When it comes to the brain, hormonal influences are the butt of many tactless jokes and at the heart of Rhonda Voskuhl's seminal findings regarding neurodegenerative disease and protection.
Speeding down the length of the axon, nerve cell impulses, taking a fraction of a second to travel from head to toe, orchestrate choreographed muscle movements. This process is so in sync with our will that most of us can take our ability to walk, see and swallow for granted. But when it breaks down, as it does with the disease multiple sclerosis, unwieldy symptoms emerge.
Paralysis, tingling, uncoordinated movements, blindness and cognitive defects are all symptoms that can coincide with MS — a disease affecting 2.5 million people worldwide. Nerves, normally insulated in white myelin, become demyelinated — exposed —the impulses sputter, dissipate and may never reach their destination. While the immediate cause, scar tissue (sclerosis), will show up in brain scans, the underlying issue is thought to arise from an immune system malfunction (relating to inflammation).
But naturally, it's more complicated than that with environmental as well as hereditary factors as possible contributors to the disease. And, hormones have something to do with it, too.
Research involving hormonal influences on the brain is the rage right now. Yet, while one study suggests hormone therapy in postmenopausal women is detrimental to cognition, another shows memory-enhancing properties in patients with the neurodegenerative brain disorder, Alzheimer's disease. And with regard to MS, the effects of hormones are largely anecdotal. These confounding reports make untangling the specific roles of hormones, and how they relate to disease, challenging.
But Voskuhl's laboratory in the department of neurology at University of California, Los Angeles has taken on the task with vigor. She has received the attention of seven major universities around the country and acquired $5 million in grant money from the National Institute of Health and National Multiple Sclerosis Society to further her research and clinical trials on hormone-related therapy — specifically, therapy using sex hormones.
One of the lab's recent exploratory studies showed that testosterone treatment for men afflicted with MS enhanced cognitive abilities. The therapy also stabilized brain shrinkage commonly associated with the disease. The study investigated the effect of testosterone on 10 men with MS. At the outset, the men showed testosterone levels in the low/normal range. For men, diagnosis of MS tends to coincide with age (occurring between 30 and 40 — a time when available testosterone levels gradually drop). With treatment, the levels rose but not above high/normal quantities.
Analysis from blood showed that testosterone modulates the immune system and enhances production of brain derived protective factors. This supports the idea — central to Voskuhl's research — that hormones have a dual role, anti-inflammatory and neuroprotective, in influencing the disease.
The mechanism for the testosterone results may be due to testosterone's ability to bind brain receptors directly. Alternatively, the brain protection might arise from testosterone conversion to estrogen, a hormone that is routinely generated from testosterone by the enzyme aromatase. Either way, it seems that testosterone (as with estrogen) is neuroprotective. Since MS is a degenerative disease, the ability to target a molecular controller of brain protection would be ideal.
The specific physiological role estrogen plays in disease is also a focus of Voskuhl's investigations. That MS strikes twice as many women as men, along with the phenomenon that pregnant women have a striking 80 percent remission, prompted her to investigate the role of sex hormones in protecting the brain.
Using a mouse model system, Voskuhl and her research team have been able to tease out estrogen's mechanism of action and determine that the neuroprotective attributes can be independent of the inflammation-reducing abilities. This is a remarkable distinction that may guide future therapies. The experiments in mice showed promise for a compound that binds specifically to a distinct estrogen receptor. While the compound is currently not available for clinical use, strategically selecting an estrogen that works through the same receptor is a promising option.
"We've already done a pilot study with estriol," Voskuhl commented. Estriol, a naturally occurring estrogen produced during pregnancy, doesn't have the side effects associated with estrogens traditionally used for hormone therapy. Similar to the testosterone study in men, the pilot trial using estriol in women showed decreases in MS severity. In fact, "the lesions in the brain were reduced by 80 percent," Voskuhl reported.
A larger trial using estriol to treat women with MS is under way. Given as a pill, estriol will provide patients with hormone levels equivalent to six months of pregnancy, since the last trimester of pregnancy is often a time at which MS symptoms improve and relapse rates decrease. The study, currently recruiting participants, will be a two-year placebo-controlled study and will treat patients concurrently with a standard treatment.
Future studies to explore the possibility of using or designing specific compounds that function through the distinct neuroprotective receptor hold promise beyond the standard sex hormones. These designer estrogens may provide long-term protection and be used with standard therapies.
"It's important because anti-inflammatory medications now given reduce symptoms by one-third and have only modest affects on halting permanent disability," Voskuhl noted.
To date there is no cure for the disease. There are six FDA-approved treatment options; many of which act on the immune system. They can alter the disease course, treat specific symptoms and quell disease intensity, but they do not provide the brain with the protection needed to halt, repair or prevent the disease process. The prospect that hormones can decrease inflammation and increase factors associated with promoting brain cell survival is enticing. And the notion that designer estrogens may provide brain protection in MS as well as other neurodegenerative disorders is equally alluring.
As clinicians administer medications and researchers investigate receptors, our nerve cell impulses will continue their journey. And Voskuhl's laboratory will continue theirs. She said, "There are a lot of things that have to be done."
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