-induced neurotoxicity of the dopaminergic system in rats nor in glutamate-induced neurotoxicity.
The use of testosterone cream may also lead to problems. This use must be closely followed to assure the dosage is not too high. Too high levels of testosterone in this form can be stored in body fat. This causes a disruption between hormone glands and the brain and also can lead to resistance at the hormone receptor site. A metabolic imbalance will occur, leading to symptoms of low testosterone because the hormone won’t get absorbed into the cells.
For some men, low testosterone is caused by insulin surges over a long period of time due to ingestion of large amounts of sugar and carbohydrates. This causes stress on the body, lowering testosterone and increasing the risk of dementia and Alzheimer’s. By balancing blood sugar and reducing inflammation, some men may get a return of natural testosterone from their body.
In some cases with older men who already have symptoms of one of the chronic neurodegenerative illness conditions, testosterone replacement therapy may help improve quality of life. For others, however, the testosterone is converted into estrogen through a process called aromatization. This is often seen when there is high blood sugar, insulin resistance, and prediabetes present. A brain-healthy diet can improve this situation and prevent aromatization.
It would appear the first step in changing testosterone levels is to make dietary changes to see whether the body will return to making testosterone itself. If this fails, bioidentical testosterone should be the one to use.
Hypothalamus Hormones, Estrogen and Dementia
Estradiol has been shown to be effective in preventing the degeneration seen in women at risk for developing dementia. This remediation effort appears to be most effective when started soon after menopause.
Investigators at the Stanford University School of Medicine also found the use of Premarin, another synthetic estrogen replacement, not to have this protective factor. There are over 30 substances in Premarin, which is produced from pregnant mare urine. Only 17 percent of Premarin is estradiol. This study looked at brain metabolism as it is affected by stopping or continuing hormone therapy.
Findings showed the neurological effects of hormone therapy on women at risk of dementia depended critically on when the hormone therapy was started and on whether estradiol or Premarin was used.
Metabolic activity in the area of the brain in and around the hippocampus was preserved when women were started on estradiol within a year of menopause and stayed on it. However, when this regimen was stopped, the metabolic activity decreased significantly.
Women who were started on Premarin at the same time experienced more metabolic decline. When progestin, a synthetic progesterone, was added to either estradiol or Premarin, the decline was worse. With estradiol, the progestin countered totally the neurological benefit of estradiol. With Premarin, the metabolic decline increased dramatically.
It does appear that estradiol started when the beginning signs of dementia are seen has a neuroprotective function in women. This function is so robust, it could put off dementia if started early enough.
Another study at Stanford University supported these findings. A number of women under 60, in good overall health, who started hormone replacement therapy within a year of onset of menopause were studied. All were at increased risk of development of dementia due to having either a history of major depression, a first-degree relative with Alzheimer’s, or are positive for the ApoE4 allele. This gene variant is well known for increasing women’s risk of Alzheimer’s.
PET scans at the beginning of the study and again two years later were obtained. Those women who continued on the estradiol therapy showed metabolic activity in the medial prefrontal cortex to be better preserved than those women who stopped the therapy.
Metabolic activity in another brain area, precuneus/posterior cingulate region, important in predicting visible signs of dementia, was very well-preserved in women who remained on the estradiol regimen. However, in women who stopped the therapy, this region was very negatively affected.
Women in Premarin usage showed no lessening of deterioration of metabolic activity in this region. If progesterone was added to either replacement hormone, the results were significantly worse.
While estradiol has very beneficial effects on brain preservation, there is also an increased risk of breast and uterine cancer. Women should consult their primary health care professional to determine risk versus benefit.
© Copyright 2018 Michael Lam, M.D. All Rights Reserved.