There has been much recent speculation as to whether or not the condition of low testosterone (hypogonadism) is related to, and more specifically may be a cause of brain disease.  This article will provide some background for, and address questions surrounding, the primary male sex hormone testosterone and its research founded relationship to the brain and to brain dysfunction.

Testosterone’s Production and Functions

Partly produced by the brain, the male sex hormone testosterone is actually produced within the testicles via a joint process, which includes a subsystem of the endocrine system, i.e. two different parts of the brain known as hypothalamus and the pituitary gland.  This testosterone making system, named after these organs and glands is called the Hypothalamic-Pituitary-Testicular axis or HPTA for short.  Testosterone serves as the male body’s primary natural hormone, and is responsible for the proper development of male sexual characteristics.  Although often referred to as a sex hormone, testosterone actually governs several areas within the body including a man’s development from birth onward with responsibility for everything from determining gender, through pubertal changes and male potency (libido & sexual functioning), to the partitioning of bodily muscle and fat distribution.  It is also an integral component in men’s sense of well-being, playing a major role in physiological, biological, and sexual health, while positively influencing:  stress coping capacity; bone density; immune system support; red blood cell production; sperm production and motility; and mental acuity (clarity, memory and recall, concentration and focus).  Although testosterone is present in both males and females, males produce approximately ten times more than their estrogen-based female counterparts.

Low Testosterone and Neurological Diseases

Although there may be symptom overlap, the majority of research on diseases of the brain do not appear to be caused by low testosterone, but are rather found in conjunction with hypogonadism in what is called co-morbidity (when two or more medical conditions exist at the same time).

Belonging to a group of conditions known as motor system disorders, Parkinson’s disease, and other group members are the result of the loss of dopamine-producing brain cells.  Parkinson’s disease has four primary symptoms which include:  tremors, or trembling in hands, arms, legs, jaw, and face; bradykinesia, or slowness of movement; postural instability, or impaired coordination and balance; and rigidity, or stiffness of the limbs and trunk.  As these symptoms become more pronounced, patients may experience difficulty talking, walking, and even completing simple tasks.  Parkinson’s disease generally affects people 50 years of age and older.  The early symptoms of Parkinson’s disease are subtle, occurring gradually over time.  However, some people with the disease experience a more rapid progression.  As the disease progresses, the tremors or shaking, which affects the majority of Parkinson’s disease patients eventually starts to interfere with daily activities.  Additional symptoms may include depression and other emotional changes; skin problems; difficulty in speaking, chewing, and swallowing; sleep complications; and urinary problems or constipation.

New research suggests that testosterone replacement therapy (TRT) may help some men when it comes to treating neurological diseases.  The primary areas of study include helping men reduce their risk of stroke as well as improve symptoms of Parkinson’s disease.  At the annual meeting of the American Academy of Neurology, two promising studies on the effects of testosterone were presented.  In the first, Monika Hollander, MD (study author) of the Erasmus Medical Center in the Netherlands, and her colleagues found that men with low testosterone levels had a higher risk of suffering a stroke than those with normal and/or high testosterone levels.  Furthermore, they discovered that testosterone replacement therapy only provided protective effects for nonsmokers, and that the risk of stroke was not reduced in smokers.Continue reading below….

The second study, presented by Mahlon DeLong, MD of Emory University suggests testosterone treatment can alleviate certain symptoms of Parkinson’s disease in men who have low testosterone levels.  When the patients studied received testosterone replacement therapy, researchers found symptoms such as fatigue, depression, anxiety, and even sexual dysfunction greatly improved as a direct result of therapy.  Testosterone deficiency has been estimated as affecting 20% to 25% of males over age 60 within the general population, and according to Dr. DeLong this deficiency may account for some of the symptoms seen in Parkinson’s that aren’t muscle related.

Though a larger number of patients is needed to confirm the prevailing theory, most researchers believe that testosterone treatment may be a valuable alternative to other medications (such as antidepressants) that don’t tend to work well in the treatment of Parkinson’s patients with low testosterone levels.

Testosterone Replacement Therapy as a Brain Disease Treatment

Although several neurological diseases may benefit from treatment by testosterone replacement therapy, Parkinson’s disease seems to be at the forefront of clinical research.  Based primarily on studies of death rates and recorded incidences, Parkinson’s appears to occur more commonly in men than women.

In recent years, several population based incidence studies on Parkinson’s disease have included the capturing (by researchers) of sex-related data.  These studies were conducted in a variety of populations in different countries throughout the world, but the bulk of such studies seem occur in university settings.  For example, in 2004 GF Wooten, et al of the Department of Neurology, within the University Health System at University of Virginia School of Medicine, Charlottesville, published a meta-analytical study (a secondary research study which examines the primary research from other studies) in the Journal of Neurological Neurosurgery and Psychiatry entitled, ‘Are men at greater risk for Parkinson’s disease than women?’.  Wooten found a significantly higher incidence rate of Parkinson’s disease among men (with the relative risk of 1.5 times greater) than women.  These researchers, based on their findings, suggested the following reasons for increased male Parkinson’s disease risk, specifically:  men have greater toxicant exposure; are more often prone to head trauma; have greater incidences of mitochondrial dysfunction, and may be more likely to possess X linkage genetic risk factors.

However, treatment using testosterone replacement therapy in neurological dysfunction is not exclusive to Parkinson’s disease, but rather extends to all forms of brain disease including:

• Dementia – not actually a specific disease, but would more accurately be described as a group of debilitating neurological symptoms under which several diseases are classified.  While memory loss is a common, and often the most generally associated symptom of dementia, memory loss alone does not mean that a person has dementia.  Dementia patients have significantly impaired intellectual functioning, which interfere with normal activities and relationships.  Eventually they lose the ability to solve problems, maintain emotional control, and may experience personality changes and/or behavioral problems such as hallucinations, agitation, and delusions.  Physicians will render a diagnose of dementia only if two or more brain functions become significantly impaired without the loss of consciousness.  For example, a dementia patient may suffer from both memory loss and diminished language skills.
• Huntington’s Disease (HD) – results from genetically programmed degeneration of brain cells (called neurons) in certain areas of the brain.  Such degeneration causes emotional disturbances, loss of intellectual faculties, and uncontrolled movements.  Huntington’s disease is a familial (genetic or hereditary) disease, passed from parent to child through a mutation in the normal gene.  Each child of an HD parent has a 50% chance of inheriting the HD gene.  If a child does not inherit the HD gene, he or she will not develop the disease and cannot pass it to future generations.  A person who does inherit the Huntington’s disease gene will eventually develop the disease.
• Alzheimer’s Disease (AD) – a progressive (develops over a period of years), irreversible, age-related brain disorder.  Initially, Alzheimer’s patients experience bouts of memory loss and confusion, which may be mistaken for the normal kind of memory changes sometimes associated with aging.  However, the symptoms of AD gradually lead to a decline in cognitive abilities such as decision-making and language skills, behavior and personality changes, and problems recognizing family members and friends.  AD ultimately leads to a severe loss of mental function that’s related to increasingly deteriorating breakdown of the connections between specific neurons in the brain.

In 2006 the Archives of Neurology published an article by Po H. Lu, et al of the Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA entitled, ‘Effects of Testosterone on Cognition and Mood in Male Patients With Mild Alzheimer Disease and Healthy Elderly Men’.  Lu and his colleagues felt that there was a compelling need for therapies which prevent, defer the onset of, slow the progression of, and improve the symptoms of Alzheimer’s disease.  Their expressed objective in this study was to evaluate the effects of testosterone therapy on neuropsychiatric symptoms, cognition, and overall quality of life in male patients suffering from mild Alzheimer’s.  Their study design included a twenty-four (24) week, double-blind (neither group knew about the other), randomized (group members were randomly assigned), placebo-controlled (one group received a placebo, or useless non-medication treatment), parallel-group study.  Using memory disorders clinics as well as general neurology and medicine clinics, from University of California medical centers in the cities of Los Angeles, San Francisco, and Irvine participants were comprised of 16 male patients with Alzheimer’s and 22 healthy male control subjects.  The healthy control men were recruited from within the community via posted advertisements, and through the university-based clinics.  The treatment interventions included testosterone in the form of a 75 mg hydroalcoholic gel that was applied daily to the skin of the participants, and a placebo.  The primary outcome measuring instruments, those used to assess subjects both before and after treatment for:  cognitive functioning included the Developmental Test of Visual-Motor Integration, California Verbal Learning Test, Block Design Subtest, Judgment of Line Orientation; neuropsychiatric symptoms testing included the Neuropsychiatric Inventory; global functioning testing included the Clinician’s Interview-Based Impression of Change; and quality of life testing included the Quality of Life–Alzheimer Disease Scale.  Lu, et al hypothesized that testosterone therapy would yield benefits in cognition, mood, and quality of life.  In their results they cited that patients with Alzheimer’s in the testosterone-treated group had significantly greater improvements in the scores on the caregiver version of the overall quality-of-life scale, with some improvements in cognition as well.

Further Implications for Testosterone Therapy

Although technically classified as an autoimmune disease, multiple sclerosis (MS) is a largely unpredictable disease that attacks the central nervous system with results that are related to neurological diseases.  The adverse effects of MS vary greatly ranging from the relatively benign (mild symptoms), to the largely disabling (severe symptoms), to completely devastating (profound symptoms).  Multiple sclerosis is marked by the brain’s inability to communicate with the other parts of the body.  Most MS patients experience muscle weakness in their extremities, along with difficulty maintaining coordination and balance.  These symptoms may be severe enough to impair walking or even standing, and in the most severe cases, MS can produce partial or complete paralysis of the body.

Since multiple sclerosis is a chronic inflammatory disease of the central nervous system with a pronounced neurodegenerative component, some researchers are examining novel treatment alternatives that target both aspects of this disease.  Early evidence from both basic and clinical studies suggests that testosterone has an immunomodulatory (ability to modify or regulate one or more immune functions), as well as a potential neuroprotective (guarding or protecting against destructive or poisonous actions towards nerve tissue) effect that could be beneficial in the treatment of MS.  In July 2008 the Journal of Neuroinflammation published a study by SM Gold, et al of the Department of Neurology at the University of California at Los Angeles entitled, ‘Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone’.  Comprised of 10 male MS patients, this study treated each subject with a 10 g gel, which contained 100 mg of testosterone in a cross-over design (6 month observation period followed by 12 months of treatment).  Researchers obtained blood samples at three-month intervals during both the observation and treatment periods.  In short without getting too clinical, isolated blood peripheral mononuclear cells (PBMCs) served as the primary measurement from which lymphocyte subpopulation was examined.  SM Gold, et al found that testosterone treatment:  significantly reduced DTH recall responses and induced a shift in peripheral lymphocyte composition; significantly decreased PBMC production of IL-2; and increased TGFbeta1 production.  Such results are consistent with an ability to modify or regulate one or more immune functions, while increasing the production of BDNF and PDGF-BB which suggests a potential nerve protecting effect.

Produced in part by the brain, testosterone secretion can be adversely affected by injuries and diseases, which affect testosterone-related brain sections.  Although there can be some symptomatic overlap, there is presently no conclusively reliable clinical evidence that links testosterone usage to brain disease.  Testosterone therapy in the treatment of non-hypogonadic (low testosterone) diseases, such as neurological and autoimmune disease is still a relatively new venture.  However, as evidenced by the presented studies, the outlook for the novel treatment of such diseases with testosterone therapy is quite positive. 

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