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Middle Aged Men, Too, Can Blame Estrogen for That Waistline

It is the scourge of many a middle-aged man: he starts getting a pot belly, using lighter weights at the gym and somehow just doesn’t have the sexual desire of his younger years.

The obvious culprit is testosterone, since men gradually make less of the male sex hormone as years go by. But a surprising new answer is emerging, one that doctors say could reinvigorate the study of how men’s bodies age. Estrogen, the female sex hormone, turns out to play a much bigger role in men’s bodies than previously thought, and falling levels contribute to their expanding waistlines just as they do in women’s.

The discovery of the role of estrogen in men is “a major advance,” said Dr. Peter J. Snyder, a professor of medicine at the University of Pennsylvania, who is leading a big new research project on hormone therapy for men 65 and over. Until recently, testosterone deficiency was considered nearly the sole reason that men undergo the familiar physical complaints of midlife.

The new frontier of research involves figuring out which hormone does what in men, and how body functions are affected at different hormone levels. While dwindling testosterone levels are to blame for middle-aged men’s smaller muscles, falling levels of estrogen regulate fat accumulation, according to a study published Wednesday in The New England Journal of Medicine, which provided the most conclusive evidence to date that estrogen is a major factor in male midlife woes. And both hormones are needed for libido.

“Some of the symptoms routinely attributed to testosterone deficiency are actually partially or almost exclusively caused by the decline in estrogens,” said Dr. Joel Finkelstein, an endocrinologist at Harvard Medical School and the study’s lead author, in a news release on Wednesday.

His study is only the start of what many hope will be a new understanding of testosterone and estrogen in men. Dr. Snyder is leading another study, the Testosterone Trial, which measures levels of both hormones and asks whether testosterone treatment can make older men with low testosterone levels more youthful — by letting them walk more quickly, feel more vigorous, improve their sexual functioning and their memories, and strengthen their bones. Smaller studies have been promising but unreliable, and estrogen has not been factored in.

“We had ignored this hormone in men, but we are studying it now,” said Dr. Alvin M. Matsumoto, a testosterone and geriatrics researcher at the University of Washington School of Medicine and the V.A. Puget Sound Health Care System, who is a Testosterone Trial researcher. “We are just starting out on this road.”

Both men and women make estrogen out of testosterone, and men make so much that they end up with at least twice as much estrogen as postmenopausal women. As levels of both hormones decline with age, the body changes. But until now, researchers have focused almost exclusively on how estrogen affects women and how testosterone affects men.

Dr. Finkelstein’s study provides a new road map of the function of each hormone and its behavior at various levels. It suggests that different symptoms kick in at different levels of testosterone deficiency. Testosterone, he found, is the chief regulator of muscle tone and lean body mass, but it takes less than was thought to maintain muscle. For a young man, 550 nanograms of testosterone per deciliter of blood serum is the average level, and doctors have generally considered levels below 300 nanograms so low they might require treatment, typically with testosterone gels.

But Dr. Finkelstein’s study found that muscle strength and size turn out to be unaffected until testosterone levels drop very low, below 200 nanograms. Fat accumulation, however, kicks in at higher testosterone levels: at 300 to 350 nanograms of testosterone, estrogen levels sink low enough that middle-aged spread begins.

As for sexual desire and performance, both require estrogen and testosterone, and they increase steadily as those hormone levels rise. Researchers say it is too early to make many specific recommendations, but no one is suggesting that men take estrogen, because high doses cause feminine features like enlarged breasts.

Although doctors prescribe testosterone gels for men whose levels fall below 300 nanograms per deciliter, that cutoff point is arbitrary, and there is no clinical rationale for it, Dr. Finkelstein said. Often men take the hormone to treat complaints like fatigue, depression or loss of sexual desire, which may or may not be from low levels of testosterone. The data suggest that men with levels around 300 nanograms who complain of sexual problems may want to try testosterone, but those who complain of flagging muscle strength should not blame testosterone deficiency, Dr. Finkelstein said. But, he added, “symptoms of low testosterone tend to be quite vague.”

Today, millions of men are using testosterone gels, fueling a nearly $2 billion market.

For their study, Dr. Finkelstein and his colleagues recruited 400 men aged 20 to 50 who agreed to have their testosterone production turned off for 16 weeks. Half then received varying amounts of

It turned out to be surprisingly easy to recruit subjects, Dr. Finkelstein said. One, Ben Iverson, joined in part for the $1,000 subjects were paid. “That, to me, was enticing,” he said. He was a 28-year-old Harvard graduate student at the time and is now an assistant professor of finance at Northwestern University.

Although Mr. Iverson’s wife looked askance at the injections to block testosterone production, Mr. Iverson ended up getting enough testosterone in the gel he was assigned to use. The worst were the testosterone-suppressing injections, which required him to use a huge needle in his abdomen once a month, he said.

He found out when the study ended that he was in a group that got enough testosterone to keep his levels in a normal range. “I literally did not notice any difference at all,” Mr. Iverson recalled.

The worst symptoms were in men whose estrogen production was shut down — they got intense hot flashes.

Now Dr. Finkelstein is repeating the study with older men. The Testosterone Trial is looking at them too.

For that study, Dr. Snyder and his colleagues recruited nearly 800 men aged 65 and older who have low testosterone levels. The men take either a placebo or enough testosterone to bring their level to between 400 and 800. Investigators are assessing walking speed, sexual functioning, vitality, memory, red-blood-cell count, bones and coronary arteries. The yearlong study will be completed next year.

Next, researchers said, they want to do a large study like one conducted with thousands of women in 2002 that asked about long-term risks and benefits of hormone therapy. Does testosterone therapy lead, for example, to more prostate cancer? Does it prevent heart attacks?

“We still don’t know the answers to the clinical questions,” Dr. Matsumoto said. “Does it prevent things that are really important?”

By GINA KOLATA, Published: September 11, 2013, source:

Late-life depression increases risk of dementia


Late-life depression increases risk of dementia




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Depression in late life can accelerate cognitive decline. A new study shows that depression in older adults significantly increased the risk of all-cause dementia, Alzheimer’s disease, and vascular dementia.

Depression after age 50 years increased the risk of all-cause dementia by 1.85 times, Alzheimer’s disease by 1.65 times, and vascular dementia by 2.52 times, according to the results of a study published in the May issue of the British Journal of Psychiatry.

The meta-analysis, conducted by Dr. Breno S. Diniz and his associates at Western Psychiatric Institute and Clinic at the University of Pittsburgh Medical Center, is the first of its kind to examine both the risk of Alzheimer’s disease and vascular dementia in older adults with depression. Alzheimer’s disease is the most common form of dementia, followed by vascular dementia, which is characterized by impaired judgment or an inability to plan and complete tasks.

Dr. Breno S. Diniz

Dr. Diniz and his colleagues said their study also distinguished itself in another way. “This is the first study to show that late-life depression increases the risk of vascular dementia, and that the risk of vascular dementia is greater than the risk of Alzheimer’s disease for older adults with depression,” they wrote.

A meta-analysis of 23 prospective community-based cohort studies was conducted to calculate the pooled risk of all-cause dementia, Alzheimer’s disease, and vascular dementia. Only studies with baseline cases of depression in adults aged 50 years or older were included. Data from 49,612 participants were used for the pooled analysis for all-cause dementia; 28,746 participants were included in the pooled analysis for Alzheimer’s disease; and 14,901 participants were included in the pooled analysis for vascular dementia. The median follow-up interval for all-cause dementia studies was 5 years. For Alzheimer’s disease studies, the median follow-up interval was 5 years and for vascular dementia studies, it was 6.1 years (Br. J. Psychiatry 2013;202:329-35).

After excluding studies that did not report risk measures adjusted for multiple confounders, a reduced, although statistically significant, association was found between late-life depression and the risk of all-cause dementia, Alzheimer’s disease, and vascular dementia. The adjusted pooled risk for all-cause dementia was 1.59 and 1.55 for Alzheimer’s. For vascular dementia, the adjusted pooled risk was 2.02, with a confidence interval of 95%.

They said their results were in line with a report showing an increased risk of all three conditions among participants with mid- and late-life depression. These findings came from a retrospective analysis of 13,535 older participants who were followed on the Kaiser Permanente Medical Care Program of Northern California (Arch. Gen. Psychiatry 2012;69:493-8).

In the current meta-analysis, the researchers recommended conducting new clinical trials to investigate the potential impact of depression prevention on the risk of cognitive impairment and dementia among older adults.

“Also, the prevention and treatment of cardiovascular risk factors and an improvement of general health in people with late-life depression may have a significant impact not only in a reduction of late-life depression cases but also [in the] reduction of dementia cases (vascular dementia and Alzheimer’s disease) associated with this disorder,” the authors commented.

The researchers cited several limitations. Among them is that their meta-analysis was limited to PubMed and Scopus databases. A search of international databases such as EMBASE and PsychINFO might have led to additional studies, but they believe that their literature search was comprehensive.

In the past 3 years, Dr. Diniz received payment for lectures from Novartis and has had travel/meeting expenses covered by Pfizer. His colleagues reported associations with several organizations, including Northstar Neuroscience, Medtronic, Bristol-Myers Squibb, and Forest Laboratories This work was supported in part by the John Hartford Foundation, the University of Pittsburgh Medical Center Endowment in Geriatric Psychiatry, and the National Institutes of Health.


Copyright © 2013 International Medical News Group, LLC. All rights reserved.
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Recharge With Pregnenolone

Recharge With Pregnenolone
This little-known hormone fights fatigue, boosts memory, and more.
By Dave Tuttle

One of the most frustrating aspects of aging is memory loss. Whether as benign as forgetting where you left the car keys or as debilitating as Alzheimer’s disease, this reduction in mental function challenges us and makes us long for the mental vigor of our youth.

Traditionally, scientists have thought that little could be done about deteriorating brain function. New research has shown, however, that this kind of mental decline is not inevitable. Scientists have found that a naturally occurring hormone called pregnenolone not only improves memory and concentration, but also fights fatigue, relieves arthritis, speeds injury recovery, and enhances mood.

An Essential Hormone

Testosterone, estrogen, cortisol, DHEA, and pregnenolone are members of a family of natural hormones that are essential for human survival. All of these hormones contain four carbon-ring structures attached to each other, and appear very similar.1Small differences in structure, however, produce dramatic changes in function. Testosterone, the “male” hormone, is only slightly different chemically from estrogen, the “female” hormone. Yet this minor dissimilarity causes men to grow facial hair and women to develop breasts.
Another thing these hormones have in common is that they are made from cholesterol. While often vilified, cholesterol is an indispensable raw material that the body uses for several essential biological reactions. It is required for the production of vitamin D, the absorption of calcium, and the production of bile. Cholesterol also is needed to make myelin, the fatty coating that surrounds the nerves in the brain and spinal cord.

Each of the body’s cells contains mitochondria. Primarily involved with energy production, these organelles also contain an enzyme that breaks off a few side chains from the cholesterol molecule to turn it into pregnenolone. This enzyme is more active in some tissues and organs than in others, and as a result some parts of the body produce more pregnenolone than others. The primary sources of this hormone are the adrenal glands, liver, and gonads (testicles and ovaries). Scientists have discovered that pregnenolone also can be manufactured in the brain from cholesterol instead of being transported through the blood-brain barrier from other parts of the body. This supports recent findings showing that pregnenolone is involved in a variety of brain-related functions such as memory, concentration, and mood.

Pregnenolone also can be converted into the other hormones, which is why it is sometimes referred to as the mother of those hormones. Hormones released by the pituitary gland regulate these conversions. The body can change pregnenolone into DHEA or progesterone, depending on its needs at a given moment. In turn, both of these hormones can be chemically manipulated to produce androstenedione, the direct precursor to the sex hormones, which include testosterone and other androgens as well as estradiol and the other estrogens. The progesterone molecule also can be altered to make cortisol (the so-called “stress hormone”) and aldosterone (involved in blood pressure regulation). None of this would be possible if the body did not contain pregnenolone.
Clearly, pregnenolone is an essential hormone in people of all ages. The average young adult produces about 14 mg per day. As with other hormones, however, pregnenolone production declines with age. At age 75, the body produces about 60% less pregnenolone than it did at age 35.2 As the body’s supply of pregnenolone diminishes, so does the availability of its other related hormones. This has led scientists to consider pregnenolone supplementation as a way to turn back the clock on aging and counter the consequences of this dramatic drop in hormone levels.

Less Fatigue, More Endurance

Because pregnenolone concentrations in the brain are much higher than those found in blood plasma,3 it is not surprising that this hormone has a number of mental benefits. Several classic studies have found that oral administration of pregnenolone reduces fatigue while providing more endurance.4 In one experiment, five college students trained at a constant pace on a machine that produced exhaustion. At different times, they were given oral pregnenolone, an oral adrenal cortical hormone, or injected progesterone. Only the pregnenolone had a significant influence on their scores during a three-hour run.

A study of aviators found that pregnenolone improved their functioning and perception of their work. Fourteen subjects took 50 mg of pregnenolone daily and performed tests with an automatic scoring device that operated like the joystick for a video game. Researchers found that the improvements the aviators experienced during the two weeks of administration had a cumulative effect that continued for several days afterward.

In another experiment, 25-75 mg of pregnenolone were given daily to 8 leather cutters, 12 lathe operators, and 77 optical workers. While there was little benefit compared to placebo when the workers were not “under pressure,” productivity rose when the level of work-related stress was higher. Once again, the effect outlasted the length of the study. The subjects also felt that they tired less easily and were better able to cope with the demands of their jobs. No side effects were reported in any of these studies.

Potent Memory Enhancer

When older people are asked about the negative consequences of aging, memory loss is usually at the top of their list. The inability to recall a lifetime’s most memorable moments (or even where you left an important document) is frustrating at best and debilitating at worst. Several factors are responsible for this decline in memory.5 As we age, the functioning of the brain’s neurotransmission system deteriorates. This leads to negative changes in the release of a key neurotransmitter known as acetylcholine, ranging from a minor decline to severe alterations (as in the case of Alzheimer’s disease). The creation of brain cells also is diminished, at least in the hippocampus. Scientists have found that pregnenolone effectively combats both these factors.

Pregnenolone and its sulfated form, pregnenolone sulfate, are able to work their magic on memory and mental function in surprisingly small doses. This is because they work simultaneously on two receptor complexes. Pregnenolone sulfate is able to reduce the activity of a receptor complex known as GABAa. GABA is a neurotransmitter that literally cools the brain, protecting the nerve cells from burning out from all their activity.6 Too much GABA, however, can depress brain function, making the brain sluggish. By altering the extent of GABA-induced changes in membrane permeability, pregnenolone is able to reduce the increase in GABA transmission that occurs normally in older individuals.7 This counteracts the aging brain’s decline in mental sharpness.
Pregnenolone also works the other side of the equation by increasing the activity of the NMDA (N-methyl-D-aspartate) subtype of glutamate receptors. Glutamate is a major excitatory neurotransmitter whose enhanced action recharges the brain and makes it more capable of handling the day’s activities. These dual changes induce increased acetylcholine release in the parts of the brain most involved with cognitive processes.8

Pregnenolone also promotes greater growth of brain cells. A recent study revealed that pregnenolone sulfate counteracted the usual age-related decline in neurogenesis in the hippocampuses of rats.5 The researchers found a 55% increase in cell proliferation in the dentate gyrus, where newborn cells differentiate into neurons. This effect continued for several weeks after a single infusion, suggesting that long-lasting benefits could be achieved from ongoing supplementation. Of course, the more brain cells you have, the more memories you are likely to retain.
Various animal studies have demonstrated pregnenolone’s effectiveness in enhancing learning and memory. A French study of young and aged rats found the older rats had significantly lower levels of pregnenolone sulfate.9 This was associated with poor performance in two mazes that measured various aspects of spatial memory. Seven hours after the older rats were injected with pregnenolone sulfate, they performed significantly better in both mazes. There were also dramatic relative increases in the amounts of the hormone in the plasma and hippocampuses of the older rats, indicating that at least some of the pregnenolone sulfate was able to cross the blood-brain barrier. The researchers noted that the seven-hour time delay in improvement was such that a mechanism involving any of pregnenolone’s metabolites could have been responsible for the memory enhancements.

Other scientists have explored pregnenolone’s benefits for conditioned learning tasks. These involve passive or active avoidance exercises that measure memory of a negative experience, as well as reinforcement experiments in which animals learn to operate a lever to gain access to a stimulus such as water or food. In one experiment, 3- and 16-month-old mice performed a passive-avoidance task that involved learning to not step down a device.10 Before receiving pregnenolone sulfate injections, the older mice showed a substantial deficit in memory retention. After a pretraining injection of pregnenolone sulfate, however, the retention performance of the older mice after a 24-hour delay improved in a dose-dependent fashion.
Subsequent comparison of the results showed a positive correlation between the rats’ learning performance and concentrations of pregnenolone sulfate in their hippocampuses. Interestingly, no such correlation was found between levels of the hormone and changes in other brain areas such as the cortex or amygdala, suggesting that the hippocampus is primarily where pregnenolone plays its role in memory enhancement.

Several other studies have confirmed these results. One performed at the Universite de Lille in France infused pregnenolone sulfate into rat brains.11 The scientists found that the infusion not only improved recognition memory of a familiar environment, but also boosted acetylcholine release by more then 50%. This underscores the link between pregnenolone and the vital neurotransmitter

Another French study examined the relationship between pregnenolone and cognitive performance.12 Rats with memory impairment exhibited low pregnenolone sulfate concentrations compared to animals with normal memory performance. An intracerebral infusion of pregnenolone sulfate reversed these memory deficits. The researchers also found that the injections dramatically increased neurogenesis (the creation of new brain cells). These findings indicate the extent to which pregnenolone sulfate can influence cognitive processes, particularly in older subjects.

Counteracting Depression

Another likely benefit of pregnenolone is a reduction in depression and related disorders. Historically, the relatively high incidence of depression in older adults has been attributed to the loss of loved ones or the negative psychological effects of debilitating disease. Although these factors can certainly influence a person’s mood, in recent years scientists have found that depression is usually associated with levels of serotonin and other neurotransmitters. For example, the antidepressant Prozac® increases serotonin levels in the brain by inhibiting the reuptake of this neurotransmitter. The inhibition of GABA release is also thought to enhance mood by preventing the brain from becoming too sluggish and lethargic. Pregnenolone’s ability to control GABA levels strongly suggests that this hormone may be a valuable addition to the arsenal of antidepressant medications, especially considering its lack of side effects.
While human studies of pregnenolone supplementation have not been completed, compelling evidence suggests that pregnenolone plays a role in depression. In a study of 27 patients with depression and 10 healthy volunteers, the depressed subjects had lower levels of pregnenolone in their cerebrospinal fluid than the healthy individuals.13 Cerebrospinal fluid circulates in the spinal column and brain, indicating that the brains of the depressed patients were exposed to less pregnenolone than those of the healthy subjects. In another study that matched 12 healthy controls with 12 men who had generalized social phobia and were not taking medication, concentrations of pregnenolone sulfate were significantly lower in the plasma of the patients with social phobia, again implying that pregnenolone plays a role in mood states.14

Help for Spinal Cord Injuries

Because pregnenolone is naturally found in the cerebrospinal fluid, researchers have sought to determine whether it can help accident victims with spinal cord injuries. Pregnenolone was found to promote recovery when used in combination with other drugs.15
Researchers gave pregnenolone, indomethacin (an anti-inflammatory substance), and bacterial lipopolysaccharide (a stimulator of cytokine secretion) to rats both individually and in combination for 21 days. While the use of indomethacin and lipopolysaccharide eased the histopathological damage to some extent, there was little recovery of motor function. Adding pregnenolone to the mix produced a striking reduction in histopathological damage, and the tissue was spared from secondary injury (a common occurrence with spinalcord victims when the components of the inflammatory response become destructive). This three-way combination worked so well that 11 of the 16 animals were able to stand and walk after 21 days, four of them almost normally. The survival rate improved as well, possibly due to the protection that pregnenolone offered against the toxic effects of the other two drugs. Pregnenolone also increased the vascularization of the spared tissue and made the cellular matrix denser, while reducing the extent to which cavities formed on the injured tissue.
The researchers concluded that pregnenolone facilitated recovery by giving rise to the greatest number of other hormones, which are known to assist with coordinative processes within and between the neural, metabolic, and immune systems. Because of its dual action in inhibiting GABA release and boosting glutamate levels, pregnenolone can “exert remarkable synergistic amplification of excitatory transmission,”15 triggering the cascade of reactions needed for cell recovery.
Pregnenolone holds great promise in helping accident and trauma victims recover from their injuries. While the extent of benefit still must be quantified, it seems clear that the cascade of reactions produced by pregnenolone may be valuable in addressing a variety of medical conditions.

Benefits for Rheumatoid Arthritis

Pregnenolone has been shown to relieve the symptoms of rheumatoid arthritis. As noted earlier, this hormone alters the permeability of cell membranes, lessening swelling and associated pain with a resulting increase in strength. Pregnenolone also may play a role in reducing the formation of COX-2, which would counteract the availability of various inflammatory compounds.
A number of studies have confirmed that pregnenolone has dramatic anti-arthritic effects, though the daily oral dosage required—approximately 500 mg—is significantly more than the dose needed to realize mental improvements.4 Pregnenolone is most helpful in the initial stages of arthritis before the pathological process has progressed too far. Moreover, a comparative study of cortisone and pregnenolone found that improvements lasted longer after the study ended when pregnenolone was administered. Because cortisone has several negative side effects, concurrent use with pregnenolone should permit a reduction in the cortisone dosage, helping to reduce the suffering of persons with rheumatoid arthritis. More research is needed, however, to determine the ideal combination dosage. Unfortunately, pregnenolone is not beneficial for osteoarthritis, a condition in which little inflammation exists.


Physicians have recommended hormone-replacement therapy to older individuals for many years. Usually, however, the hormones replaced are the end-product hormones: testosterone or estrogen. Recent research suggests that there may be another way. By providing your body with the mother of hormones—pregnenolone—you can let your body decide through its various feedback mechanisms which hormones it needs. If more DHEA is required, the supplemental pregnenolone will be converted to this hormone, and if estrogen or testosterone is in short supply, the pregnenolone molecule will be altered to produce the optimal amount. If your physiological requirement is a combination of hormones, this, too, can be achieved.
By its very nature, pregnenolone works with your body to achieve optimal health and longevity. Pregnenolone’s many functions underscore its role as one of the most important hormones in the human body. Pregnenolone reduces fatigue and increases endurance. It also provides the brain with the hormonal and neurotransmitter support it needs to retard memory loss, thus helping to improve concentration and focus. Moreover, it helps those with arthritis, depression, and traumatic injuries.
Although pregnenolone has long been overlooked because it is “upstream” on the hormone pathway, its many benefits to human health suggest that this vital hormone has just begun to receive the attention it so richly deserves.

1. Sahelian R. Pregnenolone: A Practical Guide. Marina del Rey, CA: Longevity Research Institute; 1996.
2. Havlíková H, Hill M, Hampl R, Stárka L. Sex- and age-related changes in epitestos- terone in relation to pregnenolone sulfate and testosterone in normal subjects. J Clin Endocrinol Metab. 2002 May;87(5):2225-31.
3. Lanthier A, Patwardhan VV. Sex steroids and 5-en-3b-hydrosteroids in specific regions of the human brain and cranial nerves. J Steroid Biochem. 1986 Sep;25(3):445-9.
4. Roberts E. Pregnenolone from Selye to Alzheimer and a model of the pregnenolone sulfate binding site on the GABAa receptor. Biochem Pharmacol. 1995 Jan 6;49(1):1-16.
5. Mayo W, George O, Darbra S, et al. Individual differences in cognitive aging: implication of pregnenolone sulfate. Prog Neurobio. 2003 Sep;71(1):43-8.
6. Regelson W, Colman C. The Superhormone Promise: Nature’s Antidote to Aging. New York, NY: Simon & Schuster; 1996.
7. Roberts E, Sherman MA. GABA—the quintessential neurotransmitter: electroneutrality, fidelity, specificity, and a model for the ligand binding site of GABAa receptors. Neurochem Res. 1993 Apr;18(4):365-76.

Individual differences in cognitive aging: implication of pregnenolone sulfate.

Mayo W, George O, Darbra S, Bouyer JJ, Vallée M, Darnaudéry M, Pallarès M, Lemaire-Mayo V, Le Moal M, Piazza PV, Abrous N.
INSERM U588, Institut François Magendie, Rue Camille Saint-Saens, 33077 Bordeaux Cedex, France.

In humans and animals, individual differences in aging of cognitive functions are classically reported. Some old individuals exhibit performances similar to those of young subjects while others are severely impaired. In senescent animals, we have previously demonstrated a significant correlation between the cognitive performance and the cerebral concentration of a neurosteroid, the pregnenolone sulfate (PREG-S).Neurotransmitter systems modulated by this neurosteroid were unknown until our recent report of an enhancement of acetylcholine (ACh) release in basolateral amygdala, cortex and hippocampus induced by intracerebroventricular (i.c.v.) or intracerebral administrations of PREG-S. Central ACh neurotransmission is known to be involved in the regulation of memory processes and is affected in normal aging and severely altered in human neurodegenerative pathologies like Alzheimer’s disease.In the central nervous system, ACh neurotransmission is also involved in the modulation of sleep-wakefulness cycle, and particularly the paradoxical sleep (PS). Relationships between paradoxical sleep and memory are documented in the literature in old animals in which the spatial memory performance positively correlates with the basal amounts of paradoxical sleep. PREG-S infused at the level of ACh cell bodies (nucleus basalis magnocellularis, NBM, or pedunculopontine nucleus, PPT) increases paradoxical sleep in young animals.Finally, aging related cognitive dysfunctions, particularly those observed in Alzheimer’s disease, have also been related to alterations of mechanisms underlying cerebral plasticity. Amongst these mechanisms, neurogenesis has been extensively studied recently. Our data demonstrate that PREG-S central infusions dramatically increase neurogenesis, this effect could be related to the negative modulator properties of this steroid at the GABA(A) receptor level.Taken together these data suggest that neurosteroids can influence cognitive processes, particularly in senescent subjects, through a modulation of ACh neurotransmission associated with paradoxical sleep modifications; furthermore, our recent data suggest a critical role for neurosteroids in the modulation of cerebral plasticity, mainly on hippocampal neurogenesis.
PMID: 14611866 [PubMed – indexed for MEDLINE]

Neurosteroids: Deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus

1. Monique Vallée*†,
2. Willy Mayo*†‡,
3. Muriel Darnaudéry*,
4. Colette Corpéchot§,
5. Jacques Young§,
6. Muriel Koehl*,
7. Michel Le Moal*,
8. Etienne-Emile Baulieu§,
9. Paul Robel§, and
10. Hervé Simon*
Author Affiliations
1. Contributed by Etienne-Emile Baulieu


Pregnenolone sulfate (PREG S) is synthesized in the nervous system and is a major neurosteroid in the rat brain. Its concentrations were measured in the hippocampus and other brain areas of single adult and aged (22–24 month-old) male Sprague–Dawley rats. Significantly lower levels were found in aged rats, although the values were widely scattered and reached, in about half the animals, the same range as those of young ones. The spatial memory performances of aged rats were investigated in two different spatial memory tasks, the Morris water maze and Y-maze. Performances in both tests were significantly correlated and, accompanied by appropriate controls, likely evaluated genuine memory function. Importantly, individual hippocampal PREG S and distance to reach the platform in the water maze were linked by a significant correlation, i.e., those rats with lower memory deficit had the highest PREG S levels, whereas no relationship was found with the PREG S content in other brain areas (amygdala, prefrontal cortex, parietal cortex, striatum). Moreover, the memory deficit of cognitively impaired aged rats was transiently corrected after either intraperitoneal or bilateral intrahippocampal injection of PREG S. PREG S is both a γ-aminobutyric acid antagonist and a positive allosteric modulator at the N-methyl-d-aspartate receptor, and may reinforce neurotransmitter system(s) that decline with age. Indeed, intracerebroventricular injection of PREG S was shown to stimulate acetylcholine release in the adult rat hippocampus. In conclusion, it is proposed that the hippocampal content of PREG S plays a physiological role in preserving and/or enhancing cognitive abilities in old animals, possibly via an interaction with central cholinergic systems. Thus, neurosteroids should be further studied in the context of prevention and/or treatment of age-related memory disorders.

Pregnenolone and Mental Function

Pregnenolone is the precursor (building-block) for all other steroid hormones. It is converted directly into DHEA and/or progesterone. DHEA converts to testosterone and estrogens; progesterone converts to estrogens, cortisol, and aldosterone. It is this succession of conversions that makes human life possible. Without pregnenolone, there can be no human steroid hormone production.

Made from cholesterol, pregnenolone is a natural steroid hormone produced primarily in the adrenal glands, but in smaller amounts by many other organs and tissues of the human body, including liver, brain, skin, gonads, and even the retina of the eye.

Like many health-promoting hormones, levels of pregnenolone drop with age. Although the data are not as abundant or definitive for pregnenolone as they are for DHEA, Dr. Eugene Roberts, a pioneer in hormone research, believes that the age-related drop in pregnenolone is as dramatic as the drop in DHEA. At 75, our bodies typically make 60% less pregnenolone than at age 35. This is a point of great concern, considering pregnenolones numerous protective, health-promoting properties.

Energizing, Anti-stress Benefits
Some of the earliest investigations of pregnenolone showed it to be an energizing, anti-stress biochemical. During the 1940s, Drs. Pincus and Hoagland gave 50-100 mg/day of pregnenolone to various types of factory workers, as well as pilots and students trained to use a flight simulator. The factory workers noted improved production rates while taking pregnenolone. They felt less fatigued, better able to cope with their jobs and experienced an enhanced sense of happiness and well-being. Interestingly, workers in stressful job environments improved more with pregnenolone than those with less demanding tasks.

The flight simulation machine was designed to test hand-eye coordination, learning, memory and stamina. The subjects were to ‘fly’ the ‘plane’ correctly, avoiding obstacles and crashes. Half the subjects were airplane pilots; half were not. Tests conducted over several weeks showed that the ability of all subjects to ‘fly’ the simulated airplane improved significantly after taking 50 mg pregnenolone before each test run. The improvement was especially noticeable after the subjects had taken pregnenolone for at least two weeks. This suggests pregnenolones anti-stress benefits may be cumulative. Also, the professional pilots reported that they performed better in their real flying jobs and that they suffered less fatigue during their pregnenolone-supplementing period.

Pro-memory Effects
Animal studies by Isaacson, Flood, Morely and Roberts have shown that injection of as few as 15 to 145 molecules (!) of pregnenolone directly into the areas of the brain that are thought to www.e memory improved the ability of mice to more quickly remember the way out of a maze that they had run before. Preliminary results of St. Louis School of Medicine researcher R. Sih have shown definite memory enhancement with pregnenolone. Dr. Sih gave 500 mg pregnenolone or a placebo to men and women three hours before they were asked to perform standard memory tests. Pregnenolone resulted in improved memory in both men and women, improved spatial memory and perception in men, and improved verbal recall memory in women.

Mood Elevation
Pregnenolone is known to modulate at least two key nerve receptor systems in the brain: NMDA receptors and GABA receptors. NMDA receptors, which weaken with age, are involved in learning, memory, and alertness. Pregnenolone enhances NMDA receptor function. GABA receptors promote relaxation, mental slowing, sedation and sleep. Benzodiazepine drugs (Valium, Librium, Xanax, etc.) activate GABA receptors, while pregnenolone inhibits GABA receptors. Thus, too little NMDA activity combined with excessive GABA activity would tend to promote mental sluggishness and depression. Since pregnenolone raises NMDA activity and lowers excessive GABA activity, pregnenolone seems to be a natural antidepressant. Indeed a recent study of 27 depressed patients found that their cerebrospinal fluid (which circulates through the brain and spinal cord) was significantly lower in pregnenolone than in 10 non-depressed volunteers. Cerebrospinal fluid levels are generally believed to accurately reflect levels of various biochemicals in the brain.

Anti-arthritis Effects
During the 1940s, pregnenolone was used successfully as a treatment for rheumatoid arthritis. A 1950 review article on pregnenolone reported on a study by Henderson and colleagues which found that 300 mg pregnenolone/day for 40 days resulted in a significant decrease in joint pain, tenderness, and spasticity, with improved strength and range of motion. Another study by Freeman and colleagues, with 64 patients, used 500 mg of pregnenolone daily for periods of 2 to 30 weeks. 24 patients showed striking improvements, and 20 showed minor improvements.

Unfortunately, the advent of the ‘wonder drug’ cortisone (Cortisol) in the 1950s caused pregnenolone to be passed by for arthritis treatment, since pregnenolones results were much slower to manifest. ‘Coincidentally’, pregnenolone couldnt be patented by the drug companies whereas synthetic variants of cortisone could be (and were) patented. By the time the nightmarish side-effects of excessive cortisone were widely known by the medical community in the 1960s (these side effects could include psychotic breakdown, adrenal failure, and even death), pregnenolone had been completely forgotten.

Pregnenolones Cortisol-neutralizing Power
Small amounts of cortisol are essential to promote health and even for life itself. Yet under the prodding of chronic stress and aging, our adrenal glands often over-produce cortisol. Indeed, cortisol is the only steroid hormone whose levels tend to increase with age. The level of all other steroids, including pregnenolone, tend to decrease (often radically) with age. Excessive cortisol promotes a host of negative side-effects. High cortisol levels promote depression, as does chronic, unremitting stress in many people (which results in chronically elevated cortisol). Experimental subjects such as factory workers and airplane pilots who were given pregnenolone under stressful conditions actually reported an enhanced sense of well-being and happiness.

Excessive Cortisol
The following are indications of an excessive cortisol level:
(1) accelerated skin aging and deterioration;
(2) damaged structure and function of mid-brain regions involved in memory;
(3) impaired wound healing, poor skin quality and excessive scar tissue;
(4) excess fluid retention and puffy, flabby skin.
(5) poor quality of sleep.

Most of these adverse effects of cortisol are directly counteracted by pregnenolone. For example, Papa and Kligman reported in 1965 that topical application of a pregnenolone-containing skin cream restored youthful properties to aged skin.

Experiments with humans and animals show that pregnenolone enhances the function of the same pro-memory areas of the mid-brain that are damaged by cortisol. A 1994 report by Guth and colleagues found that pregnenolone actually promoted successful healing of otherwise crippling spinal cord injuries in rats. Ray Peat, Ph.D., has reported successful use of pregnenolone to rid the body of cortisol-induced excessive fluid and puffiness, promoting a more lean and taut, youthful appearance to the face. Steiger (1993) used a mere 1 mg of pregnenolone in human volunteers to increase the restorative delta, slow-wave, stage IV sleep. (Larger doses of pregnenolone taken inappropriately at night may, however, also promote insomnia through ‘over-energization’). Thus, pregnenolone seems in many ways to be a natural ‘antidote’ to the ‘dark side’ of cortisol, which tends to manifest ever more with aging and chronic stress.

Chemo-protective Action
A major determinant of the bodys ability to detoxify poisonous chemicals — such as pesticides, medical drugs, industrial contaminants and auto exhaust — is the health and effectiveness of the Cytochrome P450 enzyme system in the liver. This is one of the most broad-spectrum, universal detoxifying enzyme systems possessed by all mammals, including humans. Moderate levels of cortisol (the ‘state-of-siege’ anti-stress hormone) promote the activity of this detox system. However, larger amounts of cortisol (which is all-too-often over-produced by our adrenal glands due to aging or prolonged stress) degrade the P450 systems anti-toxin effects. Although pregnenolone does not affect the rate of synthesis of the enzymes in the P450 system, it does stabilize these enzymes against the digestive activity of liver proteolytic enzymes which would tend to break down the P450 enzymes. Pregnenolone thus increases overall P450 detox enzyme power by promoting conservation of existing P450 enzymes.

Fortunately, pregnenolone is amazingly safer than other steroids. Pregnenolone researchers working with both human and animal subjects since the 1940s have consistently commented on pregnenolones virtual absence of toxicity. For example, the classic review article on pregnenolone by Henderson and colleagues in 1950 states: ‘It [pregnenolone] has an extremely low order of toxicity; [it] has not shown any adverse effects on endocrine [hormone] physiology ….’

Pregnenolone has been given orally to humans at doses as high as 500 mg/day for as long as 30 weeks without evidence of adverse effects. Mice given 5 grams (1/6 ounce) per kilogram (2.2 pounds) of body weight suffered no ill effects. This would be equivalent to a 154 pound (70 kilogram) human ingesting 350 grams (approximately 3/4 pound) per day! In a long-term study, mice that were given one gram pregnenolone per kilogram of body weight three times weekly for 50 doses suffered no toxic reactions — including no changes in the size and condition of offspring produced after the 50 doses.

In one human study, eight people received 50 to 150 milligrams per day by intramuscular injection for 75 days, with no reported side effects. Dr. Eugene Roberts gave 20 Alzheimers patients 525 mg/day for three months with no toxicity. During rheumatoid arthritis experiments with pregnenolone, Dr. H. Freeman and colleagues gave 500 mg pregnenolone/day for up to 30 weeks, with no toxicity. And Drs. Pincus and Hoagland, two of the pioneer researchers on pregnenolone use by humans in the 1940s, found no toxic reactions with pregnenolone used by hundreds of men and women at dosages of 100 mg/day for four months.

The classic studies on pregnenolone and stress in the 1940s by Pincus and Hoagland generally used only 50 mg/day to achieve excellent results, while arthritis studies typically used 200-500 mg daily. Thus, although pregnenolone appears amazingly safe and beneficial, there are still many unanswered questions regarding proper dosage, metabolism, and clinical effects. Keeping these uncertainties in mind, here are some recommendations for dosage.

For those wishing to err on the side of caution, 50 to 100 mg pregnenolone per day would probably be suitable for use without physician monitoring. Perhaps an additional safety margin (for this already amazingly-safe substance) could be achieved through discontinuing use for one week every month. Those wishing to use the higher, anti-arthritis doses (200 – 500 mg/day) should probably do so only under the supervision of their physician, even though many human clinical studies with arthritis at these dosages yielded no problems or toxicities. Morning is the perfect time to take pregnenolone, and a single daily dose is probably best, since pregnenolone is fat-soluble, and probably follows the circadian highs and lows of DHEA and cortisol (highest in the morning, with a drop to baseline by late afternoon). On an anecdotal note, there have been patients taking 100 – 1,000 mg pregnenolone/day intermittently since 1987, with no discernible negative side effects.

While there has been no definite information published as to who should not take pregnenolone, on theoretical grounds, a few cautions can be suggested. Since pregnenolone (especially at high doses) may (in some people) increase estrogen or testosterone levels, I believe that men with prostate cancer (which may be worsened by testosterone) and women with breast or ovarian cancer (which may be worsened by estrogen) should probably take pregnenolone only with their doctors consent and supervision. Men with high PSA (prostate specific antigen) blood levels (possible indicator for undiagnosed or future prostate cancer) should also proceed with caution with pregnenolone use. Lastly, because of pregnenolones anti-GABA, pro-NMDA action, persons known to suffer from epileptic seizures or who are taking an anti-seizure medication such as Dilantin, Depakote or Tegretol should probably only use pregnenolone with their doctors supervision. Finally, as we age, the body produces ever-less of the enzyme which converts pregnenolone to DHEA. Thus, while supplementary pregnenolone taken during middle age and beyond will produce at least some normalization back toward more youthful (and healthful) levels of other steroid hormones, pregnenolone will not completely substitute for other steroid hormone supplements in those with medically demonstrated needs for various specific steroids i.e., DHEA, cortisol, estrogen, etc.

Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

Christine E Marx1,2,3, Richard S E Keefe1, Robert W Buchanan4, Robert M Hamer5, Jason D Kilts1,2,3, Daniel W Bradford1,2, Jennifer L Strauss1,2,3, Jennifer C Naylor1,2,3, Victoria M Payne1,2,3, Jeffrey A Lieberman6, Adam J Savitz7, Linda A Leimone2,3, Lawrence Dunn1,2, Patrizia Porcu5, A Leslie Morrow5 and Lawrence J Shampine1,2,3

1. 1Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
2. 2Durham Veterans Affairs Medical Center, Durham, NC, USA
3. 3Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center (VISN6), Durham, NC, USA
4. 4Maryland Psychiatric Research Center, University of Maryland, Baltimore, MD, USA
5. 5Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA
6. 6Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA
7. 7Department of Psychiatry, Weill Medical College of Cornell University, New York, NY, USA

Correspondence: Dr CE Marx, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham VA Medical Center, 508 Fulton Street, MHSL 116A, Durham, NC 27705, USA. Tel: +919 286 0411 Ext. 7426; Fax: +919 286 6811; E-mail:
Received 16 September 2008; Revised 16 January 2009; Accepted 2 February 2009; Published online 1 April 2009.


The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n=9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change=10.38) compared with patients receiving placebo (mean change=2.33), p=0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs=0.81, p=0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs=0.74, p=0.046). In addition, baseline pregnenolone (rs=−0.76, p=0.037), pregnenolone sulfate (rs=−0.83, p=0.015), and allopregnanolone levels (rs=−0.83, p=0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs=0.74, p<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.

Individual differences in cognitive aging:

implication of pregnenolone sulfate


In humans and animals, individual differences in aging of cognitive functions are classically reported. Some old individuals exhibit
performances similar to those of young subjects while others are severely impaired. In senescent animals, we have previously demonstrated
a significant correlation between the cognitive performance and the cerebral concentration of a neurosteroid, the pregnenolone sulfate

Neurotransmitter systems modulated by this neurosteroid were unknown until our recent report of an enhancement of acetylcholine
(ACh) release in basolateral amygdala, cortex and hippocampus induced by intracerebroventricular (i.c.v.) or intracerebral administrations
of PREG-S. Central ACh neurotransmission is known to be involved in the regulation of memory processes and is affected in normal aging
and severely altered in human neurodegenerative pathologies like Alzheimer’s disease.
In the central nervous system, ACh neurotransmission is also involved in the modulation of sleep–wakefulness cycle, and particularly
the paradoxical sleep (PS). Relationships between paradoxical sleep and memory are documented in the literature in old animals in
which the spatial memory performance positively correlates with the basal amounts of paradoxical sleep. PREG-S infused at the level
of ACh cell bodies (nucleus basalis magnocellularis, NBM, or pedunculopontine nucleus, PPT) increases paradoxical sleep in young

Finally, aging related cognitive dysfunctions, particularly those observed in Alzheimer’s disease, have also been related to alterations
of mechanisms underlying cerebral plasticity. Amongst these mechanisms, neurogenesis has been extensively studied recently. Our data
demonstrate that PREG-S central infusions dramatically increase neurogenesis, this effect could be related to the negative modulator
properties of this steroid at the GABAAreceptor level.
Taken together these data suggest that neurosteroids can influence cognitive processes, particularly in senescent subjects, through a
modulation of ACh neurotransmission associated with paradoxical sleep modifications; furthermore, our recent data suggest a critical role
for neurosteroids in the modulation of cerebral plasticity, mainly on hippocampal neurogenesis.
© 2003 Elsevier Ltd. All rights reserved.

‘Fountain of Youth’ Steroids Could Protect Against Heart Disease

… from universities, journals, and other research organizations

May 23, 2010 — A natural defence mechanism against heart disease could be switched on by steroids sold as health supplements, according to researchers at the University of Leeds.

The University of Leeds biologists have identified a previously-unknown ion channel in human blood vessels that can limit the production of inflammatory cytokines — proteins that drive the early stages of heart disease.

They found that this protective effect can be triggered by pregnenolone sulphate — a molecule that is part of a family of ‘fountain-of-youth’ steroids. These steroids are so-called because of their apparent ability to improve energy, vision and memory.

Importantly, collaborative studies with surgeons at Leeds General infirmary have shown that this defence mechanism can be switched on in diseased blood vessels as well as in healthy vessels.
So-called ‘fountain of youth’ steroids are made naturally in the body, but levels decline rapidly with age. This has led to a market in synthetically made steroids that are promoted for their health benefits, such as pregnenolone and DHEA. Pregnenolone sulphate is in the same family of steroids but it is not sold as a health supplement.

“The effect that we have seen is really quite exciting and also unexpected,” said Professor David Beech, who led the study. “However, we are absolutely not endorsing any claims made by manufacturers of any health supplements. Evidence from human trials is needed first.”

A chemical profiling study indicated that the protective effect was not as strong when cholesterol was present too. This suggests that the expected benefits of ‘fountain of youth’ steroids will be much greater if they are used in combination with cholesterol-lowering drugs and/or other healthy lifestyle strategies such as diet and exercise.

“These ‘fountain of youth’ steroids are relatively cheap to make and some of them are already available as commercial products. So if we can show that this effect works in people as well as in lab-based studies, then it could be a cost-effective approach to addressing cardiovascular health problems that are becoming epidemic in our society and world-wide,” Professor Beech added.