Selye Research Articles

Early contributions of Russian stress and exercise physiologists.

In Russia, the free development of scientific ideas was suppressed in 1950 as a result of the actions of the Joint Session of the Academy of Sciences and the Academy of Medical Sciences of the USSR. Hans Selye's theory on the general adaptation syndrome was considered unscientific. From 1956 to 1958, Pjotr Anokhin and Pjotr Gorizontov presented definitive arguments for having the theory accepted by scientists while the significance of hormones in adaptation became a topic of endocrine studies (Boris Aleshin, Igor Eskin, Vassily Komissarenko, Samuel Leites, and Michael Kolpakov). Later, Felius Meerson made essential contributions to the adaptive significance of protein synthesis and stress-limiting systems. The area of exercise physiology dealing with acute and chronic adaptation to strong physiological stressors was founded by Leon Orbeli and developed by Aleksei Krestovnikov. Significant contributors to this area were Vladimir Farfel, Nikolai Yakovlev, and Nikolai Zimkin. Although the majority of their publications have remained unknown outside of Russia, it is interesting that many of their results have been "rediscovered" by others. Yakovlev also deserves recognition because he was among the founders of contemporary exercise biochemistry and because his research has provided the foundation for current investigations. Several generations of young scientists have been inspired by the above-mentioned Russian scientists. Today, however, the research activities of scientists are no longer limited by political pressures but by financial resources instead.

Socio-cultural stress in modern societies and the myth of anxiety in Eastern Europe.

The word “stress” has become very popexamining the interrelationships between stressors and their consequences. The conular—not only in scientific literature, but also in everyday life—since Hans Selye cept of stress is both multiand inter-disciplinary, since stress research involves difwrote his book on the stress of life in 1956. Coping with stress is one of the ferent views within several scientific fields, such as medicine at both pre-clinical and greatest challenges of modern life, and a considerable amount of research has been clinical levels, psychology, philosophy, anthropology, and sociology. generated over the past several decades in In Selye’s view, stress represents the general response of the organism to environmental demands, which is neither posiBettina F. Piko, M.D., Ph.D., is a Senior Lective nor negative in nature but merely a turer in behavioral sciences in the Department physiological mechanism that covers an of Psychiatry at the University of Szeged in alarm reaction preparing the organism for Hungary. She worked as an Eotvos Fellow and action and adaptation. Furthermore, he Visiting Research Professor in the Department of Sociology at the University of Alabama at Birmakes the distinction between “eustress” mingham (UAB), USA, supported by the Minisand “distress” (stress at a moderate level try of Education in Hungary and The School of and stress at a high level). The latter type Social and Behavioral Sciences at UAB when of stress causes pathological changes in preparing the manuscript. The author thanks Kevin M. Fitzpatrick for the body; therefore, it is viewed as a negahis helpful comments on the paper and also tive factor in one’s life. He called the acDarlene R. Wright, Sara M. Daum, Emily D. tual environmental inputs “stressors” beNorman, and Godfrey F. Noe who helped her cause they could produce stress, while the understand democracy. She dedicates this artiresponses to stress as consequences could cle to Thomas S. Szasz. Address for correspondence: Dr. Bettina F. be viewed as outputs. Piko, University of Szeged, Department of PsyThe stress process itself is a physiologichiatry, Behavioral Sciences Group, 6722 cal mechanism called General Adaptation Szeged, Szentharomsag u. 5., Hungary. E-mail: Syndrome (GAS), which is mediated by pikobettina@yahoo.com. Web site: http:// www.szote.u-szeged.hu/nepsy/piko/. hormonal changes in the hypothalamic-pi-

The physiology of mind-body interactions: the stress response and the relaxation response.

There are key differences between mind-body medicine and alternative medicine. A central tenet of mind-body medicine is the recognition that the mind plays a key role in health and that any presumed separation of mind and body is false. Alternative medicine, however, does not focus on the role of thoughts and emotions in health and, therefore, is separate from mind-body medicine. Also, while there has been little scientific research on alternative medicine, the literature on mind-body medicine comprises more than 2000 peer-reviewed studies published in the past 25 years. The groundwork for understanding the physiology of mind-body interactions was established by pioneering studies in the 1930s by Walter Cannon, and in the 1950s by Walter Hess and by Hans Selye that led to an understanding of the fight-or-flight response. Later work by Holmes and Rahe documented measurable relationships between stressful life events and illness. Other research has shown clinical improvement in patients treated with a placebo for a variety of medical problems. The effectiveness of placebo treatment can be interpreted as compelling evidence that expectation and belief can affect physiological response. Recent studies using spectral analysis and topographic electroencephalographic (EEG) mapping of the relaxation response demonstrate that by changing mental activity we can demonstrate measurable changes in central nervous system activity. These, and other, studies demonstrate that mind-body interactions are real and can be measured.

Low cortisol and a flattening of expected daytime rhythm: potential indices of risk in human development.

Since the work of Hans Selye, stress has been associated with increased activity of the limbic-hypothalamic-pituitary-adrenocortical (LHPA) axis. Recently, a number of studies in adults have shown that this neuroendocrine axis may be hyporesponsive in a number of stress-related states. Termed hypocortisolism, the paradoxical suppression of the LHPA axis under conditions of trauma and prolonged stress presently challenges basic concepts in stress research. Adverse conditions that produce elevated cortisol levels early in life are hypothesized to contribute to the development of hypocortisolism in adulthood. However, as reviewed in this paper, hypocortisolism also may be a common phenomenon early in human childhood. Although preliminary at this point, the ubiquity of these findings is striking. We argue that developmental studies are needed that help explicate the origins of low cortisol and to determine whether the development of hypocortisolism is, in fact, preceded by periods of frequent or chronic activation of the LHPA axis. We also argue that developmental researchers who incorporate measures of salivary cortisol into their studies of at-risk populations need to be aware of the hypocortisolism phenomenon. Lower than expected cortisol values should not necessarily be relegated to the file drawer because they contradict the central dogma that stress must be associated with elevations in cortisol. Lastly, we note that evidence of low cortisol under adverse early life conditions in humans adds to the importance of understanding the implications of hypocortisolism for health and development.

Mechanismen der Bewältigung von Stress

Abstract. Title of the paper: Coping strategies during stress The response to Stressors requires a progression of events beginning with sensing and signalling the animal's various biological mechanisms that a threat exists. These events are followed by activation of neurophysiological mechanisms to mount a biological effort to resist and prevent major damage. The various sensory detectors not only receive the information but transform that information into neural signals that are transmitted to either or botn cognitive and non-cognitive centres of the nervous system to generate a co-ordinated response to the challenge. The hypothalamic-adrenal medullary system involves the hypothalamus, pituitary gland, the sympathetic neural pathways to the adrenal medulla, and the release of epinephrine by the adrenal gland. This short acting stressresponse was originally proposed by W. Cannon and is referred to as the Fight-Flight Syndrome (FFS). The hypothalamic-pituitary-adrenocortical (HPA) stress-response System represents a longer-term, sustained response to Stressors and was conceptualised by Hans Selye (General Adaptation Syndrome, GAS). The major adrenal cortical hormones are corticosteroids and aldosterone. These two classical stress response Systems have been linked to different coping pattern in that FFS is primarily activated in situations of threat of control, whereas the pituitary-adrenocortical System is activated in situations of loss of control. Besides these classical physiological Systems other Systems are activated during stress, including the immune system. Recent research suggests that the endocrine, immune and central nervous Systems interact and respond to stressful Stimuli in a co-ordinated manner. The presence of hormones, neurotransmitters and receptors common to all three Systems Supports the view that communication exists between these Systems. Psychological Stressors perceived as threats may be equally important as those of a physical nature in challenging coping mechanisms. Situations of uncertainty, social pressure and fear are potent Stressors with relevance for the well-being of animals, leading to severe damage to specific target organs and tissues or even to death in some species. Studies on stress responses in farm animals are often conducted on the basis of single physiological alterations or irregular behavioural phenomena that might be difficult to interpret. Non-invasive methods for measuring stress-indicating parameters have been developed in addition to classical descriptive behavioural observations, allowing an evaluation of stress by multiple criteria under different housing conditions and handling procedures.

Regulation of adrenocorticotropic hormone secretion: lessons from mice deficient in corticotropin-releasing hormone.

Regulation of adrenocorticotropic hormone secretion: lessons from mice deficient in corticotropin-releasing hormone.

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stress-response or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole.

Coping with stress in the elderly

In terms of adaptability, unlike inanimate objects, living organisms exist in a dynamic balance between "wear and tear" and "repair and recovery". We regarded 17-hydroxycorticosteroids (17-OHCS) as a compound related to tissue "wear and tear" (Hans Selye) and sought for a compound related to tissue "repair and recovery". This led us to the discovery of 17-ketosteroid sulfates (17-KS-S) in urine. Elderly persons, unlike young adults, show low levels in 17-KS-S and little diurnal changes. In an elderly person 17-KS-S can decrease on significant life events (e.g. a spouse's death) and remain at low levels for a long time. Elderly persons with frailty need to improve their lifestyle (meals, exercise, rest, sleep, etc.) qualitatively and quantitatively to adapt themselves to stress adequately. Increased 17-KS-S levels were to be related to improvement in lifestyle.

Putting Stress in Life

Hans Selye discovered Stress in 1935 as a syndrome occurring in laboratory rats. In the modern world, Stress has become a universal explanation for human behaviour in industrial society. Selye's discovery arose out of widespread interest in the stability of bodily systems in 1930s' physiology; however, his findings were rejected by physiologists until the 1970s. This analysis is framed in terms of Latour's actor-network theories, and traces the translation of Stress from the animal laboratory into the narratives of modern life experience. This mapping reveals that translation was brought about by Selye's recruitment of a broadly based constituency outside of academic physiology, whose members each saw in Stress a validation of their pre-existing ideas of the relationship of the human mind and body in industrial civilization. While Selye was successful in realizing Stress as a scientific fact, he was unable to make his institute the obligatory passage point for Stress research. Selye's notion of a universal non-specific reaction has become accepted in almost all forms of human discourse about life and health, and physiologists in the 1990s use Stress as a unifying concept to understand the interaction of organic life with the environment. However, this modern use of Stress contains none of the physiological postulates of Selye's original findings.

Hans Selye and the development of the stress concept. Special reference to gastroduodenal ulcerogenesis.

Hans Selye has a historic role in the development of the stress concept. Before his short article in Nature in 1936, the neuroendocrine response to nonspecific injury was thought to be restricted to the release of catecholamines, as recognized by Cannon. Selye was the first to appreciate the crucial role of the adrenal cortex/hypophysis axis in the stress response. He also insisted on the nonspecificity of this neuroendocrine response, and he named the stress-causing agent "stressors". His last major contribution was the distinction between negative, that is, distress, and positive, that is, eustress reactions. The "triad of stress" (adrenal hypertrophy, gastrointestinal ulcers, thymolymphatic atrophy) was also first described by Selye, who was fascinated by the fact that in stressed rodents only gastric and not duodenal ulcers would develop. It was not until the recognition of duodenal ulcerogenic properties of propionitrile and cysteamine as well as the subsequent quantitative structure-activity studies predicting the duodenal ulcerogenic action of complex molecules that pathogenetic investigations allowed a molecular and mechanistic approach for studying the etiology and pathogenesis of duodenal ulceration. Recent studies on the role of sulfhydryls, TRH, ET, and growth factors provide new insights into central and peripheral pre-ulcer pathways. We were surprised to learn that an organ-specific ET-1 release may play a role both in ulcer induction and healing, which seems to start with the expression of immediate early genes such as egr-1 and stimulation of the local synthesis of growth factors such as bFGF and PDGF. Thus, a historic review originating with Hans Selye and extending through the next 60 years allows a cellular and molecular approach to the better understanding of stress-related disorders such as gastroduodenal ulceration.

Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture.

Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture.

The stress concept and neuroimmunoregulation in modern biology.

Sixty years ago Hans Selye discovered that the neuroendocrine and immune systems interact during stress. The pathophysiological significance of neuroendocrine-immune interaction during injury has only been recognized recently. Today it is rapidly emerging that, in addition to defense against exogenous pathogenic agents, the immune system plays a key role in host defense against injury. During acute-phase reactions to infection/injury, when there is no time to mount a specific immune response, the neuroimmunoregulatory network suppresses specific immunity while rapidly elevating the production of acute-phase proteins (APP) in the liver. APP recognize microbes and abnormal cells/tissues and activates the immune system nonspecifically to fight infection or injury. There is a remarkable similarity between the stress syndrome as outlined by Selye in 1946 and the acute-phase response as we know it today. Moreover, it is becoming clear that the immune system participates in the normal physiological regulation of the body, which was also recognized by Selye in his later years. Although with much delay, the scientific community is beginning to fully appreciate Selye's ingenious discoveries which were far ahead of his time.

Hans Selye and the Field of Stress Research

T next article in our series is one of the first reports from Hans Selye, who pioneered research on biological effects of exposure to stressful stimuli. This article is a cornerstone of neuropsychiatry because it led to the study of the effects of stress and hormones, particularly corticosteroids, on brain function. Hans Selye (1907–1982), a native of Hungary, founded the Institute of Experimental Medicine and Surgery at the University of Montreal and later the International Institute of Stress. During the half-century of his research career he authored or co-authored more than 1,700 publications, including 40 books. The brief report reprinted below summarizes, in five dense paragraphs, several years of experimentation that formed the empiric foundation of Dr. Selye’s concept of the General Adaptation Syndrome. This syndrome consists of an enlargement of the adrenal gland; atrophy of the thymus, spleen and other lymphoid tissue; and gastric ulcerations. He describes in this report three stages of adaptation, including an initial brief alarm reaction, followed by a prolonged period of resistance and a terminal stage of exhaustion and death. This foundational work led to a rich line of research on the biological functioning of glucocorticoids. Dr. Selye was greatly influenced by Walter B. Cannon, who had focused on the role of the sympathetic nervous system in adaptation and coined the terms “fight-orflight responses” and “homeostasis.” Although Dr. Selye’s view that stress responses are nonspecific has been challenged (for review, see Goldstein), his legacy of empiric research remains extremely influential today.

A syndrome produced by diverse nocuous agents. 1936.

A syndrome produced by diverse nocuous agents. 1936.

Reminiscences of Hans Selye and the birth of ‘stress’

The stress concept is one of the most commonly applied constructs in all of mental health. While the nature of stress is relatively well known, little is known of the man who pioneered the field. This paper provides the reader with a rare glimpse at the birth of the concept of stress and the man who was its father: Hans Selye.

Reminiscences of Hans Selye and the birth of ‘stress’

Stress MedicineVolume 14, Issue 1 p. 1-6 Editorial Reminiscences of Hans Selye and the birth of ‘stress’ Paul J. Rosch M.D., F.A.C.P., Paul J. Rosch M.D., F.A.C.P.Search for more papers by this author Paul J. Rosch M.D., F.A.C.P., Paul J. Rosch M.D., F.A.C.P.Search for more papers by this author First published: 04 December 1998 https://doi.org/10.1002/(SICI)1099-1700(199801)14:1<1::AID-SMI777>3.0.CO;2-WCitations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume14, Issue1January 1998Pages 1-6 RelatedInformation

Stress and anticortisols--17-ketosteroid sulfate conjugate as a biomarker in tissue repair and recovery

We attempted to determine compounds in human urine which, differing from cortisol (17-OHCS), show high values in healthy individuals, decrease with failing health, clearly decline with advancing disease and finally reach very low values in severe disease. We have eventually established that 17-ketosteroid sulfate conjugates (17-KS-S) are the compounds we were searching for. Hans Selye regarded stress as the rate of wear and tear and 17-OHCS as its indicator, but we considered that, differing from inanimate objects, living organisms consume energy to cope with stress and "repair" "wear and tear" of the tissue and "recover" its function. This concept led us to determine the organism's requirement for two mechanisms: "Wear and tear" which could be represented by the secretion of 17-OHCS (Selye), and "repair and recovery", which could be determined by the amounts of 17-KS-S derived from dehydroepiandrosterone (DHEA)-sulfate, a product of the adrenal cortex, which enhances neuronal survival, longterm memory, maintains the function of peripheral tissues, and stimulates immune system (17-KS mainly consists of 17-KS-S and 17-KS glucuronides 17-KS-G, the latter derived from cortisol, DHEA and testosterone). We hold that stress response is a series of biological process, beginning from CRH.ACTH and catecholamines, cortisol (17-OHCS), followed by insulin, acting as an anabolic agent and finally DHEA (17-KS-S) leads the tissues to repair by utilizing produced energy. Balanced changes of hormones, such as 17-KS-S, 17-OHCS, cortisol, catecholamines and insulin are seen in healthy individuals under healthy lifestyles and disruption of the balance brings apparent reduction in 17-KS-S. From this standpoint, we wish to develop research in interrelations between biologically antagonistic 17-KS-S and 17-OHCS, focusing particularly at 17-KS-S, which represents a contact point for mind and body, the healthy state of which is kept by appropriate sleeping and exercise programs on the basis of adequate food intake. The above three factors, 17-KS-S, 17-OHCS, and 17-KS-G, are expressed in creatinine ratio (mg/g creatinine).

Hans Selye and beyond: responses to stress.

Hans Selye and beyond: responses to stress.

The relation between the aging of the steroid generating system and the geneses of cancers of the stomach, the breast and the uterine cervix

The purpose of the present study is to test the validity of the steroid carcinogenesis hypothesis in humans by investigating the problem whether or not a cancer-specific change of the hormonal milieu emerges at a specified stage of life where the growth rate of cancer risk is at its zenith. A case-control study of 14 urinary steroid excretions was conducted for each of 3 human neoplasias. The identification and the size (in parenthesis) of the population units used in this study were,given as follows: a) the male gastric cancer group (421); b) the male control group (104); c) the female breast cancer group (245); d) the cervical cancer group (345); e) the female control group (127). Two kinds of steroid parameters were employed for the statistical analysis of hormonal data: a) the logarithm of a steroid excretion figure (mu g/day), as expressed by log x; b) the logarithm of a relative weight of a given steroid to tetrahydrocortisol, as expressed by log x/THF. The case-control difference for each parameter was expressed in terms of a t-value of Student's t-test. The steroid deviation profile was prepared for each neoplasia and for each of the log x data set and the log x/THF data set. The results obtained are as follows: a) the 2 steroid parameters (log x and log x/THF) for each of 14 urinary steroids were both subject to change with the progress of host age. The rate of age-dependent change was different for each steroid parameter and for each population unit. b) The above differential age dependency of the steroid parameters gave rise to a continual transition of the steroid deviation profile in the course of aging. c) The hormonal traits of male gastric cancer, female breast cancer and cervical cancer were described each as a complex of androgen depression and glucocorticoid stimulation (male gastric cancer), a sequential emergence of premenopausal progestin depression and postmenopausal predominance of glucocorticoid over androgen (female breast cancer), and a complex of androgen-glucocorticoid depression over progestin (cervical cancer). d) The emergence of the above cancer-specific steroid disorders chronologically coincided with the quasiexponential growth phase of cancer risk (and slow growth phase of cancer risk in postmenopausal breast cancer). e) The usefulness of the log x/THF type deviation profile for the assessment of the hormonal milieu of the host was verified by both theoretical approach to the problem and its application to the real data of a case-control study. f) The age dependent decline of androgens was generally much faster in their progressions than that of glucocorticoids - a finding to suggest the possibility that the production of a cancer-specific steroid deviation profile might have taken the form of the stress shift of Hans Selye, since both phenomena share depletion of gonadal steroids relative to glucocorticoid in common. The etiological relevancy of the 3 cancer-specific steroid changes to the geneses of 3 cancers:was discussed in the light of the experimental pathology studies in our laboratory as well as in other laboratories.

Neurosteroid modulation of native and recombinant GABAA receptors.

1. The pioneering work of Hans Selye over 50 years ago demonstrated that certain steroid metabolites can produce a rapid depression of central nervous system activity. 2. Research during the last 10 years has established that such effects are mediated by a nongenomic and specific interaction of these steroids with the brain's major inhibitory receptor, the GABAA receptor. 3. Here we describe the molecular mechanism of action of such steroids and review attempts to define the steroid binding site on the receptor protein. The therapeutic potential of such neurosteroids is discussed.