Acromegaly pathophysiology

Acromegaly Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Acromegaly from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X Ray
CT
MRI
Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Radiation Therapy
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Acromegaly pathophysiology On the Web
Most recent articles
cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Acromegaly pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Acromegaly pathophysiology
CDC on Acromegaly pathophysiology
Acromegaly pathophysiology in the news
Blogs on Acromegaly pathophysiology
Directions to Hospitals Treating Acromegaly
Risk calculators and risk factors for Acromegaly pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Overview

Acromegaly is caused by prolonged overproduction of GH by the pituitary gland. GH is part of a cascade of hormones that, as the name implies, regulates the physical growth of the body. This cascade begins in a part of the brain called the hypothalamus. The hypothalamus makes hormones that regulate the pituitary. One of the hormones in the GH series, or "axis," is growth hormone-releasing hormone (GHRH), which stimulates the pituitary gland to produce GH.

Secretion of GH by the pituitary into the bloodstream stimulates the liver to produce another hormone called insulin-like growth factor I (IGF-I). IGF-I is what actually causes tissue growth in the body. High levels of IGF-I, in turn, signal the pituitary to reduce GH production.

The hypothalamus makes another hormone called somatostatin, which inhibits GH production and release. Normally, GHRH, somatostatin, GH, and IGF-I levels in the body are tightly regulated by each other and by sleep, exercise, stress, food intake, and blood sugar levels. If the pituitary continues to make GH independent of the normal regulatory mechanisms, the level of IGF-I continues to rise, leading to bone overgrowth and organ enlargement. High levels of IGF-I also cause changes in glucose (sugar) and lipid (fat) metabolism and can lead to diabetes, high blood pressure, and heart disease.

Pathophysiology

Growth hormone is synthesized and stored in somatotroph cells, which account for >50% of pituitary hormone secreting cells. Growth hormone production and secretion is regulated by hypothalamic GH-releasing hormone, ghrelin and somatostatin. IGF-1 inhibits growth hormone secretion by both direct effect on the somatrophs and indirectly through stimulation of somatostatin that inhibits growth hormone secretion. Growth hormone is secreted in sporadic pulses with minimal basal secretion determined by sex, age, neurotransmitters, exercise and stress.

Growth hormone action is achieved via its interaction with a single-chain transmembrane glycoprotein receptor (GHR). The growth hormone molecule interacts with a preformed dimer of identical GHR pairs, causing internalization of the receptor to initiate signaling. As a consequence, two Janus tyrosine kinase 2 molecules undergo autophosphorylation and in turn phosphorylate the GHR cytoplasmic domain. This activates intracellular proteins involved in signal transduction and transcription (STAT).

The gene encoding the GHR is ubiquitously expressed, particularly in liver, fat and muscle. Growth hormone activation of the intracellular molecule STAT5b induces transcription of IGF-1. Systemic IGF-1 is synthesized primarily in the liver but also in extraheptatic tissues including bone, muscle and kidney and in the pituitary gland itself. IGF-1 circulates in serum bound to IGF-1 binding protein (IGFBP-3), or IGFBP-5, and acid-labile subunit in a 150-kD complex. Less than 1% of total serum IGF-1 circulates as a free hormone. The IGF-1 cellular effects are mediated by the IGF-1 receptor (IGF-1R), a heterotetrameric protein structurally similar to the insulin receptor. IGF-1 acts to mediate tissue growth or locally synthesized IGF-1 acts in a paracrine manner to regulate local GH target tissue growth.

Pathogenesis

• The exact pathogenesis of [disease name] is not fully understood.

OR

• It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
• [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
• Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
• [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
• The progression to [disease name] usually involves the [molecular pathway].
• The pathophysiology of [disease/malignancy] depends on the histological subtype.

Genetics

• [Disease name] is transmitted in [mode of genetic transmission] pattern.
• Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
• The development of [disease name] is the result of multiple genetic mutations.

Gross Pathology

• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].