Medical Endocrinology / Introduction 6

Medical Endocrinology / Introduction 6

Medical Endocrinology
قد يكون الإنسان قبطان اجله لكنه يكون أيضا فريسة سكر دمه
Wilfred Oakley
قد تبدو زيادة النبض , عمق التنفس , زيادة سكر الدم , إفرازات الغدة الكظرية , أشياء غير مترابطة . وفي ذات ليلة أرقتها توجهت في ذهني فكره تقول بأن كل هذه التغيرات يمكن آن تفهم على إنها جهود يبذلها الجسم لغرض الفٌر والكٌر
Walter, B. Cannon

The nervous and endocrine systems are the two major regulatory systems of the body, and together they regulate and coordinate the activity of essentially all other body structures. The nervous system functions something like telephone messages sent along telephone wires to their destination. It transmits information in the form of action potentials along the axons of nerve cells. Chemical signals in the form of neurotransmitters are released at synapses between neurons and the cells they control. The endocrine system is more like radio signals broadcast widely that everyone with radios tuned to the proper channel can receive. It sends information to the cells it controls in the form of chemical signals released from endocrine glands. The chemical signals are carried to all parts of the body by the circulatory system. Cells that are able to recognize the chemical signals respond to them and other cells do not.
The term endocrine is derived from the Greek words endo, meaning within, and crino, to separate. The term implies that cells of endocrine glands secrete chemical signals that influence tissues that are separated from the endocrine glands by some distance.
The endocrine system is composed of glands that secrete chemical signals into the circulatory system . In contrast,exocrine glands have ducts that carry their secretions to surfaces.
1. Hormones are chemical substances, involved in cell-to-cell communication, that promote the maintenance of homeostasis.
2. There are six classes of steroid hormones, based on their primary actions.
3. Most polypeptide hormones are initially synthesized as preprohormones.
4. Steroid hormones and thyroid hormones are generally transported in the bloodstream bound to carrier proteins, whereas most peptide and protein hormones are soluble in the plasma and are carried free in solution.
5. RIA and ELISA have provided major advancements in the field of endocrinology, but each type of assay has limitations.
6. Altered hormone-receptor interactions may lead to endocrine abnormalities.


The location of major endocrine glands in the human body.
The secretory products of endocrine glands are called hormones , a term derived from the Greek word hormon, meaning to set into motion.
Traditionally, a hormone is defined as a chemical signal, or ligand, that
(1) Is produced in minute amounts by a collection of cells;
(2) Is secreted into the interstitial spaces;
(3) Enters the circulatory system, where it is transported some distance;
(4) Acts on specific tissues called target tissues at another site in the body to influence the activity of those tissues in a specific fashion.

Although the stated differences between the endocrine and nervous systems are generally true, exceptions exist. For example, some endocrine responses are more rapid than some neural responses, and some endocrine responses have a shorter duration than some neural responses.
Some neurons secrete chemical signals called neurohormones into the circulatory system, which function like hormones. Also, some neurons directly innervate endocrine glands and influence their secretory activity.
Neurons release chemical signals at synapses in the form of neurotransmitters and neuromodulators, and the membrane potentials of some endocrine glands undergo depolarization or hyperpolarization, which results in either an increase or a decrease in the rate of hormone secretion. Conversely, some hormones secreted by endocrine glands affect the nervous system and markedly influence its activity.
Intercellular chemical signals
Intercellular chemical signals allow one cell to communicate with other cells. These signals coordinate and regulate the activities of most cells. Neurotransmitters and neuromodulators are intercellular chemical signals that play important roles in the function of the nervous system .
Hormones are intercellular chemical signals secreted by endocrine glands.
Autocrine chemical signals are released by cells and have a local effect on the same cell type from which the chemical signals are released. Examples include prostaglandin like chemicals released from smooth muscle cells and platelets in response to inflammation. These chemicals cause the relaxation of blood vessel smooth muscle cells and the aggregation of platelets. As a result, the blood vessels dilate and blood clots.
Paracrine chemical signals are released by cells and affect other cell types locally without being transported in the blood. For example, a peptide called somatostatin is released by cells in the pancreas and functions locally to inhibit the secretion of insulin from other cells of the pancreas .
Pheromones are chemical signals secreted into the environment that modify the behavior and the physiology of other individuals. For example, pheromones released in the urine of cats and dogs at certain times are olfactory signals that indicate fertility. Evidence supports the existence of pheromones produced by women that influence the length of menstrual cycles in other women.
Functional Classification of Intercellular Chemical Signals
Intercellular
Chemical
Signal Description Example
Autocrine Secreted by cells in a local area and influences the
activity of the same cell
type from which it was
secreted Prostaglandins
Paracrine Produced by a wide variety of tissues and secreted into tissue spaces; usually has
a localized effect on other
tissues Histamine , prostaglandins
Hormone Secreted into the blood by specialized cells; travels
some distance to target
tissues; influences specific
activities Thyroxine, insulin

Neurohormone Produced by neurons and functions like hormones Oxytocin, antidiuretic hormone

Neurotransmitter or neuromodulator



Produced by neurons and secreted into extracellular spaces by presynaptic nerve terminals; travels short distances; influences postsynaptic cells Acetylcholine, epinephrine
Pheromone Secreted into the environment; modifies physiology and behavior of other individuals Sex pheromones are released by humans and many other animals. They are released in the urine & other external secretions.Pheromones produced by women influence the length of the menstrual cycle of other women.
A hormone is a chemical messenger released by an endocrine gland into the circulation. Once released, a hormone travels in the bloodstream and affects only cells in the body that have receptors (binding sites) specific to it. Cells that respond to a particular hormone are called target cells for that hormone. Typically, a hormone is released in bursts from an endocrine gland in a pattern that often follows an inherent daily (diurnal) rhythm. The burst of hormone release can be increased or decreased above or below baseline level by various inputs to the gland. Inputs that affect hormone release involve:
(1) stimulation by another hormone or neurotransmitter, or
(2) stimulation caused by a decrease or increase in a certain ion or nutrient.
Examples of hormones that cause an increase or decrease in another hormone s release include all the hypothalamic hormones affecting the anterior pituitary.
Examples of neurotransmitters affecting a hormone s release include the release of insulin in response to epinephrine and norepinephrine stimulation. Ions that influence the release of a hormone include calcium ion s effect on parathyroid hormone, and sodium ion s effect on aldosterone.
Nutrients that affect the release of hormones include the amino acids that stimulate the release of insulin and growth hormone. Frequently, one endocrine gland is stimulated simultaneously by several different inputs.
Chemical Structure of Hormones
There are three broad categories of hormones: peptide, steroid, and amino acid. Most hormones, including all the hypothalamic and pituitary hormones, are peptide hormones. The steroid hormones are made from cholesterol and are soluble across the cell membrane. The amino acid hormones are made from the amino acid tyrosine.
Peptide Hormones
Peptide hormones range in size from a few amino acids to relatively large protein complexes. Peptide hormones circulate in the plasma to their target organs and exert their effects by binding to specific receptors present on the outside of target cell membranes.
By binding to its receptor, a protein hormone changes the cell s permeability to water, electrolytes, or organic molecules such as glucose, or causes the activation of intracellular messengers, which then causes enzyme activation or protein synthesis.
Examples of intracellular messengers include the G proteins, which many protein hormones first activate during receptor binding, and the second messengers such as cyclic adenosine monophosphate (cyclic AMP) and calcium, which are subsequently activated by the G proteins.

Peptide Hormones
Hypothalamic-Releasing and -Inhibiting Hormones and Factors





Thyrotropin-releasing hormone (TRH)
Corticotropin-releasing hormone (CRH)
Growth hormone releasing factor (GRF)

Somatostatin (growth hormone inhibiting hormone)

Gonadotropin-releasing hormone (GnRH)

Prolactin-inhibiting factor (PIF)
Prolactin-releasing hormone (PRH)
Substance P
Anterior Pituitary Protein Hormones Thyroid-stimulating hormone (TSH)
Adrenocorticotropic hormone (ACTH)
Growth hormone (GH)
Follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
Prolactin
Melanocyte-stimulating hormone
Posterior Pituitary Hormones Antidiuretic hormone (ADH)
Oxytocin
Hormones of Digestion and Metabolism Insulin
Glucagon
Calcitonin
Parathyroid hormone
Cholecystokinin
Gastrin
Secretin
Hormone of Blood Pressure and Electrolyte Balance Angiotensin II
Hormone for Red Blood Cell Development Erythropoietin
Hormone to Modulate Stress and Pain Endorphin


Steroid Hormones
Steroid hormones are cholesterol-based, lipid-soluble molecules produced by the adrenal cortex and the sex organs.
Because steroid hormones are lipid-soluble, they can cross the cell membrane and bind to receptors or carriers inside the cell. Once inside a cell, the steroid hormone travels to the cell nucleus, where it influences the cell by affecting DNA replication, transcription of DNA into RNA, or translation of RNA into proteins.
Steroid Hormones
Gonadal hormones
Estrogens
Progesterone
Androgens (primarily testosterone)
Hormones of the Adrenal Cortex
Aldosterone
Glucocorticoids (primarily cortisol)
Androgens (primarily testosterone)
Estrogens

Amine Hormones
The amine hormones are derivatives of the amino acid tyrosine and include thyroid hormone and the catecholamines (epinephrine, norepinephrine, and dopamine).
Epinephrine, norepinephrine, and dopamine also act as neurotransmitters in the central and peripheral nervous systems. The catecholamine hormones travel in the blood to their target cell and bind to the plasma membrane at specific receptor sites.
Binding of catecholamine activates the cyclic AMP second messenger system and alters enzyme activity or membrane permeability. Thyroid hormone travels in the blood mostly bound to carrier proteins with a smaller amount circulating free. Once at the target cell, free thyroid hormone crosses the cell membrane and binds to the nuclear DNA, directly affecting DNA transcription. Therefore, free hormone, although lesser in quantity, is the active hormone.
Amine Hormones
Amine Hormones
Thyroid hormones
Epinephrine
Norepinephrine
Melatonin (from the anterior pituitary)


Control Of Hormone Secretion
The release of most hormones occurs in short bursts, with little or no secretion between bursts. When stimulated, an endocrine gland will release its hormone in more frequent bursts, increasing the concentration of the hormone in the blood.
In the absence of stimulation, the blood level of the hormone decreases. Regulation of secretion normally prevents overproduction or underproduction of any given hormone.
Most hormones are not secreted at a constant rate. Instead, most endocrine glands increase and decrease their secretory activity dramatically over time. Hormones function to regulate the rates of many activities in the body.
The secretion rate of each hormone is controlled by a negative-feedback mechanism , so that the body activity regulation is maintained within a normal range and homeostasis is maintained.
Hormone secretion is regulated by:
(1) signals from the nervous system,
(2) chemical changes in the blood, and
(3) other hormones.
For example, nerve impulses to the adrenal medullae regulate the release of epinephrine; blood Ca2+ level regulates the secretion of parathyroid hormone; and a hormone from the anterior pituitary (adrenocorticotropic hormone) stimulates the release of cortisol by the adrenal cortex. Most hormonal regulatory systems work via negative feedback (see Figure), but a few operate via positive feedback (see Figure ). For example, during childbirth, the hormone oxytocin stimulates contractions of the uterus, and uterine contractions in turn stimulate more oxytocin release, a positive feedback effect.

: Homeostatic regulation of blood pressure by a negative feedback system. Note that the response is fed back into the system, and the system continues to lower blood pressure until there is a return to normal blood pressure (homeostasis).
If the response reverses the stimulus, a system is operating by negative feedback.

: Positive feedback control of labor contractions during birth of a baby. The solid return arrow symbolizes positive feedback.
If the response enhances or intensifies the stimulus, a system is operating by positive feedback.
Hormones have three major patterns of regulation
1. One pattern involves the action of a substance other than a hormone on the endocrine gland. Figure describes the influence of blood glucose on insulin secretion from the pancreas. An increasing blood glucose level causes an increase in insulin secretion from the pancreas. Insulin increases glucose movement into cells, resulting in a decrease in blood glucose levels, which in turn causes a decrease in insulin secretion. Thus insulin levels increase and decrease in response to changes in blood glucose levels.

2. A second pattern of hormone regulation involves neural control of the endocrine gland. Neurons synapse with the cells that produce the hormone, and, when action potentials result, the neurons release a neurotransmitter. In some cases, the neurotransmitter is stimulatory and causes the cells to increase hormone secretion. In other cases the neurotransmitter is inhibitory and decreases hormone secretion. Thus sensory input and emotions acting through the nervous system can influence hormone secretion. Figure illustrates the neural control of epinephrine and norepinephrine secretion from the adrenal gland. In response to stimuli such as stress or exercise, the nervous system stimulates the adrenal gland to secrete epinephrine and norepinephrine, which help the body respond to the stimuli .When the stimuli are no longer present, secretion of epinephrine and norepinephrine decreases.

Nervous System Regulation of Hormone Secretion
The sympathetic division of the autonomic nervous system stimulates the adrenal gland to secrete epinephrine and norepinephrine.


Neural Control of Insulin Secretion:
Blood glucose levels regulate insulin secretion, but insulin secretion is also regulated by the nervous system. When action potentials in parasympathetic neurons that innervate the pancreas increase, the neurotransmitter acetylcholine is released. Acetylcholine causes depolarization of pancreatic cells, and insulin is secreted. When action potentials in sympathetic neurons that innervate the pancreas increase, the neurotransmitter norepinephrine is released. Norepinephrine causes hyperpolarization of pancreatic cells, and insulin secretion decreases. Thus, nervous stimulation of the pancreas can either increase or decrease insulin secretion.
3. A third pattern of hormone regulation involves the control of the secretory activity of one endocrine gland by a hormone or a neurohormone secreted by another endocrine gland. Figure illustrates how thyroid-releasing hormone (TRH) from the hypothalamus the brain stimulates the secretion of thyroid-stimulating hormone (TSH) from the anterior pituitary gland, which, in turn, stimulates the secretion of thyroid hormones from the thyroid gland. A negative-feedback mechanism for regulating thyroid hormone secretion exists because thyroid hormones can inhibit the secretion of TRH and TSH. Thus, the concentrations of TRH, TSH, and thyroid hormone increase and decrease within a normal range.

One of these three major patterns by which hormone secretion is regulated applies to each hormone, but the complete picture isn’t quite so simple. The regulation of hormone secretion often involves more than one mechanism. For example, both the concentration of blood glucose and the autonomic nervous system influence insulin secretion from the pancreas.
A few examples of positive-feedback regulation in the endocrine system exist. Prior to ovulation, estrogen from the ovary stimulates luteinizing hormone (LH) secretion from the anterior pituitary gland. LH, in turn, stimulates estrogen secretion from the ovary. Consequently, blood levels of estrogen and LH increase prior to ovulation . The release of oxytocin during delivery of an infant is another example .

In cases of positive feedback, negative feedback limits the degree to which positive feedback proceeds . For example, after ovulation the ovary secretes progesterone, which inhibits LH secretion.

Some hormones are in the circulatory system at relatively constant levels, some change suddenly in response to certain stimuli, and others change in relatively constant cycles . For example, thyroid hormones in the blood vary within a small range of concentrations that remain relatively constant. Epinephrine is released in large amounts in response to stress or physical exercise; thus its concentration can change suddenly .Reproductive hormones increase and decrease in a cyclic fashion in women during their reproductive years.


Hormone Interactions
The responsiveness of a target cell to a hormone depends on
(1) the hormone’s concentration,
(2) the abundance of the target cell’s hormone receptors, and
(3) influences exerted by other hormones.
A target cell responds more vigorously when the level of a hormone rises or
when it has more receptors (up-regulation).
In addition, the actions of some hormones on target cells require a simultaneous or recent exposure to a second hormone.
In such cases, the second hormone is said to have a Permissive Effect.
For example, epinephrine alone only weakly stimulates lipolysis (the breakdown of triglycerides),but when small amounts of thyroid hormones (T3 and T4) are present, the same amount of epinephrine stimulates lipolysis much more powerfully.
Sometimes the permissive hormone increases the number of receptors for the other hormone, and sometimes it promotes the synthesis of an enzyme required for the expression of the other hormone’s effects.
When the effect of two hormones acting together is greater or more extensive than the effect of each hormone acting alone, the two hormones are said to have a Synergistic Effect. For example, normal development of oocytes in the ovaries requires both follicle-stimulating hormone from the anterior pituitary and estrogens from the ovaries. Neither hormone alone is sufficient.
When one hormone opposes the actions of another hormone, the two hormones are said to have Antagonistic Effects. An example of an antagonistic pair of hormones is insulin, which promotes synthesis of glycogen by liver cells, and glucagon, which stimulates breakdown of glycogen in the liver.

PERMISSIVE EFFECTS-One H. can not exert its effects fully unless a 2nd H. is present & the action of 1st hormone enhances response to 2nd hormone eg. (Up-regulation of progesterone receptor in response to estrogen)& (The maturation of the reproductive system is under the control of GnRH from hypothalamus ; Gonadotropins from adenohypophysis & steroid H. from the gonads. However; if thyroid H. are not present in sufficient amounts ‘maturation of the reproductive system is delayed .Because T.H. by itself can not stimulate maturation of the reproductive system ).
T.H. is considered to have a PERMISSIVE EFFECT on sexual maturation:
-T.H. alone : No development of the reproductive system.
- Reproductive H. alone :Delayed development of the reproductive system.
- Reproductive H. +T.H.: Normal development of the reproductive system.

SYNERGISTIC EFFECTS-The combined effect of 2 H. is greater than the sum of the effects of the 2 H.taken individually (Eg.
- Epinephrin elevates blood glucose 5mg/dl blood
-Glucagone elevates blood glucose 10mg/dl blood
Epinephrin+ Glucagoneelevates blood glucose 22mg/dl blood).
So both hormones must act simultaneously to function effectively (eg. FSH & testosterone for sperm production)

ANTAGONISTIC EFFECTS -2 hormones have opposite effects (work against each other ,one diminishing the effectiveness of the other) eg. Insulin & glucagon (glucagon & growth H. ,both of which raise the conc. Of glucose in the blood ,are ANTAGONISTIC to insulin , which lowers the conc. Of glucose in the blood (One H. may decreases No. of receptors for opposing H.(( Eg. G.H. decreases No. of insulin receptors providing part of its ANTAGONISTIC EFFECTS on blood glucose conc.)).

Hormone ANTAGONISTIC & Cancer:
Tamoxifen is a drug used for the treatment of Breast Cancer when the cancer cells have estrogen receptors & are stimulated by endogenous estrogen. Tamoxifen acts as an ANTAGONIST by competing with estradiol for binding to estrogen receptors .Once Tamoxifen binds it block estradiols action.

Transport and Metabolism of Hormones
Once a hormone is released into the bloodstream it may circulate freely, or it may be bound to a carrier protein. In general, catecholamines, peptides, and proteins circulate in free form whereas steroids and thyroid hormones are bound to transport proteins. Plasma proteins such as albumin and prealbumin have the capacity to nonselectively transport a variety of low molecular weight hormones.
These proteins have a very high capacity to weakly associate with many types of compounds, such as steroid hormones, free fatty acids, and calcium. The binding is said to be nonspecific and the equilibrium constant for dissociation is relatively high. In contrast, there are specific transport proteins for several hormones. These are globulins produced in the liver that have saturable, high-affinity binding sites for the hormones they carry. These proteins include thyroxine-binding globulin (TBG), testosterone-binding globulin (TeBG), and cortisol-binding globulin (CBG).

Binding of hormones to carrier proteins has important consequences:
1) it prevents small hormone molecules from passing out in the urine because the carriers are too large to be filtered by the glomerulus;
2) it slows liver metabolism of the hormone to an inactive form;
3) it acts as a reservoir;
4) it keeps the hormone in an inactive state until the target organ is reached.


An equilibrium is established between carrier-hormone complex and free hormone in serum. As free hormone enters the target cell, the equilibrium shifts to the right and a new equilibrium is established by dissociation of the complex to restore free hormone concentration. In this way, the complexed hormone acts as a reservoir and maintains the hormone in an inactive state.
In general, changes in the plasma levels of binding proteins are rapidly followed by adjustments in the secretion rate of the corresponding hormone, so that the fraction of hormone readily available for tissue delivery remains constant and endocrine function thus remains normal. One well-known example of this is the increase in CBG concentration that occurs during pregnancy as a consequence of estradiol stimulation. While the total plasma cortisol rises as a result of the increased CBG levels, the cortisol available to the tissues remains normal.
As the concentration of CBG increases, there is a temporary shortage in the cortisol available to target tissues as more is bound to CBG. This results in a temporary increase in ACTH by activation of feedback mechanisms and increased cortisol secretion to bring the total plasma concentration of cortisol to a higher level and return tissue delivery of cortisol to normal. Thus, in the steady state with intact control mechanisms, alterations in hormone-binding proteins do not affect endocrine status.
The metabolic clearance rate (MCR) of a hormone defines quantitatively its removal from plasma. Under steady-state conditions the MCR represents the volume of plasma cleared of the hormone per unit of time; usually the units employed are milliliters per minute. Suppose a radioactive hormone is infused into the bloodstream until a constant level is reached. The infusion is then stopped, the disappearance rate of the labeled hormone from the plasma can be determined, and the plasma half-life of the hormone calculated.
The plasma half-life of a hormone is inversely related to its MCR metabolic clearance rate , i.e., a long half-life indicates a slow clearance rate. Usually, the larger molecules have the longer half-life. Of course, small hormone molecules that form complexes with serum proteins would not follow this rule. Such hormones would have much a half-life much longer than expected based on its size since the carrier proteins protects it from metabolism.
Thyroid hormones and steroid hormones are good examples. Thyroid hormones are small molecules of modified amino acids with a half-life of 7 days for thyroxin and 8-24 hours for triiodothyronine. Thyroxin is more tightly bound to TBG than triiodothyronine. Steroid hormones such as cortisol which is transported tightly bound to CBG (transcortin, as the human serum protein is called) has a half-life of about 90 minutes whereas aldosterone and angiotensin II which circulate free in serum have half-lives of about 15 minutes and 1-3 minutes, respectively.
The bulk of hormone clearance is done by the liver and the kidneys. This process includes degradation by a variety of enzymatic mechanisms such as hydrolysis, oxidation, hydroxylation, methylation, decarboxylation, sulfation, and glucuronidation. In general only a small fraction (<1%) of any hormone is normally excreted intact in the urine or feces.
The interaction of hormones with their target tissues apparently is followed by intracellular degradation of the hormone. In the case of protein hormones and catecholamines, degradation occurs after their binding to membrane receptors, internalization of the hormone-receptor complex, and the dissociation of this complex into its two components, which occurs in lysosomes.



Peripheral Conversion of Hormones
In some instances an inactive or less active form of a hormone may be secreted by an endocrine cell into the general circulation and then converted to a more active form by another tissue. This type of peripheral conversion occurs in blood, liver, kidney, lung, and in the target tissues of some hormones. These tissues contain enzymes capable of interconversion of hormones.

Examples:
1. As much as 60% of plasma testosterone in women results from peripheral conversion in liver of androstenedione (weak androgen), which is normally secreted by the adrenal cortex;
2. Renin is a proteolytic enzyme from the kidney and is released into the blood stream in response to a fall in blood pressure. Renin converts angiotensinogen to angiotensin I in blood and, in turn, angiotensin I is converted in the lungs to angiotensin II, a powerful vasopressor and stimulator of aldosterone secretion from the adrenal cortex;
3. Testosterone is secreted by testicular Leydig cells and is converted to a more potent form, 5 alpha-dihydrotestosterone, in the target cell; and
4. The liver converts thyroxine T4 (less active) to triiodothyronine T3 (more active).


HORMONE RECEPTORS
The biological effects of H. are dependent upon hormonal binding to RECEPTORS .These RECEPTORS are:
Made up of glycoproteins.
Present in different sites of the cell:
-On cell mem.(cell mem.receptors)as catecholamine &insuline receptors.
-In cytoplasm(cytoplasmic receptors) as in steroid H. receptors.
-Nuclear receptors as thyroid H.&vit.D receptors.
Specific for H. type.
Different in No. & affinity depending on the hormonal effective level (Up Regulation:Increase in No. & affinity if H. level is low )(Down Regulation :Decrease in No. & affinity if H. level is high)

INTERACTION OF HORMONES WITH TARGET TISSUES
DOWN -REGULATION-the number of receptors decreases rapidly after exposure to certain hormones. Found in tissues adapted to respond to short-term increases in hormone levels.
UP-REGULATION- an increase in the number of receptors upon exposure to hormone eg. FSH causing increase in ovarian LH receptors.



Thank You
Prof. Dr. Sa ad Merza Alaraji