The Biology of Stress and Depression Pt. 3: Pregnenolone

(These are all of the posts we have on this topic)

1st Post on Stress and Depression Why the Current Theory Fails So Often

2nd Post on Stress and Depression Cortisol

3rd Post on Stress and Depression Pregnenolone

4th Post on Stress and Depression DHEA

5th Post on Stress and Depression BDNF
6th Post on Stress and Depression: The Cholesterol/Dopamine Connection
7th Post on Stress and Depression: Increasing levels of Brain Derived Neurotrophic Factor (BDNF)

Hello again,

Welcome to our third post on the biology of Stress and Depression.  Just to recap the previous posts, please review the following:

The current model regarding the problem of depression sees it as a lack of neurotransmitters (dopamine, serotonin & nor-adrenaline). This view sees depression as a “lack of happiness”. If you want to treat a depressed patient you give him/her drugs to increase the presence of these deficient hormone(s).  Increasing amounts of these hormones should, in theory, make people happier. The trouble is that in the light of other theories of depression, this theory is very limited.  In addition, it does not take into account the impact of stress on the body.

Current research clearly shows us that stress leads to depression.  Excessive amounts of stress lead to the gradual destruction of the hippocampus.  The hippocampus controls the the body's reaction to stressors. Increasing amounts of stress and the consequential destructive impact on the hippocampus lead to a reduced ability to handle further stress. It can become a vicious cycle.  That cycle is highlighted by research finding that untreated stress/depression is linked to having a smaller hippocampus which in turn is directly linked to being predisposed to depression, largely because of reduced ability react appropriately to stressors.  Clearly, stress does lead to depression. 

Note that stress is also often regarded as something people have control over. This is often not the case.  Stressors are not just psychological. They can be biological or physical in nature and either is often completely out of our control.  

In order to cut depression off at the source, we need to find ways to deal with stress. One step, which your body does naturally, is to produce a neurochemical called pregnenolone. Pregnenolone is a steroidal hormone produced naturally in the body. Pregnenolone is a precursor hormone synthesized from cholesterol. It is primarily found in the adrenal glands but it is also generated by the liver, skin, brain, testicles, ovaries, and the retina of the eyes. Pregnenolone may be one of the most important neurochemicals because it seems to have a regulating effect on other steroidal hormones.

Steroids in general are a large group of structurally related biochemicals that encompass anti-inflammatory, sex-determining, and growth-regulating functions. Pregnenolone is the grand precursor from which almost all of the other steroidal hormones are made.  These other hormones include: DHEA, progesterone, testosterone, the various estrogens, and cortisol.

Pregnenolone has been shown to be up to 100 times more efficient for memory enhancement than other steroids or steroid-precursors, in laboratory animals. Pregnenolone seems to be the most powerful memory enhancer ever reported on in animal studies. Pregnenolone has been reported to not only make people sharper mentally, but also happier.  It’s also may enhance the ability to perform on the job while consecutively heightening feelings of well-being.  Not surprisingly, pregnenolone has also been reported to reduce high stress induced fatigue. Its importance in decreasing the impact of stress is significant.

Effects of pregnenolone also include stress reduction and increased resistance to effects of stress, improvement of mood and energy, reduced symptoms of PMS and menopause, improved immunity, and repair of myelin sheaths. Myelin sheaths are like insulators on your nerves. They help make sure that electro/chemical impulses say strong and going in the right direction along the nervous system. Pregnenolone also functions as a potent neurosteroid in the brain. It controls and strengthens the transmission of messages from neuron to neuron and strongly influences learning and memory processes.

As is the case with other steroid-hormone precursors, pregnenolone levels decline with age. By the age of 75 our bodies produce 60% less pregnenolone than the levels produced in our mid-thirties. For this reason pregnenolone is considered one of the biomarkers of aging. Like counting the rings of a tree, by evaluating the level of pregnenolone at any given point of a person's life, it is often conceivable to make a guess as to their age.

Other hormones which decline with age are: DHEA, the estrogens, testosterone, progesterone and growth hormone. These are also considered biomarkers of aging. Pregnenolone provides the initial raw material from which most steroid hormones are made. Consequently, many of the bodies' other hormones will decline in a parallel fashion.

How does pregnenolone relate to depression?  Please review the following list of effects it has on the nervous system in general.

Enhancing Memory and Cognition

Increasing acetylcholine levels, improving neurogenesis (the formation of new neurons), and adjusting gamma-aminobutyric acid (GABA) are among the avenues pregnenolone uses to increase memory and mental function.  Acetylcholine is a critical neurotransmitter that assists brain cells in communicating with each other. Many Alzheimer’s medications ( Aricept® and Reminyl®) work by reducing the breakdown of acetylcholine. In a recent study, French researchers discovered that infusing pregnenolone sulfate (a sulfated derivative of pregnenolone) into the brains of rats boosted acetylcholine release by 50% while improving cognitive recognition of a familiar environment.

Neurons created through neurogenesis are cells that send and receive electrical signals to and from other parts of the body.  This is a vital mechanism in both humans and animals. The potential to boost neurogenesis gives hope to those with chronic, debilitating diseases such as Alzheimer’s, Huntington’s and Parkinson’s.  Aware that neurogenesis is sensitive to hormonal influences, researchers in the study mentioned above examined the effect of pregnenolone sulfate on neurogenesis in young and old rats.  Infusion with pregnenolone sulfate increased nerve growth in both 3- and 20-month-old rats. The researchers concluded that pregnenolone could prevent the appearance of age-related cognitive disturbances.

GABA is another critical neurotransmitter related to proper mental function.  An inhibitory neurotransmitter that aids in relaxation and sleep, GABA acts as a “balancer” for the brain, helping us balance excitation with inhibition. There are encouraging indications that pregnenolone may both inhibit and enhance the activity of GABA receptors, thus helping modulate nervous system function.

Countering Fatigue and Stress

As was discussed in previous posts, there is a direct connection between excessive stress and depression. This included a discussion of ways in which treating stress and depression may lead to cognitive improvements.

A research group studied pregnenolone effects on improving job performance in students and workers. They found that pregnenolone helped both groups learn and remember tasks which were challenging enough to be stressful. Pregnenolone not only boosted job performance, but it also helped produce heightened feelings of well-being in the test subjects as well as decreases in fatigue.

During periods of stress, our output of adrenal hormones increases. Increased output of these hormones has been associated with increased fatigue in army pilots, resulting in poor performance. In a study of pilots under stress, 50 mg of pregnenolone daily improved performance with no adverse side effects.

Combating Depression

Antidepressant medications not only are associated with a host of adverse side effects, including: loss of libido, weight gain, constipation, and insomnia, but also do little to address underlying foundations of depression. Numerous studies demonstrate that a deficiency of pregnenolone may be  a much stronger link to depression than deficiencies in neuro-transmitters such as dopamine, serotonin and nor-adrenaline .

In one study, subjects with either current depression or a history of depression exhibited significantly lower levels of pregnenolone than non-depressed individuals. Additionally, patients with active depression had lower levels of pregnenolone compared to those in remission but with a prior history of depression. 

Pregnenolone has a defined role in mental health.  The goal of this post is not simply to encourage supplementation. Rather, the aim is to shed light on other aspects of depression that are not currently being addressed by anti-depressant medications.  Future posts will be looking into other hormones and factors related to depression.

Stay Tuned!