New research using a murine model (mice) suggests that a sudden decrease in testosterone levels in men can create Parkinson's Disease symptoms in men. In the study, mice that were castrated experienced dramatic increases in brain levels of inducible nitric oxide synthase (iNOS) and nitric oxide. Too much nitric oxide (which are generated by the iNOS) kills neurons in the brain. The researchers note, "Interestingly, castration does not cause Parkinson's like symptoms in male mice deficient in iNOS gene, indicating that loss of testosterone causes symptoms via increased nitric oxide production."
Further, "We found that the supplementation of testosterone in the form of 5-alpha dihydrotestosterone (DHT) pellets reverses Parkinson's pathology in male mice."
Currently, it's not clear if the sudden decrease in testosterone has the same effect in human males. But further research is planned.
If this result can be replicated in humans, there are serious implications for male health. Testosterone levels are clearly linked to many disease processes. In most males, testosterone levels reach their peak from late teens to late 20s. Here is a sample distribution from the study cited below.
Simon D. Nahoul K. Chades MA. (1996). Sex hormones, ageing, ethnicity and insulin sensitivity in men: An overview of the Telecom study. In: Androgens and the ageing male. Eds. Oddens B. Vermeulen A. Parthenon Publishing. New York.
Testosterone levels measured in ng/dlHowever, testosterone levels may fall drastically due to chronic stress or highly stressful life events (death, divorce, job less, and so on). Other factors for low testosterone can be environmental toxins (xenoestrogens, for example), inflammation, free radicals (causing mitochondrial damage), dietary choices (soy extracts [genistein, daidzein], black licorice extract [a sweetener], alcohol), and obesity (increases estrogen levels and causes inflammation) This list could go on an on.
Age Subjects Mean Standard Deviation Median < 25 125 692 158 697 25-29 354 669 206 637 30-34 330 621 194 597 35-39 212 597 189 567 40-44 148 597 198 597 45-49 154 546 163 527 50-54 164 544 187 518 55-59 155 552 174 547
Finally, there is one other major concern here. One half of all men will be diagnosed with prostate cancer in their lifetimes (and the other half would if they lived long enough). One of the frontline treatments, despite a lot of evidence that the health risks for those who survive far outweigh the extra few months a man might get if his cancer is aggressive and terminal, is androgen depletion therapy (ADT). Never let a doctor do this to you. Aggressive (i.e., deadly) forms of prostate cancer are NOT androgen-dependent - they are estrogen dependent.
ADT has been linked to muscle loss, weight gain, gynecomastia, diabetes, impotence, depression, bone loss, and a series of other issues. According to this new study, we may be able to add Parkinson's Disease to that list.
July 26, 2013 — The results of a new study by neurological researchers at Rush University Medical Center show that a sudden decrease of testosterone, the male sex hormone, may cause Parkinson's like symptoms in male mice. The findings were recently published in the Journal of Biological Chemistry.
One of the major roadblocks for discovering drugs against Parkinson's disease is the unavailability of a reliable animal model for this disease.
"While scientists use different toxins and a number of complex genetic approaches to model Parkinson's disease in mice, we have found that the sudden drop in the levels of testosterone following castration is sufficient to cause persistent Parkinson's like pathology and symptoms in male mice," said Dr. Kalipada Pahan, lead author of the study and the Floyd A. Davis endowed professor of neurology at Rush. "We found that the supplementation of testosterone in the form of 5-alpha dihydrotestosterone (DHT) pellets reverses Parkinson's pathology in male mice."
"In men, testosterone levels are intimately coupled to many disease processes," said Pahan. Typically, in healthy males, testosterone level is the maximum in the mid-30s, which then drop about one percent each year. However, testosterone levels may dip drastically due to stress or sudden turn of other life events, which may make somebody more vulnerable to Parkinson's disease.
"Therefore, preservation of testosterone in males may be an important step to become resistant to Parkinson's disease," said Pahan.
Understanding how the disease works is important to developing effective drugs that protect the brain and stop the progression of Parkinson's disease. Nitric oxide is an important molecule for our brain and the body.
"However, when nitric oxide is produced within the brain in excess by a protein called inducible nitric oxide synthase, neurons start dying," said Pahan.
"This study has become more fascinating than we thought," said Pahan. "After castration, levels of inducible nitric oxide synthase (iNOS) and nitric oxide go up in the brain dramatically. Interestingly, castration does not cause Parkinson's like symptoms in male mice deficient in iNOS gene, indicating that loss of testosterone causes symptoms via increased nitric oxide production."
"Further research must be conducted to see how we could potentially target testosterone levels in human males in order to find a viable treatment," said Pahan.
Other researchers at Rush involved in this study were Saurabh Khasnavis, PhD, student, Anamitra Ghosh, PhD, student, and Avik Roy, PhD, research assistant professor.
This research was supported by a grant from the National Institutes of Health that received the highest score for its scientific merit in the particular cycle it was reviewed.
Parkinson's is a slowly progressive disease that affects a small area of cells within the mid-brain known as the substantia nigra. Gradual degeneration of these cells causes a reduction in a vital chemical neurotransmitter, dopamine. The decrease in dopamine results in one or more of the classic signs of Parkinson's disease that includes resting tremor on one side of the body; generalized slowness of movement; stiffness of limbs and gait or balance problems. The cause of the disease is unknown. Both environmental and genetic causes of the disease have been postulated.
Parkinson's disease affects about 1.2 million patients in the United States and Canada. Although 15 percent of patients are diagnosed before age 50, it is generally considered a disease that targets older adults, affecting one of every 100 persons over the age of 60. This disease appears to be slightly more common in men than women.
The above story is based on materials provided by Rush University Medical Center.
S. Khasnavis, A. Ghosh, A. Roy, K. Pahan. (2013, Jun 6). Castration Induces Parkinson Disease Pathologies in Young Male Mice via Inducible Nitric-oxide Synthase. Journal of Biological Chemistry; 288 (29): 20843-20855. DOI:10.1074/jbc.M112.443556
Full Title and Abstract:
Castration Induces Parkinson Disease Pathologies in Young Male Mice via Inducible Nitric-oxide Synthase
Saurabh Khasnavis, Anamitra Ghosh, Avik Roy, and Kalipada Pahan
- Background: Developing a simple irreversible animal model to study nigrostriatal pathologies is important for Parkinson disease (PD).
- Results: Castration induces glial activation and death of dopaminergic neurons in wild type, but not iNOS−/−, young male mice.
- Conclusion: Castration induces nigrostriatal pathologies via iNOS.
- Significance: Castrated male mice may be used as a simple, toxin-free, nontransgenic, and irreversible animal model for PD.
Although Parkinson disease (PD) is a progressive neurodegenerative disorder, available animal models do not exhibit irreversible neurodegeneration, and this is a major obstacle in finding out an effective drug against this disease. Here we delineate a new irreversible model to study PD pathogenesis. The model is based on simple castration of young male mice. Levels of inducible nitric-oxide synthase (iNOS), glial markers (glial fibrillary acidic protein and CD11b), and α-synuclein were higher in nigra of castrated male mice than normal male mice. On the other hand, after castration, the level of glial-derived neurotrophic factor (GDNF) markedly decreased in the nigra of male mice. Accordingly, castration also induced the loss of tyrosine hydroxylase-positive neurons in the nigra and decrease in tyrosine hydroxylase-positive fibers and neurotransmitters in the striatum. Reversal of nigrostriatal pathologies in castrated male mice by subcutaneous implantation of 5α-dihydrotestosterone pellets validates an important role of male sex hormone in castration-induced nigrostriatal pathology. Interestingly, castration was unable to cause glial activation, decrease nigral GDNF, augment the death of nigral dopaminergic neurons, induce the loss of striatal fibers, and impair neurotransmitters in iNOS−/− male mice. Furthermore, we demonstrate that iNOS-derived NO is responsible for decreased expression of GDNF in activated astrocytes. Together, our results suggest that castration induces nigrostriatal pathologies via iNOS-mediated decrease in GDNF. These results are important because castrated young male mice may be used as a simple, toxin-free, and nontransgenic animal model to study PD-related nigrostriatal pathologies, paving the way for easy drug screening against PD.