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Smart Basics August 1996 IntelliScope

The Plieotropic Parent Steroid

By Alan E. Lewis

PREGNENOLONE is the ultimate parent steroid compound. All steroid hormones in the body-cortisone, testosterone, estrogen, progesterone, DHEA, and others-are produced from pregnenolone, which is in turn synthesized from cholesterol.

Progesterone and DHEA are also parent steroids in the sense that they can give rise to a number of other steroid species, but only pregnenolone is the ultimate precursor of all other steroid hormones. This unique position, it will become evident, has special significance and potential relevance to numerous aspects of health.

Pregnenolone is "pleiotropic", a term borrowed from genetics, meaning the control of more than one characteristic by a single gene. Pleio means more (or multiplicity), and tropic indicates movement in the furtherance of the previously specified action. Hence pleiotropic, in a more liberal usage, indicates action on a multiplicity of physiologic targets, or otherwise multiple actions or roles.

Pregnenolone: A Classic Steroid Hormone Precursor

Pregnenolone is only one biosynthetic step past cholesterol, and has the advantage of cholesterol (parent to all steroids) without the metabolic disadvantages. The only question is whether or not oral administration of pregnenolone results in significantly altered blood levels of end-product steroid hormones, or in steroid receptor activation sufficient to influence cells and tissues. Several studies suggest that the answer is `yes.'

The possibility remains, and given the totality of the evidence described herein, it is likely, that pregnenolone subtly supports the function of the adrenals and other steroid-synthesizing glands, normalizing deficits that may not constitute pathologic deficiency (e.g. as in Addison's disease) but are of sufficient magnitude nevertheless to influence function and well-being.

An elegant statement of this point of view was made by Hans Selye-an early leader in steroid hormone research, and the original exponent of the General Adaptation Syndrome (the "stress response"); to wit:

"In most respects the compound [pregnenolone] is quantitatively not very potent. It distinguishes itself from other steroids, however, because it possesses so many different activities. Thus the compound possesses-at least in traces-every independent main pharmacological action which has hitherto been shown to be exhibited by any steroid hormone. In the light of these observations it was tempting to speculate on the possible role of the compound as an undifferentiated hormone-precursor from which the organism may-according to its needs-produce compounds in which one effect is particularly developed at the expense of other activities of the multipotent parent substance."


Pregnenolone was used in medicine as early as the mid-1940's when it was given to scores of subjects with rheumatoid arthritis in doses ranging from 50-700 mgs/day for several weeks or months. These studies were not blinded or otherwise designed in a manner that would pass contemporary muster, and there was considerable variation in individual responses.

Nevertheless, the overall pattern of results clearly suggests that pregnenolone is an effective ameliorant of rheumatoid arthritis. The larger doses (over 200 mgs) generally were more efficacious than the smaller. Pregnenolone in any dose is much safer than the corticoids, salicylates, gold and other drugs used in conventional practice. Some problems (local irritation) developed from the use of pregnenolone by intramuscular injection, probably on account of the very poor solubility of the compound. These problems are completely unnecessary since pregnenolone is so well absorbed when given orally.

Pregnenolone (50-600 mgs/day) was also used with some success in other rheumatologic and connective tissue disorders, including osteoarthritis, scleroderma, psoriasis, lupus erythematosus, and ankylosing spondylitis.

In osteoarthritis the benefit of pregnenolone was most evident in those cases with pain, in whom the pain diminished and the range of motion and mobility increased; some bedridden cases became ambulatory.

Pregnenolone: Erogenesis

A series of studies in the late 40's assessed the value of pregnenolone as an ergogenic (anti-fatigue agent) and modulator of the stress response. The urinary excretion of 17-ketosteroids-metabolites of sex steroids-has been used as an index of stress in humans. The administration of pregnenolone (50 mgs/day) markedly reduced 17-ketosteroid excretion while improving other objective and subjective measures of psychomotor performance in stressed pilots.

Pregnenolone supplementation also improved the performance of factory workers (leather cutters, lathe operators and optical workers) with respect to total productivity, frequency of errors or material wastage, and quality of the finished products. Subjective benefits such as reduced tiredness and better overall coping ability were also noted.

It is interesting that the doses used in these studies, about 50 mgs/day, was much lower than the doses used in the arthritis studies. This would tend to argue for mechanism 2 (direct effects on brain) for these small doses, while large doses might be required to influence peripheral steroid metabolism sufficiently to alter arthritic symptoms.

Pregnenolone In Neuropsychiatry

The brain accumulates pregnenolone and its sulfate (as well as DHEA and DHEA(s), suggesting a role there, either structural or functional. In experimental studies pregnenolone has cognition-activating properties, opposing amnesia induced by NMDA receptor antagonists (NMDA receptors are an emergent class of excitatory receptors in the central nervous system). Pregnenolone sulfate antagonizes barbiturate-induced hypnosis.

In 1995 a remarkable paper was published in the prestigious Proceedings of the National Academy of Sciences. In this study, rats subjected to a maze-learning routine were given various steroids to determine the effects, if any, on learning ability. Pregnenolone was far more effective than the other steroids, and was active in almost unbelievably-small doses-as low as 150 molecules, injected into relevant brain areas. 150 molecules represents an infinitesimal amount of pregnenolone (or any substance), probably in the nanogram (one thousandth of a microgram) range or lower. Again, however, the pregnenolone was injected into the brain of these animals, and they are much smaller than humans; i.e. to effect neurochemistry in humans using oral pregnenolone would call for much larger doses. Still, this study demonstrated the extremely potent nature of pregnenolone as a cognition enhancer.

As of this writing a formal clinical trial is underway using pregnenolone (525 mg/day) in the treatment of Alzheimer's disease-a logical application. Publication of the results will probably come later this year, and will be of great interest, not only with respect to any therapeutic activity demonstrated, but as a very current human toxicology and pharmacokinetic study.

Potential Applications

Dermal Rejuvenation: One double-blind study reported marked hydrating effects of pregnenolone acetate, topically applied (.5 per cent cream) for 3 months, in a large group of women with signs of skin aging. Pregnenolone was incorporated into a Revlon product ("Eterna 27") in the early 1960's. Other steroid hormones, particularly the sex steroids, have been used for skin rejuvenation.

Immune Stimulation: Both pregnenolone and DHEA up-regulate aspects of immunity, probably via 7-hydroxylated metabolites that act locally (particularly at the portals of entry: skin and GI tract) to enhance resistance. Apparently, both pregnenolone and DHEA act to down-regulate glucocorticoid binding to nuclear receptors-a finding with great potential significance for immunity and resistance to age-related loss of lean tissue.

Fatigue: Ergogenesis is obviously an application with great appeal. Individuals with Chronic Fatigue Syndrome and AIDS -in which adrenocortical deficiency has been demonstrated-would also be interested. It is likely that athletes and other healthy individuals seeking optimal athletic performance will also be interested; pregnenolone is of course the precursor of the anabolic steroid testosterone as well as the anti-catabolic DHEA.

Arthritis: The well-documented effects in rheumatoid arthritis, along with the more spotty record in other connective tissue diseases, will ensure a place for pregnenolone in the experimental self-care of arthritic diseases. The clinical experience with pregnenolone in the more common age-related arthritis-osteoarthritis -is fragmentary, but it looks promising, at least in cases involving pain and inflammation.

Alzheimer's Disease (and age-related cognitive impairment): The emerging role of pregnenolone as a neurosteroid with cognition-activating properties likewise ensures that it will have a place in self-care of age-related cognitive decline and even full-blown Alzheimer's Disease (in which a clinical trial with pregnenolone is currently underway), probably in combination with DHEA. Of course, healthy and younger individuals seeking optimal cerebral function will also be interested.

Aging: If pregnenolone acts to ameliorate arthritis, age-related cognitive dysfunction, and fatigue, then it obviously has a premier potential role as a general anti-aging supplement. Pregnenolone (with or without DHEA) could be seen as reciprocal to melatonin, melatonin being the nighttime/sleep and trophogenic (recovery) agent, and pregnenolone being the day-time/activity and ergogenic agent. Hence, a complementary pair for homeostasis, stress control and recovery, and resistance to age-related deterioration on all levels. It is interesting in this connection that blood levels of both melatonin and pregnenolone decline from youth to old age, and that both have been suggested (with a fair amount of supportive evidence) as treatments for an array of age-related disorders.

Women's Health Problems: There is a very large mass of information on the therapeutic activity of natural progesterone in the Premenstrual Syndrome (PMS) and other women's health problems. Recently, a spate of topical products have been released claiming the activity of progesterone, but containing only Mexican Yam root as the source of "progesterone precursors". As it turns out, there is no evidence that the steroids (principally diosgenin) in Mexican Yam can be converted to progesterone in human bodies, though they can be (and have been) converted to progesterone in pharmaceutical factories. Sooner or later the fraud will become evident (no results from the Yam creams); this will be an opportunity to introduce a real progesterone precursor: pregnenolone.

Cardiovascular: Eugene Roberts has suggested using pregnenolone as a neuroprotectant supplement for those using HMGCoA reductase inhibitors (e.g. lovastatin) to lower blood cholesterol. Populations using these drugs have reduced their risk of heart death, but increased their risk of death by suicide, "accident" or violence. It is possible that the use of these blood cholesterol-lowering drugs also reduces the brain's reserves of both cholesterol and pregnenolone (and all of the steroids that issue from them), with potentially disastrous consequences in sensitive individuals. Pregnenolone could be used adjunctively to maintain normal brain steroid levels without interfering with the primary aim of the therapy.

Pharmaceutical And Pharmacokinetic Considerations:

Pregnenolone is readily absorbed when given orally and causes rather prolonged (5-10 hours) elevations of both pregnenolone and its sulfate, suggesting that first-pass liver metabolism is not a significant limiting factor. Interestingly, pregnenolone incubated with submaxilliary (salivary) glands is converted to a slight extent to progesterone and DHEA.


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