Testosterone and Neuroprotection

Testosterone, the gonadal sex steroid hormone, has various effects on numerous body tissues, including the brain. Beyond its reproductive function, this hormone is responsible for increased muscle mass, sexual function and libido, body hair and decreased risk of osteoporosis. It's not surprising that our levels of testosterone are understood to affect our behaviour. Testosterone receptors are found in our brain, which means the hormone interacts and binds with our neurons, relaying to them important messages for action. Testosterone also takes part the in nervous system development. As with most of our hormones, blood levels of testosterone vary according to our stress levels, or other demands on our bodies. As well as providing fabulous fodder for research, this presents a dilemma for scientists. Gender-specific morphological and behavioral patterns of the adult are determined by the presence or absence of this hormone during certain critical periods of the central nervous system (CNS) development.

A testosterone level test is helpful in measuring total levels of testosterone produced by the body. Testosterone saliva testing only measures total testosterone. If the reason for testing has to do with patient symptoms similar to those experienced during andropause, measurements of total testosterone are not always helpful. Testosterone is physiologically secreted by testes and adrenal glands and transported by the sex hormone binding globulins (SHBG) and albumins. About 60-70% of testosterone is tightly bound to SHBG, whereas the remaining 30-40% is bound loosely to albumin. Only 0.5-2% of testosterone is free.

Testosterone acts via androgen receptors (ARs). Regulation of AR protein and/or AR mRNA by androgens has been observed in mammals in multiple androgen-responsive tissues, such as the brain, prostate, testes, ovary and adrenal glands. ARs are found in neurons throughout the brain. The distribution of these receptors in mammals is identified using biochemical and immunocytochemical methods. There are sex-related differences in AR distribution.

One of the less known testosterone action is neuroprotection. By definition, the neuroprotection is an effect that may result in salvage, recovery or regeneration of the nervous system, its cells, structure and function. Testosterone, as the endogenous agent, may in the free form cross the blood-brain barrier and influence neuronal cells. Testosterone might act directly through androgen pathway or indirectly via conversion to estrogen. Doses of testosterone might prevent a key brain abnormality associated with Alzheimer's disease, say US researchers. Their work in rats suggests that older women as well as men should be given testosterone to help prevent or treat the disease, they say. This finding suggests that testosterone shares with estrogen the ability for neuroprotection but testosterone induces this cellular action through a separate mechanism.

The cellular effects of testosterone can be grouped into genomic and nongenomic categories. Genomic effects relate to transcription and translation of new gene products and often require many hours to fully develop. Nongenomic effect occurs very rapidly and involves ion movements and/or initiation of signal transduction cascades.

Flutamide antagonizes genomic actions resulting from activation of AR. Some evidence suggests that flutamide may fail to block some nongenomic AR-mediated effects. In addition, some observations suggest that flutamide and other antiandrogens not only failed to block AR-dependent testosterone actions but mimicked them as well.

Recent data suggest that testosterone may also exert neurotrophic actions. For example, Beyer et al. and Lustig have observed neuronal differentiation and increase in neurite outgrowth after activation of androgen pathways in the cultured neural cells. Beyer et al. prepared gender-specific primary cell cultures from embryonic day 15 mouse hypothalamus and cortex. As with most of our hormones, blood levels of testosterone vary according to our stress levels, or other demands on our bodies. As well as providing fabulous fodder for research, this presents a dilemma for scientists. Aromatase activity was higher in male compared with female tissues in the absence of sex steroids and significantly increased in males and females after testosterone treatment. Other experiments in male rodents suggest that testosterone is linked to an increase in neuron somal size, neuritic growth, plasticity and synaptogenesis in both motoneurons of the spinal nucleus of the bulbocavernosus and several populations of pelvic autonomic neurons. Other data suggests that post-menopausal women given hormone replacement therapy - containing oestrogen - have a much lower risk of developing Alzheimer's disease. The hormone reduced the extent of spinal cord damage in vitro.

There are also evidences against the neuroprotective action of testosterone. There is also evidence that testosterone did not provide significant neuroprotection against glutamate-induced neurotoxicity. Glutamate-induced neurotoxicity is a model of oxidative stress, which plays an important role in Parkinson's disease. In contrast, estradiol protected mesencephalic neurons against neuronal death induced by glutamate. The exact interplay of sex hormones and Alzheimer's risk factors remains unclear. But the new work suggests that maintaining normal levels of testosterone in ageing men, and adding testosterone to oestrogen supplements for postmenopausal women, could help reduce their risk of developing the disease, say the Texas researchers.

The question regarding the neuroprotective activity of anabolic steroids has not yet been fully answered. It is known that e.g. epitestosterone blocks the action of testosterone and has antiandrogenic activity. Epitestosterone administration reduced the effect of testosterone propionate (TP) on body weight, weight of seminal vesicles and kidneys in castrated male mice. Some studies show that also neurosteroids, which are synthesized within the nervous system by neurons and glial cells may exert neurotrophic actions. Some neurosteroids show an anticonvulsant effect. Intraperitoneal administration of androsterone protects mice agains NMDA-induced seizures and mortality. A similar anti-seizure effect has 5a-androstane-3a, 17ß-diol (3a -Diol) in the kainic acid model of epilepsy. Frye and Reed reported that subcutaneous administration of 3a-Diol prior to kainic acid injection decreases the number and duration of partial and full seizures in female ovariectomized rats.