Low testosterone levels associated with disability in male MSers

Do you have symptoms of low testosterone levels? #MSBlog #MSResearch

"There has been a lot of recent comments about the effect of sex hormones on disease outcomes in both men and women with MS. This is an important area of research and there are several ongoing studies testing whether or not oestrogens (the so called female hormone) is disease-modifying in MSers. At this year's American Academy of Neurology (AAN) meeting in Philadelphia Rhonda Voskuhl, from the University of California Los Angeles, will be presenting the results of her oestradiol trial in RRMS. There is also an emerging literature of oestrogens being neuroprotective in multiple sclerosis. As a result of this someone asked about testosterone in men."

"The following abstract describes an observational study, which links low levels of testosterone in male MSers with disease progression. Interestingly, low testosterone levels in this study did not stimulate the feedback loop from the brain to increase testosterone levels implying that the problem may be a result of MS affecting a part of the brain that produces luteinizing hormone or LH. LH is produced in the hypothalamus and is released into the blood. LH then stimulates the testes in men to make testosterone. We know from pathology studies that MSers have a lot lesions in the hypothalamus."

"Please note that this is an observational study and it simply describes an association between low levels of testosterone and disability; it does not tell us that this relationship is causal i.e. that low testosterone levels drives disability. It could be reverse causation, i.e. the processes that causes disability also causes low testosterone levels. The only way to tease these apart is to do an intervention study, i.e. a randomised double-blind controlled study to see if testosterone has any disease-modifying effects. There are animal studies suggesting this may be the cases (please see Ziehn et al. below)."

"Should we act on these results? I am not sure. It may be worth measuring testosterone levels in male MSers who have symptoms compatible with low levels and putting them on testosterone replacement therapy. The problem we face clinically is that the symptoms of low testosterone are very non-specific and occur frequently in MSers: low sex drive (libido), poor erections (maintenance and strength), depression, mental fogginess/fuzziness, difficulty concentrating, anxiety, muscle loss, weight gain, decreased facial hair, decreased pubic hair and poor sleep quality. This is clearly something that needs to be looked at in more detail, particularly in male MSers with sexual dysfunction and mood disorders."

Epub: Bove et al. Low testosterone is associated with disability in men with multiple sclerosis.
Mult Scler. 2014 Apr.

BACKGROUND: Gonadal steroids may modulate disease course in MS.

OBJECTIVE:To assess the prevalence and clinical associations of hypogonadism in men with MS.

METHODS: Male patients, aged 18-65 years, with relapsing-remitting MS (RRMS) or clinically-isolated syndrome (CIS) and their first symptom < 10 years prior were selected from a longitudinal clinical study. We measured their hormones in stored morning blood samples, and collected their Expanded Disability Status Scale (EDSS) scores every 6 months and their Symbol Digit Modalities Test (SDMT) results annually.

SDMT = This is a brief and easy to administer test that is sensitive in detecting cognitive impairment in MSers and is sensitive to changes in cognitive functioning over time and in response to treatment. The SDMT involves a simple substitution task. Using a reference key, the MSers has 90 seconds to pair specific numbers with given geometric figures. Because MSers can give either written or spoken responses, the test can be done by individuals who have upper limb motor disabilities (weakness or incoordination) or speech disorders. Because it involves only geometric figures and numbers, the SDMT is relatively culture free and can be administered to individuals who do not speak English.

RESULTS: Our analysis included 96 men with a mean age of 40 years, EDSS of 1.1 and disease duration of 4.6 years. Of these men, 39% were hypogonadal (total testosterone < 288 ng/dL); none showed compensatory elevations in luteinizing hormone (this is the hormone that the brain releases to try and push-up levels of testosterone). Their low testosterone levels and testosterone:oestradiol ratios were negatively correlated with body mass index (BMI) and leptin, and showed no correlation with 25-hydroxy-vitamin D levels. In our primary cross-sectional analyses, there was a negative age-adjusted correlation between total testosterone and EDSS (p = 0.044). In the age-adjusted longitudinal analyses, higher baseline testosterone levels were associated with less decline in SDMT (p = 0.012).

CONCLUSIONS: Men with MS may experience hypogonadotropic hypogonadism. Low testosterone levels may be associated with worse clinical outcomes.

"The following animal study shows that testosterone treatment is neuroprotective in EAE and animal model of MS."

Ziehn et al. Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci. 2012 Sep 5;32(36):12312-24.

Over 50% of multiple sclerosis (MS) patients experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in >30% of these patients. While postmortem pathology studies and in vivo magnetic resonance imaging demonstrate that the hippocampus is targeted in MS, the neuropathology underlying hippocampal dysfunction remains unknown. Furthermore, there are no treatments available to date to effectively prevent neurodegeneration and associated cognitive dysfunction in MS. We have recently demonstrated that the hippocampus is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. The objective of this study was to assess whether a candidate treatment (testosterone) could prevent hippocampal synaptic dysfunction and underlying pathology when administered in either a preventative or a therapeutic (postdisease induction) manner. Electrophysiological studies revealed impairments in basal excitatory synaptic transmission that involved both AMPA receptor-mediated changes in synaptic currents, and faster decay rates of NMDA receptor-mediated currents in mice with EAE. Neuropathology revealed atrophy of the pyramidal and dendritic layers of hippocampal CA1, decreased presynaptic (Synapsin-1) and postsynaptic (postsynaptic density 95; PSD-95) staining, diffuse demyelination, and microglial activation. Testosterone treatment administered either before or after disease induction restores excitatory synaptic transmission as well as presynaptic and postsynaptic protein levels within the hippocampus. Furthermore, cross-modality correlations demonstrate that fluctuations in EPSPs are significantly correlated to changes in postsynaptic protein levels and suggest that PSD-95 is a neuropathological substrate to impaired synaptic transmission in the hippocampus during EAE. This is the first report demonstrating that testosterone is a viable therapeutic treatment option that can restore both hippocampal function and disease-associated pathology that occur during autoimmune disease.

Labels: , , ,