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6. GENERAL ENDOCRINOLOGY

HORMONES

Hormones are potent regulators of biological functions, which act through receptors located in different structures of the cells. Hormones are produced, distributed and used

within the animals in which they are synthesized (Fig. 6-1).

There are other similar compounds called pheromones, which are produced by an animal and released into the environment to act on other animals.

Based on their chemical nature, many hormones can be grouped in families of related molecules. For example, several versions of growth hormones can be produced by one species. Several forms of estrogens exist. These related hormones usually exert similar effects but each has a different potency. Although some hormones may be synthesized by a very specific tissue, the majority of hormones are synthesized at multiple sites. For example, steroids are produced in the gonads, placenta and adrenal glands; somatostatin (SS) is produced in the pancreatic islets, thyroid gland, gastrointestinal tract, and brain. Therefore, depending on what the cell of origin was, some of these compounds could also be associated with the traditional endocrine system, the neuroendocrine system or the nervous system.

The secretion of some hormones is controlled by the presence of other chemicals in circulation. Sugar influences the concentration of insulin; calcium influences calcitonin. Other hormones’ concentration is controlled through the nervous system. The pineal gland produces melatonin, regulated by light stimulus which is conveyed through the nervous system, while the adrenal medulla

releases catecholamines in response to internal or external stimuli delivered through nervous impulses. The endocrine and the nervous systems are intimately related. They produce both hormones and neurotransmitters. A compound, which at one point is considered a hormone because it is released into circulation to reach its target, can also be considered a neurotransmitter when it is delivered directly into a synaptic junction. Although the compound could be the same, it is considered within the endocrine system if the hormone is secreted by a secretory cell and travels to the target cell (Fig. 6-2). The compound is part of the neuroendocrine system if it is synthesized in and released from a neuron into circulation in order to reach its target tissue somewhere else in the body. Finally, a compound is within the nervous system if it is produced by a neuron and

released directly into the target tissue.

Depending on their water solubility, hormones can move through circulation free or bound to other proteins. They can also diffuse to nearby cells or act within the same cell, in which they are produced, without entering circulation.

Those compounds acting on the same cell, in which they are produced, are considered autohormones. Most prostaglandins operate in this manner. Those compounds acting in adjacent cells, thus not entering circulation, are called parahormones. Again, many prostaglandins, as well as estrogens and testosterone can operate in this manner (Fig. 6-3).

Hormones

Potent regulators of biological functions

Their biosynthesis, storage, excretion and metabolism depends on their chemical structure and composition

Figure 6-1. Characteristics of hormones

Figure 6-2. Variations in the type of secretory cells and means of reaching the target tissue

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Some hormones are specific for an organ. Such is the case of adrenocorticotropic hormone (ACTH) which stimulates the zona fasciculata of the adrenal gland. Other hormones are extremely general as is the case with estrogens which influence the ovaries, oviducts, uterus,

vagina, mammary gland, bones, bone marrow, liver, thymus, pituitary gland, and brain. Specificity is due to the availability of receptors in the target tissue.

Hormones control biochemical processes, which in turn are responsible for regulation of cell specialization, nutrition, metabolism, and behaviour. The biochemical processes in which they are involved could deal with self-regulation or regulation of receptors. From a functional point of view, the hormone concentration alone is meaningless, because an outcome also depends on many other factors such as availability of receptors.

Hormonal classification

Hormones can be classified according to several criteria. Among the most common, we can find the source of origin or tissue which produces them, the mechanism of activation, the chemical composition of the molecules and the function they exert in the organism (Fig. 6-4).

Structure and composition

Following the criterion of chemical composition, hormones can be divided into three large groups (Fig. 6-5).

Amino acids and their derivatives. Compounds

are derived from one amino acid, such as melatonin,

histamine, or gamma amino butyric acid (GABA). A large majority of the neurotransmitters fall within one of these categories? (Fig. 6-6).

Iodinated hormones. This is a special group of

amino acid derivatives, characterized by the inclusion of iodine in the molecule. All iodinated hormones are synthesized in the thyroid gland. The biologically active hormones are thyroxine (T4) and triiodothyronine (T3).

Protein Hormones. This group of hormones vary in

size and structure. They range from a few amino acids to large and complex groups of proteins (Fig. 6-7). These in turn can be sub-divided according to the size and type of molecules.

Polypeptides. Hormones in this group have a large

number of amino acids and some may include the presence of sulphate bonds whose role is to provide the three-dimensional shape or quaternary structure of the molecule. Within this group, we can find insulin, growth

Classification

Origin

o Pituitary, thyroid, gonad

Activation

o Direct synthesis, conversion, cleavage

Chemical composition

o Amino acids, lipids, proteins

Function / action

o Neurotransmitters, inhibitors

Figure 6-4. Variations on the classification criteria for hormones

Type of hormones

Amino acid derivatives

Proteins

Lipid derivatives

Figure 6-5. Classification of hormones based on their chemical composition

Figure 6-3. Classification of hormones based on the distance and route traveled between the secretory and target cell

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hormones (GH), Müllerian inhibitory substance (MIS), also known as the antimüllerian hormone (AMH).

Glycoproteins. These hormones are made up of a

large number of amino acids with a significant percentage of sugars. The sugars serve to enhance the binding ability as well as to facilitate the attainment of the final structure. In some cases, the added sugar provides protection against catabolism, thus, increasing the half-life of the hormone. Many of the hormones in this group are made of two sub units such as luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and inhibins.

Lipids. There are several groups of hormones derived

from lipids (Fig. 6-8). The most common ones are steroids and prostaglandins.

Steroids. Steroids are hormones derived from

cholesterol. Usually the cholesterol is taken from circulation, mainly from low density lipoproteins (LDL); although high density lipoproteins (HDL) can also be used as a source of cholesterol. If needed however, the steroid secreting cells can synthesize cholesterol de novo in situ.. The most common steroids are estrogens, androgens, and corticosteroids.

Prostaglandins. These are hormones derived from arachidonic acid such as prostaglandin F2α (PGF2α) and

prostaglandin E1 (PGE1).

Biosynthesis of hormones

Amino acid derivative. Amino acid derivatives are

water-soluble compounds whose synthesis depends normally on one enzyme. When several steps are required with the conversion of the precursor to the final hormone, one of them becomes the rate limiting step and most likely this is the point of control (Figs. 6-9, 9-10). Some of the amines can be stored in granules which serve to protect cells, to prevent metabolism, act as a

Proteins

Small peptides

TRH 3 aa

Polypeptides

GnRH 10 aa, ACTH 41 aa

Glycoproteins

LH, FSH, TSH

Figure 6-7. Protein based hormones

Amino acid derivatives

Neurotransmitters

o Catecholamines (Tyrosine derivative)

Epinephrine

Norepinephrine

Dopamine

o GABA

Thyroid hormones

o Triiodothyronine (T3)

o Thyroxine (T4)

Figure 6-6. Hormones derived from amino acids

Lipids

Steroids

o Progestogens, glucocorticoids, mineralocorticoids

21 C progesterone, cortisol, aldosterone

o Androgens

19 C testosterone

o Estrogens

18 C estrone, estradiol, estriol

o Prostaglandins

PGF2α, PGE, PGH

Figure 6-8. Hormones derived from lipids

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secretory mechanism, or permits re-uptake and release of the hormones / neurotransmitters for recycling purposes.

Small peptides. The majority of the small peptides are

assembled by cytoplasmic enzymes, not by ribosomes.

They could also be cleaved from a larger peptide.

Thyrotropin releasing hormone (TRH), for example is a tripeptide produced in the hypothalamus. Melanocyte

inhibiting factor I (MIF-I) is a tripeptide cleaved from a larger peptide this is a part of oxytocin (Ot). Oxytocin and

antidiuretic hormone (ADH) are synthesized in the hypothalamus and released in the neurohypophysis; they differ only in two aa (Fig. 6-11).

Intermediate size peptides. This group is made

of larger polypeptides which are put together directly by

ribosomal assembly or by a split from larger polypeptides. Gastrin with all its derivatives falls within this group.

Large peptides. Large peptides are made by

ribosomes usually from a larger protein from which parts were cleaved i.e.:

Glucagon is a hormone of pancreatic origin with 29 aa which are identical in many species. The entire molecule is needed to maintain activity. There are several closely related molecules such as immunoreactive glucagon (IRG) or glucagon-like immunoreactivity (GLI) which are not as active as glucagon.

Secretin is a 27 aa peptide, 14 of which are identical to glucagons’. It has glucagon-like activity as well as other specific functions similar to those of gastric inhibitory polypeptide (GIP).

Insulins. Pro-insulin forms one chain which, upon cleavage of the connective peptide (C peptide), changes its tridimensional configuration and becomes the activated form. The final structure is composed of two chains joined by disulfide bonds (Fig. 6-12).

Figure 6-9. Simple conversion of an amino acid (in this case a hormone itself) into another active hormone

Figure 6-10. Multi-step conversion of an amino acid into several hormones

Figure 6-11. Slight variation in small peptides yield hormones with totally different functions

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Protein (polypeptide). Amino acids from circulation

are put together in cells under mRNA codes to form a large preprohormone. Such is the case with the parathyroid hormone (PTH) which is derived from an initial protein containing 115 aa. The first two aa are the initiator peptide which is cleaved after the chain has reached a size of about 20-30 aa long. The following signal sequence facilitates entrance into the rough endoplasmic reticulum. As soon as the transcription is finished the signal sequence is chopped and rapidly degraded. What is left is a prohormone which, together with some active hormones, is packed into granules in the Golgi apparatus. Intracellular movement of the hormones happens through microtubules. About 70% of the hormone enters the cytoplasm and is digested.

Glycoproteins. Some hormones have sugars that are

not needed for biological activity as it is the case of ACTH. Other hormones such as FSH and LH require carbohydrates (CHOs) to be active. There are species differences, but some glycoprotein hormones can also work in other species. This compatibility is exploited to produce potent therapeutic compounds that are widely used in the veterinary field. The use of Human Chorionic Gonadotropin (HCG) and pregnant mare serum gonadotropin (PMSG) in reproductive manipulation and in therapy are excellent examples. Variation in CHOs content influences the potency of the hormone but not its effect.

Glycoproteins may contain several added molecules, such as sialic acid, which is abundant in TSH and important in FSH; glucose, which is present in most glycoproteins; and fructose which is also widely distributed.

Sub units. As mentioned above, many glycoprotein

hormones of hypophyseal or placental origin contain two glycosylated polypeptide chains held by non-covalent links. These are called subunits (Fig. 6-13). Inhibin is also composed of subunits, but these are linked by disulfide bonds.

Within a species the α subunits of several hormones are

similar and essential to the formation of the final hormone while the β subunits are different. The β subunits provide

Figure 6-12. A protein hormone secreted as a zymogen has to be converted to the active form

Figure 6-13. Many hormones are made of subunits. One of these is common to several hormones and the other confers the biological activity to the hormone

Figure 6-14. The same α subunit is used by both LH and FSH but the β subunit determines the biological activity

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the biological activity of the hormone. Independent units are biologically inactive (Fig. 6-14). The subunits are coded by different genes. The exception is the joining of two β subunits of the inhibin hormone which exerts activin activity in FSH but not in LH.

Secretion of protein related hormones

Protein hormones can leak out of the secretory cells, especially the small hormones. The majority, however, are packed in secretory granules destined for exocytosis. Exocytosis involves the adherence of the secretory granule to the plasma membrane followed by the fusion of the granule. The plasma membrane then culminates in the discharge of the granules content, on the outside of the cell. Next the extra membrane is reabsorbed by the cell and degraded. Membranes are internalized; some

recycled, some digested.

Iodinated Hormones

As the name indicates, this group of hormones is characterized by the presence of iodine. These hormones are synthesized in the thyroid gland. The most important are tetraiodothyronine, also known as thyroxine or T4, and triiodothyronine or T3 (Fig. 6-15).

If the internal ring of the hormone is de-iodinated it becomes an inactive compound called reverse T3 or rT3. When the hormone is being catabolized, further de-iodination takes place in the other sites.

Steroids

Steroids are liposoluble compounds derived from circulating cholesterol or synthesized from Acetyl Co A (ACoA). They have several structural features, but the most important is that of the cyclopentanopherhydro-phenanthrene nucleus, which is common to all steroids (Fig. 6-16).

Depending on the number of carbons in the basic structure

(Fig. 6-17), steroids can be classified as:

Figure 6-15. Structure of biologically active thyroid hormones, their precursors and the inactive form

Figure 16. Structure of the steroid nucleus cyclopentanopherhydrophentanthrene

Figure 6-17. Structures of cholestane and cholesterol

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Pregnanes. Pregnanes are compounds with 21

carbons such as progestogens, glucocorticoids and mineralocorticoids (Fig. 6-18). Androstanes. Androstanes are compounds with 19

carbons, as it is with all androgens (Fig. 6-19).

Estranes. Estranes are compounds with 18 carbons,

like all estrogens (Fig. 6-20). The name of each compound can be determined following simple nomenclature rules (Fig. 6-21). An example of how to name them is presented in figure 6-22.

Prostaglandins. Prostaglandins are 20 carbon fatty

acid derivatives. The limiting factor for their biosynthesis is the availability of precursor arachidonic acid; initially derived from cell membrane lipid components by the enzyme phospholipase A2 and then converted to prostaglandin G2 (PGG2) by the enzyme cyclooxygenase (Fig. 6-23). Prostaglandins are synthesized in most cells. They have local and systemic effects, thus can be considered autohormones, parahormones or hormones. Prostaglandins have a short half-life, in the range of seconds, due to pulmonary degradation.

Figure 6-18. Structures of pregnane and the hormone progesterone

Figure 6-19. Structures of androsterone and the hormone testosterone

Figure 6-20. Structures of estrane and the hormone estradiol

Steroid nomenclature

Prefix Suffix Indicates

Hydroxy -ol Hydroxyl group (-OH)

β-OH - Hydroxyl above plane

α-OH - Hydroxyl below plane

Oxo one Keto or carbonyl group (C=O)

- al Aldehyde (-CHO)

Carboxy -oic acid Carboxylic acid (COOH)

- -ene Double bond (-C=C-)

- -yne Triple bond (-C=C-)

- -ane Saturated ring

Figure 6-21. Basic nomenclature used to name steroid compounds

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The structure of the pentane ring determines the letter of the name and it identifies the family of hormones. The number of double bonds in the structure is reflected in the number of the name (Fig. 6-24).

MECHANISMS OF HORMONE ACTION

Anatomical aspects

Hormones act on similar or different cells to produce similar or different effects. They are considered endocrine substances if they reach circulation and exert their action far from the site of synthesis. They are considered apocrine (parahormones) substances if they diffuse to a nearby cell to exert their action. They are considered autocrine (autohormones) if their action takes place in the same cell in which they are synthesized (Fig. 6-3).

Mechanism of binding

The manner in which hormones exert their biological effects is by attaching themselves to specific protein structures in the target cell called receptors. The attachment is non-covalent; therefore, they cannot separate unless part of the effect involves self-degradation or internalization.

Hormones may require prolonged or short bindings to elicit a response. There are several proposed mechanisms of action.

Multiple primary sites. One hormone has the

potential to bind multiple sites in a cell and triggers several biochemical processes. It is estimated that on the average each cell contains between 103 to 105 receptors.

Simple cascade. One hormone binds to a receptor

and generates a multiplicative effect in an organized

Figure 6-22. Structure and name of cortisol Pregn-ene-3,20 dione, 11β, 17α, 21-triol or 11β, 17α, 21-trihydroxypregn-4-ene-3,20dione

Figure 6-23. Structure of arachidonic acid, the precursor of all prostaglandins and one prostaglandin E

Figure 6-24. Differences in the pentane ring configuration determine the class of prostaglandins

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manner. Cascades increase biological responses to low hormonal concentrations.

Complex cascade. One hormone binds to a receptor

and generates multiple simultaneous sequences of events in the cell.

Domino effect. The hormone binds to a receptor and

starts a single chain of events which cannot be stopped until the final product is complete, even if the hormone has detached from the receptor.

Sustained action. The hormone needs to be bound to

the receptor for a long period of time to complete the desired effect Latent period. The period between hormone binding

and the visible or measurable effect is the latent period. Latent periods can be very fast, in seconds, when the effect is the depolarization of tissue such as in the case of oxytocin action on smooth myoepithelial cells. It can also be rather slow, it may take weeks, when the effect involves biosynthesis of many other substances, as in the case with thyroid hormones (Fig. 6-25)

MECHANISMS OF PROTEIN HORMONES' ACTIONS

Second messenger theory

Protein hormones do not enter cells. They bind to a surface receptor to activate an effector protein (Fig. 6-26).

The effector protein activates an enzyme that mediates the formation of a second messenger (Fig. 6-27). This second messenger is a cytoplasmic generated molecule which affects cell function. One of the most common second messengers are cAMP, Ca++ in association with calmodulins, and inositol phosphate.

Adenylate cyclase and cyclic adenosine monophosphate

Between the receptor and adenylate cyclase there is a complex called the G protein which transduces the hormone influence into the cell. G proteins are made up of three G units: Gα, Gβ and Gγ. Upon the binding of the

hormone to the membrane receptor, the guanosine diphosphate (GDP), which is normally attached to the Gα

unit, gets exchanged for guanosine triphosphate (GTP). This exchange facilitates the dissociation of Gα-GTP from the remainder Gßγ dimer. The Gα-GTP complex becomes

Latent period

Ultra short (Seconds) Pre-existing

enzymes,

permeability

Very short (minutes) Enzymatic cascades

Short (1/2- 1 hour) Peptide assembly

Long (hours) Protein induction

Very long (days) Growth, cell

proliferation

Ultra long (Weeks) Cell

enhancement

Figure 6-25. Latent period of hormone action or the time elapsed between the release of the hormone and an observable effect

Figure 6-26. Transmembrane receptor attached to an effector protein. In this case G protein

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activated and then it activates adenylate cyclase to convert intracellular ATP into cAMP, the second messenger. Elevated concentrations of cAMP act on protein kinases and regulatory enzymes, to catalyse the transfer of phosphates from ATP to many other molecules including enzymes (Fig. 6-27).

Several types of Gα have been isolated, some are stimulatory (Gαs), others are inhibitory (Gαi) or transducers (Gαt) and there are still others whose functions are not yet understood (Gαo).

After the expected outcome has been attained the Gα-GTP will revert to Gα-GDP, re-associate with the Gßγ complex and stop the adenylate cyclase activity. When this occurs the system is turned off until a new hormonal receptor binding takes place. There are other systems, which use the action of the Gßγ protein complex to activate the enzyme to produce the second messenger.

Inositol phosphate and calcium

Another second messenger system, also controlled by a G protein, slightly different than the one involved with the adenylate cyclise, is the inositol phosphate and calcium. In this system a Gα protein unit dissociates from Gßγ and stimulates the activity of phospholipase C. This in turn cleaves phosphoinositol from the cell membrane, into two molecules, inositol triphosphate and diacyl glycerol (DG). Inositol phosphate binds intracellular receptors which in turn control Ca++ channels and hence intracellular

Ca++, the second messenger, concentrations. DG activates protein kinase C and in turn regulates the biochemical reactions characteristic of that particular cell.

Calcium interacts with calmodulins. Upon hormone binding to the surface receptor, the cell membrane permits an influx of Ca++ which attaches to an intracellular protein (four per protein). This forces the protein to make a three dimensional change to make it capable of starting intracellular enzymatic changes as a response.

Steroid hormones. When steroid hormones (S) enter

the cell, they do not require a second messenger. They stimulate a response by directly influencing the formation of a particular mRNA encoding for a protein.

There are three mechanisms for steroid action within the cell. The earliest recognized mechanism suggests that steroids enter freely into cells where they bind cytoplasmatic receptors (R). This mechanism is now recognized as being used by glucocorticoids. These receptors consist of two molecules, the receptor and a molecule called heat shock proteins (hsp). After binding, these steroid-receptor (SR) complexes change structure or become "activated." The activation consists of the separation of the hsp from the other receptor molecules, thus permitting the SR complex to attach to the DNA hormone response element (hRE), once it migrates to the nucleus. The result is the generation of specific mRNA. This mRNA goes to the ribosomes to serve as a blueprint for protein synthesis. The newly formed protein mediates the cellular changes known as the response. The response could be in the form of other hormones, or other receptors, enzymes, etc.

The second mechanism is the one used by most steroids. The steroids diffuse through the cytoplasm into the nucleus where they bind to a similar receptor to that outlined previously.

The steroid-receptor complex becomes activated and continues its action as indicated in the former model (Fig. 6-28).

The third proposed mechanism consists of membrane bound receptors which are used for fast response processes. Both, these and the nuclear receptors, are derived of the same transcription.

Iodinated hormones. Thyroid hormones exert their

function by diffusion to the nucleus where they attach directly to a similar receptor mechanism to that of steroids. To be functional T4 gets converted to T3 before it can attach the receptor.

Figure 6-27. Sequence of events leading to the formation of the second messenger

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HORMONAL INTERACTIONS

Some hormones affect the biosynthesis, release, metabolism or function of other hormones. Some hormones interact among themselves.

One hormone may affect secretion of others hormones through a variety of mechanisms. A hormone may directly stimulate the secretion of a second hormone. Some hormones maintain the target tissue functioning for another hormone to act on it i.e. TRH and gonadotropin releasing hormone (GnRH). There are yet other hormones which will exert their intended effect only if other factors are met i.e. GH and somatomedins need adequate levels of nutrition in the organism. Finally, some hormones decrease or inhibit the secretion of a second hormone.

Competition

Two hormones may compete for a binding site. This depends on their affinity for receptors and their concentration (i.e. aldosterone has high mineralocorticoid characteristics while P4 is weak), but in very high concentrations P4 may trigger a significant mineralocorticoid response.

Synergism and potentiation

Two hormones can bind the same receptors, increasing the number of activated receptors or, two hormones may bind different receptors but influence the same enzyme.

Additive (Synergism). Both TSH and norepinephrine (NE) activate adipocyte lipase. This works to a point of maximum response. Super additive (Potentiation). Two hormones trigger the same response through different means. The total retention of H2O is larger than the maximal possible response triggered by ADH or Aldosterone acting independently. Hormones can enhance each other (i.e. estrogens [Es] stimulate cells with progesterone [P4] receptors).

Antagonistic influences

Two hormones act on enzymes to send a reaction in the opposite direction until a certain equilibrium is reached i.e. insulin and glucagon.

Indirect Antagonism

It occurs when two different hormones activate separate mechanisms to exert opposite effects.

Permissive Actions

A hormone does not influence the outcome of the response directly, but it facilitates the work of other hormones.

RECEPTORS

A cell can only respond to hormonal stimulation when the hormone binds to a membrane, cytoplasmic or nuclear molecule called a receptor (Fig. 6-29).

Receptors bind the hormone at the binding site and trigger the response through an effector site. A mechanism of transduction or coupling between these two components of

Figure 6-28. Classic steroid action. The hormone is released from the carrier protein, enters into the cytoplasm and nucleus, binds a receptor and activates a hRE in the DNA

Receptor

Structure to which a hormone binds to trigger a biological response

It is composed of a binding site joined by a transduction or coupling mechanism to an effector site

Figure 9-29. Receptors

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the receptor, transmits the required information to the effector site to trigger a response (Fig. 6-30).

CLASSES OF RECEPTORS

There are two types of receptors, membrane bound and intracellular. Intracellular receptors could be cytoplasmic or nuclear. Membrane bound receptors are activated by amines, peptides and proteins which cannot cross the plasma membrane. Although prostaglandins and some steroids can readily cross plasma membranes, they also use membrane bound receptors. Intracellular receptors are used by molecules which can diffuse through the plasma membrane such as steroids and thyroid hormones.

Based on the functioning mechanism, membrane bound receptors can be further classified into three other classes for a total of four main classes of receptors (Fig. 6-31):

Intracellular receptors capable of interacting with DNA; these are used by steroids and iodinated hormones.

Membrane bound receptors which are themselves enzymes.

Membrane receptors which are coupled to enzymes via G protein.

Membrane receptors linked to or forming part of a channel system.

CHARACTERISTICS OF RECEPTORS

All receptors have certain characteristics regarding their ability to bind hormones.

Hormone specificity

Receptors can bind one hormone only (Fig. 6-32). Agonists and antagonists can also bind the receptors. Many neurohormonal ligands and hormones can bind several different receptors usually within the same

Figure 6-30. Components of a receptor

Figure 6-31. Types of receptors based on location and function

Figure 6-32. Specificity of a receptor for a hormone determine the magnitude of the response

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molecular family of receptors (i.e. epinephrine binds α1, α2, β1, and β2 adrenergic receptors).

Affinity

Affinity refers to the concentration of hormones required to activate sufficient receptors to trigger a biological effect (Fig. 6-33).

Mathematically, the association constant (KA) is the reciprocal of the dissociation constant (KD). Non-specific binding of hormones to other sites reduces the biological effectiveness of the hormone.

Limited number of receptors

On average, a diploid cell may have receptors in the order of 103 to 105. Lower numbers of receptors can sometimes be compensated by higher affinity of the receptor for the hormone (Fig. 6-34).

Specificity of tissue

The presence of the appropriate type of receptors in the respective tissue is essential for proper hormone function (Fig. 6-35).

Absent or defective receptors result in pathological situations as is in the case of testicular feminization syndrome (tfm).

Receptor binding

Binding is a non-covalent and reversible interaction between the hormone and its receptor. Binding follows the law of mass action and depends on the concentration of the two components.

REGULATION OF NUMBER AND FUNCTION OF RECEPTORS

In general, receptors are specific for some hormones or groups of hormones. The overall biological activity exerted by a hormone depends on several factors related to the

Figure 6-33. The affinity determines the concentration of the hormone required to attain a response

Figure 6-34. The number of receptor sites can determine the magnitude of the response

Figure 6-35. A tissue has to have the appropriate type of receptors to respond to a given hormone

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hormone itself as well as several factors related to the receptors (Fig. 6-36).

Spare receptors

Response depends on cell type:

Response with binding. Response is maximal with only a few receptors bound by the proper hormone. The rest of the receptors can be bound by hormones with low affinity or they can be involved in negative feedback.

Negative cooperativity

After a few molecules of hormones bind to their respective receptors, the affinity of other receptors for the same hormone decreases. Blockers can bind a receptor, reduce affinity of others, or never trigger a response.

Positive cooperativity

After a few molecules bind some of their receptors, the affinity of other receptors for the same hormone increases.

Down regulation

After a hormone binds its receptors and exerts its biological effect, in order to prevent over stimulation, the cell internalizes some of the bound receptors and most unoccupied ones (Fig. 6-37). The result is the maintenance of a low response.

Up regulation

It is the exact opposite of down regulation, like priming with the same hormone. The result of the initial attachment of a hormone to the proper receptor is a moderate response with a significant increase in the production of the same type of receptors which, after being positioned in the proper site, are bound by the same type of hormone resulting in a full cellular response (Fig. 6-38).

Figure 6-36. Factors influencing availability of hormones and receptors, which ultimately determine biological activity

Figure 6-38. As a result of the initial stimulation, the cell generates more receptors for the same hormone in order to increase its rate of stimulation

Figure 6-37. After the initial response is completed, the cell internalizes receptors to reduce the rate of stimulation

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Desensitization

It is the gradual loss of sensitivity to a potent regulator. Some step in the response is impaired due to lack of substrate.

Heteroregulation

Upon binding to its receptor, hormone one triggers a response consisting in the production of receptors for hormone two. The binding of hormone two triggers the final biological response (Fig. 6-39).

REGULATORY PATTERNS AND FEEDBACK LOOPS After a hormone has exerted its effect and the stimulated cells have carried out their function (secreted a protein or enzyme, increased a compound or hormone, etc.), the organism has to return to a basal state. This would eventually prevent over stimulation or excess elevation in certain compounds. The compound(s) resulting from the initial endocrine stimulation enters into circulation and either directly or indirectly communicates these changes to the original stimulated cell which in turn reduces the rate of response, and / or production of the compound. These mechanisms are called negative feedback (Fig. 6-40). A typical example is the elevation of cortisol in response to elevations of ACTH, which in turn is a general response to stress. The elevation in cortisol signals the cells producing ACTH to reduce their secretion, thus, reducing further elevations in cortisol.

In other cases, the production of certain hormones leads to further stimulation which increases the production of the original hormone. This mechanism is called positive feedback (Fig. 6-41). A classic example is the production of estrogen in response to gonadotropins. The consequences (or the outcome?) of increased estrogen production are the further production of gonadotropins, thus promoting more estrogen production.

Figure 6-39. The response to the initial stimulation by one hormone is the production of receptors for a second hormone, which then stimulates the cell to cause the final response

Figure 6-40. Negative feedback mechanism

Figure 6-41. Positive feedback mechanism

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Depending on the physical anatomical distance between the responding cells with respect to the cell which triggers the stimulation, the feedback loops can be described as:

Ultra short, (within the same organ or cell).

Short (when there is some physical separation such as the hypothalamus and the hypophysis).

Long (between the hypophysis and the thyroid or adrenal gland) (Fig. 6-42).

Figure 6-42. Types of feedback loops are determined by the distance between the cell producing the stimulatory effect and the target tissue releasing a hormone which feeds back