George P. Chrousos

Developmental processes in early adolescence: Relationships between adolescent adjustment problems and chronologic age, pubertal stage, and puberty-related serum hormone levels

Relations between adolescent psychosocial adjustment problems and markers of biologic development, including chronologic age, pubertal status, and serum hormone levels, were examined in 56 normal boys and 52 normal girls, ages 9 to 14 years. Adolescent psychosocial adjustment was assessed by adolescent self-ratings of various aspects of self-image (Offer Self-Image Questionnaire for Adolescents) and parent ratings of adolescent behavior problems (Child Behavior Checklist). The pubertal status measure used in the analyses was Tanner genital stage for boys and Tanner breast stage for girls. The hormone measures, determined by radioimmunoassay, were serum levels of gonadotropins (luteinizing hormone and follicle stimulating hormone), sex steroids (testosterone and estradiol), and adrenal androgens (dehydroepiandrosterone and its sulfate, and androstenedione). The testosterone/estradiol ratio also was computed. Overall, findings were stronger, more consistent, and more generalized for boys than for girls. For boys, adjustment problems typically were associated with a multivariate profile that may be characteristic for later maturers: relatively low sex steroid levels, or lower pubertal stage, and relatively high adrenal androgen (androstenedione) levels, frequently in conjunction with higher chronologic age. Univariate relations predominated for girls; that is, associated with adjustment problems for girls were relatively high levels of gonadotropins, relatively low levels of dehydroepiandrosterone sulfate, and relatively high levels of androstenedione on their own or in conjunction with lower pubertal stage. Higher levels of androstenedione, a steroid particularly responsive to stress, were associated with adjustment problems in both boys and girls. This relation may reflect the stress of later maturation, which could result from environmental factors, such as adolescent self-comparisons with same-age peers, or endogenous effects of hormones.

Corticotropin-releasing hormone and cortisol : Longitudinal associations with depression and antisocial behavior in pregnant adolescents

OBJECTIVEnTo examine the concurrent and longitudinal associations between corticotropin-releasing hormone (CRH) and cortisol concentrations and depression and antisocial behavior (conduct disorder symptoms) in pregnant adolescents.nnnMETHODnFifty-nine adolescents were evaluated in early pregnancy (9-21 weeks gestation), late pregnancy (32-34 weeks gestation), and the postpartum period (4-5 weeks postpartum). Symptoms of depression and conduct disorder were obtained from the Diagnostic Interview Schedule for Children.nnnRESULTSnLower concentrations of CRH were related to a greater number of depression symptoms in early pregnancy (p < .05) and in late pregnancy (p < .05). Lower concentrations of CRH also were related to a greater number of conduct disorder symptoms in early pregnancy (p < .06) and in the postpartum period (p < .05).nnnCONCLUSIONnThe findings support the long-standing hypothesis that stress-related products of the hypothalamic-pituitary-adrenal axis are associated with emotions and behavior during pregnancy.

Response to oCRH in Depressed and Nondepressed Adolescents: Does Gender Make a Difference?

OBJECTIVEnTo examine the hypothesis that hypothalamic-pituitary-adrenal responses to stress vary across gender, contributing to gender differences in the prevalence of depression.nnnMETHODnThis study examined gender differences between depressed (n = 21) and control (n = 20) adolescents in adrenocorticotropic hormone (ACTH) and cortisol response to two ovine corticotropin-releasing hormone (oCRH) tests, at baseline and following a cognitive stressor.nnnRESULTSnBoys had higher (p < .05) measures of ACTH than girls, regardless of depression status, whereas corresponding cortisol parameters were similar in both groups. Cortisol measures were higher (p < .05) at time 1 than at time 2 in both groups, a phenomenon that might reflect the novelty of the situation.nnnCONCLUSIONSnGender differences in hormone responses may be related to differences in peripheral metabolism of ACTH, resulting in changes of immunoreactivity but not bioactivity or a different set point of the hypothalamic-pituitary-adrenal axis. The pattern of ACTH and cortisol responses to oCRH and the 24-hour excretion of free cortisol was normal in adolescents with depression, probably reflecting normal negative feedback mechanisms at this age or that most of these patients suffer from atypical rather than melancholic depression.

Introduction: The Concept of Stress and Its Historical Development

The terra “stress” has been used, and occasionally abused, by scientists and by the lay public, in almost every single language of the civilized world. Many definitions and meanings have been ascribed either consciously or unconsciously to the word. Nevertheless, despite a lack of general agreement about its meaning, the term has prevailed because it attempts to address a basic principle of Nature, that of maintenance of balance, equilibrium, or harmony in the face of disturbing forces on the one hand and counteracting reestablishing forces on the other. One potential reason for the confusion surrounding the term “stress” is that it has been variously used to describe the disturbing forces, the disturbed balance or disequilibrium, and/or the results of the counteracting, reestablishing forces.

Clinical Presentation and Diagnosis of Cushing’s Syndrome

Prolonged exposure to high levels of glucocorticoids results in a syndrome first described by Cushing. Harvey Williams Cushing (1869–1939) reported the clinical syndrome of amenorrhea, bruising, cutaneous striae, facial plethora, high blood pressure, hirsutism, and myopathy and attributed it to “pituitary basophilism” (1). Bishop and Close were the first to name the new syndrome after Cushing in a case recognized as such the year Cushing published his paper (2). Albright was the first to recognize the role of glucocorticoids in this syndrome (3). A few years later, excessive secretion of corticotropin (ACTH) from pituitary was shown to be the cause of Cushing’s disease (4). The ectopic ACTH syndrome was described by the same person who later established the dexamethasone suppression test, the long-standing golden standard for the differential diagnosis of Cushing’s syndrome (5).

Molecular Development of the Hypothalamic-Pituitary-Adrenal (HPA) Axis

The human hypothalamus lies ventrally to the thalamus and extends from the rostral part of the optic chiasm to the caudal edge of the mamillary bodies. It originates in the alar plate of diencephalon, its sulcus becoming identifiable by the 5th wk of gestation. The hypothalamus is a highly complex organ coordinating central nervous system (CNS) centers and neuroendocrine, metabolic, autonomic nervous and behavioral functions. A system of nerve fibers and portal vessels connects the hypothalamus to the pituitary. The axon terminals of neurons originating in several hypothalamic nuclei, including the supraoptic, the paraventricular, the arcuate, and the ventromedial nucleus, form the median eminence located rostrally to the mamillary bodies. The median eminence communicates with the anterior pituitary via a local portai venous System, which permits the direct hematogenous communication between neurons and endocrine cells. The hypothalamic neurons regulating the function of anterior pituitary corticotrophs are located in the parvocellular part of the paraventricular hypothalamic nucleus. They synthesize the neuropeptides corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP), which, packaged in secretory vesicles, travel the neural axons and reach the median eminence, where they are placed in specifie secretory areas beneath the subplasmalemal actin network ready to be secreted into the portai System.

Corticotropin Releasing Factor (Hormone): Physiological and Clinical Implications

In 1948, Harris suggested the possibility of humoral control of the pituitary gland by the hypothalamus (1–3). Saffran and Schally (4), and Guillemin and Rosenberg (5) demonstrated the presence of a hypothalamic corticotropin releasing (CRF) factor in 1955. Vale and coworkers isolated ovine CRF (oCRF) in 1981 (6). Shortly thereafter, Schally et al. described the composition of porcine CRF (pCRF) (7), and Rivier et al. that of rat CRF (rCRF) (8). Finally, the genes of both ovine and human CRF (hCRF) were sequenced and the amino acid composition of the corresponding peptides deduced (9,10). Rat and human CRF appear to be chemically identical. The structures of oCRF and hCRF (or rCRF) are shown in Figure 1. Human CRF differs from the oCRF molecule by 7 amino acids, giving the two peptides 83% homology.