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HORMONES

TABLE OF CONTENTS

Hormone Basics
Classifying Hormones
Steroid Hormones
Peptide Hormones
Eicosanoids

 


HORMONE BASICS

Hormones are chemicals produced and secreted by the endocrine system. Typically they enter the bloodstream which carries them to target tissues. Hormones regulate variety of functions; cell growth and differentiation, transcription/protein synthesis, etc. Many diseases arise from dysfunctions of the endocrine system. In some cases the hormone producing cells will become overactive, either due to the effects of another hormone, or because of tumors of the gland (hyperfunction). In other cases, the disease is a result of insufficient production (hypofunctions) of the hormone by the gland or sufficient but biologically inactive hormone production (hormone sensitivity defects). Insufficient production can be caused by numerous dysfunctions of the endocrine system, including lack of necessary nutrients in diet and autoimmune attacks on the glandular cells.

Hormones are usually classified based on their chemical composition. There are many classes for hormones: steroid hormones derived from cholesterol, peptide hormones, which are protein molecules, eicosanoids, which are derivatives of arachidonic acid, thyroid hormones, which are also derived from peptides, and catecholamines, such as epinephrine and norepinephrine.


CLASSIFYING HORMONES

Hormones can be classified by the types of ligands: agonists, antagonists, partial agonist-partial antagonists, and inactive compounds. Agonist is a compound that binds to a receptor and transmits a signal which has some effect on cell functions. Most hormones produced in normal conditions are agonists. Antagonists are compounds that bind to receptors but do not transmit any signals and prevent agonists from binding to the receptor. Antagonists are similar to competitive inhibitors, which take up the active site of an enzyme and block the real substrate from binding. A very small amount of antagonists are produced by the body, thus their inhibitory effects are minimal. These compounds also have very low affinity for the receptors, thus slightly increasing the concentration of an agonist will overcome the effects of the antagonist. Partial agonist-partial antagonists are compounds that bind to receptors and transmit signals which are weaker than that of a complete agonist. These compounds have been identified, however, very few examples of them are known. Yet another group of mixed agonist-antagonists has been identified. These are also known as heterologous agonist-antagonists. They are compounds that act as agonists in one type of tissue and act as antagonists in another.

STEROID HORMONES

Steroid hormones, as stated previously, are derivatives of cholesterol (see figure 1.1 for the basic cholesterol structure). They are produced and secreted by cells found in the ovaries, testes, adrenal cortex, and placenta (see table 1.1). The cells have three sources for cholesterol synthesis: acetate, cholesterol esters in steroidogenic cells or dietary sources. About 80% of cholesterol comes from dietary sources which is carried in the bloodstream. Cholesterol molecules are lipid soluble, which means that they cannot travel in the blood without some sort of a transport system. These molecules form complexes with Low Density Lipoproteins (LDL), which carries them to the target cells. C:LDL complexes are recognized by LDL receptors on cell surfaces. Once the C:LDL binds to the receptor, the complex enters the cell by endocytosis. The C:LDL:Receptor complex is digested by an enzyme called Lysosome Cholesterol Esterase. The cholesterol is released from the rest of the complex. Since cholesterol is still in a hydrophilic environment, it must bind to another carrier. Cholesterol binds to a carrier protein called Sterol Carrier Protein 2 or SCP-2. This specialized protein has a very short half-life when it is not bound to cholesterol. With the help of this protein, cholesterol is transported to the mitochondria. Another protein called Steroidogenic Acute Regulator or StAR binds to cholesterol and transports it into the intermembrane space of the mitochondria. Once cholesterol enters the mitochondria, it is converted to numerous compounds, some of them classified as prehormones, and some of them as hormones. The enzyme that catalyzes most of these steroidogenic reactions is cytochrome P450, which is also one of the major enzymes for oxidative phosphorylation. There are six different types of cytochrome P450 enzymes, which have been identified as steroidogenic enzymes. These different enzymes are compartmentalized in different types of cells/tissues, which explains the tissue specific steroid hormone production. Figure 1.2 summarizes the conversion reactions of cholesterol to different steroid hormones.


Cholesterol
Table 1.1  
Clinical and chemical names of steroid hormones.
Clinical Name
Chemical Name
Aldosterone 11b,21-Dihydroxy-3,20-dioxo-4-pregnen-18-al
Corticosterone 11b,21-Dihydroxy-4-pregnene-3,20-dione
Cortisol 11b,17a,21-Trihydroxy-4-pregnene-3,20-dione
Cortisone 17a,21-Dihydroxy-4-pregnene-3,11,20-trione
Dehydroepiandrosterone 3b-Hydroxy-5-androsten-17-one
11-Deoxycorticosterone 21-Hydrox-4-pregnene-3,20-dione
11-Deoxy-17-hydroxycorticosterone 17a,21-Hihydroxy-4-pregnene-3,20-dione
Estradiol 1,3,5(10)-Estratriene-3,17b-diol
Pregnenolone 3b-Hydroxy-5-pregnen-20-one
Progesterone 4-Pregnene-3,20-dione
Testosterone 17b-Hydroxy-4-androsten-3-one
Allopregnanolone 5a-Pregnan-3a-ol-20-one
Dexamethasone 9a-Fluoro-11b,17a,21-trihydroxy-16a-methylpregna-1,4-diene-3,20-dione
Betamethasone 9a-Fluoro-11b,17a,21-trihydroxy-16b-methylpregna-1,4-diene-3,20-dione
Prednisone 17a,21-Dihydroxypregna-1,4-diene-3,11,20-trione
Prednisolone 11b,17a,21-Trihydroxypregna-1,4-diene-3,20-dione
Spironolactone 4,17a-Pregnen-21-carboxylicic acid-17b-ol-3-one-7a-thiol-21,17 g-lactone, 7-acetate
Triamcinolone 9a-Fluoro-11b,16a,17a,21-tetrahydroxypregna-1,4-diene-3,20-dione


Steroid hormones diffuse out of cells and go into the blood. Their hydrophobic nature requires them to bind to transport proteins in the blood. There are many types of transport proteins and they are specific for different hormones. Some examples are; Transcortin or Corticosteroid-Binding Globulin (CBG),which transports cortisol, Sex Hormone Binding Globulin (SHBG), which is the carrier protein for estrogen, estradiol, and testosterone, Albumin and Prealbumin which transport many different types of steroid hormones. All steroid hormones are active in their unbound state. About 99% of testosterone is bound to carrier proteins. Also, about 90% of cortisol is bound, whereas only 50% of aldosteroneis found it its bound state. Bound steroid hormones act like reserves. As the concentration of unbound hormones decreases, the bound steroid hormones dissociate from their carrier molecules. In other words, the bound and unbound steroid hormones are in an equilibrium. Most of the steroid hormone metabolismoccurs in the liver followed by excretion through feces. Some of the water soluble conjugates end up in the kidneys and excreted out through urine. The half life of most steroid hormones is form hours to days.

Click here to see more details about specific Steroid hormones.


PEPTIDE HORMONES

Peptide hormones, as well as all other proteins, are made up of chains of amino acids (see amino acids & proteins for structures). They are made in many different organ systems. The number of amino acids can range from 3 to 200. Protein hormones are lipid insoluble, therefore they must use membrane bound receptors. The steps involved in peptide hormone synthesis are as follows:

1. Gene expression and transcription in the nucleus

2. Translation of the mRNA by the ribosomes in the cytosol

3. Transport of the peptide chain into the Endoplasmic Reticulum (ER) lumen

4. Co & post-translational modifications of the protein in the ER lumen

5. Transport of proteins to the cis-Golgi cisternae

6. More post-translational modifications in the Golgi Apparatus

7. Formation of vesicles containing the peptide hormone

8. Storage or secretion of the hormone


(see Protein Synthesis or Vesicular Transport for more detailed explanations).

During peptide hormone synthesis, most hormones start out as prohormones, which are inactive forms of the hormones. These are subjected to proteolytic enzymes, which convert the inactive prohormones to active forms of the hormone. This usually occurs either in the Golgi Apparatus, vesicles or while circulating. Most of the post-translational modifications include glycosylation (addition of oligosaccharides)
and sulfonation (formation of sulfide bonds).


Peptide hormones can be release in two different way: constitutive release, or regulated release. During constitutive release, the hormone is secreted into the interstitial fluid continuously. A more common type of release for peptide hormones, regulated release, secretes the hormone only when the cell producing the hormone has some sort of a stimulus, either by another hormone, an action potential, or anything that would generally increase the cytosolic Ca
2+ concentration. A general effect of increased Ca2+ concentration in the cytosol is the fusion of vesicles with the plasma membrane. Here is a more detailed mechanism of the stimulus and its effects on a peptide hormone releasing cell:

1. If the stimulus is initiated by another hormone, the Phosphoinositol system
    is used to increase the concentration of cytosolic Ca2+

2. Ca2+ binds with Calmodulin and activate Ca2+:CAM Dependent Kinase II

3. Ca2+:CAMKII uses ATP to phosphorylate Synapsin I, which is a protein that
    binds to cytoskeleton microfilaments and specific membrane proteins on the
    vesicle.

4. The phosphorylated Synapsin I releases the vesicle which allows it to fuse
    with the membrane.

5. After releasing the hormone into the interstitial fluid, the vesicles reform.

6. Phosphatases dephosphorylate Synapsin I which binds to the reformed
    vesicle.

Peptide hormones generally don't bind to carrier proteins when being transported in the plasma. However, there are a few carrier proteins, which increase the half life of the hormones. Some examples are; Insulin, Growth hormone, ADH & Oxytocin. Peptide hormones are metabolized in two ways. In the blood, they can be degraded by proteases. The products of these degradations are excreted in the urine and some get recycled. The other way to get rid of peptide hormones is by internalization. By this process, the hormone molecules are endocytized by special cells. The vesicles full of hormone molecules fuse with lysosomes, which are specialized membrane compartments full of digestive enzymes.

The duration of action for peptide hormones tend to be short, because of their short half life in the blood. On contrast, steroid hormones can last longer in the blood, because most of them are bound to carrier proteins, which protect them from enzymatic degradation. The half life of peptide hormones is from minutes to hours. Hypofunctions of a peptide hormone producing cell will have a faster effect on the organism.


EICOSANOIDS

Derived from Arachidonic acid, eicosanoids are lipid soluble, however, unlike steroid hormones, they use membrane-bound receptors. Eicosanoids are made in most cells and they usually act locally. Their half life is very short, seconds to minutes. Arachidonic acid is mostly synthesized from linoleic acid by desaturating and elongating the fatty acid. Eicosanoids are not stored in cells, but their precursor is. Arachidonic acid is cleaved from the 2 position of phospholipids located in the lipid bilayer of the cells. This process is catalyzed by Phospholipase A2 (PLA2). But there are many other reactions that can lead to the production of arachidonic acid. One such reaction is the conversion of diacylglycerol to arachidonic acid by DAG lipase (remember that diacylglycerol is the product of the phosphoinositol bisphosphate system). There are many types of eicosanoids; leukotrienes, Prostoglandins, Thromboxanes, Prostacyclins, to name a few. Leukotriene synthesis is catalyzed by Lipoxygenase, and the syntheses of the latter three is catalyzed by Cyclooxygenase.

Eicosanoids have many different actions in the body; inflammation, smooth muscle contraction, platelet aggregation, immune response, fever and pain. Many medications targeted to inhibit some of the listed actions of eicosanoids, act by interfering with the synthesis of eicosanoids. Cortisol blocks PLA2 in order to decrease inflammation and immune response. Aspirin blocks the cyclooxygenase system all over the body. This also decreases inflammation and platelet aggregation. By inhibiting the actions of cyclooxygenase, the overall reaction of eicosanoid synthesis is shifted towards the lipoxygenase catalyzed reaction, which produces leukotrienes. Leukotrienes cause bronchoconstriction. About 10% of the population is sensitive to aspirin and causes major asthmatic effects when they use Aspirin.


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