Neurodegeneration and sex hormones
Some four and a half million Americans show neurodegeneration which will lead to Alzheimer’s disease (AD) and one and a half million have Parkinson’s disease (PD). These two common neurodegenerative conditions manifest with disordered cognition and motor movement. The first is characterized by memory loss, impairment of behavior, language, visual spatial skills, and ultimately, death. Brain pathology shows the typical amyloid plaques and some Lewy bodies. Parkinson’s disease is characterized by resting tremor, bradykinesia (slow movements), rigidity, and postural instability. Brain pathology shows the typical Lewy bodies.
We don’t associate sex hormones — testosterone, estrogen and progesterone — with brain disease. We associate anabolic steroids with male secondary sex characteristics, muscle growth, libido and aggressive behavior. We associate estrogen and progesterone with bone health and osteoporosis and mood swings when absent or out of balance.
But both the effect on libido and on mood imply that the sex hormones do something in the brain.
Let’s take a closer look.
Higher testosterone and lower estrogen are associated with less dementia
A research group in Baltimore produced an elegant longitudinal study of 574 community-dwelling men from age 32 to 87 and followed them for an average of 19 years. Fifty-four men were diagnosed with AD through standard testing plus neurological and neuropsychological examinations. Those with clear dementia underwent additional CT scanning for confirmation.
The researchers measured testosterone in this group and found the Free Testosterone Index (total testosterone/sex hormone binding globulin) showed an inverse relationship to risk of developing AD. Higher levels of free testosterone were associated with a lower risk of Alzheimer’s.
Another group in California showed that sex hormone levels predicted later cognitive function in 547 men age 59 to 87 living in a community setting in 1988 and 1991. Low estradiol and high testosterone correlated with better performance on 12 neuropsychological tests. The association of higher testosterone with lower risk for AD has been shown by other researchers as well.
Moreover, we also see this correlation in animals as diverse as rats and fish. We can find abundant amyloid beta in spawning Kokanee salmon. Amyloid deposits dramatically increase between sexual maturity of the fish and spawning, the last step before senescence and death.
Higher testosterone levels are associated with less dementia, but is the testosterone responsible for the lower risk? Association does not prove causation.
Amyloid deposits are the hallmark of late onset AD and are found in 95% of all cases. These extracellular plaques are the result of an overabundance of amyloid beta peptides and are especially concentrated in the hippocampus and frontal cortex of the brain. These plaques may be the result of previous injuries to the brain. We also see neurofibrillary “tangles” known as Tau filaments which can be the result of chronic inflammation. Glucose transport, mitochondrial changes, cell cycle changes, oxidative stresses and metal ion accumulations are other possible causes of damage to the brain.
There is evidence that both estradiol and testosterone effect the central nervous system from basic cell culture experiments to animal studies. In 1999, Gouras of the Rockefeller University in New York demonstrated that adding testosterone to isolated rat embryonic cerebral cortical neurons decreased the deposits of amyloid so characteristic of AD. He showed that testosterone increased the secretion of non-amyloidogenic APP fragments and decreased the secretion of amyloid beta peptides.
This raised the possibility that testosterone supplementation may prevent AD in humans.
Animal models show that sex hormones seem to modulate the amyloid deposits. Bowen of Australia using mice and cell cultures of neurons showed that estradiol and testosterone seem to modulate amyloid beta processing toward a path that does not deposit plaques. He suggested that perhaps the high luteinizing hormone (LH) from the pituitary gland with declining testosterone or estradiol may be the culprit responsible for the eventual amyloid deposits.
Secretion of sex hormones are controlled from the brain
Among the strongest predictors of late onset AD are the decline of estradiol in females and testosterone in males. With the sex hormone decline in aging men and women, there is a concomitant rise in the pituitary gonadotropins LH and follicle stimulating hormone (FSH). What is so interesting is that the LH and FSH levels are two to three times higher in patients with AD compared to age matched elderly populations.
Women who replace hormones after menopause have a lower risk of developing AD. Unfortunately, once you get AD, taking hormones will not reverse the process. It also appears that bioidentical hormones have a stronger preventive effect on women against AD than synthetic or animal-derived hormones which are in more common use.
LH receptors can be found in the hippocampus and neocortical regions of the brain, the same areas where amyloid deposits associated with AD occur. In contrast, there are no FSH receptors in the brain. Nevertheless, some research suggests that gonadotropins may participate in the initial cascade of events in the pathogenesis of AD. Men with Down Syndrome have a higher LH and normal sex hormones. They also develop AD earlier than normal populations.
In addition, men with suspected AD have a slower progression of the dementia when treated with a gonadotropin releasing hormone (GNRH) agonist which blocks the production of GNRH and with it the release of LH from the pituitary.
GNRH blockers are used a lot in prostate cancer treatment.
Human Studies with Prostate Cancer Patients
For over sixty years, castration has been a mainstay of prostate cancer treatment in the belief that testosterone enhances the growth of prostate cancer. We know that testosterone positively affects the brain in a multitude of ways ranging from mood to visual spatial cognition. Many of the mental symptoms of eliminating testosterone overlap with dementia. In surgically castrated patients, the LH remains high as the hypothalamus and pituitary struggle in vain to raise testosterone to normal levels. But in chemically castrated patients, LH production is blocked. This sheds some light onto whether or not LH is responsible for stimulating the production of amyloid plaques.
Sam Gandy of Australia found higher plasma amyloid beta peptide in prostate cancer patients who were being treated with GNRH blockers to eliminate testosterone. Recent studies have warned that the risk of AD for prostate cancer victims doubles with the use of GNRH blockers.
Current research implies that normal levels of testosterone are protective against Alzheimer’s disease. Low levels of testosterone are associated with dementia irrespective of LH levels.
What about Parkinson’s disease?
Studies have also shown a link between low testosterone and Parkinson’s disease, but again, association does not imply causation. There has been more attention given to estrogen and the global consensus is that estrogen is useful in preventing or delaying Parkinson’s disease, at least in post-menopausal women. Several studies have demonstrated a correlation between low testosterone an development of PD, raising the question of whether supplementation would prevent it. The slow development of the disease — decades in most cases — means that the answer to this question will require patience.
Estrogen is one of the natural breakdown products of testosterone, so administering testosterone will also naturally raise the patient’s estrogen. Often, men who are given supplemental testosterone are also administered an aromatase inhibitor to prevent conversion to estrogen, adding another potentially confounding factor.
In any case, the importance of supporting normal, healthy levels of sex hormones into the advancing years extends beyond concern for bone density and healthy body composition. Maintaining healthy levels are important for mood, cognition and the prevention of at least two of the most devastating neurodegenerative diseases — Alzheimer’s and Parkinson’s.