Estrogen: Neuroprotection for SCI?
The hormone estrogen has broad therapeutic potential much beyond its more obvious roles, including as a possible protective agent after neurotrauma.
This ongoing Healing Options series has periodically discussed various, commonly consumed substances that may provide some neuroprotection when administered soon after spinal-cord injury (SCI). Examples include the cholesterol-lowering statin drugs (e.g., Lipitor), painkiller ibuprofen, herbal remedy Ginkgo biloba, sleep-inducing hormone melatonin, cancer-fighting quercetin found in foods, and the ubiquitous supplement vitamin E (all reviewed at www.sci-therapies.info). This update specifically discusses another potential neuroprotectant with extensive human use—the hormone estrogen.
What Is It?
Although estrogen exerts many physiological effects in women and men, it is most well known as the female sex hormone. In women, estrogen is primarily produced by the ovaries. It regulates the female estrous or reproductive cycle and promotes the development of secondary sexual characteristics.
In men, the hormone is produced at a much lower level by the testis and plays a key role in testicular function. In aging men, elevated estrogen levels are associated with an increased risk of stroke, heart disease, and prostate problems, and low levels with osteoporosis and bone fractures.
Estrogen derivatives are a key component of many oral contraceptives and have been used for postmenopausal hormone-replacement therapy. Although estrogen’s reproductive roles receive the most attention, this potent, multiactive hormone can influence diverse physiological processes. As such, it theoretically has broad therapeutic potential much beyond its more obvious roles, including as a possible protective agent after neurotrauma.
Estrogen & SCI
The SCI neuroprotective possibilities have been extensively studied by Dr. Naren Banik and colleagues at the Medical University of South Carolina using animal models of SCI as well as cultures of neuronal cells.
SCI was produced by accessing the thoracic spinal cord of rats through laminectomy and dropping a weight on the exposed cord. Essentially, this is an experimental version of the sort of contusion injury experienced by many people with SCI. The rats were then treated intravenously with estrogen 15 minutes and 24 hours after injury, and, for the next five days, with a single daily dose injected into the body cavity. Recovery of locomotor function was followed for six weeks, and the amount of improvement observed compared to similarly injured control rats that received no estrogen.
Locomotion was assessed using the BBB scale, a commonly used animal test that measures recovery of hind-limb function on a scale from 0 (no hind-limb movement) to 21 (normal walking). At the end of the observation period, the average BBB score for the estrogen-treated rats was 13, compared to 9 for the controls.
Dr. Naren Baik and colleagues at the Medical University of South Carolina have investigated estrogen's neuroprotective possibilities for spinal-cord injury.
Functionally, these statistically significant differences mean that when compared to controls, the estrogen-treated rats were better able to support their body weight, make weight-supported steps, and coordinate hind-limb/
forelimb stepping. The investigators concluded “estrogen treatment significantly increased the locomotor function in the injured animals over the 42-day postinjury period….”
These investigators and others have devoted much effort trying to understand the specific biological mechanisms by which estrogen mediates neuroprotection. The damage-spreading, pathophysiological cascade after the initial physical insult is extraordinarily complex and is the reason SCI has been difficult to understand at a molecular level. Given this complexity, as well as estrogen’s increasingly documented, powerful multifaceted role in the body, the hormone could target many possible biological systems. Some possibilities are briefly highlighted below. However, these are often complex interlinked and interdependent processes.
(1) Calcium influx: Neuronal conduction depends upon the right balance of calcium ions between a cell’s inside and outside. Normally, a lot of calcium exists outside the neuron and relatively little inside. Injury disrupts the equilibrium, allowing excessive calcium to flow into the cell. This influx initiates a neural-destructive cascade that damages other neurons. By inhibiting the calcium influx into the cells, estrogen lessens this damaging-perpetuating cascade.
(2) Apoptosis: Cells at the injury site die of necrosis, while cells surrounding the site often die from apoptosis. As a crude analogy, necrotic cell death is like a quick death from being shot, and apoptotic cell death is more like a lingering death from cancer. Because apoptosis is potentially reversible, treatments that turn this process around should help minimize postinjury cell degeneration. By modulating the activity of certain enzymes that promote postinjury apoptosis, estrogen slows down degeneration.
(3) Excitotoxicity: Routinely, certain amino acids, like glutamate, are released from a presynaptic neuron and flow to a nearby postsynaptic neuron, promulgating the nerve impulse. However, after injury, cells burst, releasing too much glutamate. Through interactions with receptors on neighboring cells, this excessive glutamate will initiate a neurotoxic biochemical cascade. Estrogen protects against this excitotoxicity-caused cell death.
(4) Edema: Fluid accumulation at the injury site creates damaging edema swelling. Estrogen-treated rats exhibit less edema.
(5) Inflammation: Inflammatory cells infiltrate into the lesion area, which promotes secondary cell death. Estrogen treatment lessens infiltration.
(6) Myelin: The fatty insulation surrounding axons, myelin enables neurons to propagate a signal. SCI often results in axonal demyelination, another process that is attenuated by estrogen.
(7) Blood flow: Injury compromises regeneration-promoting blood flow, contributing to secondary cell death. Estrogen promotes the growth of new blood vessels (i.e., angiogenesis), enhancing postinjury blood flow.
(8) Antioxidant: After the initial mechanical injury in SCI, free radicals are generated. Called lipid peroxidation, these free radicals can steal electrons from neighboring cell membranes, resulting in further cell death. A potent antioxidant, estrogen may reduce free-radical-induced oxidative stress.
Given these findings and the fact that women have much higher levels of estrogen than men, it is interesting to note that studies suggest women recover more function after neurotrauma.
New Treatment Options Needed
Before you grab your wife’s birth-control pills, remember—estrogen’s promising neuroprotective potential is based on animal studies often using high dosing, which doesn’t necessarily translate into human efficacy. Nevertheless, we clearly need to develop new SCI-treatment options.
Since the 1990s, the big tamale for treating acute injury has been high-dose methylprednisolone (MP), a synthetic glucocorticoid steroid. Unfortunately, this therapeutic tamale is causing heartburn for a growing number of scientists.
Although several large clinical trials sponsored by the National Institutes of Health (NIH) suggested MP preserves function, more recent studies are questioning these conclusions. For example, emerging research suggests high-dose MP therapy damages muscles and that functional improvement attributed to MP may merely be due to the recovery of muscle damage caused by the drug itself. In addition, a recent Japanese study indicates MP-treated patients actually had less improvement than non-MP-treated patients.
Because MP was so wholeheartedly embraced by SCI-health policymakers, the consideration of other options was regrettably pushed to the back burner. Although we could argue endlessly on MP’s true therapeutic value, it certainly won’t hurt to expand our SCI-healing armamentarium through a renewed focus on potential alternatives.
Although the neuroprotective potential of estrogen and the substances listed previously have been explored mostly in animals, their widespread human consumption and the physiological understandings gained from such consumption give them a leg up in the translation into real-world therapies.
Note: Key references are posted at www.sci-therapies.info.
Estrogen: Neuroprotection for SCI?
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