Introduction to Endocrinology

Endocrinology is a study of hormones. The properties of hormones are as follows:

Hormones are Blood Borne Messengers

• Hormones are chemical agents:
• Produced by one organ
• Secreted into the blood
• Carried to all parts of the body by the blood
• Only those organs having the specific receptors respond to the hormone
• Rapidly destroyed so that new messages can be sent
• Involved in homeostasis and adaptation
• Endocrine organs secrete chemical messengers (hormones) into the blood
• Exocrine glands secrete material into the digestive tract (enzymes, bile) or skin surface (sweat)

Many Hormones Control the Activity of Other Endocrine Glands

• Control of endocrine glands by the tropic hormones of the anterior pituitary (ACTH, TSH, FSH. LH)
• There are many other interactions between endocrine glands for example, epinephrine increases the secretion of glucagon

Several Hormones are Involved in Control of Salt, Water and Osmotic Pressure

• Blood pressure, activity of nerves and muscles and other functions depend upon close regulation of body salt & water
• ADH (antidiuretic hormone) causes water retention by causing water pores to be inserted in the collecting duct of the kidney
• Aldosterone increases sodium reabsorption by the kidney (distal tubule)
• Secretion of these hormones is controlled by feedback loops:
• if the blood osmotic pressure is too high, ADH secretion is increased
• if the blood volume falls, aldosterone will increase (this involves 2 more hormones, renin and angiotensin)
• a number of hormones are involved in the control of Calcium

Many Hormones Regulate Reproductive Functions

• Growth of the ovaries and testes and secretion of sex hormones is controlled by FSH and LH.
• At birth oxytocin causes contraction of uterine muscles, aiding in delivery (doctors sometimes give injections of oxytocin to produce uterine contractions.)
• Milk production involves many hormones, including prolactin
• Milk ejection (letdown) when the baby suckles, is also caused by oxytocin

Hormones Control Metabolism & Growth

• Thyroid hormone increases the metabolic rate (oxygen consumption) of many tissues
• Several hormones aid metabolism by raising blood glucose: glucagon, epinephrine, cortisol, growth hormone
• Insulin, lowers blood glucose (promotes energy storage)
• Erythropoietin supports metabolism by regulating the number of red cells in the blood
• Growth hormone is the major hormone supporting body growth- some of its effects are due to secondary hormones, called somatomedins, produced in the liver
• Thyroid hormone also extremely important in growth
• Deficiency of either growth hormone or thyroid hormone during development will produce dwarfism
• Excess growth hormone in children produces gigantism; in adults excess will produce acromegaly

Hormones Help the Body Respond to Stress

• The immediate response to stress is the fight or flight reaction, which has both nervous and hormonal components
• The hormonal component is the release of large amounts of epinephrine (and some norepinephrine) by the adrenal medulla; this hormone stimulates the heart, lungs and other organs involved in the emergency response
• Long term stress will cause release of large amounts of cortisol from the adrenal cortex (essential for life); blood glucose is raised , other effects not well understood
• Deleterious effects of prolonged stress are increased blood pressure and inhibition of the immune system

Classification of hormones: 

The classical hormones fall into three categories:

(a) Derivatives of the amino acid tyrosine;

(b) Steroids, which are derivatives of cholesterol; and

(c) Peptides and proteins, which make up the most abundant and diverse class of hormones.

Endocrine glands synthesize their secretory products from simple precursors such as amino acids and acetate or transform complex pre­cursors taken up from the blood.

All protein and peptide hormones are synthesized on ribosomes as much larger molecules (prohormones and preprohormones) than the final secretory product, and undergo a variety of postsynthetic steps of transformation into the final secretory product. Postsynthetic processing to the final biologically active form is not limited to peptide hormones. Other hormones may be formed from their precursors after secretion. Postsecretory transformations to more ac­tive forms may occur in liver, kidney, fat, or blood, as well as in the target tissues themselves. For ex­ample, thyroxine, the major secretory product of the thyroid gland, is converted extrathyroidally to triio­dothyronine, which is thought to be the biologically active form of the hormone. Testosterone, the male hormone, is converted to dihydrotestosterone within some target tissues, and can even be converted to the female hormone, estradiol, in other tissues. Periph­eral transformations add another level of complexity that must be considered when evaluating causes of endocrine disease.

Hormones in Blood

Hormones are secreted into extracellular fluid and readily enter the blood by passive diffusion driven by steep concentration gradients. Diffusion through pores in capillary endothelium also largely accounts for delivery of hormones to the extracellular fluid that bathes both target and non target cells. Receptor mediated transfer across capillary endothelial cells may facilitate delivery of insulin, and perhaps other hormones, to target cells, but the importance of this mechanism of hormone delivery has not been estab­lished. In general, hormones distribute rapidly throughout the extracellular fluid and are not preferentially directed toward their target tissues.

The classical endocrine glands are:

•         Pituitary gland
  
•        Thyroid gland
  
•        Parathyroid glands
  
•        Islets of Langerhans
  
•        Adrenal glands
•         Gonads
•        Placenta
  

Most hormones are cleared from the blood soon after secretion and have a half-life in blood of less than 30 min. The half-life of a hormone in blood is defined as that period of time needed for its concen­tration to be reduced by half. This depends on its rate of' degradation and on the rapidity with which it can escape from the circulation and equilibrate with fluids in extra vascular compartments. Some hormones, e.g., epinephrine, have half-lives on the order of seconds, whereas thyroid hormones have half-lives of the order of days.

The half-life of a hormone in blood must be distinguished from the duration of its biological effect. Some hormones produce effects virtually in­stantaneously, and the effects may disappear as rapidly as the hormone is cleared from the blood. Other hormones produce effects only after a lag time that may last minutes or even hours, and the time the maximum effect is seen may bear little relation to the time of maximum hormone concentration in the blood. Additionally, the time for decay of a hormone effect is also highly variable; it may be only a few seconds, or it may require several days. Some re­sponses persist well after hormonal concentrations have returned to basal levels. Understanding the time course of a hormone's survival in blood as well as the onset and duration of its action is obviously important for understanding normal physiology, endocrine dis­ease, and the limitations of hormone therapy.

Protein Binding

Most hormones are quite soluble, and circulate completely, dissolved in plasma water. Steroid hormones and thyroid hormones, whose solubility in water is limited, circulate bound to specific carrier proteins with only a small fraction, sometimes less than 1%, present in free solution. Protein binding is reversible; free and bound hormones are in equilib­rium. However, only free hormone can cross the capillary endothelium and reach its receptors in target cells. Protein binding protects against loss of hormone by the kidney, slows the rate of hormone degradation by decreasing cellular uptake, and buff­ers changes in free hormone concentrations.

Hormone Degradation

Implicit in any regulatory system involving hor­mones or any other signal is the necessity for the signal to disappear once the appropriate information has been conveyed. Little if any hormone is "used up" in producing biological effects and it must therefore be inactivated and excreted. Degradation of hormones and their subsequent excretion are processes that are just as important as secretion.

Inactivation of hormones occurs enzymatically in blood, extracellular fluid, liver cells, kidney cells, or in target cells themselves. Inactivation may involve complete metabolism of the hormone so that no recognizable product appears in urine, or it may be limited to some simple one- or two-step process such as addition of a methyl group or glucuronic acid. In the latter cases, recognizable degradation products are found in urine and can be measured to obtain a crude index of the rate of hormone production.

                                                 

Hormone Levels in Blood

Hormone concentrations in blood plasma fluctuate from minute to minute and may vary widely in the normal individual over the course of a day. In general, rates of hormone degradation follow first order kinetics, and are not regulated. Fluctuations in hormone levels, therefore, reflect fluctuations in rates of secretion. Hormone secretion may be episodic, pulsatile, or follow a daily rhythm (Fig. 1). The pattern of hormone secretion, as well as the amount secreted, may be of great importance in determining some hormone responses. It is noteworthy that for the endocrine system as well as the nervous system, information can be transmitted by the frequency of signal production as well as by the chemical signal itself. Because the concentrations of some hormones normally fluctuate widely, it is necessary to make multiple serial measurements be­fore a diagnosis of a hyper or hypo functional state can be confirmed. Endocrine disease occurs when the concentration of hormone in blood is inappro­priate for the physiological situation rather than because the absolute amounts of hormone in blood appear high or low.

                                                              

REGULATION OF HORMONE SECRETION

For hormones to function as carriers of critical information, their secretion must be turned on and off at precisely the right times. The organism must have some way of knowing when there is need for a hormone to be secreted and when that need has passed. The necessary components of endocrine regulatory systems include the following:

1.     Detector of an actual or threatened homeostatic imbalance

2.     Coupling mechanism to activate the secretory apparatus

3.     Secretory apparatus

4.     Hormone

5.     End organ capable of responding to the hormone

6.     Detector to recognize that the hormonal effect has occurred and that the hormonal signal can now he shut off—usually the same as component 1

7.     Mechanism for removing the hormone from target cells and blood

8.     Synthetic apparatus to replenish hormone in the secretory cell.

It is important to identify and understand the components of the regulation of each hormonal secretion because

(a) Derangements in any of the components are the bases of endocrine disease and

(b) Manipulation of any component provides all opportunity for therapeutic intervention. 

Secretion of most hormones regulated by nega­tive feedback, which means that some Consequence of hormone secretion acts directly or indirectly on the secretory cell in a negative way to inhibit further secretion. A simple example from everyday experi­ence is the thermostat. When the temperature in a room falls below some preset level, the thermostat signals the furnace to produce heat. When room temperature rises to the preset level, the signal from the thermostat to the furnace is shut off, and heat production ceases until the temperature again falls. This simple closed-loop feedback system is analogous to the regulation of glucagon secretion. A fall in blood glucose detected by the alpha cells of the islets of Langerhans causes them to secrete glucagon, which stimulates the liver to release glucose and thereby increase blood glucose concentrations.

                                                                         

With restoration of blood glucose to a predetermined level or set-point, further secretion of glucagon is inhib­ited. This simple example involves only secreting cells and responding cells. Certain other systems are considerably more complex and involve one or more intermediary events, but the essence of negative feedback regulation remains the same: hormones produce biological effects that directly or indirectly inhibit further hormone secretion.

A problem that emerges with this system of control is that the thermostat keeps room temperature constant only if the natural tendency of the temperature is to fall. If the temperature were to rise, it could not be controlled by simply turning off the furnace. This problem is at least partially resolved in hormonal systems, since the basal rate of secretion usually is not zero at physiological set-points. In the example above, even though the rate of glucagon secretion is very low at the set-point for blood glucose concen­tration, secretion can be further diminished when the glucose concentration rises above the set-point. This decrease in glucagon secretion would diminish the impetus on the liver to release glucose. Some regulation above and below the set-point can, there­fore, be accomplished with just one feedback loop; this mechanism is seen in some endocrine control systems. Regulation is more efficient, however, with a second, opposing loop that is activated when the controlled variable deviates in the opposite direction. For the regulation of blood glucose, that second loop is provided by insulin. Insulin inhibits glucose pro­duction by the liver and is secreted in response to an increase in blood glucose concentration (Fig. 4). Pro­tection against deviation in either direction is often achieved by the opposing actions of antagonistic control systems.                                                                                                       

                                                           

Closed-loop negative feedback control as described above can maintain conditions only at a state of constancy. These systems are effective in guarding against upward or downward deviations from some predetermined set-point, but changing environmen­tal demands often require temporary deviations from constancy. Deviations from constancy are achieved sometimes by adjusting the set-point and at other times by a separate signal to override the set-point. For example, epinephrine, which is secreted by the adrenal medulla in response to some emergency, inhibits insulin secretion and stimulates glucagon secretion even when the concentration of glucose in the blood is already high. Whether the set-point is changed or overridden, deviation from constancy is achieved by the intervention of some additional signal from outside the negative feedback system. In most cases, that additional signal originates in the nervous system.

Hormones also initiate or regulate processes that are not limited to steady or constant conditions, and they also frequently involve the nervous system. Virtually all of these processes are self-limiting, and their control resembles negative feedback, but of the open-loop type. For example, oxytocin is a hormone that is secreted by hypothalamic nerve cells whose axons terminate in the posterior pituitary gland. Its secretion is necessary for the extrusion of milk from the lumen of the mammary alveolus into secretory ducts so that the infant suckling at the nipple can receive milk. In this case, sensory nerve endings in the nipple convey affèrent information to the central nervous system, which in turn signals release of oxytocin from the posterior pituitary gland. Blood-borne oxytocin stimulates myoepithelial cells in the mammary glands to contract, resulting in delivery of milk to the infant. When the infant is satisfied, the suckling stimulus at the nipple ceases. 

Positive Feedback

     Positive feedback means that some consequence of hormonal secretion acts on the secretory cells to provide augmented drive for secretion. Rather than being self-limiting, as with negative feedback, the drive for secretion becomes progressively more in­tense. Positive feedback systems are unusual in biol­ogy, and terminate with some cataclysmic, explosive event. A good example of a positive feedback system involves oxytocin and its action to cause contraction of uterine muscle during childbirth (Fig. 5). In this case, the stimulus for oxytocin secretion is dilation of the uterine cervix. Upon receipt of this information through sensory nerves, the brain signals release of oxytocin from nerve endings in the posterior pituitary gland. Enhanced uterine contraction in response to oxytocin results in greater dilation of the cervix, which strengthens the signal for oxytocin release and so on until the infant is expelled from the uterine cavity. 

                                                                                         

ACTIONS OF HORMONES

     Regulation of bodily functions by hormones is achieved by regulating the activities of individual cells. Hormones signal cells to start or stop secreting, contracting, dividing, or differentiating. They may also accelerate or slow the rates of these processes, or they may modify responses to other hormones. All of these cellular actions summate to produce the biological responses we observe at the level of tissues, organs, and the whole body. Although hormones are distributed throughout the blood and extracellular fluid, only certain target cells respond to any given hormone. Some cells are targets for more than one hormone.

Whether or not a cell responds to a hormone depends upon whether or not it has receptors for that hormone. However, it is important to recognize that the specific response elicited in a given cell is determined by the cell rather than the hormone, and that different cell types may re­spond to the same stimulus in different ways. For example, both vascular smooth muscle cells and cells in the collecting ducts of renal tubules are targets for the posterior pitutary hormone vasopressin. When stimulated by vasopressin, arterioles contract, whereas collecting ducts increase their permeability to water. 

PRINCIPLES OF HORMONAL INTEGRATION

     Maintaining the integrity of the internal environ­ment or successfully meeting an external challenge typically involves the coordinated interplay of several physiological systems, and the integration of multiple hormonal signals. Solutions to physiological problems require integration of a large variety of simultaneous events that together may produce results that are greater or less than the simple algebraic sum of the individual hormonal responses. Some of the ways that endocrine regulatory systems may interact are as follows:

1- Modulation of Responding Systems

Not all aspects of hormonal control are determined simply by how much hormone is secreted or even by when a hormone is secreted. Receptivity of target tissues to hormonal stimulation is not constant and can be changed under a variety of circumstances. Receptivity of target tissues to hormonal stimulation can be expressed in terms of two separate but related aspects: sensitivity to stimulation and capacity to re­spond. Sensitivity describes the acuity of a cell’s ability to recognize a signal, and to respond in proportion to the intensity of that signal. We can define sensitivity in terms of the concentration of hormone that will produce 50% of the maximum response. The capacity to respond, or the maximum response that a tissue is capable of giving, depends on the amount of competent or differentiated cells in that tissue as well as the level of development of the enzymatic machinery within those cells (Fig. 6). Hormones regulate both the sensitivity and the capacity of target tissues to respond either to themselves or to other hormones.

                                                                        

One mechanism by which hormones determine the sensitivity of target tissues is by regulation of hormone receptors. It should be recalled that the initial event in producing a hormonal response is the interaction of the hormone with its receptor. The higher the concentration of hormone, the more likely it is that there will be an interaction with receptors. If there are no hormone receptors, however, there can be no response. The more receptors that are available to interact with hormone, the more likely it is that there will be a response. Therefore, the likelihood that hormone receptor interaction will occur is related to the abundance of both the hormone and the receptor. The affinity of the receptor for its hormone also affects the likelihood that an interaction will occur at any given abundance of hormone and receptor. By and large, however, modulation of responses usually involves regulation of the number of receptors rather than their affinity for hormone.

Some hormones decrease the number of their own receptors in target tissues. This mechanism is called down regulation and may result from inactivation of receptors at the cell surface, from an increased rate of destruction of internalized hormone receptor com­plexes, or decreased receptor synthesis. Down regu­lation, however, is not limited to surface receptors for water soluble hormones or to the effects of a hormone on its own receptor. One hormone can down regulate receptors for another hormone. This appears to be the mechanism by which triiodothy­ronine decreases the sensitivity of the thyrotropes of the pituitary to thyrotropin-releasing hormone. Similarly, progesterone may down reg­ulate both its own receptor and the estrogen receptor.

Up regulation, the increase of available receptors, also occurs and can be seen both for receptors on the cell surface and for the internal receptors of the lipid soluble hormones. Prolactin and, possibly, growth hormone may up regulate their receptors in responsive cells. Estrogen up regulates both its own receptors and those of luteinizing hormone in ovarian cells during the menstrual cycle. Up regulation such as, that produced by estrogen is initiated by a change in gene expression.

Sensitivity to hormonal stimulation can also be modulated in ways that may not involve receptors. Post receptor modulation may affect any of the steps in the biological pathway through which hormonal effects are produced. Therefore, greater or lesser responses may be seen, even when all of the receptors are occupied. Altered responsiveness to a hormone may follow from post receptor changes in both the sensitivity to hormonal stimulation and in the capacity to respond. Another aspect of hormone modulation has been called permissive action. A hormone acts permissively when its presence is necessary for, or permits, a biological response to occur, even though the hormone itself does not initiate the response. Permissive actions are not limited to responses to hormones, but pertain to any cellular response to any signal. The concept that hormones may act in a permissive manner was originally developed to ex­plain diverse actions of the adrenal cortical hormones, but it appears to pertain to the effects of other hormones as well. Although some fundamental cel­lular processes must be involved, the molecular mech­anisms that account for permissiveness are still not understood.

 2- Reinforcement

     Although a hormone may trigger an overall cellular response by affecting some fundamental rate-deter­mining reaction, more than one process may be affected. Hormonal effects exerted at several locales within a single cell summate to produce the overall response. Let us consider, for example, just some of the ways insulin acts on the fat cell to promote storage of triglycerides:

 

1.    Insulin acts at the cell membrane to increase availability of substrate for lipid synthesis.

2.    It activates several cytosolic and mitochondrial enzymes critical for fatty acid synthesis.

3.    It inhibits breakdown of already formed triglyc­erides.

4.    It induces synthesis of the extracellular enzyme lipoprotein lipase, which is needed for lipids to be taken up from the circulation.

  Any one of these effects would increase fat storage, but collectively, they reinforce each other and pro­mote a larger response in a shorter time frame than would be possible if insulin produced only one of these actions.

Reinforcement can also be observed at the level of the whole organism, where a hormone may act in different ways on different tissues to produce com­plementary effects. A good example of this is the action of adrenal glucocorticoid hormones to pro­mote gluconeogenesis. They act in peripheral tissues to mobilize substrate, and in the liver to increase conversion of precursors to glucose. Either the extra-hepatic action or the hepatic action would increase gluconeogenesis, but together, these complementary actions reinforce each other and in­crease both the magnitude and rapidity of the overall response.

 3- Redundancy

     Fail-safe mechanisms govern crucial functions. Just as each organ system has the built-in capacity to function at levels beyond the usual day-to-day de­mands, so too, is there excess regulatory capacity provided in the form of seemingly duplicative or overlapping controls. For example (Fig. 7), conver­sion of liver glycogen to blood glucose can be signaled by at least two hormones, glucagon from the alpha cells of the pancreas and epinephrine from the adrenal medulla. Both of these hormones increase adenosine 3’,5’-cyclic mono-phosphate (cAMP) production in the liver, and thereby activate the enzyme glycogen phosphorylase, which catalyzes glycogenolysis. Two hormones secreted from two different tissues, sometimes in re­sponse to different conditions, thus produce the same end result.

                                                                             

Redundancy can also be seen at the molecular level. Using conversion of liver glycogen to blood glucose as our example again, there are two molecular pathways through which epinephrine can activate glycogen phosphorylase. By stimulating 3-adrenergic receptors, epinephrine increases glycogenolysis through the cAMP mechanism, and by stimulating a-adrenergic receptors, it activates phosphorylase through the agency of increased calcium concentra­tions produced by the release of inositol trisphosphate (1P3) (Fig. 8).

                                                                  

Redundant mechanisms not only assure that a critical process will take place, but they also offer opportunity for flexibility and subtle fine tuning of a process. Though redundant in the respect that two different hormones may have some overlapping ef­fects, the actions of the two hormones are usually not identical in all respects. Within the physiological range of its concentrations in blood, glucagon’s action is restricted to the liver; epinephrine produces a variety of other responses in many extrahepatic tis­sues while increasing glycogenolysis in the liver. Variations in the relative input from both hormones allow for a wide spectrum of changes in blood glucose concentrations relative to such other effects of epi­nephrine as increased heart rate.

Two hormones that produce common effects may differ not only in their range of actions, but also in their time constants (Fig. 9). One may have a more rapid onset and short duration of action; another may have a longer duration of action, but a slower onset. For example, epinephrine increases blood concentrations of free fatty acids within seconds or minutes, and this effect dissipates as rapidly when epinephrine secretion is stopped. Growth hormone similarly increases blood concentrations of free fatty acids, but its effects are seen only after a lag period of 2 to 3 hrs and persist for many hours. A hormone like epinephrine may, therefore, be used to meet short-term needs, and another, like growth hormone, may answer sustained needs.

                                                                    

One of the implications of redundancy for the understanding both of normal physiology and en­docrine disease is that partial, or perhaps even com­plete, failure of one mechanism can be compensated by increased reliance on another mechanism. Thus, functional deficiencies may only be evident in subtle ways and may not show up readily as overt disease. Some deficiencies may only become apparent after appropriate provocation or perturbation of the sys­tem. Conversely, strategies for therapeutic interven­tions designed to increase or decrease the rate of a process must take into account the redundant inputs that regulate that process. Merely accelerating or blocking one regulatory input may not produce the desired effect since independent adjustments in re­dundant pathways may completely compensate for the intervention.

 4- Push-Pull Mechanisms

     Many critical processes are under dual control by agents that act antagonistically either to stimulate or to inhibit. Such dual control allows for more precise regulation through negative feedback. The example cited above was hepatic production of glucose, which is increased by glucagon and inhibited by insulin. In emergency situations or during exercise, epinephrine and norepinephrine released from the adrenal me­dulla and sympathetic nerve endings override both negative feedback systems by inhibiting insulin secre­tion and stimulating glucagon secretion (Fig. 10). The effect of adding a stimulatory influence and simultaneously removing an inhibitory influence is a rapid and large response, more rapid and larger than could be achieved either by simply affecting either hormone alone or by the direct glycogenolytic effect of epi­nephrine or norepinephrine.

Another type of push-pull mechanism can be seen at the molecular level. Net synthesis of glycogen from glucose depends upon the activity of two enzymes: glycogen synthase, which catalyzes the formation of glycogen from glucose, and glycogen phosphorylase, which catalyzes glycogen breakdown (Fig. 11). The net reaction rate is determined by the balance of the activity of the two enzymes. The activity of both enzymes is subject to regulation by phosphorylation, but in opposite directions: addition of a phosphate group activates phosphorylase, but inactivates synthase. In this case, a single agent, cAMP, which activates protein kinase A, increases the activity of phosphorylase and simultaneously inhibits synthase.