7/18/12 PPY224 Pathophysiology of Endocrinology, Diabetes and Metabolism, Spring 2005 - Tufts OpenCours… S e a r c h Pituitary Insufficiency Author: Ronald Lechan, MD,PhD 1. Goals Color Key Important key words or phrases. To learn the symptoms, causes and management of pituitary insufficiency Important concepts or main ideas. 2. Learning Objectives To review the physiology and anatomy of the hypothalamus/pituitary To learn the definition and causes of pituitary insufficiency To learn the symptoms of pituitary insufficiency due to deficiencies in specific hormones To learn the difference between basal and dynamic testing To become familiar with testing for the various hypohormonal states of pituitary insufficiency 3. Definition Hypopituitarism is a term that refers to the defiiciency of one or more anterior and/or posterior pituitary hormones. The deficiency may be total (panhypopituitarism) or partial, in which one or more of the pituitary hormones may be deficient. Hypopituitarism may arise as a result of congenital defects in the development of individual anterior pituitary cell types or hypothalamic function, or from acquired disease of the pituitary or hypothalamus. 4. Review of Physiology and Anatomy The major cell types and secretory products of the pituitary gland are shown in Table 1. TABLE 1. Major cell types and secretory products of the pituitary gland. Anterior Pituitary Cell Type Secretory Products Cell Population % Somatotroph Growth Hormone 50 Lactotroph Prolactin 15 Corticotroph Adrenocorticotrophic hormone 15 Thyrotroph Thyroid­stimulating hormone 10 Gonadotroph Luteinizing hormone/Follicle­stimulating hormone 10 Posterior Pituitary Cell Type Secretory Products Axon terminals of hypothalamic neurons Vasopressin and Oxytocin Understanding the neuroanatomical relationships between the hypothalamus and pituitary gland can be very helpful in understanding the mechanisms whereby hypopituitarism can result and how disorders affecting the anterior pituitary can be distinguished from disorders affecting the hypothalamus. 4.1. Anatomy of the Pituitary Gland The pituitary gland lies within a recess of the sphenoid bone called the sella turcica and is composed of two major subdivisions, the anterior pituitary and posterior pituitary. These structures can be readily visualized by magnetic resonance imaging (MRI) because the posterior pituitary appears as a bright spot on T1­weighted images, as shown in Figure 1. Figure 1. Anterior pituitary and posterior pituitary Reprinted from Endocrin Metab Clin North Am, 16(3), Lechan RM, Neuroendocrinology ocw.tufts.edu/Content/14/lecturenotes/134087 1/9 7/18/12 PPY224 Pathophysiology of Endocrinology, Diabetes and Metabolism, Spring 2005 - Tufts OpenCours… Reprinted from Endocrin Metab Clin North Am, 16(3), Lechan RM, Neuroendocrinology of pituitary hormone regulation, pp475­501, 1987, with pemission from Elsevier. The anterior pituitary makes up most of the pituitary gland and gives rise to most of the pituitary hormones. As the anterior pituitary embyrologically derives from Rathke's pouch, it is composed primarily of epithelial cells and does not have direct neuronal connections to the brain. In contrast, the posterior pituitary contains axon terminals of specialized neurons that arise within the hypothalamus and thereby, is a direct extension of the brain. While secretion from the posterior pituitary can occur as a result of neuronal stimulation in the hypothalmus, secretion from the anterior pituitary is dependent upon a vascular conduit, or portal plexus, that directly links the hypothalamus to the anterior pituitary gland. The portal plexus is comprised of capillaries located in a specialized structure at the base of the hypothalamus, termed the median eminence, supplied by arterial blood via a branch of the internal carotid artery, the superior hypophyseal artery (Figure 2). The portal capillaries give rise to long veins that extend along the pituitary stalk and terminate in capillary beds in the anterior pituitary. Thus, the portal plexus is a venous plexus and is the major source of blood flow to the anterior pituitary, as the anterior pituitary has little or no arterial innervation. Figure 2. Portal plexus 4.2. Anatomy of the Hypothalamus The median eminence is one of the most important structures in the hypothalamus because it is the final, common locus where axons containing all of the hypothalamic releasing and inhibiting factors terminate. Due to the high vascularity of this structure created by the portal plexus, the median eminence can be easily visualized by MRI following contrast administration (Figure 3A). As shown in the schematic image (Fig. 3B), axons containing the hypothalamic releasing and inhibiting factors terminate on the portal capillary plexus. Because these capillaries are fenestrated, the secretary products released from the axon terminals can be taken up into the portal system and transported via the long portal veins to the anterior pituitary. The median eminence also contains axons in its innermost zone en route to the posterior pituitary. Figure 3 A&B ­ Median eminence The origin of the hypothalamic releasing and inhibitory factors is primarily from nuclear groups that are organized in medial regions of the hypothalamus that underlie the third ventricle, including the preoptic nucleus, paraventricular nucleus periventricular nucleus and arcuate nucleus. The location of these important hypothalamic nuclear groups is shown in Figure 4 on coronal MRI images of the human hypothalamus. The specific hypothalamic releasing and inhibitory hormones produced by the hypothalamus, their origin in the hypothalamus, and the anterior pituitary hormones they regulate are listed in Table 2. Figure 4. Coronal MRI images of the human hypothalamus ocw.tufts.edu/Content/14/lecturenotes/134087 2/9 7/18/12 PPY224 Pathophysiology of Endocrinology, Diabetes and Metabolism, Spring 2005 - Tufts OpenCours… Reprinted from Endocrin Metab Clin North Am, 16(3), Lechan RM, Neuroendocrinology of pituitary hormone regulation, pp475­501, 1987, with pemission from Elsevier. TABLE 2. Hypothalamic releasing and inhibitory factors. Releasing/Inhibiting Factor Hypothalamic Origin Function Corticotropin­releasing hormone (CRH) Paraventricular Nucleus Stimulate ACTH Dopamine Arcuate Nucleus Inhibit Prolactin Growth hormone­releasing hormone (GHRH) Arcuate Nucleus Stimulate GH Gonadotropin­releasing hormone (GnRH) Preoptic Nucleus Stimulate LH/FSH Somatostatin (SRIF) Periventricular Nucleus Inhibit GH/TSH Thyrotropin­releasing hormone (TRH) Paraventricular Nucleus Stimulate TSH/Prol. In contrast, neuronal cell groups giving rise to the posterior pituitary hormones, vasopressin (or antidiuretic hormone, ADH) and oxytocin, are located more laterally in the hypothalamus in lateral portions of the paraventricular nucleus and the supraoptic nucleus. 5. Hypopituitarism 5.1. Etiology of Hypopituitarism There are many disorders that can cause hypopituitarism, either by affecting the hypothalamus or the pituitary gland. Congenital disorders are a cause for hypopituitarism presenting in children. Formation of the pituitary during embryonic development depends upon the juxtaposition of cells of neurectodermal origin, which form the posterior pituitary, and endodermal cells which form the anterior pituitary. Defects in the transcription factors HESX­1, PROP­1, and PIT­1 are known to result in various degrees of hypopituitarism. HESX­1 mutations are associated with septo­optic dysplasia, characterized by the triad of optic nerve hypoplasia, midline neuroradiological abnormalities such as agenesis of the corpus callosum, and pituitary hypoplasia with hypopituitarism. PROP­1 mutations have deficiencies in the gonadotrophs (LH and FSH), growth hormone, prolactin and TSH. PIT­1 mutations result in combined deficiencies of growth hormone, prolactin and TSH. Mutations may also selectively affect posterior pituitary function including point mutations in the vasopressin­neurophysin II gene. Most involve the neurophysin II region of the vasopressin gene, resulting in abnormal processing, transport or cleavage of the vasopressin precursor, or cytotoxicity to vasospressin­producing cells in the hypothalamus. Wolfram syndrome (DIDMOAD syndrome) is an inherited autosomal recessive disorder due to a mutation in the transmembrane protein, wolframin, and characterized by DI, Diabetes Mellitus, Optic Atrophy and Deafness. Pituitary adenomas are the most common cause for hypopituitarism in adults. Causes of hypopituitarism are listed in Table 3. TABLE 3. Causes of hypopituitarism Congenital Disorders HESX­1, PIT­1, and PROP­1 mutations, KAL and DAX­1 mutations, GnRH and GHRH receptor mutations, Kallmann, Prader Willi and Bardet­ Beidl Syndromes, Vasopressin­Neurophysin gene mutations, DIDMOAD Benign Neoplasms Malignant Neoplasms Cysts Pituitary Adenoma Germ Cell Tumors (Germinoma) Arachnoid Craniopharyngioma Lymphoma Dermoid Meningioma Plasmacytoma Epidermoid ocw.tufts.edu/Content/14/lecturenotes/134087 3/9 7/18/12 PPY224 Pathophysiology of Endocrinology, Diabetes and Metabolism, Spring 2005 - Tufts OpenCours… Optic Nerve Glioma Metastatic Disease (breast, lung) Rathke's Cleft Granulomatous Disease Vascular Disorders Infections Eosiniphilic Granuloma Aneurysm Abscess Histiocytosis X Cavernous Angioma Cysticercosis Sarcoidosis Infarction (Postpartum, D.M.) Tuberculosis Autoimmune Traumatic Other Lymphocytic Hypophysitis Pituitary Stalk Transection Cerebral Edema Vasculitis Pituitary Apoplexy Radiation Therap 5.2.