Hans Selye’s postulation of alarm, resistance and exhaustion1 succeeds in presenting an argument that is not necessarily falsifiable. The idea that so many extrinsic variables could provide a homogenous signature was critiqued not only by traditional evidence accumulation, such as new research into vasopressin, 2 but by Pacak’s controlled refutation in 1998. 3 The general adaptivity syndrome is thus a semantic result of incomplete knowledge: a cool breeze does not have the same measurable effect as an opiate.
Take carfentanyl administration as an example. According to Selye’s theory, epinephrine and norepinephrine are instantly released centrally after a stress effector. But is it quick enough to be measurable before the respiratory depression and death after a few grams of carfentanyl? It’s nearly impossible to tell. An argument can be made for massive trauma to the aorta and so on.
One of the many limitations in the first incarnation of the generalized adaptation syndrome is the in vivo differences between rats and humans. The stress system is more broadly defined as a super system between immune cycles and the nervous system. 4 Even though rats and humans have basic homology, they possess minute differences ranging from T-cells ratios and epinephrine receptor expression. 5Physical insults will be similar in effect, but infectious insults are different in mice than in humans. This may be because rats encounter a more diverse array of pathogens. 6
This immune dichotomy does not invalidate Selye’s original theorem in totality, as activation of the sympathetic nervous system has been confirmed. Finding similar quantitative equality in results with norepinephrine would have been nearly impossible in the 1930s. Assays weren’t developed until 1950, due to near-simultaneous developments Japan and the United States giving the crudest of estimates.7
From a bioethical standpoint, researchers have discerned, perhaps unfairly, that iatrogenic vivisection is permitted regardless of cruelty. To understand a modality of stress by traumatizing spinal cords is an efficient but unusual method of observing stress. Take into consideration what stress a rat in the wild encounters on a daily basis, such as an attack from a predator. Does neck trauma mimic a close
encounter (but miss) with a screech owl?
Selye goes onto address the trident concept of in his 1955 Science article titled “Stress and Disease”. It is important to consider the context of the decade when recognizing Selye’s qualitative work. To that end, it seems his core idea of singularity stress syndromes remained unchanged, albeit with a stricter definition of stress. Selye did not use the term stress frequently in his titles in his early work, rather synonyms for agent. The main criticism still exists: theoretical instead of experimental. Since Selye was so prolific (over 1600 articles)*, it’s tempting to dismiss the contributions as antiquated.
Further investigation discloses more refined articles with savory information, however. “ACTH and Cortisone”, published in 1949 in the Canadian Journal of Medicine, expounded on the idea that ACTH or cortisone would benefit rats after exposing them to an allergic challenge. The discussion concludes that cortisone may be helpful in patients with rheumatoid arthritis, a management still used today.8
The most interesting part of the discussion is Selye himself dictating that his research is ongoing. Due to
the complexity of the hypothalamic thyroid pituitary axis, he knew further research would be needed to refine his hypothesis. It’s possible the idea was presented as a springboard or oversimplification, like high school textbooks glazing over such subatomic properties like leptons.
If the reaction to Selye’s model of caused an uproar originally, it was muted within the available resources. It wasn’t until the mid-1970s that researchers began full-force critique, perhaps not coincidentally in the Journal of Human Stress. Selye helped pioneer this journal, and accepted papers from Mason et al that argued stress is actually a looser term to include psychological trauma.9
In addition, Selye’s treatise was interesting in that it recognizes the need for extra supplemented cortisol in illness. More recent literature indicates patients with intact adrenals produce more cortisol
during sepsis. If a patient does not have the required adrenal capacity, hospital length and morbidity will increase.10
Based on the information provided from quotes from Selye himself, his work on stress theory is an homage rather than a duplicate of Walter Cannon, coiner of flight or fight and cyberneticist predating Selye. The difficulty arises in that Selye disregards Cannon’s assertion of multiple responses to stress.
Selye was also challenged by missing parts of the cascade. When a system is inflicted with stress, the preliminary cascade is begun by cytokines and acetylcholine release.11 “Stress and Disease” describes these molecules as first mediators, but there existence was not defined in that regard. Therefore, Selye continued to predicate his theorem on psychological stress, although he lated stated his interests were purely biological.
Prior to the National Institutes of Health-based study by Pacak, Goldstein et al released12 their reaction to the non-specific stress theory. The Pacak study is essentially a replication of the Goldstein to a degree with immobilization and insulin (injected into the periventricular nucleus) yielding a dyssynchronous corticotropin releasing hormone response. The end result discovered an exponential increase in stress hormones based on extent of stress.
At the nadir of the stress controversy, a psychogerontologist S Hontela responded to Selye’s “The Stress Concept” with several salient points: Using single sentences like (paraphrased) humans are not exactly perfect yet and identifying a type of stress that is positive are wildly complex notions incapable of a null hypothesis.
Multiple stressors can change the response even within the same study. Graessler et al showed immobilized rats have exaggerated stress responses when incisions were completed. As it may be expected, “free range rats” had lower stress responses, possibly due to the time required for the adrenals to transmit the required stimulus to the hypothalamus. Moreover, cortisone stayed the same and adrenocorticotropic hormone was suppressed.
The Pacak study is an easily duplicated idea, and exact replication is not necessarily needed.
Researchers must felt the need “debunk” a philosophical concept of Hans Selye due to the vast promulgation of the general adaptation syndrome. The theory is presented in a historical context in mediums varying from nursing textbooks to popular psychology articles.
It was not until the late 1970s that Selye began to acknowledge conditioned responses in individuals, and thus stress can be eliminated based on therapy. Until the end of his publication history, on a steadfast note, he noted the primary watermark of stress is controlled by the psyche first, and the adrenal later. This idea is confounding within his own quotes, and he believes stress is a sole biological entity.
Selye and his idea of general adaptation syndrome can be commended for dragging physiology forward, and moving beyond the notions that illness was caused by the vapors or hysteria, but instead a tangible biologic component. The abundance of evidence indicates Selye and his group were dynamic and open-minded, but it’s possible they weren’t dynamic in terms of available data. Even so, it’s clear he formed new ideas in a vacuum and wielded a strong literary hammer.
No reviewer has measured the amount of times Selye has cited his own preliminary article. Another benefit is Selye’s fluency in eight languages, allowing for multiple publication outlets, even with fewer journals during his peak production.