Psychoendocrinology

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Hormones are substances, such as steroids and peptides, synthesized and released from endocrine glands, cell clusters, or specialized cells and spread over the brain, lungs, or gastrointestinal tract. Several of these hormones exist both in the brain and peripheral organs, where they act as an endocrine or paracrine messenger, or even as a neuro-transmitter. Most endocrine activities vary with sex and age, and many show pronounced variations over the course of the month or even the day.

Psychological events profoundly modulate the release of hormones either directly, via the brain, or indirectly, via the autonomic nervous system. These hormones, in turn, influence psychological events either directly or indirectly. Psychoendocrinology is interested in investigating the interface between the endocrine systems and mood, cognition, and behavior. Most of this research is presently done in animal experiments. However, the ability to assess steroids in saliva has considerably facilitated research with human subjects. Furthermore, new and highly sensitive immunoassays, advances in neuroendocrine techniques, and the development of specific pharmacological tools have rapidly increased our knowledge in psychoendocrinology.

The hypothalamic-pituitary-adrenal axis (HPAA) has been of particular interest as the major pathway through which the brain responds to psychological stress. Corticotropin-releasing factor (CRF) from cells of the par-aventricular hypothalamus acts as a releasing hormone for adrenocorticotropin (ACTH) in the pituitary, and ACTH releases corticosteroids from the adrenal cortex. Cortico-steroids (cortisol, corticosterone) are essential for the body and allow psychological and physical adaptation to stressors. In addition, they exert a negative feedback on the release of CRF and ACTH. Disturbances of the HPAA are associated with both mental and physical illness. CRF can easily be activated by stress and promotes depression, anxiety, and other forms of behavioral pathology. By activating the autonomic nervous system, CRF further links psychological stress to gastrointestinal and cardiovascular disorders. Although homeostasis of the HPAA is maintained by negative feedback, permanently enhanced and lowered glu-cocorticoid levels have been observed under prolonged stress. While hypercortisolemia is associated with depression, cognitive dysfunction, inflammatory diseases, and the metabolic syndrome, hypocortisolemia has been found in patients with fibromyalgia, chronic pelvic pain, irritable bowel disease, chronic fatigue syndrome, and Posttrau-matic Stress Disorder. The molecular mechanisms by which CRF and glucocorticoids facilitate these disorders are presently under investigation. New techniques allow researchers to assess receptor function and receptor polymorphisms, and to identify regions in the human body where hormones exert their behavioral effects.

The hypothalamic-pituitary-gonadal axis (HPGA) and the hypothalamic-pituitary-thyroid axis (HPTA) are other important endocrine pathways linking psychological events to organic function. Both systems are comparably controlled by negative feedback. Sexual cues can stimulate the HPGA, while stress inhibits the HPGA via CRF, thus promoting stress-induced infertility. Sex steroids such as testosterone, progesterone, and estradiol profoundly affect brain function, behavior, cognition, and mood. Such effects can become clinically relevant, as in the premenstrual syndrome or postpartum depression. Hyperthyroidism, which is usually caused by organic diseases, leads to psychological alterations such as irritability, hyperactivity, and heat intolerance. Hypothyroidism, on the other hand, provokes lethargy, depression, fatigue, and cold intolerance. Other hormones from the anterior pituitary, such as prolactin and growth hormone (GH), are also released by stress. However, there is not yet a clear picture of the role of these hormones in stress-related disorders.

Vasopressin and oxytocin are peptide hormones, mainly released by the posterior pituitary. Vasopressin has vaso-constrive and antidiuretic properties, and has been considered relevant for stress effects on blood pressure and enuresis nocturna. Recent evidence suggests that it is beneficial for psychoendocrinology not to separate the role of a given substance from its function as an endocrine messenger or a neurotransmitter. Oxytocin promotes labor in pregnant women when the baby's head distends the uterus wall, and the release of milk is initiated by the suckling newborn. Oxytocin is closely associated with social attachment and bonding, and a social partner again initiates both psychological events. Therefore, it seems that another significant individual within a reproductive context activates this substance, both as a neurotransmitter and as a hormone. While oxytocin receptor functions are facilitated by estrogens, testosterone modulates vasopressin receptors. For example, it has been shown that the flank-marking behavior of hamsters is regulated by vasopressin, but strongly dependent upon testosterone.

Recent evidence has shown that endocrine systems are strongly influenced by pre- and postnatal events. Stress or infections of the mother, raising glucocorticoid levels, or reduced maternal care after birth seem to result in a lifelong programming of specific hormone receptors. There is already strong evidence that these determinants account for later vulnerability for hypertension, diabetes II, and visceral obesity. Even later in life, chronic and traumatic stress can induce permanent endocrine changes and enhance vulnerability for specific diseases.

The endocrine system closely and bidirectionally interacts with both the autonomic nervous system and the immune system. Thus, psychoendocrinology has to consider the full interplay of biological events, which affect cognitive, affective, and behavioral events and disturbances. The rapid acquisition of data and information has already been successfully transferred into clinical applications: several endocrine challenge tests have already been developed to aid in the diagnosis of mental and stress-related disorders. Additionally, new therapeutic treatments can be developed: After the discovery of the important role of CRF and CRF-receptors in depression, for example, a new group of anti-depressants is presently being developed that block the respective CRF-receptors. Furthermore, new tools—such as the intranasal application of neuroactive hormones like melanocortin, insulin, vasopressin, oxytocin, or leptin— provide new routes for psychoactive drugs.

New hormones are continously being discovered, and it is clear that these discoveries will continue to stimulate psychoneuroendocrinology research. The peptides PYY 336 or ghrelin, for example, are gut-derived hormones, both of which regulate food intake via effects on the central nervous system. Obviously, both hormones will contribute considerably to our understanding of food intake and eating disorders, thus illustrating the complexity and potential benefits of research in psychoendocrinology.

Dirk H. Hellhammer Christine Philippsen University of Trier, Germany

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