ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 10, No. 6 Copyright © 1980, Institute for Clinical Science, Inc. Clinical Manifestations of Hypothalamic Tumors* ADOLFO D. GARNICA, M.D., MICHAEL L. NETZLOFF, M.D.,f and A. L. ROSENBLOOM, M.D. Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610 and f Department of Human Development, Michigan State University East Lansing, MI 88823 ABSTRACT The regulatory function of the central nervous system encompasses di­ verse endocrine, metabolic, and behavioral processes. Many of these origi­ nate, are integrated, or are coordinated through hypothalamic pathways or nuclei. Thus, tumors affecting areas projecting to the hypothalamus, tumors of the hypothalamus, and tumors invading or compressing the hypothalamus can produce abnormalities of hypothalamic function. Introduction tary.4,7,31 A secretory function for certain hypothalamic neurons was postulated in Until recently, no endocrine disorder 1928 and subsequently confirmed by the directly attributable to hypothalamic dys­ demonstration of hormone synthesis in function had been recognized, and the the supraoptic and paraventricular nu­ majority of endocrine-metabolic homeo­ clei.28,53 Moreover, observations on the static processes were acknowledged to be effects of environment on the menstrual under the control of the anterior pitui­ cycles of women and the study of repro­ tary.48,49 However, in 1901 Frohlich re­ ductive cycles in animals have shown a ported a patient with a suprasellar tumor, functional connection between central hypogonadism and obesity, which Erd- nervous system and pituitary.18,52 The role heim suggested were the result of of the brain as a major endocrine tissue, hypothalamic injury caused by the tumor through which the integration of neuro­ rather than a primary effect of the tumor endocrine function occurs, is now gener­ itself.19,22 Clinical observations of pitui­ ally acknowledged, and the concept of the tary dysfunction following hypothalamic hypothalamic neurosecretory neurons as injury have now defined a clear relation­ “neuroendocrine transducers” linking ship between hypothalamus and pitui- neural activity with endocrine-metabolic regulation is now accepted.28,48,49,52 f Supported in part by NIH Grant No. 1K04 Considering, therefore, the significance NS00409-01. of the central nervous system and the 474 0091-7370/80/1100-0474 $01.80 © Institute for Clinical Science, Inc. CLINICAL MANIFESTATIONS OF HYPOTHALAMIC TUMORS 475 hypothalamus, specifically, in neuroen­ tidergic pathways originate primarily in docrine function, the varied clinical man­ the mid-brain, are distributed to the ifestations of central nervous system hypothalamus, basal ganglia, forebrain neoplasms are not surprising. Indeed, and spinal cord, and influence the secre­ studies of patients with central nervous tion of the hypophysiotropic hormones, system tumors provided the first clues as the functions of drinking and eating, the to the function of the hypothalamus.4,7 Of control of body temperature, and displays all intracranial tumors, those in the region of arousal and “affect.”45,49 (Table I.) of the hypothalamus present a complex array of signs, symptoms, and chemical Endocrine Hypothalamic Functions abnormalities reflecting the involvement of hypothalamic nuclear groups and A relationship between growth distur­ pathways ,4,7> 30,31,32>35,45 bances and hypothalamic disease has been recognized since early this century. Basic Considerations Patients studied after interruption of their hypothalamic-pituitary connections by The functional endocrine unit, the pituitary stalk section demonstrate sub­ hypothalamic-neurohypophyseal system, normal growth hormone response.38 Fur­ includes the paraventricular and supra­ thermore, animal studies implicate the optic nuclei, the median eminence, the ventromedial-arcuate region of the medial pituitary stalk, the neurophypophysis, the basal hypothalamus in the neuroendo­ hypophysiotropic area, and the portal crine regulation of growth hormone secre­ system supplying the adenohypo­ tion (table I).16'38-39 This region and the physis.28,48,49,52 An extensive hormonal control of adenohypophyseal secretory T A B L E I function is exerted by the central nervous system through the mediation of neuro­ Functions of the Hypothalamus hormones elaborated from specialized nerve cells of the hypophysiotropic area Function Hypothalamic Factor and released into the pituitary via the Endocrine hypothalamohypophyseal portal system Posterior pituitary under the control of synapses with higher Water balance Vasopressin* Milk ejection, Oxytocin* hypothalamic and third ventrical re­ uterine contraction gions.28,49 The posterior pituitary hor­ Anterior pituitary Growth GH releasing factor mones, vasopressin and oxytocin, are Somatotropin release synthesized and secreted by cells of the Inhibitory hormone Gonadotropic Gonadotropin supraoptic and paraventricular nuclei of Releasing hormone Thyrotropic Thyrotropin anterior hypothalamus. Releasing hormone Seven hypophysiotropic factors have Adrenocorticotropic Corticotropin Releasing factor now been identified, including growth hor­ Mammary development, Prolactin mone releasing factor, thyrotropin re­ reproductive Inhibitory factor Melanocyte stimulation Melanocyte leasing hormone, corticotropin releasing Inhibitory factor factor, gonadotropin releasing hormone, Non-endocrine State of Consciousness prolactin inhibitory factor, somatrotropin Cognition release inhibitory hormone, and melano­ Emotional behavior Autonomic balance cyte inhibitory factor.28,49 The neurosec­ Thermor egu1ation retory cells of the hypothalamus are Caloric balance termed “peptidergic” because their sec­ *Not releasing factors. These are hormones retory products, including the hypophys­ produced in the hypothalamus. They are stored iotropic hormones, are peptides.28,49 Pep­ and released from the posterior pituitary. 476 CARNICA, NETZLOFF AND ROSENBLOOM adjacent lateral hypothalamus also func­ medial amygdaloid nucleus, the fore­ tion as the final integrative center for brain, and the brain stem. Estrogen sensi­ homeostatic regulation of energy balance tive areas in these extrahypothalamic re­ and food intake.16,38 Growth hormone se­ gions are postulated to exert modulating cretion is regulated by the stimulatory and influences on reproductive cyclicity inhibitory influences of growth hormone through the regulation of mood and releasing factor and growth hormone re­ behavior.37,52,60 lease inhibitory hormone.16,28,38,39 Nearly The homeostatic regulation of body normal basal secretion, including water and osmolality depend on interac­ pulsatile release, can be maintained by tions among thirst, drinking behavior, and the isolated hypothalamus. antidiuretic hormone (ADH) release.45,48 Animal studies, however, indicate that Hormones produced by the magnocellu- additional inputs to the medial basal lar neurons of the hypothalamic supraop­ hypothalamus also may have excitatory or tic and periventricular nuclei ensure that inhibitory influences.16,38 Phasic changes a normal serum osmolality is maintained in growth hormone secretion are thought even when the hypothalamus is isolated to be mediated by higher brain centers. from the rest of the brain. ADH is trans­ Physical and psychological stresses have ported from the hypothalamus to the me­ been shown to affect its release, and dian eminence and neurophypophysis, pulsatile bursts of growth hormone secre­ from which it is released into the blood.48 tion have been observed in subjects at rest Baseline secretion from the neurosecre­ in the absence of changes in the levels of tory cells is modulated by input from os­ plasma metabolites known to influence moreceptors or volume receptors.45,48 growth hormone secretion.16,38 Current concepts of menstrual regula­ Non-endocrine Hypothalamic Function tion characterize the brain as an endocrine organ controlling the interaction of ovary, The hypothalamus influences at least pituitary and hypothalamus.48,52,60 The ul­ six non-endocrine functions, including timate site of control of this system is state of consciousness, cognition, emo­ thought to be the central nervous tional behavior and affect, autonomic bal­ system-hypothalamic complex, subject to ance, thermoregulation, and caloric bal­ feedback control of ovarian hormones. ance (table I).45 An anterior hypothalamic Pituitary gonadotropin secretion is con­ sleep center and posterior wake center trolled by input from the hypothalamus have been postulated on the basis of subject to cyclic feedback provided by studies in humans demonstrating be­ ovarian steroids, which influence havioral unresponsiveness with anterior gonadotropin secretion by positive and hypothalamic stimulation and arousal negative feedback mechanisms.60 Es­ with posterior hypothalamic stimula­ trogen-binding neurons are present in tion.14,23,58 Destruction of the same struc­ hypothalamic and extra-hypothalamic re­ tures in animals induces wakefulness or gions.37,60 The hypothalamic arcuate variable degrees of sensorial depression nucleus-median eminence unit appears to respectively.23,41,45,58 The behavioral be critical to the control of pituitary components of hypothalamic function gonadotropin secretion, and the cyclic re­ include an influence on the intensity of be­ lease of gonadotropin is influenced by a havior, the production of behavior appro­ feedback provided by ovarian estradiol. priate to affective state and the coordina­ In extra-hypothalamic areas,