Revista de Endocrinología y Nutrición Volumen Suplemento Julio-Septiembre Volume 13 Supplement 1 July-September 2005 Artículo: Hypopituitarism Derechos reservados, Copyright © 2005: Sociedad Mexicana de Nutrición y Endocrinología, AC Otras secciones de Others sections in este sitio: this web site: ☞ Índice de este número ☞ Contents of this number ☞ Más revistas ☞ More journals ☞ Búsqueda ☞ Search edigraphic.com Revista de Endocrinología y Nutrición Vol. 13, No. 3. Supl.1 Julio-Septiembre 2005 pp S47-S51 Hipófisis Hypopituitarism Mark E. Molitch* * Division of Endocrinology, Metabolism and Molecular Medicine. Northwestern University Feinberg School of Medicine. Hypopituitarism indicates the diminished production of one Gene mutations have been found at several steps lead- or more anterior pituitary hormones. Although the recog- ing to pituitary hormone secretion, including those for the nition of complete or panhypopituitarism is usually straight- hypophysiotropic releasing factor receptors for GnRH, GHRH, forward, the detection of partial or selective hormone and TRH; those for the pituitary hormone structures for GH, deficiencies is more challenging. Pituitary hormone defi- ACTH, and the a subunits of FSH, TSH, and LH; and those for ciencies can be caused by loss of hypothalamic stimula- the target organ receptors for GH, ACTH, TSH, and LH. Best tion (tertiary hormone deficiency) or by direct loss of pi- studied are mutations of the GH gene, which include large tuitary function (secondary hormone deficiency). The deletions and point mutations; some of these can be inher- distinction between hypothalamic and pituitary causes of ited in an autosomal dominant manner, apparently because hypopituitarism is important for establishing the correct the mutant hormone impairs GH biosynthesis and normal diagnosis and but less so when applying and interpret- function of the somatotroph cell. Mutations of the other types ing the relevant diagnostic endocrine tests. With improved described earlier generally cause autosomal recessive forms procedures for testing the hypothalamic-pituitary axis, it of selective hormone deficiencies. is apparent that hypothalamic causes of hypopituitarism The most common embryopathic disorders to affect are more common than previously appreciated. When the hypothalamus are the midline cleft syndromes, which hypopituitarism is accompanied by diabetes insipidus or cause varying degrees of defects of midline structures, hyperprolactinemia, one should particularly consider hy- especially the optic and olfactory tracts, the septum pel- pothalamic causes of pituitary dysfunction. lucidum, the corpus callosum, the anterior commissure, the hypothalamus, and the pituitary. The clinical features CAUSES OF HYPOPITUITARISM of patients with midline cleft defects varies in severity from cyclopia to cleft lip and from isolated hypothalamic A variety of congenital and acquired causes of hypopitu- hormone defects to panhypopituitarism. The combination itarism have been described (Table I). Sporadic and fa- of absent septum pellucidum associated with optic nerve milial forms of panhypopituitarism occur, but the underly- hypoplasia is referred to as septo-optic dysplasia and is ing genetic or developmental defects have not been associated with abnormalities of hypothalamic and other elucidated. Congenital combined deficiencies of GH, PRL, diencephalic structures. Some patients with septo-optic and TSH are caused by mutations in the gene encoding dysplasia and hypothalamic hypopituitarism have sexual Pit-1, a pituitary-specific transcription factor that is involved precocity, presumably caused by a lack of inhibitory influ- in the development of somatotroph, lactotroph, and thy- ences from other parts of the hypothalamus and intact rotroph cell lineages. Different types of Pit-1 mutationsedigraphic.comGnRH-producing structures. Children with very mild mid- are inherited in an autosomal dominant or recessive pat- line cleft defects consisting of just cleft lip, cleft palate, or tern. When gonadotrophs are also deficient, mutations both have been found to have a markedly increased risk may be present in the genes for transcription factors that of having GH and other pituitary hormone deficiencies. are active earlier in the development of the pituitary lin- Recent MRI studies of patients with “idiopathic” GH defi- eages, such as Lhx3 and Prop-1. ciency show absence of the infundibulum in nearly 50%. S48 Mark E. Molitch. Hypopituitarism Table 1. Causes of hypopituitarism. Mutations responsible for these developmental defects are the subject of active investigation. One possible mu- Genetic defects tation that has been found is in the Hesx1 gene (also Hypophysiotropic hormone gene defects called Rpx, for Rathke’s pouch homeobox), which is a Hypophysiotropic hormone receptor gene defects member of the paired-like class of homeobox genes ex- GHRH receptor defect pressed in the thickened layer of oral ectoderm that gives GnRH receptor defect rise to Rathke’s pouch. Many other transcription factors TRH receptor defect have been described that are expressed sequentially Pituitary hormone gene defects during embryogenesis in Rathke’s pouch that are impor- Gonadotropins: LH β- and FHS β-subunit gene defects Growth hormone: defects in GH gene tant in the ultimate development of the normal pituitary Thyrotropin: defects in TSH β-subunit cell lineages. Mutations have been found in many of these Multiple hormone (GH, PRL, TSH) defects: due to mutation in transcription factors genes, including Pit-1 and Prop-1 Pit-1 gene and Propl gene (discussed above); Lhx3 and Lhx4 which give similar clin- Pituitary hormone receptor genetic defects ical findings to Prop-1 mutations but have additional cer- Growth hormone receptor defects: GH insensitivity syndrome vical spine and skull base abnormalities; and Sox3, which (Laron-type dwarfisin) gives rise to isolated GH deficiency and variable mental ACTH receptor defects: congenital insensitivity to ACTH retardation and facial abnormalities . Combined pituitary LH receptor defects hormone deficiency has an incidence of about 1 in 8,000 FSH receptor defects births and about 10% have an affected relative; it ap- TSH receptor defects pears that more than half of these cases are due to Pit-1 or Prop-1 deficiencies. Congenital embryopathic defects Neoplastic lesions, particularly pituitary adenomas, are Anencephaly Midline cleft defects: septo-optic dysplasia, basal encephalo- the most common cause of acquired hypopituitarism. Pi- cele, cleft lip and palate tuitary adenomas cause hypopituitarism in several differ- Pituitary aplasia ent ways. In some cases, there is direct destruction or Kallmann’s syndrome (GnRH defect with anosmia) compression of the normal pituitary. Compression of the pituitary stalk can impair blood supply to the pituitary as Acquired defects well as decrease input from hypothalamic hormones. Tumors: pituitary adenomas, craniopharyngiomas, dysgermi- Hemorrhage into tumors can lead to pituitary infarction. nomas, meningiomas, gliomas, metastatic tumors, hamarto- When tested carefully, most patients with macroadenom- mas, Rathke’s cleft cysts as have partial deficiencies of one or more pituitary hor- Irradiation mones, most often involving GH and gonadotropins. A Trauma: surgery, external blunt trauma mild degree of hyperprolactinemia is characteristic of dis- Empty sella syndrome orders that cause stalk compression, and hyperprolactine- Vascular mia further impairs gonadotropin secretion. A variety of Pituitary apoplexy other neoplasms that occur near the sella, such as cran- Sheehan’s syndrome Internal carotid aneurysm iopharyngiomas, can also cause hypopituitarism. Vasculitis Radiation causes hypopituitarism primarily because of Inflammatory/infiltrative diseases its effects on hypothalamic function, although high-dose Sarcoidosis radiation (e.g., proton beam) can also cause direct pitu- Langerhans’ cell histiocytosis (histiocytosis X, eosinophilic itary damage. The sellar region is subjected to radiation granuloma) in the treatment of pituitary adenomas, craniopharyngi- Tuberculosis, syphilis omas, optic gliomas, meningiomas, dysgerminomas, and Meningitis neoplasms of the oropharynx. Importantly, the effects of Lymphocytic hypophysitis, infundibulohypophysitis radiation can be delayed as much as several years, and Metabolic patients at high risk should be evaluated at about yearly Hemochromatosis intervals for radiation-induced hypopituitarism. Although Amyloidosis GH and gonadotropin deficiencies develop first in most Critical illness edigraphic.com patients, ACTH or TSH deficiencies occasionally occur first, Malnutrition Anorexia nervosa emphasizing the need to evaluate each of the major axes. Psychosocial deprivation Empty sella syndrome can occur as a primary or as an Idiopathic acquired condition. It is caused by defects in the diaphrag- ma sellae that allow herniation of the arachnoid membrane Revista de Endocrinología y Nutrición 2005;13 No. 3 Supl. 1 MG S49 into the hypophyseal fossa. In long-standing cases, sellar nancy, anticoagulation, sickle cell anemia, and diabetes enlargement occurs, probably because of persistent trans- mellitus. Pituitary infarction in the peripartum period is mission of intracranial pressure. With appropriate imaging referred to as Sheehan’s syndrome and is usually associ- studies, the pituitary gland can be seen as a flattened rim of ated with significant obstetric hemorrhage and hypov- tissue along the floor of the sella. Primary empty sella oc-