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Loss of function of the anterior pituitary gland may result from disease of the pituitary itself or from hypothalamic disease In either event, it leads to a number of clinical abnormalities, each predicated on the de ciency of one or more hormones that depend on the pituitary trophic factors described earlier The condition of panhypopituitarism represents the more serious illness in that it requires supplementation with multiple hormones Hypopituitarism may have its onset in childhood, either as an inherited process that affects individual or multiple hormones or as a secondary process due to a destructive lesion of the pituitary or the hypothalamus from tumor, eg, craniopharyngioma Later in life the causes vary, but the most common are pituitary surgery, infarct of the gland from a rapidly growing adenoma (pituitary apoplexy, page 577), involutional changes that occur at the end of pregnancy (Sheehan syndrome), cranial irradiation for cerebral tumors other than those in the pituitary fossa, lymphocytic hypophysitis, and granulomatous and neoplastic invasion The clinical features of pituitary failure vary, but impairments of thyroid function tend to be more prominent than those of adrenal failure The neurologic accompaniments of pituitary failure depend on the underlying cause; Lamberts and colleagues have reviewed the endocrinologic aspects
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Other Hypothalamic Syndromes
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Apart from diabetes insipidus and SIADH, there are a variety of other special clinical phenomena resulting from disease of the hypothalamus These usually occur not in isolation but in various combinations, comprising a number of rare but well-characterized syndromes Precocious Puberty This term refers to the abnormally early onset of androgen secretion and spermatogenesis in boys and of estrogen secretion and cyclic ovarian secretion in girls It is associated with the premature development of secondary sexual characteristics The occurrence of precocious puberty always calls for a neurologic as well as an endocrine investigation In the male, one searches for evidence of a teratoma of the pineal gland or mediastinum or an androgenic tumor of the testes or adrenals In the female with early development of secondary sexual characteristics and menstruation, one seeks other evidence of hypothalamic disease as well as an estrogen-secreting ovarian tumor
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THE HYPOTHALAMUS AND NEUROENDOCRINE DISORDERS
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alterations in several hypothalamic functions, including appetite, temperature control, and menstruation In all likelihood, these alterations are not the result of a primary dysfunction of hypothalamic nuclei but are secondary to the extreme weight loss, which is the primary feature of the disease However, a causal link between these idiopathic diseases and hypothalamic dysfunction has been suggested by the rare patients with anorexia nervosa who were later found to have hypothalamic tumors (Bhanji and Mattingly, Berek et al, and Lewin et al) Anorexia nervosa and bulimia are probably best regarded as disorders of behavior, in this case an obsession with thinness; they are therefore discussed with the psychiatric disorders (see page 1304) But the developmental nature of the disease (arising in early adolescence), its virtual absence in men, and the hypothalamic alterations mentioned above do not allow the dismissal of a primary disorder of the brain s appetite centers Abnormalities of Growth Presumably, in most instances of growth retardation, there is a de ciency of GHRH or of GH per se In the Prader-Willi syndrome (obesity, hypogonadism, hypotonia, mental retardation, and short stature), Bray and Gallagher found the de ciency to be one of GHRH In certain congenital and developmental diseases, the hypothalamus appears to be incapable of releasing GH This appears to be the case, in the de Morsier septooptic defect of the brain (median facial cleft, cavum septum pellucidum, optic defect), Stewart and colleagues found an isolated de ciency of GH In children with idiopathic hypopituitarism in whom stunting of growth is associated with other endocrine abnormalities, the de ciency is probably in the synthesis or release of GHRH In some dwarfs (Laron dwarf, Seckel bird-headed dwarf), there are extremely high levels of circulating GH, suggesting either a defect in the GH molecule or an unresponsiveness of target organs Many patients with the more severe forms of mental retardation are subnormal in height and weight, but the explanation for this has not been ascertained It has not been reducible to changes in the level of GHRH or GH Of course, the vast majority of unusually short children who are otherwise healthy do not have a recognizable defect in GH or GHRH Often their parents are short The therapeutic use of GH in such children is a controversial matter The hormone effects a spurt in growth during the rst year of its administration, but whether it signi cantly in uences growth in the long term is still under investigation There is concern about the risk of transmitting prion or viral diseases through administration of the biologically derived hormone; this problem is obviated if genetically produced hormone is used In gigantism, most of the reported cases have been due to pituitary adenomas that secrete an excess of GH This must occur prior to closure of the epiphyses Hypersecretion of GH after closure of the epiphyses results in acromegaly The notion of a purely hypothalamic form of gigantism or acromegaly (hypothalamic acromegaly) has been af rmed by Asa and associates, who described six patients with hypothalamic gangliocytomas that produced GHRH The possibility of an ectopic source of GH must also be considered The mentally retarded individuals with gigantism described by Sotos and coworkers were found to have no abnormalities of GHRH, GH, or somatomedin Disturbances of Temperature Regulation Bilateral lesions in the anterior parts of the hypothalamus, speci cally of temperaturesensitive neurons in the preoptic area, may result in hyperthermia
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The heat-dissipating mechanisms of the body, notably vasodilation and sweating, are impaired This effect has followed operations or other trauma in the region of the oor of the third ventricle but we have seen it most often after massive rupture of an anterior communicating artery aneurysm The temperature rises to 41 C (106 F) or higher and remains at that level until death some hours or days later, or it drops abruptly with recovery Acetylsalicylic acid has little effect on central hyperthermia; the only way to control it is by active evaporative cooling of the body while administering sedation A less dramatic example of the loss of natural circadian temperature patterns is seen in patients with postoperative damage in the suprachiasmatic area (Cohen and Albers) and suprachiasmatic metastasis (Schwartz et al) These types of lesions are invariably associated with other disorders of intrinsic rhythmicity, including sleep and behavior It should be emphasized, however, that instances of central fever are rare, and unexplained fever of moderate degree should not be attributed to a putative brain lesion Hyperthermia is also part of the malignant hyperthermia syndrome, in which, in a small number of cases, there is an inherited (autosomal dominant) susceptibility to develop hyperthermia and muscle rigidity in response to inhalation anesthetics and skeletal muscle relaxants (page 1272) It has been found to be due in these few instances to a defective ryanodine receptor Closely related is the neuroleptic malignant syndrome, which is the result of an idiosyncratic reaction to neuroleptic drugs (page 1025) Wolff and colleagues have described a syndrome of periodic hyperthermia, associated with vomiting, hypertension, and weight loss and accompanied by an excessive excretion of glucocorticoids; the symptoms had no apparent explanation, although there was a symptomatic response to chlorpromazine Lesions in the posterior part of the hypothalamus have had a different effect; ie, they often produce hypothermia (a persistent temperature of 35 C or less) or poikilothermia (equilibration of body and environmental temperatures) The latter may pass unnoticed unless the patient s temperature is taken after lowering and raising the room temperature Somnolence, confusion, and hypotension may be associated Spontaneous periodic hypothermia, probably rst described by Gowers, has been found in association with a cholesteatoma of the third ventricle (Pen eld) and with agenesis of the corpus callosum (Noel et al) Episodically, there are symptoms of autonomic disturbance salivation, nausea and vomiting, vasodilation, sweating, lacrimation, and bradycardia; the rectal temperature may fall to 30 C and seizures may occur Pen eld referred to these attacks incorrectly as diencephalic epilepsy (page 466) Between attacks, which last a few minutes to an hour or two, neurologic abnormalities are usually not discernible and temperature regulation is normal Chronic hypothermia is a more familiar state than hyperthermia, being recorded in cases of hypothyroidism, hypoglycemia, and uremia; after prolonged immersion or exposure to cold; and in cases of intoxication with barbiturates, phenothiazines, or alcohol It tends to be more frequent among elderly patients, who are often found to have an inadequate thermoregulatory mechanism Cardiovascular Disorders with Hypothalamic Lesions Ranson demonstrated a number of autonomic effects upon stimulation of the hypothalamus; these effects as well as hypertension were recorded in Pen eld s case of diencephalic epilepsy, mentioned above Since Byer and colleagues description of large, upright T waves and prolonged QT intervals in patients with stroke, it has been appreciated that acute lesions of the brain particularly sub-
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