Objective. —This article defines stress and related concepts and reviews their historical development. The notion of a stress system as the effector of the stress syndrome is suggested, and its physiologic and pathophysiologic manifestations are described. A new perspective on human disease states associated with dysregulation of the stress system is provided. Data Sources. —Published original articles from human and animal studies and selected reviews. Literature was surveyed utilizing MEDLINE and the Index Medicus . Study Selection. —Original articles from the basic science and human literature consisted entirely of controlled studies based on verified methodologies and, with the exception of the most recent studies, replicated by more than one laboratory. Many of the basic science and clinical studies had been conducted in our own laboratories and clinical research units. Reviews cited were written by acknowledged leaders in the fields of neurobiology, endocrinology, and behavior. Data Extraction. —Independent extraction and cross-referencing by the authors. Data Synthesis. —Stress and related concepts can be traced as far back as written science and medicine. The stress system coordinates the generalized stress response, which takes place when a stressor of any kind exceeds a threshold. The main components of the stress system are the corticotropin-releasing hormone and locus ceruleus-norepinephrine/autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. There has been an exponential increase in knowledge regarding the interactions among the components of the stress system and between the stress system and other brain elements involved in the regulation of emotion, cognitive function, and behavior, as well as with the axes responsible for reproduction, growth, and immunity. This new knowledge has allowed association of stress system dysfunction, characterized by sustained hyperactivity and/or hypoactivity, to various pathophysiologic states that cut across the traditional boundaries of medical disciplines. These include a range of psychiatric, endocrine, and inflammatory disorders and/or susceptibility to such disorders. Conclusions. —We hope that knowledge from apparently disparate fields of science and medicine integrated into a working theoretical framework will allow generation and testing of new hypotheses on the pathophysiology and diagnosis of, and therapy for, a variety of human illnesses reflecting systematic alterations in the principal effectors of the generalized stress response. We predict that pharmacologic agents capable of altering the central apparatus that governs the stress response will be useful in the treatment of many of these illnesses. ( JAMA . 1992;267:1244-1252)

The Concepts of Stress and Stress System Disorders: Overview of Physical and Behavioral Homeostasis

There is currently widespread interest in the IGFs (IGF-I and IGF-II) and their roles in the regulation of growth and differentiation of an ever increasing number of tissues are being reported. This selective review focused on the current state of our knowledge about the structure of mammalian IGFs and the multiple forms of mRNAs which arise from alternative splicing and promoter sites which arise from gene transcription. Current progress in the immunological measurement of the IGF is reviewed including different strategies for avoiding binding protein interference. The results of measurements of serum IGF-I and IGF-II in fetus and mother and at various stages of postnatal life are described. Existing knowledge of the concentration of these peptides in body fluids and tissues are considered. Last, an attempt is made to indicate circumstances in which the IGFs are exerting their actions in an autocrine/paracrine mode and when endocrine actions predominate. In the latter context it was concluded that an important role for GH action on skeletal tissues via hepatic production of IGF-I and endocrine action of IGF-I on growth cartilage is likely.

Insulin-Like Growth Factors I and II. Peptide, Messenger Ribonucleic Acid and Gene Structures, Serum, and Tissue Concentrations

▪  The stress response is subserved by the stress system, which is located both in the central nervous system and the periphery. The principal effectors of the stress system include corticotropin-releasing hormone (CRH); arginine vasopressin; the proopiomelanocortin-derived peptides α-melanocyte-stimulating hormone and β-endorphin, the glucocorticoids; and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development and may account for a number of endocrine, metabolic, autoimmune, and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors, and the timing of the stressful events, given that prenatal life, infanc...

Endocrinology of the stress response.

Nutrition is one of the main regulators of circulating IGF-I. In humans, serum IGF-I concentrations are markedly lowered by energy and/or protein deprivation. Both energy and proteins are critical in the regulation of serum IGF-I concentrations. Indeed, after fasting, optimal intake of both energy and protein is necessary for the rapid restoration of circulating IGF-I. We believe, however, that in adult humans energy may be somewhat more important than protein in this regard. While the lowest protein intake is able to increase IGF-I in the presence of adequate energy, there is a threshold energy requirement below which optimal protein intake fails to raise IGF-I after fasting. When energy intake is severely reduced, the carbohydrate content of the diet is a major determinant of responsiveness of IGF-I to GH. The essential amino acid content of the diet is also critical for the optimal restoration of IGF-I after fasting, when protein intake is reduced. The exquisite sensitivity of circulating IGF-I to nutrients, the nycthemeral stability of its concentrations and its relative short half-life constitute the basis for its use as a marker of both nutritional status and adequacy of nutritional rehabilitation. For these indications, IGF-I measurement is more sensitive and more specific than measurement of the other nutrient-related serum proteins (albumin, prealbumin, transferrin, retinol-binding protein). Animal models have been developed to investigate the mechanisms responsible for the nutritional regulation of IGF-I. There is no doubt that many mechanisms are involved (Fig. 12). Decline of serum IGF-I in dietary restriction is independent of the diet-induced alterations in pituitary GH secretion. The role of the liver GH receptors is dependent on the severity of the nutritional insult. In severe dietary restriction (fasting), a marked decrease of the number of somatogenic receptors supports the role of a receptor defect in the decline of circulating IGF-I. In contrast, in less severe forms of dietary restriction (protein restriction), the decline of IGF-I results from a postreceptor defect in the GH action at the hepatic level. Nutritional deprivation decreases hepatic IGF-I production by diminishing IGF-I gene expression. Decline in IGF-I gene expression is mainly caused by nutrient deficiency and less importantly by the nutritionally induced hormonal changes (insulin and T3). Diet restriction also increases the clearance and degradation of serum IGF-I through changes in the levels of circulating IGFBPs.(ABSTRACT TRUNCATED AT 400 WORDS)

Nutritional Regulation of the Insulin-Like Growth Factors*

The Brush Foundation studies on human growth and development, begun in 1931 and terminated in 1942, have been intensively reviewed and studied by Dr Greulich and Miss Pyle in the formulation of this Radiographic Atlas of Skeletal Development of the Hand and Wrist Serial radiographs of from 2 to 20 hand-films made at successive examinations of each of 1000 boys and girls made up the radiographic material Standards were selected that were judged to be the most representative of the central tendency or anatomic mode of each chronologic age group from birth through 18 years

Radiographic Atlas of Skeletal Development of the Hand and Wrist

We performed a prospective study of 28 initially untrained college women with documented ovulation and luteal adequacy to determine whether strenuous exercise spanning two menstrual cycles would induce menstrual disorders. To ascertain the influence, if any, that weight loss might exert, we randomly assigned the subjects to weight-loss and weight-maintenance groups. Subjects were expected to run 4 miles (6.4 km) per day, progressing to 10 miles (16.1 km) per day by the fifth week, and to engage daily in 31/2 hours of moderate-intensity sports. The normalcy of the menstrual cycles during the period of exercise was judged independently according to clinical and hormonal criteria, the latter comprising serial measurements of gonadotropin and sex-steroid excretion. A higher percentage of abnormalities proved to be detectable by hormonal means (P less than 0.02). Only four subjects (three in the weight-maintenance group) had a normal menstrual cycle during training. In the weight-loss group, the number of women who had luteal abnormalities as compared with those who lost the surge in luteinizing hormone altered significantly over time, the latter occurring more frequently (P less than 0.01) as training progressed. Within six months of termination of the study, all subjects were again experiencing normal menstrual cycles. We conclude that vigorous exercise, particularly if compounded by weight loss, can reversibly disturb reproductive function in women.

Induction of Menstrual Disorders by Strenuous Exercise in Untrained Women

We have assessed the effect of fasting for 10 days on plasma concentrations of immunoreactive somatomedin C and urinary urea excretion in seven obese male volunteers. From a mean prefast value of 0.83 U/ml, plasma somatomedin C fell to 0.21 U/ml after 10 days of fasting. A prompt increase was observed with refeeding. The change in somatomedin C during fasting showed a highly significant correlation with the change in urinary urea nitrogen excretion (r = 0.74; P < 0.001). It also was shown that inhibitors which interfere with quantitation in somatomedin bioassays are not observed in the RIA for somatomedin C. The results of this study suggest that measurement of plasma somatomedin C provides a sensitive indicator of nitrogen loss and may be useful in monitoring the changes in protein metabolism that occur during alterations in nutritional status.

Reduction of Plasma Immunoreactive Somatomedin C during Fasting in Humans

HYPERPROLACTINEMIA is a relatively common clinical problem, occurring in more than 25 per cent of women who present with secondary amenorrhea.1 , 2 Amenorrhea, anovulation, and galactorrhea are wel...

Decreased bone density in hyperprolactinemic women

I Introduction FOLLICLE-stimulating hormone (FSH), one of the major hormones produced by the anterior pituitary gland, is involved in the regulation and maintenance of essential reproductive processes, such as gametogenesis, follicular development, and ovulation (1–4) Like other glycoprotein hormones, FSH exists as a family of isohormones which have been identified within the anterior pituitary, serum, and urine of several mammalian species, including man (5–10) (Table 1) These isoforms differ in their oligosaccharide structures, including the degree of terminal sialylation and/or sulfation (5, 7, 9) The resulting acidic-basic charge differences provide the major basis for separation, with the number of isoforms identified often being a function of the resolution of the separation technique employed Structural differences in these isoforms alter their MCRs and biological and immunological potency relationships (6–8) Consequently, target tissues within the gonads are exposed to a mixture of circulati

Follicle-Stimulating Isohormones: Characterization and Physiological Relevance

We measured plasma insulin-like growth factor I/somatomedin-C (IGF-I/SmC) concentrations and mean 24-h GH secretion serially before and during therapy with the long-acting somatostatin analog SMS 201-995 in 21 patients with acromegaly. When mean plasma GH was elevated above 12.0 +/- 0.6 (+/- SE) micrograms/L, plasma IGF-I/SmC concentrations were uniformly high, but a decline of mean plasma GH below this value was accompanied by a linear decrease in IGF-I/SmC concentrations (r = 0.89; P less than 0.001). Even mildly abnormal mean GH concentrations (greater than 4.6 but less than 10 micrograms/L) were accompanied by high plasma IGF-I/SmC values. The log dose-response interrelation between mean 24-h plasma GH and IGF-I/SmC concentrations was linear (r = 0.86; P less than 0.001). We conclude that 1) an excellent log dose-response correlation between mean 24-h plasma GH and IGF-I/SmC concentrations is present in patients with acromegaly; 2) normalization of plasma IGF-I/SmC occurs only in patients with mean daily GH output within the normal range; and 3) determination of plasma IGF-I/SmC is an accurate indicator of normalcy of GH secretion and should be used in the diagnosis of active acromegaly as well as in monitoring the progress of therapy.

Inese Z. Beitins

Papers

Induction of Menstrual Disorders by Strenuous Exercise in Untrained Women

Reduction of Plasma Immunoreactive Somatomedin C during Fasting in Humans

Decreased bone density in hyperprolactinemic women

Follicle-Stimulating Isohormones: Characterization and Physiological Relevance

Plasma Insulin-Like Growth Factor-I/Somatomedin-C in Acromegaly: Correlation With the Degree of Growth Hormone Hypersecretion