Hypopituitarism¶
Chapter 391 | Harrison's 22e · Part 12 – Endocrinology & Metabolism
Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition
🔑 Key Clinical Points¶
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📑 Table of Contents¶
📋 Figures in This Chapter¶
| # | Type | Description |
|---|---|---|
| 1 | 🔀 Flowchart | Management of adult growth hormone (GH) deficiency |
RAW CONTENT¶
[PAGE 2992] 2992 PART 12 Endocrinology and Metabolism TABLE 391-1 Etiology of Hypopituitarisma 391 Hypopituitarism Development/structural Midline cerebral defect syndromes Shlomo Melmed, J. Larry Jameson Pituitary dysplasia/aplasia Primary empty sella Congenital hypothalamic disorders (septo-optic dysplasia, Prader-Willi Deficient production of anterior pituitary hormones leads to features syndrome, Bardet-Biedl syndrome, Kallmann syndrome) of hypopituitarism. Impaired production of one or more of the anterior Congenital central nervous system mass, encephalocele pituitary trophic hormones can result from inherited disorders; more Genetic commonly, adult hypopituitarism is acquired and reflects the com- Combined pituitary hormone deficiencies pressive mass effects of tumors or the consequences of local pituitary Isolated primary hormone deficiencies or hypothalamic traumatic, autoimmune, inflammatory, or vascular Traumatic damage. These processes also may impair synthesis or secretion of Surgical resection hypothalamic hormones, with resultant pituitary failure (Table 391-1). Radiotherapy damage ■ DEVELOPMENTAL CAUSES OF HYPOPITUITARISM Head injuries Pituitary dysplasia may result in aplastic, hypoplastic, or ectopic Neoplastic pituitary gland development. Because pituitary development follows Pituitary adenoma midline cell migration from the nasopharyngeal Rathke’s pouch, mid- Parasellar mass (germinoma, ependymoma, glioma) line craniofacial disorders may be associated with pituitary dysplasia. Rathke’s cyst Acquired pituitary failure in the newborn also can be caused by birth Craniopharyngioma trauma, including cranial hemorrhage, asphyxia, and breech delivery. Hypothalamic hamartoma, gangliocytoma A large number (>50) of transcription factors and growth factors are Pituitary metastases (breast, lung, colon carcinoma) critical for the development of the hypothalamus and pituitary gland Lymphoma and leukemia and the function of differentiated anterior pituitary cell lineages. Muta- tions have been described in the HESX1, SOX2, SOX3, LHX3, LHX4, Meningioma OTX, GLI2, PAX6, BMP4, ARNT2, FGF8, FGFR1, SHH, PROKR2, Infiltrative/inflammatory GPR161, IGSF1, PITX2, and CHD7 genes, among others. Heterozygous Lymphocytic hypophysitis loss-of-function or autosomal recessive mutations disrupt hypothalamic Hemochromatosis and pituitary development at different developmental stages, causing a Sarcoidosis wide array of phenotypes ranging from severe syndromic midline and Histiocytosis X other defects to combined pituitary hormone defects or isolated hor- Granulomatous hypophysitis mone deficiencies. Depending on the gene involved, the pituitary may Transcription factor antibodies be hypoplastic, hyperplastic, or ectopic. Midline defects include variable Immunotherapy combinations of abnormal development of the eyes, corpus collosum, Vascular vertebrae, and genital systems. Pituitary dysfunction ranges from iso- Pituitary apoplexy lated hormone deficiency to combined pituitary hormone deficiency Pregnancy-related (infarction with diabetes; postpartum necrosis) (CPHD) and arginine vasopressin deficiency (AVP-D). In addition to these syndromic developmental disorders, some Subarachnoid hemorrhage mutations affect specific pituitary cell lineages. For example, Pit-1 Sickle cell disease mutations cause combined growth hormone (GH), prolactin (PRL), Arteritis and thyroid-stimulating hormone (TSH) deficiencies. These patients Snake bite venom usually present with growth failure and varying degrees of hypothy- Infections roidism. The pituitary may appear hypoplastic on magnetic resonance Fungal (histoplasmosis) imaging (MRI). Prop-1 is expressed early in pituitary development Parasitic (toxoplasmosis) and appears to be required for Pit-1 function. Familial and sporadic Tuberculosis PROP1 mutations result in combined GH, PRL, TSH, and gonado- Pneumocystis jirovecii tropin deficiency. Over 80% of these patients have growth retarda- Drug-induced tion; by adulthood, all are deficient in TSH and gonadotropins, and CTLA-4 inhibitors a small minority later develop adrenocorticotropic hormone (ACTH) PD-1/PD-L1 inhibitors deficiency. Because of gonadotropin deficiency, these individuals do not enter puberty spontaneously. In some cases, the pituitary gland aTrophic hormone failure associated with pituitary compression or destruction appears enlarged on MRI. TPIT mutations result in ACTH deficiency usually occurs sequentially: growth hormone > follicle-stimulating hormone > luteinizing hormone > thyroid-stimulating hormone > adrenocorticotropic hormone. associated with hypocortisolism. Mutations in NR5A1 (also known as During childhood, growth retardation is often the presenting feature, and in adults, steroidogenic factor 1 [SF1]) impair development of gonadotropes, as hypogonadism is the earliest symptom. well as adrenal/gonadal development. Abbreviations: CTLA-4, cytotoxic T lymphocyte antigen 4; PD-1, programmed cell death protein 1; PD-L1, programmed cell death protein ligand 1. ■ HYPOTHALAMIC ENDOCRINE DYSFUNCTION Hypothalamic disorders can affect temperature regulation, appetite, such as mirror movements. The initial genetic cause was the X-linked sleep-wake cycles, autonomic systems, behavior, and memory, as well KAL gene, mutations of which impair embryonic migration of GnRH as multiple endocrine systems. Selected examples of hypothalamic dis- neurons from the hypothalamic olfactory placode to the hypothala- orders that affect the endocrine system are described below. mus. Since then, more than a dozen additional genetic abnormalities, Kallmann Syndrome Kallmann syndrome results from defective in addition to KAL mutations, have been found to cause isolated hypothalamic gonadotropin-releasing hormone (GnRH) synthesis and GnRH deficiency. Autosomal recessive (i.e., GPR54, KISS1) and is associated with anosmia or hyposmia due to olfactory bulb agenesis dominant (i.e., FGFR1) modes of transmission have been described, or hypoplasia (Chap. 403). Classically, the syndrome may also be asso- and there is a growing list of genes associated with GnRH deficiency ciated with color blindness, optic atrophy, nerve deafness, cleft palate, (including GNRH1, PROK2, PROKR2, CHD7, PCSK1, FGF8, NELF, renal abnormalities, cryptorchidism, and neurologic abnormalities WDR11, TAC3, TACR3, and SEMA3E). Some patients have oligogenic
[TABLE] TABLE 391-1 Etiology of Hypopituitarisma Development/structural Midline cerebral defect syndromes Pituitary dysplasia/aplasia Primary empty sella Congenital hypothalamic disorders (septo-optic dysplasia, Prader-Willi syndrome, Bardet-Biedl syndrome, Kallmann syndrome) Congenital central nervous system mass, encephalocele Genetic Combined pituitary hormone deficiencies Isolated primary hormone deficiencies Traumatic Surgical resection Radiotherapy damage Head injuries Neoplastic Pituitary adenoma Parasellar mass (germinoma, ependymoma, glioma) Rathke’s cyst Craniopharyngioma Hypothalamic hamartoma, gangliocytoma Pituitary metastases (breast, lung, colon carcinoma) Lymphoma and leukemia Meningioma Infiltrative/inflammatory Lymphocytic hypophysitis Hemochromatosis Sarcoidosis Histiocytosis X Granulomatous hypophysitis Transcription factor antibodies Immunotherapy Vascular Pituitary apoplexy Pregnancy-related (infarction with diabetes; postpartum necrosis) Subarachnoid hemorrhage Sickle cell disease Arteritis Snake bite venom Infections Fungal (histoplasmosis) Parasitic (toxoplasmosis) Tuberculosis Pneumocystis jirovecii Drug-induced CTLA-4 inhibitors PD-1/PD-L1 inhibitors [/TABLE]
[PAGE 2993] 2993 CHAPTER 391 Hypopituitarism mutations in which mutations in a combination of different genes lead hypothalamic and pituitary neuronal and neurochemical tracts. Con- to the phenotype. Associated clinical features, in addition to GnRH sequently, AVP-D is a common presentation, reported in half of deficiency, vary depending on the genetic cause. GnRH deficiency patient
Flowcharts & Algorithms¶
Reproduced from Harrison's 22nd Edition.
Flowchart 1¶
Caption: FIGURE 391-1 Management of adult growth hormone (GH) deficiency. IGF, insulin- like growth factor; Rx, treatment.
Generated from Harrison's Principles of Internal Medicine, 22nd Edition.