'Pregnenolone Steal' and the Stress Effect

by Spencer Reed

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 imbalance.  

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. Depending on the level of hormones in the body at a given time, pregnenolone can be shunted down different pathways and converted into a variety of different hormones, all of which are necessary for survival. 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. This concept of pregnenolone steal could be extremely detrimental, obscuring the normal hormonal balance and causing complications in nearly all body systems, including the brain. For example, testosterone supports the survival of neurons and those with suboptimal testosterone levels are at an increased risk for Alzheimer’s disease; Pregnenolone supports memory and has a neuroprotective role; estrogen plays a role in supporting neurons from degradation thus preventing dementia (2).

The basic science behind this concept demonstrates that the process is more complicated, and a simple ‘steal’ of a precursor hormone is indeed an oversimplification. Rather, 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). But without a full lesson on the nuances of the physiology, the general implications behind a pregnenolone ‘steal’ is both accurate and alarming. 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 hormones 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.