1. Goal

To learn the principles that underlie the pathophysiology of the endocrine system

2. Learning Objectives

• Multiple important and complex interactions exist between the endocrine and other systems (e.g. immune, nervous).
• Definition of hormones: circulating molecules with a site of action distant from site of origin with ability to bind to cellular receptors and initiate signal transduction via conformational changes in the receptor.
• Hormones participate in growth and development, reproduction, energy metabolism and maintenance of the internal environment.
• In general, hormones are protein-derived molecules that bind to cell surface receptors or steroid hormones that bind to nuclear receptors. An exemption is thyroid hormone, a modified amino acid that binds to nuclear receptors.
• Integrated feedback loops are very characteristic to the endocrine system and critical in maintaining normal hormonal function. Two major types of control exist: the hypothalamic-pituitary-peripheral organ unit and the free standing endocrine gland.
• Pathology in endocrinology is due to abnormal hormone activity or neoplasms, leading to endocrine hyperfunction/hyperfunction or structural abnormalities.
• To accurately assess endocrine, measurement of basal hormone levels and/or dynamic testing are needed.
• Endocrine biochemical testing should be done prior to endocrine imaging.
• Endocrine imaging can be either functional or structural.
  
  

3. Review: The Endocrine System

Traditionally, three main systems of extracellular communication were thought to exist that acted in an integrated fashion helping the organism survive in its environment. These systems are (1) the immune system which protects the organism against external and internal perturbances (viruses, bacteria, carcinoma) (2) the nervous system whose signals travel by means of electrochemical signals and neurotransmitters between the brain and peripheral tissues and (3) the endocrine system which denotes "internal" secretion of substances (hormones) which are released into the circulation by various endocrine glands and act at a site distant from their site of origin. As these systems were studied in detail the distinction between them has blurred. It is now clear that the nervous system cannot be separated from the endocrine system. For example, external and internal inputs to the brain alter the expression of hypothalamic releasing and inhibitory hormones that are released into the portal capillary system to be delivered to the anterior pituitary. In turn, the pituitary gland, often called the master gland, secretes various hormones that regulate other endocrine organs such as the thyroid, adrenal glands and gonads. Furthermore, certain molecules may act as hormones and neurotrasmitters, (e.g. cathecolamines). The immune system also interacts with the endocrine system both under physiologic and pathophysiologic conditions. For example, endocrine dysfunction is often autoimmune in nature (Hashimoto's hypothyroidism , Graves' hyperthyroidism, type 1 diabetes mellitus). Another example is type 2 diabetes where low-grade systemic inflammation is a major pathophysiologic component.

4. Review: Definition of Hormones

Hormones are molecules secreted by various endocrine organs and released into the circulation to act at a site distant from their site of origin (endocrine fashion). Hormones may also act on the same cell (autocrine fashion), or on nearby cells (paracrine fashion). Examples include: insulin is secreted by beta islet cells and acts on skeletal muscle to enhance glucose uptake (endocrine), on beta islet cells to inhibit release of insulin (autocrine) and on nearby alpha islet cells to suppress secretion of glucagon (paracrine). The actions of hormones are mediated through binding to specific cellular receptors (membrane, cytoplasmic or nuclear) which have two main properties: recognition of the hormone (the ability to distinguish from other molecules) and signal tranduction (the ability to transmit a message intracellularly).

The physiology of hormonal regulation is beautifully complex and it involves multiple steps: synthesis, secretion, transport in the bloodstream, binding to specific receptor and elimination. Any of these steps may be affected in disease states.

It is crucial to appreciate that although many major hormones have been identified and characterized, new hormones are being discovered , many with important functions that add to our understanding of endocrine physiology and pathophysiology. Along the way, endocrine organs are also being discovered! One recent example is the hormone leptin secreted by the adipose tissue. The discovery of leptin not only helped us better understand the mechanisms underlying growth and development, sexual function, and food intake but also added the adipose tissue to the endocrine organ family.

5. Review: Functions of Hormones

Hormones affect all tissues and organs in the body. Major functions of hormones include:

1. Growth and Development
2. Reproduction
3. Energy metabolism (intake, production, utilization and storage of energy)
4. Maintenance of the internal environment (regulation of blood volume, electrolytes, body temperature, calcium homeostasis etc.)
5. Multiple effects on other organs (skeleton, heart, CNS etc)

There are many ways a hormone can exert its functions:

6. Review: Chemical Nature of Hormones

Hormones are derived from other molecules used by the body. Hormones, therefore, can be amino acid derivatives (Thyroxine), modified amino acids (Epinephrine), peptides (ACTH), glycoproteins (Growth Hormone, Luteinizing Hormone), or cholesterol-derived (sex steroids, glucocorticoids, vitamin D). In general, protein-derived hormones bind to cell membrane receptors that transmit the hormonal signal into the cell while cholesterol-derived hormones bind to nuclear receptors that interact either directly with the regulatory portions of genes (promoter) or via other transcription factors to alter gene expression (Figure 1). Exception: one class of peptide derived hormone, Thyroxine (T4) and Thyronine (T3), whose structure is based on two tyrosine amino acids fused together exert its effects through binding to nuclear receptors.

Figure 1. Chemical nature of hormones and site of action

7. Review: Feedback Relationships

Characteristic to the endocrine system is the integrated feedback control. Hormones secreted by endocrine organs travel in the circulation and exert their actions in peripheral (distant) organs. Hormones, as well as the end products of their action, will feedback to inhibit or stimulate further secretion of stimulatory/inhibitory hormones in an effort to keep peripheral hormonal levels and endocrine function tightly regulated. Virtually all hormone secretion is under feedback control by one or more of the following mechanisms:

1. The secreted hormones themselves (e.g. thyroid hormone will feedback on TRH and TSH and release from hypothalamus and pituitary respectively, glucocorticoids will feedback on CRH and ACTH release)
2. Other hormones (somatostatin regulates insulin and glucagon secretion by islet cells)
3. Other internal/external stimuli (starvation, fear)
4. The end product/effect of hormone action:
   • cations (calcium regulates PTH secretion)
   • metabolites (glucose regulates insulin and glucagon secretion)
   • osmolality or extracellular fluid volume (which regulate vasopressin, renin and aldosterone secretion)

Hormones and their functions are tightly controlled in a coordinated fashion by their closed feedback loops. There are two major types of control of endocrine function:

7.1. The hypothalamic-pituitary-peripheral organ unit

The hypothalamic-pituitary-peripheral organ unit controls the function of multiple peripheral endocrine organs (thyroid, adrenal cortex, gonads, breast etc.) - Figure 2. The hypothalamus contains two types of neurosecretory cells:

7.1.1. Hypophysiotropic neurons

Hypophysiotropic neurons release hormones into the portal capillary system to be delivered to the anterior pituitary gland (adenohypophysis). Most of these hormones are stimulatory (Gonadotropin Releasing Hormone [GnRH], Corticotropin Releasing Hormone [CRH], Thyrotropin Releasing Hormone [TRH], Growth Hormone Releasing Hormone [GHRH]) but others are inhibitory (Dopamine, Somatostatin). These hormones, in turn, bind to specific receptors at specific cells in the anterior pituitary gland to regulate synthesis and release of hormones (LH, FSH, ACTH, TSH, GH, Prolactin-[PRL]). Some hypothalamic hormones can regulate more than one pituitary hormone (TRH can stimulate TSH and prolactin) while some pituitary hormones are regulated by more than one hypothalamic hormone (e.g. prolactin is inhibited by dopamine and stimulated by TRH). Anterior pituitary hormones act on peripheral organs (thyroid, adrenal cortex, gonads, liver, breast etc.) to release more hormones (thyroid, cortisol, testosterone, estrogen, IGF-1) or to have an effect (galactorrhea in women post-partum).

7.1.2. Neurohypophysial neurons

Neurohypophysial neurons transverse the pituitary stalk and release hormones (Anti Diuretic Hormone [ADH], oxytocin) in the posterior pituitary (neurohypophysis). From there, these hormones are released directly in the systemic circulation.

The hormones released by the peripheral target organ (and/or their end-products) exert negative feedback control on the hypothalamus and pituitary to maintain peripheral hormone levels and endocrine function tightly regulated.

Figure 2. The hypothalamic-pituitary-peripheral organ axis

7.2. The free standing endocrine gland

The free standing endocrine glands (parathyroid, islet cells, - Figure 3) release hormones that act on peripheral tissues to produce an effect (for example, parathyroid glands secrete parathyroid hormone-PTH which acts on the bone and kidney to regulate serum calcium concentration). The effect of the hormone action exerts feedback on the endocrine gland to control its function and maintain homeostasis (for example, rise in the calcium level will decrease PTH secretion)

Figure 3. The free standing endocrine gland

8. Pathology in Endocrine Systems

Endocrine pathology is derived from defects found at any point in the hormonal synthesis, secretion, transport, action, or regulatory control of a hormone. Endocrine pathology often occurs in one of the following broad categories:

1. Abnormal Hormone Activity which can be subdivided into:
   • Endocrine organ hypofunction
     • Primary endocrine organ failure can be genetic or acquired
       • Endocrine organ agenesis (absence)
       • Genetic defect in hormone biosynthetic pathway (e.g. adrenal insufficiency due to 21-hydroxylase deficiency)
       • Destruction due to
         • 1. Autoimmune disease (e.g. Hashimoto's hypothyroidism)
         • 2. A tumor, infection or hemorrhage
       • Deficiency of precursor (e.g. iodine deficiency leading to decreased thyroid hormone synthesis)
     • Production of abnormal hormone resulting in hypofunction (e.g. abnormal glycosylation of TSH). Secondary endocrine organ failure (e.g. hypothyroidism due to hypopituitarism)
   • Endocrine organ hyperfunction.
     • Primary endocrine organ process due to a benign condition (e.g. autoimmune thyroid gland stimulation in Graves' disease) or benign neoplasm (e.g. primary hyperparathyroidism causing hypercalcemia). Endocrine cancers are rare but they may also release hormones that cause endocrine hyperfunction (e.g. adrenocortical carcinoma secreting excessive androgens causing virilization).
       • Benign condition (e.g. thyroid gland stimulation in Graves' disease by autoantibodies against the TSH receptor)
       • Benign neoplasm (e.g. primary hyperparathyroid adenoma secreting excessive PTH causing hypercalcemia).
       • Endocrine cancers (e.g. adrenocortical carcinoma secreting excessive androgens causing virilization).
     • Secondary due to stimulation by a trophic/stimulatory hormone, most often due to a benign neoplasm (e.g. hypersecretion of cortisol from adrenal cortex due to and ACTH-secreting pituitary adenoma).
     • Less commonly, ectopic production of a hormone may lead to endocrine hyperfunction (e.g. ACTH released from small cell lung cancer cause hypersecretion of cortisol by adrenal glands).
   • Abnormality in hormone transport or metabolism (e.g. genetic defects of abnormal thyroid binding globulin)
   • Abnormal hormone receptor binding and/or signal transduction. Most often causing endocrine hypofunction due to resistance to the action of hormone. The receptor itself being unable to bind the hormone (e.g. thyroid hormone resistance) or there may be a defect in post-receptor signal transduction (e.g. type 2 diabetes mellitus). Occasionally, abnormal hormone signaling may lead to endocrine hyperfunction (e.g. Gs protein mutation leading to unregulated secretion of Growth Hormone).
2. Neoplasms. They can be both benign or malignant. Symptoms develop either due to
   • Overproduction of hormone by the tumor (e.g. ACTH producing pituitary adenoma causing hypersecretion of cortisol)
   • Underproduction of nearby hormones due to mass effect (e.g. pituitary hormone production is often affected by large pituitary tumors)
   • Structural damage (e.g. hypothalamic-pituitary tumors causing headache, visual problems).
3. Iatrogenic. Most common iatrogenic cause of endocrine abnormality is exogenous administration of glucocorticoids (give to treat non-endocrine conditions, e.g. rheumatoid arthritis).

9. Assessment of Endocrine Disease

In assessing endocrine disease, the physician should keep two concepts in mind: (1) function and (2) structure. All symptoms of endocrine disease derive from these two concepts. The evaluation always begins with the history and physical examination. The clinical findings - symptoms and physical signs - often raise the suspicion of endocrine dysfunction, but they are rarely diagnostic as endocrine symptoms and signs tend to be non-specific especially in cases of mild endocrine disease. Because of the diverse functions of hormones on multiple organs, endocrine dysfunction is often not diagnosed until the disease is advanced unless the physician is trained to recognize the apparently disparate symptoms and signs of endocrine dysfunction. Objective testing is always needed to establish the diagnosis. Testing should assess abnormal function and structure. A main principle in Endocrinology is that, in general, biochemical dysfunction is assessed first, prior to testing for abnormal structure.

9.2. Endocrine Imaging

Endocrine imaging is done with general radiology procedures to assess structure (e.g. CT, MRI, Ultrasound) as well as with endocrine-specific imaging that takes advantage of known endocrine physiology and pathophysiology (e.g. radioiodide-123 thyroid scan). Endocrine imaging is divided as follows:

9.2.1. Functional Imaging

To differentiate among various possibilities of endocrine dysfunction. In general, a precursor required for biosynthesis of a hormone is given as a radiotracer and radionuclide imaging of the endocrine organ in performed. Examples of functional imaging include: thyroid scan with radioidodide (I-123) to differentiate between causes of hyperthyroidism (see Figure 4), adrenal gland imaging with radio-iodocholesterol to look for an aldesteronoma.

Figure 4. Radioiodide (I-123) uptake of the thyroid gland showing a toxic adenoma (Panel A) and a multimodal goiter (Panel B).

9.2.2. Structural Imaging

To confirm the presence of an endocrine tumor following diagnosis based on biochemical testing (e.g. Technicium pertechnate parathyroid scan to confirm the presence of a parathyroid adenoma which has been diagnosed biochemically). As a general rule, imaging is not done to diagnose disease but to confirm the diagnosis and to help the endocrine surgeon (or radiation oncologist) locate and remove (or radiate) the tumor.

To assess structural damage caused by endocrine dysfunction, either by direct anatomic relationship (e.g. sellar MRI to look for a pituitary tumor causing visual loss by pressing on the optic chiasm) or by hormonal action distantly (e.g. bone density scan to look for osteoporosis caused by a PTH secreting parathyroid adenoma).

10. References

• Greenspan FS and Gardner DG. Basic and Clinical Endocrinology, 6th edition. Lange Medical Books, McGraw-Hill, 2001.
• Wilson, JD, Foster, DW, Kronenberg, HM, and Larsen, PR. Principles of Endocrinology. In: Williams Textbook of Endocrinology, 9^th edition, W.B. Saunders, Philadelphia, 1998.