Advancing years are said to impart us with wisdom, a certain philosophy of life; yet aging is often accompanied by functional decline, which often can include diminishing cognitive abilities. How many of us have asked ourselves, “Where the heck did I put my keys?” or “What’s his name — it’s on the tip of my tongue?” In addition to waning memory, other more serious conditions such as depression, Alzheimer’s disease and arthritis may present themselves in later years.

Research has shown that a naturally occurring hormone, pregnenolone, may hold the key to growing older with reduced consequences of “aging.”

Pregnenolone is synthesized directly from cholesterol in the mitochondria, (the cellular energy-producing “factories”). Pregnenolone may exert its biological action molecularly unaltered, or through either of two metabolic pathways, may convert to dehydroepiandrosterone (DHEA) or progesterone, before cascading down to estrogen, testosterone, cortisol, and other hormones (see Figure 1). Since pregnenolone is a hormonal precursor, it is sometimes called the “Mother Hormone.”

At about the age of 35 the body’s production of pregnenolone, DHEA, and other hormones begins to decline, often accompanied by age-related diseases and symptoms. In fact, blood measurements of pregnenolone and DHEA concentrations are useful tools as biomarkers of aging. Low pregnenolone levels can also be caused by stress, hypothyroidism, toxic exposure and depression. Physicians often prescribe supplemental bio-identical hormones to treat deficiencies and rejuvenate the body to a more youthful status, but they often, leave the “Mother Hormone” out of their patients’ regimens — quite an oversight for such a physiologically important therapeutic agent.

Pregnenolone was studied as an anti-inflammatory therapy for rheumatoid arthritis during the 1940’s and 1950’s. Despite its proven safety and efficacy, it was abandoned in favor of synthetic cortisone derivatives promoted by the drug industry. (Naturally occurring compounds, like pregnenolone, are not patentable and of little interest to pharmaceutical marketers). However, interest in pregnenolone was revived in the 1990’s and since that time hundreds of research studies have demonstrated its physiological and cognitive benefits.

“The Most Potent Memory Enhancer Yet Reported”

Pregnenolone is known as a “neurosteroid,” a term coined by the prominent French researcher, Dr. Etienne-Emile Baulieu — it is synthesized at least partially in the brain and modulates the activities of the central nervous system. Besides pregnenolone, other neurosteroids include DHEA, and the sulfate derivatives, pregnenolone sulfate (Preg-S) and DHEA sulfate (DHEA-S), among others. Interestingly, researchers have determined that pregnenolone is the most highly concentrated steroid hormone in the human brain. (1) [Note: Steroids are a class of fat-soluble compounds distinguished by a typical fused four -ring structure with differing side chains that elicit a range of biological functions. Hormones are a subset of the steroid family. The terms “steroids,” “hormones,” and “steroid hormones” are used interchangeably in the literature in reference to pregnenolone and its metabolites].

While the neurological benefits of DHEA have been extensively documented, recent animal studies show pregnenolone is a more potent memory-booster.

In the early 1990’s, Drs. Flood, Morley and Roberts conducted their pioneering research on the memory-enhancing properties of various steroids. One study, published in the Proceedings of the National Academy of Sciences, involved memory retention experiments performed on mice placed in a T-shaped maze consisting of a start box at one end and two goal boxes at the other. The animals were trained to enter a designated “correct” goal box through the use of an “active avoidance” paradigm — if the mouse entered the wrong box, an electrical foot shock was applied until the correct path was taken. Solutions of Preg-S, DHEA-S and corticosterone were administered into various regions of the brain two minutes after training. One week later, T-maze training was resumed until each mouse successfully ran the maze in five out of six consecutive trials; retention of learned information was measured by the number of runs required for the mouse to meet this requirement. Of all steroids tested, Preg-S was the most effective in boosting performance — and at a remarkably low concentration — leading the researchers to establish it as “the most potent memory enhancer yet reported.” (2)

Among scores of other published research on the cognitive effects of pregnenolone, memory retention studies of rodents in an alternate contraption — the Y-maze — are noteworthy. (The Y-maze consists of three arms, one of which, the “novel arm,” is selectively closed off at specific time intervals.) In one study, administration of Preg-S significantly increased recognition of the novel arm in young adult male mice. (3) Similarly, other researchers found that poor performance in the maze was correlated with low concentrations of Preg-S in the brains of aged rats and that memory deficits were markedly improved by intra-hippocampal injection of the steroid. (The hippocampus is an area of the brain involved in the formation of memories.) The scientists concluded, “Preg-S may reinforce some neurotransmitter systems that decline with age.” (4)

Pregnenolone’s Mechanisms of Action

But just which neurotransmitter systems are associated with memory and cognitive function and how does pregnenolone impact these processes and stem their decline?

Pregnenolone binds to and regulates several types of neurotransmitter receptor sites: it is a negative modulator (i.e., attenuator) of the inhibitory, calming gamma-aminobutyric acid type A (GABAA) receptor complex and positive modulator (i.e., enhancer) of the excitatory N-methyl-d-aspartate (NMDA) receptor complex. These mechanisms synergistically raise the excitability of the system, (2,5,6) thus imparting a stimulatory effect on the brain. Pregnenolone also acts as sigma-1 receptor agonist, resulting in the increased release of acetylcholine, (7) a neurotransmitter involved in memory and learning. Acetylcholine typically declines in normal aging and is severely altered in neurodegenerative diseases such as Alzheimer’s. Preg-S infused into the brains of rats was shown to augment acetylcholine release by more than 50% while improving recognition of a familiar environment. (8) In addition, stimulation of acetylcholine release induces an increase in paradoxical, or REM, sleep, which has been shown to influence memory processes. (9,10)

Besides its function as a regulator of neurotransmitter function, pregnenolone has been shown to stimulate growth of new nerve tissue (known as neurogenesis). (7,9) Previously, scientists believed that brain damage was irreversible and that neural repair was impossible; but recently researchers discovered that the brain is, in fact, capable of generating new neurons — good news for those with neurodegenerative diseases and declining cognitive function. In a fascinating study, researchers demonstrated that infusion of Preg-S into the brains of both young (3 months) and old (20 months) rats stimulated neurogenesis. (11)

Effects on Mood, Stress and Depression

Pregnenolone modulates the response to stress, anxiety and depression (12,13,14) and may be a safe and non-toxic alternative to the panoply of side-effect laden anti-depressants, anxiolytics, and other psychiatric drugs. Several studies demonstrate pregnenolone’s mood-enhancing effects, which may be achieved by its inhibitory effect on GABAA receptors and stimulatory action on NMDA and sigma-1 receptors. Mice medicated with DHEA-S and Preg-S exhibited a significant reduction in fear response when placed in a stressful environment in which they had previously been subjected to footshock or forced swimming. (15) In humans, pregnenolone’s stress-buffering capacity was tested on army pilots undergoing rigorous activities. Daily administration of 50 mg of pregnenolone for two weeks mediated stress and improved performance with no adverse effects. (16)

Low levels of pregnenolone may be associated with the incidence of psychiatric disorders. Researchers analyzed levels of pregnenolone in the cerebrospinal fluid of 27 patients with affective disorder and 10 healthy controls. Pregnenolone concentrations in the disturbed subjects were indeed lower than in the controls, especially during episodes of active depression. (17) Other researchers found reduced plasma levels of Preg-S in 12 male patients with generalized social phobia and anxiety disorder, compared to a group of 12 healthy men. (18)

Further investigation into pregnenolone’s use as an anti-depressive, anti-anxiety and stress-buffering agent in humans is clearly warranted.

Arthritis Relief

A Medline search revealed at least two dozen journal articles from the 1950’s documenting the efficacy of pregnenolone, or pregnenolone in combination with other steroids, in reducing the pain and inflammation associated with rheumatoid arthritis. As noted earlier, research on pregnenolone’s therapeutic benefits was discontinued with the advent of synthetic corticosteroids and resumed in the past several years. A recent study demonstrated moderate to substantial improvement in joint pain and mobility in six out of 11 patients on pregnenolone therapy; interestingly, one person with previously unresolvable gout experienced a dramatic response within a few days of receiving intramuscular pregnenolone injections. (16)

The daily oral dosage required for arthritis relief — 500 mg — is significantly higher than the dose used for cognitive enhancement.

Cholesterol Reduction

The damaging effects of elevated cholesterol, from heart disease to atherosclerosis, have been well documented and extensively publicized, leading to the wide array of cholesterol-lowering drugs on the market. But recent research indicates that restoration of hormonal balance to youthful levels naturally brings cholesterol within the normal range. Twenty patients with hypercholesterolemia received treatment with pregnenolone, DHEA, tri-estrogen, progesterone and testosterone. Mean serum total cholesterol was impressively lowered from 264 to 188 mg/dL after treatment, with 60% of the subjects demonstrating a drop below 200 mg/dL. The researchers concluded that their findings “support the hypothesis that hypercholesterolemia is a compensatory mechanism for [age-related] down-regulation of steroid hormones and that broadband steroid hormone restoration is associated with a substantial drop in serum total cholesterol in many patients.” (19) These results underscore the importance of including pregnenolone in a ccomprehensive hormone replacement regimen.

Conclusion

Pregnenolone is an intriguing subject of medical research. Extensive animal studies in the area of memory enhancement have been performed; future efforts should focus on clinical studies to further our understanding of this unique compound’s role in human disease prevention and treatment. This safe, non-toxic substance is has wide-reaching therapeutic potential — from treating neurodegenerative and psychiatric diseases and reversing age-related cognitive impairment, to alleviating the pain and inflammation of arthritis and rejuvenating the body’s hormonal balance — and without the dangerous side-effects and toxicity of most drugs.

Dosage and Use

Typical doses range from 25mg to 100 mg and must be followed up with blood testing within a few weeks to determine hormone levels; physician supervision is highly recommended and mandatory for those already on a hormonal replacement protocol. Higher doses, such as those prescribed for treatment of arthritis must be administered under a physician’s care.

Caution: Pregnenolone should be avoided by people with epilepsy, a predisposition to seizures, or hormonal-related cancers such as prostate and breast cancer.

References

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