'Pregnenolone Steal' and the Stress Effect

Got Stress? Obviously. We experience stress in almost every facet of our everyday lives. We get stressed out because of work and upcoming deadlines, social interactions and events, or even because of what we’re seeing on the news. Because of our inherent nature to experience stress, the human body has come up with unique ways to combat these situations.

In response to stress, the body produces the hormone cortisol, which has a wide range of effects. Cortisol promotes energy mobilization and metabolism; increases cardiac output (increasing heart rate/ oxygen consumption and constricting blood vessels), and suppresses the immune system. When we experience stress, cortisol gives us the extra boost needed to manage the situation at hand.

Stress and cortisol in short bursts are beneficial and allow us to deal with various scenarios. Imagine our early human ancestors, and the burst of adrenaline and cortisol needed to flee from predatory animals. We would have died out as a species if we were unable to initiate the fight or flight response. However, chronic stress- the stress the modern human experiences day in and day out for decades- can be extremely detrimental to our overall health because it inhibits many important biological processes that are essential for a healthy life.

Chronic stress disrupts the body’s regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is a collection of structures that regulate the body’s response to stress. More specifically, it regulates the body’s ability to initiate a stress response (like running from a tiger), and then restabilize following the stressful event (1). The problem is that the chronic, ongoing stress that overwhelms our lives overrides this tight regulatory control, resulting in HPA axis dysfunction.

One proposed theory of how HPA axis dysregulation and cortisol take a negative toll is known as “Pregnenolone Steal” (2). Cortisol—along with testosterone, estrogen, aldosterone, and various other hormones—is synthesized from a precursor molecule called pregnenolone. The general idea is that under chronic stress conditions, the cortisol pathway ‘steals’ the pregnenolone from the other sex hormone pathways, in reaction to the stress response, in theory, not leaving enough pregnenolone for conversion of other essential hormones. While this seems extremely concerning, and despite this concept of “pregnenolone steal” being discussed often in the functional medicine world, the physiology doesn’t back this concept up. Different classes of hormones are produced in different tissues within the adrenal glands, and each one of these tissues has its own pregnenolone to pull from. Thus, there is no one communal pool of pregnenolone from which all of these hormones are produced, and at this time, there is no known mechanism that suggests that the pregnenolone could be transferred from one tissue or layer of the adrenals to another.

So, while this idea of pregnenolone steal is an oversimplification, the science shows us that the upregulation of cortisol under chronic stress has a subsequent impact on precursor hormones that results in downstream imbalances in sex hormones (3,4,5). Because of this, when we live our lives with chronic stress, we put ourselves at a higher risk of suffering from cognitive decline and developing Alzheimer’s disease.

Acute stress is part of life, and the acute stress response is healthy and normal. It’s the chronic stress that throws the body and hormone levels out of balance, resulting in widespread and potentially devastating health outcomes. It is for this reason that stress management in an ever stressful world has become paramount to overall health. Strive to remove stressors from your life whenever possible, and for the things that you can’t remove or change, find the stress management techniques that work best for you.

References:

1. Smith, S. M., & Vale, W. W. (2006). The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues in Clinical Neuroscience, 8(4), 383–395.
2. Bredesen, D.E. The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline. New York: Avery, 2017.
3. Mulrow, P. J., Cohn, G. L., & Kuljian, A. (1962). CONVERSION OF 17-HYDROXY-PREGNENOLONE TO CORTISOL BY NORMAL AND HYPERPLASTIC HUMAN ADRENAL SLICES. Journal of Clinical Investigation, 41(8), 1584–1590.
4. McDermott, W. V., Fry, E. G., Brobeck, J. R., & Long, C. N. H. (1950). Mechanism of Control of Adrenocorticotrophic Hormone . The Yale Journal of Biology and Medicine, 23(1), 52–66.
5. Genazzani, A. D. (2005). Neuroendocrine aspects of amenorrhea related to stress. Pediatr Endocrinol Rev. 2(4), 661-668.