Elsewhere, we have discussed the neuroprotective potential of estrogen, a female-associated hormone also produced by men at lower levels. Estrogen inhibits a variety of neuron-damaging physiological processes that occur after spinal cord injury (SCI) and may promote functional recovery.

This update will specifically review progesterone-related neuroprotection. Although called the “pregnancy hormone,” it is also synthesized to a lesser degree by men. Because women possess higher levels of these hormones, when it comes to neurological trauma, they are probably the stronger sex.

Progesterone

Progesterone is synthesized from cholesterol by the ovaries, adrenal glands, and placenta. In the menstrual cycle, progesterone levels are relatively low before ovulation and elevated afterwards. Hormone levels are much higher throughout pregnancy, drop to low levels after birth and during lactation, and recede after menopause. In men, progesterone is produced by the testes and, paradoxically, is the biochemical precursor to the defining male hormone testosterone.

In part by affecting the expression of other body-regulating hormones, progesterone exerts many biological influences throughout the body above and beyond its more well-known effects in reproduction. Overall, our optimal functioning is dependent upon a complex, interacting hormonal milieu, whose composition is dependent on many factors, including gender, age, diet, life style, and overall health.

Neurosteroid

With paradigm-expanding implications, progesterone is also produced by and influences the nervous system and, as such, has been termed a “neurosteroid.” Due to this localized synthesis, nervous-tissue progesterone levels are not necessarily a function of plasma levels of the hormone produced by more traditional sources. Neurons and neuronal support cells (called glia) actually have unique progesterone receptors on their outer membrane surface. Like a key fitting in a lock, progesterone’s interactions with these receptors can initiate complex, nervous-system-unique biological responses. Although these responses are only beginning to be understood, they seem to enhance neuronal health and viability.

Many studies suggest that progesterone treatment is neuroprotective after trauma by limiting the loss of neuronal tissue and, as a consequence, preserving function. Because membrane-soluble progesterone can readily diffuse cross the blood-brain-barrier, externally administered progesterone has the ability to reach the nervous system. As a result, it has the opportunity to interact with the various progesterone receptors on neuronal cells, shifting the nervous-system environment into a more neuroprotective mode.  

Although we must be careful in extrapolating results to humans, progesterone neuroprotection has been documented in numerous animal models of  neurological disorders, including traumatic brain injury (TBI) and spinal cord dysfunction, such as SCI, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). For example, in animal models of MS, progesterone treatment lessens disease severity, reduces inflammation, and restores the conduction-promoting, insulating myelin sheath surrounding neurons (see below). In ALS animal models, the hormone inhibits the degeneration of motor neurons  

TBI

Probably the most research has been directed to TBI, partly because early studies suggested gender differences in recovery after injury. For example, reproductive-cycling female rats with high progesterone levels have less post-injury cerebral edema (swelling) than male rats with inherently low progesterone. Pseudopregnant rats (a pregnancy-like condition), whose progesterone levels are especially high, had little post-injury edema.

Several clinical trials have examined progesterone’s neuroprotective potential in humans. In the first, Emory University investigators (Atlanta, GA) evaluated outcomes in a 100 acutely injured subjects treated with either intravenous progesterone or placebo for three days. Thirty-days post injury, progesterone treatment when compared to controls 1) reduced mortality in the severely injured, and 2) and improved functional outcomes in the moderately injured.  

In a second trial, Chinese researchers randomized 159 patients with severe TBI to receive five days of either progesterone or placebo injections intramuscularly. Six months later, progesterone-treated patients showed greater functional improvement and lower mortality.

SCI

TBI research findings often, but not always, have relevance to SCI. Although human studies are lacking, extensive animal research supports progesterone’s neuroprotective potential for SCI. Given the complex physiological cascade that occurs after injury, there are many interacting, biological processes that progesterone could target. For example, studies suggest that post-injury progesterone treatment:

Remyelination

In addition to the aforementioned, evidence indicates that progesterone promotes the post-injury remyelination of neuronal axons. Myelin is the fatty insulating material enveloping axons, i.e., the fibers that conduct electrical impulses away from the neuron’s cell body to other nerves or muscles.  When axons are demyelinated, channels between the inside and outside of the axon are exposed, in turn, causing disruption in the ionic equilibrium needed for neural transmission. Although most associated with MS, demyelination frequent occurs after SCI. Intact neurons may still traverse the injury site, but because they have lost their insulation, they no longer conduct. In theory, therapies that help restore the myelin sheath should re-establish some function-restoring conduction.

In the spinal cord, myelin is produced by oligodendrocytes, a neuronal support cell which is formed through the differentiation of oligodendrocyte precursor cells. Because oligodendrocytes are extremely sensitive to injury, much-needed remyelination capability is lost. Evidence indicates that progesterone treatment enhances the proliferation of the normally quiescent precursor cells into mature, myelin-producing oligodendrocytes, enhancing the conduction of injury-waylaid neurons.

It is important to note when discussing potential restorative treatments, only a relatively small percentage of intact, functioning neurons are needed to regain significant function. In other words, if progesterone-triggered remyelination can jump-start a few neurons, significant function may accrue.

Hindlimb Functional Recovery

In spite of this promising research, animal studies directed toward recovery of function after SCI are limited and ambiguous in results.  In one study, scientists at the Henry Ford Health Sciences Center (Detroit, MI) evaluated the effect of progesterone treatment in rats with SCI produced by contusion, the sort of injury common in humans. After injury, rats received progesterone injected into the body cavity periodically for five days. Compared to controls, six weeks after injury, progesterone-treated animals recovered more function and had greater tissue preservation at the injury site.

However, research by University of Kentucky investigators (Lexington, KY) could not replicate these benefits. Specifically, after an experimental contusion injury, rats were treated with progesterone with several dosing regimens for up to 14 days. Three weeks after injury, no significant improvement in hindlimb function was observed between the progesterone-treated and control animals.

Conclusion

Although the jury is still out on progesterone’s true SCI neuroprotective potential, a growing foundation of evidence suggests the topic warrants further investigation. Given the paucity of real-world SCI therapies, the idea that a hormone, which has been shown to be not only produced by the nervous system but to influence nervous-system viability,  may help repair a damaged spinal cord makes a lot of sense.

References: An extensive list of references is posted at www.sci-therapies.info (Click on Bibliography in the Table of Contents and scroll down to “Pharmaceutical Approaches for Acute SCI.”)

Adapted from article appearing in June 2011 Paraplegia News (For subscriptions, call 602-224-0500) or go to www.pn-magazine.com. 

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