XIII Endocrinology

by He Wei Department of Physiology Zhengzhou University

What is hormone?
Chemical substances that are produced in the endocrine glands and traveled in the blood to target cells or organs where they exert the physiological control. A given hormone usually affects only a limited number of cells, which are called target cells. A target cell responds to a hormone because it bears receptors for that hormone.

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Two important terms are used to refer to molecules that bind to the hormonebinding sites of receptors:
Agonists are molecules that bind the receptor and induce all the post-receptor events that lead to a biologic effect. In other words, they act like the "normal" hormone, although perhaps more or less potently. Antagonists are molecules that bind the receptor and block binding sites of the agonist, but fail to trigger intracellular signaling events.

What is endocrine system?

A system of glands that works with the nervous system in controlling the activity of internal organs, and in coordinating the long-range response to external stimuli.

Endocrine Gland and Exocrine Gland

Hormones groups

Steroids: testosteroneestradiol adrenal cortex hormones Peptides: most hormones Amines: thyroid hormone norepinephrine epinephrine

Mechanisms of Hormonal Action

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By activating the cyclic AMP system of the

cells, which in turn activates multiple other intracellular functions. By activating the genes of the cell, which causes the formation of intracellular proteins that in turn initiate specific cellular function.

The Cyclic AMP Mechanism for Controlling Cell Function----A Second Messenger for Hormone Mediation
Nonsteroid hormones (water soluble) do not enter the cell but bind to plasma membrane receptors, generating a chemical signal (second messenger) inside the target cell. Second messengers activate other intracellular chemicals to produce the target cell response.

The specific action that occurs in response to cAMP in each type of target cell depends upon the nature of the intracellular machinery. Different functions are elicited in different target cells ------ such functions as:
Initiating synthesis of specific intracellular

chemicals; causing muscle contraction or relaxation; initiating secretion by the cells; altering the cell permeability; and many other possible effects.

cascade of enzymes

Action of Steroid Hormones on the Genes to Cause Protein Synthesis

The steroid hormones enters the cytoplasm of the cell,

where it binds with a specific receptor protein to form a hormone-receptor complex. The complex is transported into the nucleus. The complex then actives specific genes to produce mRNA. The mRNA diffuses into the cytoplasm, where it promotes the translation process at the ribosomes to produce new proteins.

Control of Endocrine Activity

The concentration of hormone as seen by target cells is determined by three factors:
Rate of production Rate of delivery Rate of degradation and elimination

Feedback Control of Hormone Production

Feedback circuits are at the root of most control mechanisms in physiology, and are particularly prominent in the endocrine system. Instances of positive feedback certainly occur, but negative feedback is much more common.

Neurons in the hypothalamus secrete thyroid releasing hormone (TRH), which stimulates cells in the anterior pituitary to secrete thyroid-stimulating hormone (TSH). TSH binds to receptors on epithelial cells in the thyroid gland, stimulating synthesis and secretion of thyroid hormones, which affect probably all cells in the body. When blood concentrations of thyroid hormones increase above a certain threshold, TRHsecreting neurons in the hypothalamus are inhibited and stop secreting TRH. This is an example of "negative feedback".

The Pituitary Gland, Its Multiple Control Functions, and Its Relationship to The Hypothalamus

The pituitary gland (often called the master gland) is located in a small bony cavity at the base of the brain. A stalk links the pituitary to the hypothalamus, which controls release of pituitary hormones. The pituitary gland has two lobes: the anterior lobe and posterior lobe. The anterior pituitary is glandular. The hypothalamus contains neurons that control releases from the anterior pituitary. Hypothalamic hormones are released into a portal system connecting the hypothalamus and pituitary, and cause targets in the pituitary to release hormones.

Growth Hormone
Growth hormone, also known as somatotropin, is a protein hormone of 191 amino acids that is synthesized and secreted by cells called somatotrophs in the anterior pituitary. It is a major participant in control of several complex physiologic processes, including growth and metabolism.

Metabolic Effects (Direct )

Increased rate of protein synthesis in all

cells of body; Increased mobilization of fatty acids from adipose tissue, and increased use of the fatty acids for energy; Decreased rate of glucose utilization throughout the body.

Growth Effects (Indirect)

Growth is a very complex process, and requires the coordinated action of several hormones. The major role of growth hormone in stimulating body growth is to stimulate the liver and other tissues to secrete several small proteins called somatomedins, which stimulates proliferation of cartilage cells, resulting in bone growth.

Regulation of GH Secretion
Starvation, hypoglycemia, exercise,

excitement, trauma; Stress status; Growth hormone-releasing hormone (GHRH) from hypothalamus; Sleep

Abnormalities of GH Secretion
Dwarfism

Giantism
Acromegaly

 Age: 22
Sex: male Height: 75cm Weight: 12.5kg

Thyroid Hormones
The thyroid gland is a very vascular and

butterfly shaped gland that is located in the neck. The thyroid gland secretes three hormones: thyroxine(T4), triiodothyronine(T3), and calcitonin(detailed latter). Both of T3 and T4 require iodine for their synthesis and have a profound effect on the metabolic rate of body.

Thyroid follicles serve as both factory and warehouse for thyroid hormones.

Formation and Secretion of the Thyroid Hormones

Accumulation of the raw materials
Synthesis of the hormones and storage Release of the free hormones and

secretion into blood

Two Principle Raw Materials

Tyrosine is provided from a large glycoprotein

called thyroglobulin, which is synthesized by thyroid epithelial cells and secreted into the lumen of the follicle . Iodine, or more accurately iodide (I-), is avidly taken up from blood by thyroid epithelial cells, which have iodide pumps on their membrane.

Iodination of Tyrosine and Formation of the Thyroid Hormones

Iodination of tyrosines on thyroglobulin and

formation of monoiodotyrosine and diiodotyrosine

Synthesis of T4(di+di) or T3(mono+di)

Release of T4 and T3 from the Thyroid Gland

Thyroid epithelial cells ingest colloid by endocytosis from

their apical borders - that colloid contains thyroglobulin decorated with thyroid hormone.
Colloid-laden endosomes fuse with lysosomes, which

contain hydrolytic enzymes that digest thyroglobluin, thereby liberating free thyroid hormones.
Finally, free thyroid hormones diffuse out of lysosomes,

through the basal plasma membrane of the cell, and into blood where they quickly bind to carrier proteins for transport to target cells.

Functions of the Thyroid Hormones

It is likely that all cells in the body are targets for thyroid hormones. While not strictly necessary for life, thyroid hormones have profound effects on many "big time" physiologic processes, such as development, growth and metabolism.

Effect of Thyroid Hormone on Cellular Metabolic Activity

The thyroid hormones increase the metabolic activities of all or almost all the tissues of the body. The basal metabolic rate can increase to as much as 60 to 100 per cent above normal when large quantities the hormones are secreted. The rate of utilization of foods for energy is greatly accelerated .

Effect of Thyroid Hormone on Development and Growth

Stimulation of skeletal growth in childhood.

In those who are hypothyroid, the rate of growth is greatly retarded.

Promotion of normal brain development in

the early postnatal period. Those who are hypothyroid will remain mentally deficient throughout life.

Metabolic Effects
Elevation of basal metabolic rate with increased O2

consumption and heat production; Stimulation of carbohydrate metabolism with increases in gastrointestinal and cellular absorption of glucose, glycolysis and gluconeogenesis; Stimulation fat mobilization, leading to increased concentrations of fatty acids in plasma. Increased oxidation of fatty acids in many tissues. Increased protein synthesis and breakdown.

Systemic Effects
Cardiovascular system: Thyroid hormones

increases heart rate, cardiac contractility and cardiac output. They also promote vasodilation, which leads to enhanced blood flow to many organs to fit for the increased need for O2 and nutrition by them. Central nervous system: Individual with too little thyroid hormone tends to feel mentally sluggish, while too much induces anxiety and nervousness.

 Respiration system: Increased rate and depth of

respiration. WHY? Gastrointestinal tract: In addition to increased appetite and food intake, thyroid hormone increases gastrointestinal motility and secretion. Body weight: Greatly increased thyroid hormone always decreases the body weight. Sleep: Because of the excitable effects of thyroid hormone, it is difficult to sleep. Eyes: Many, but not all persons with hyperthyroidism develop protrusion of the eyeballs.

Patient with exophthalmic hyperthyroidism

Regulation of TH Secretion

Hypothalamus--Anterior Pituitary--Thyroid gland (TRH) (TSH) (TH) Negative feedback

Calcitonin
This hormone is secreted by the C cells of the thyroid gland. It participates in calcium and phosphorus metabolism.

Physiologic Effects of Calcitonin

Bone: Calcitonin inhibits the activity of osteoclasts,

a cell type that "digests" bone matrix, releasing calcium and phosphorus into blood.
Kidney: Calcium and phosphorus are prevented

from being lost in urine by reabsorption in the kidney tubules. Calcitonin inhibits tubular reabsorption of these two ions, leading to increased rates of their loss in urine.

Control of Calcitonin Secretion

The most prominent factor controlling calcitonin secretion is the plasma concentration of Ca2+. Elevated blood calcium levels strongly stimulate calcitonin secretion, and secretion is suppressed when calcium concentration falls below normal.

Parathyroid Hormone
Parathyroid hormone is the most important

endocrine regulator of calcium and phosphorus concentration in extracellular fluid. This hormone is secreted from cells of the parathyroid glands and finds its major target cells in bone and kidney.

Physiologic Effects of Parathyroid Hormone

Mobilization of calcium from bone: Although the

mechanisms remain obscure, a well-documented effect of parathyroid hormone is to stimulate the activity of osteoclasts, liberating calcium into blood.
Enhancing absorption of calcium from the small

intestine: Facilitating calcium absorption from the small intestine would clearly serve to elevate blood levels of calcium. Parathyroid hormone stimulates this process, but indirectly by stimulating production of the active form of vitamin D in the kidney. Vitamin D induces synthesis of a calcium-binding protein in intestinal epithelial cells that facilitates efficient absorption of calcium into blood.

 Suppression of calcium loss in urine: In addition to

stimulating fluxes of calcium into blood from bone and intestine, parathyroid hormone puts a brake on excretion of calcium in urine, thus conserving calcium in blood. This effect is mediated by stimulating tubular reabsorption of calcium. Another effect of parathyroid hormone on the kidney is to stimulate loss of phosphate ions in urine.

Control of Parathyroid Hormone Secretion

Parathyroid hormone is released in response to

low extracellular concentrations of free calcium. Changes in blood phosphate concentration can be associated with changes in parathyroid hormone secretion, but this appears to be an indirect effect and phosphate is not a significant regulator of this hormone.

The Adrenocortical Hormones

The adrenal produces three major classes of hormones, each of which aid in dealing with the multitude of small and large stresses faced by animals and people almost daily. There is no doubt that at least two of these groups - glucocorticoids and mineralocorticoids - are necessary for life.

Mineralocorticoid
--Aldosterone
Removal of the adrenal glands leads to death within just a few days. Observation of such a unfortunate subject would reveal several key derangements: the concentration of potassium in extracelluar fluid becomes dramatically elevated urinary excretion of sodium is high and the concentration of sodium in extracellular fluid decreases significantly volume of extracellular fluid and blood decrease the heart begins to function poorly, cardiac output declines and shock ensues

Physiologic Effects of Aldosterone

Increased resorption of sodium: sodium loss in

urine is decreased under aldosterone stimulation.

Increased resorption of water, with consequent

expansion of extracellular fluid volume. This is an osmotic effect directly related to increased resorption of sodium.
Increased renal excretion of potassium.

Control of Aldosterone Secretion

Concentrations of K+ and Na+ in extracellular

fluid: Small increase of K+ and decrease of Na+ in blood levels strongly stimulate aldosterone secretion.
Angiotensin II: Activation of the renin-angiotensin

system as a result of decreased renal blood flow (usually due to decreased vascular volume) results in release of angiotensin II, which stimulates aldosterone secretion.

Glucocorticoid
---Cortisol
In contrast to loss of mineralocorticoids, failure to produce glucocorticoids is not acutely life-threatening. Nevertheless, loss or profound diminishment of glucocorticoid secretion leads to a state of deranged metabolism and an inability to deal with stressors which, if untreated, is fatal.

Effects on Metabolism
The name glucocorticoid derives from early observations that these hormones were involved in glucose metabolism. In the fasted state, cortisol stimulates several processes that collectively serve to increase and maintain normal concentrations of glucose in blood. These effects include:

 Stimulation of gluconeogenesis, particularly in the liver:

This pathway results in the synthesis of glucose from nonhexose substrates such as amino acids and lipids and is particularly important in carnivores and certain herbivores. Enhancing the expression of enzymes involved in gluconeogenesis is probably the best known metabolic function of glucocorticoids. Mobilization of amino acids from extrahepatic tissues: These serve as substrates for gluconeogenesis. Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose. Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis are used for production of energy in tissues like muscle, and the released glycerol provide another substrate for gluconeogenesis.

Stress Resistance
The increased Cortisol levels stimulated by stressful conditions, such as trauma, starvation, infection, intense heat or cold, surgery, debilitating disease. Availability of glucose: Cortisol promotes a rapid supply of glucose to the body tissues through its metabolic effects. Cardiovascular effects: Cortisol plays a permissive role in the cardiovascular responses to stress through increased sympathetic activity. This causes vascular construction, which helps to maintain arterial pressure and directs blood towards the most vital organs.

Effects on Inflammation and Immune Function

Glucocorticoids have potent antiinflammatory and immunosuppressive properties. Cortisol inhibits lymphocyte activation and as a consequence, it is widely used as drugs to treat inflammatory conditions such as arthritis or dermatitis, and as adjunction therapy for conditions such as autoimmune diseases.

Control of Cortisol Secretion

Hypothalamus--Anterior Pituitary--Adrenal gland

(CRH)
Stress

(ACTH)

(Cortisol)