## Hormones

### Learning Objectives

By the end of this section, you will be able to:

• List and describe the endocrine glands.
• Describe the chemical classes of hormones, and provide an example for each.
• Differentiate between direct and indirect mechanisms of hormone action.
• Describe how hormone secretions are regulated by negative feedback processes. Describe a specific example.

Although a given hormone may travel throughout the body in the bloodstream, it will affect the activity only of its target cells; that is, cells with receptors for that particular hormone. Once the hormone binds to the receptor, a chain of events is initiated that leads to the target cell’s response. Hormones play a critical role in the regulation of physiological processes because of the target cell responses they regulate. These responses contribute to human reproduction, growth and development of body tissues, metabolism, fluid, and electrolyte balance, sleep, and many other body functions. The major hormones of the human body and their effects are identified in Table 1.

Table 1. Endocrine Glands and Their Major Hormones
Endocrine gland Associated hormones Chemical class Effect
Pituitary (anterior) Growth hormone (GH) Protein Promotes growth of body tissues
Pituitary (anterior) Prolactin (PRL) Peptide Promotes milk production
Pituitary (anterior) Thyroid-stimulating hormone (TSH) Glycoprotein Stimulates thyroid hormone release
Pituitary (anterior) Adrenocorticotropic hormone (ACTH) Peptide Stimulates hormone release by adrenal cortex
Pituitary (anterior) Follicle-stimulating hormone (FSH) Glycoprotein Stimulates gamete production
Pituitary (anterior) Luteinizing hormone (LH) Glycoprotein Stimulates androgen production by gonads
Pituitary (posterior) Antidiuretic hormone (ADH) Peptide Stimulates water reabsorption by kidneys
Pituitary (posterior) Oxytocin Peptide Stimulates uterine contractions during childbirth
Thyroid Thyroxine (T4), triiodothyronine (T3) Amine Stimulate basal metabolic rate
Thyroid Calcitonin Peptide Reduces blood Ca2+ levels
Parathyroid Parathyroid hormone (PTH) Peptide Increases blood Ca2+ levels
Adrenal (cortex) Aldosterone Steroid Increases blood Na+ levels
Adrenal (cortex) Cortisol, corticosterone, cortisone Steroid Increase blood glucose levels
Adrenal (medulla) Epinephrine, norepinephrine Amine Stimulate fight-or-flight response
Pineal Melatonin Amine Regulates sleep cycles
Pancreas Insulin Protein Reduces blood glucose levels
Pancreas Glucagon Protein Increases blood glucose levels
Testes Testosterone Steroid Stimulates development of male secondary sex characteristics and sperm production
Ovaries Estrogens and progesterone Steroid Stimulate development of female secondary sex characteristics and prepare the body for childbirth

## Types of Hormones

The hormones of the human body can be divided into two major groups on the basis of their chemical structure. Hormones derived from amino acids include amines, peptides, and proteins. Those derived from lipids include steroids (Figure 1). These chemical groups affect a hormone’s distribution, the type of receptors it binds to, and other aspects of its function.

Figure 1. Amine, Peptide, Protein, and Steroid Hormone Structure

## Amine Hormones

Hormones derived from the modification of amino acids are referred to as amine hormones. Typically, the original structure of the amino acid is modified such that a $-\text{COOH}$, or carboxyl, group is removed, whereas the $\text{NH}^{+}_{3}$, or amine, group remains.

Amine hormones are synthesized from the amino acids tryptophan or tyrosine. An example of a hormone derived from tryptophan is melatonin, which is secreted by the pineal gland and helps regulate circadian rhythm. Tyrosine derivatives include the metabolism-regulating thyroid hormones, as well as the catecholamines, such as epinephrine, norepinephrine, and dopamine. Epinephrine and norepinephrine are secreted by the adrenal medulla and play a role in the fight-or-flight response, whereas dopamine is secreted by the hypothalamus and inhibits the release of certain anterior pituitary hormones.

## Peptide and Protein Hormones

Whereas the amine hormones are derived from a single amino acid, peptide and protein hormones consist of multiple amino acids that link to form an amino acid chain. Peptide hormones consist of short chains of amino acids, whereas protein hormones are longer polypeptides. Both types are synthesized like other body proteins: DNA is transcribed into mRNA, which is translated into an amino acid chain.

Examples of peptide hormones include antidiuretic hormone (ADH), a pituitary hormone important in fluid balance, and atrial-natriuretic peptide, which is produced by the heart and helps to decrease blood pressure. Some examples of protein hormones include growth hormone, which is produced by the pituitary gland, and follicle-stimulating hormone (FSH), which has an attached carbohydrate group and is thus classified as a glycoprotein. FSH helps stimulate the maturation of eggs in the ovaries and sperm in the testes.

## Steroid Hormones

The primary hormones derived from lipids are steroids. Steroid hormones are derived from the lipid cholesterol. For example, the reproductive hormones testosterone and the estrogens—which are produced by the gonads (testes and ovaries)—are steroid hormones. The adrenal glands produce the steroid hormone aldosterone, which is involved in osmoregulation, and cortisol, which plays a role in metabolism.

Like cholesterol, steroid hormones are not soluble in water (they are hydrophobic). Because blood is water-based, lipid-derived hormones must travel to their target cell bound to a transport protein. This more complex structure extends the half-life of steroid hormones much longer than that of hormones derived from amino acids. A hormone’s half-life is the time required for half the concentration of the hormone to be degraded. For example, the lipid-derived hormone cortisol has a half-life of approximately 60 to 90 minutes. In contrast, the amino acid–derived hormone epinephrine has a half-life of approximately one minute.

## Pathways of Hormone Action

The message a hormone sends is received by a hormone receptor, a protein located either inside the cell or within the cell membrane. The receptor will process the message by initiating other signaling events or cellular mechanisms that result in the target cell’s response. Hormone receptors recognize molecules with specific shapes and side groups, and respond only to those hormones that are recognized. The same type of receptor may be located on cells in different body tissues, and trigger somewhat different responses. Thus, the response triggered by a hormone depends not only on the hormone, but also on the target cell.

Once the target cell receives the hormone signal, it can respond in a variety of ways. The response may include the stimulation of protein synthesis, activation or deactivation of enzymes, alteration in the permeability of the cell membrane, altered rates of mitosis and cell growth, and stimulation of the secretion of products. Moreover, a single hormone may be capable of inducing different responses in a given cell.

### A review of Receptor Function

Receptors are specialized proteins that detect chemical signals by binding signaling compounds with specific binding pockets. The binding of a signaling compound (ligand) induces a change in the shape of the receptor, which in turn, enables the receptor to interact with intracellular signaling compounds.  It is this shape change and resulting signaling activity that will ultimately result in a change in cellular activity.

Figure 2. Structure versus function: A receptor’s specificity is determined by its ligand binding pocket.  The shape of the binding pocket determines what compound a receptor can detect.  A hydrophilic ligand will require a binding pocket that has a hydrophilic surface that fits the shape of that ligand perfectly.  If the binding pocket is too small, or has a hydrophobic surface, the ligand will be unable to bind, resulting in a receptor that is unable to detect that hydrophilic ligand.

1. You are a chemist hired by a pharmaceutical company to develop a new drug that binds and activates the nicotinic acetylcholine receptor (nAChR). (If you recall from the muscular system and nervous system units, nAChR is found in both the brain and neuromuscular junction.)  This receptor binds and is activated by both the neurotransmitter acetylcholine, and the drug nicotine. What should the molecule you are designing look like?

### Pathways Involving Intracellular Hormone Receptors

Intracellular hormone receptors are located inside the cell. Hormones that bind to this type of receptor must be able to cross the lipophilic cell membrane. Steroid hormones are derived from cholesterol and therefore can readily diffuse through the lipid bilayer of the cell membrane to reach the intracellular receptor (Figure 3). Thyroid hormones, which contain benzene rings studded with iodine, are also lipid-soluble and can enter the cell.

Steroid and thyroid hormones bind to their intracellular receptors, generating a hormone-receptor complex that interacts with DNA and triggers transcription of a target gene. The resulting mRNA moves to the cytosol and directs the synthesis of a specific protein by ribosomes.

Figure 3. Binding of Lipid-Soluble Hormones

Hydrophobic steroid and thyroid hormones directly initiate the production of proteins within a target cell. Steroid hormones easily diffuse through the cell membrane. The hormone binds to its receptor in the cytosol, forming a receptor–hormone complex. The receptor–hormone complex then enters the nucleus and binds to the target gene on the DNA. Transcription of the gene creates a messenger RNA that is translated into the desired protein within the cytoplasm.

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### regulating a cell’s activity through protein synthesis

Cell activity is determined by the proteins currently expressed in the cell.  Receptors, enzymes, and structural proteins dictate how a cell behaves at a given moment.  Proteins, much like cell phones and cars, work hard and eventually stop functioning. Therefore, they are continually being replaced. This replacement process provides an opportunity to change a cell’s activity by either decreasing or increasing the amount of a particular protein in a cell. The process of making new proteins is called protein synthesis.

The binding, for example, of a steroid hormone to its receptor, will cause the receptor to change shape, resulting in a signal in the nucleus that alters the synthesis of a particular protein in the cell.  The rate of protein synthesis of the protein could either increase or decrease, depending upon the effects of the particular hormone.  If the protein being synthesized is an enzyme, the steroid hormone could be increasing or decreasing the rate of a chemical reaction that the enzyme regulates.

Protein synthesis: transcription and translation

We have inherited instructions on how to make all the proteins needed in human cells from our parents.  All proteins are made from building blocks called amino acids.  There are 20 amino acids used to make all human proteins.  Each protein’s structure is a unique sequence of amino acids in a chain, that is then folded to make a 3-dimensional structure that is able to perform the specific task the protein is designed to do.

Genes are segments of our DNA that provides instructions on what amino acids to put in what specific order to make a particular protein.  If a cell needs to make more of a particular protein (for example, the growth hormone receptor), your cell will find the gene for the growth hormone receptor within the DNA in its nucleus, and it will make a copy of that particular gene.  This process of making an mRNA copy of a gene is called transcription.

The mRNA then leaves the nucleus and is read by many ribosomes during a process called translation.  Each ribosome will bind to the mRNA, and will gradually follow the instructions found on the mRNA, building a chain of amino acids called a peptide.  The peptides are then folded to make mature proteins inside the rough endoplasmic reticulum.

How does activation of a receptor result in a change in the amount of protein being made?

In the case of a steroid hormone receptor, the activated receptor is able to enter the nucleus and directly stimulate or prevent transcription of a particular gene’s mRNA.  This will result in either more or less mRNA for ribosomes to read, which will, in turn, result in more or less of that protein being made.

1. A steroid hormone is responsible for decreasing the protein synthesis of an enzyme that causes excessive swelling following an injury.  This swelling is often responsible for causing more damage to the injured area. What would happen to a patient if they suddenly produced much less of that steroid hormone?

### Multiple Hormones influencing the same tissue

Many hormones are coursing through your blood at any given moment. Each hormone influences the behavior of its target tissue. It is not uncommon for two hormones to target the same tissue. In this instance, one of the hormones may influence the effect of the second hormone.

• Synergism describes the physiological response of a tissue to a combination of two hormones that greatly exceeds the tissue’s response to a single hormone. One classic example of synergism is the effect of insulin and adiponectin upon a tissue. Adiponectin by itself has no detectable action on lowering blood glucose levels. Insulin is well known lower blood glucose levels. When adiponectin and insulin are present together, adiponectin enhances cell sensitivity to glucose.
• Antagonism describes the physiological response of a tissue to one hormone having an opposing effect on another hormone. For example, this interaction can be seen with estrogen and progesterone. Estrogen will cause an increase in progesterone receptors in the uterus. After ovulation when progesterone levels are high, progesterone will cause the estrogen receptor to down regulate limiting the effect of progesterone on the uterus.
• Permissiveness describes the physiological response where one hormone cannot exert its full effect on an organ without the presence of another hormone. For example, leptin is needed in adequate levels to desensitize the hypothalamus to estrogen as puberty nears. This allows for gonadotropin releasing hormone to have a rhythmic effect on the release on follicle stimulating hormone and luteinizing hormone.

### Pathways Involving Cell Membrane Hormone Receptors

Hydrophilic hormones indirectly initiate the production of proteins within a target cell. Hydrophilic, or water-soluble, hormones are unable to diffuse through the lipid bilayer of the cell membrane and must therefore pass on their message to a receptor located at the surface of the cell. Except for thyroid hormones, which are lipid-soluble, all amino acid–derived hormones bind to cell membrane receptors that are located, at least in part, on the extracellular surface of the cell membrane. Therefore, they do not directly affect the transcription of target genes, but instead initiate a signaling cascade that is carried out by a molecule called a second messenger. In this case, the hormone is called a first messenger.

The second messenger used by most hormones is cyclic adenosine monophosphate (cAMP). In the cAMP second messenger system, a water-soluble hormone binds to its receptor in the cell membrane (Step 1 in Figure 4). This receptor is associated with an intracellular component called a G protein, and binding of the hormone activates the G-protein component (Step 2). The activated G protein in turn activates an enzyme called adenylyl cyclase, also known as adenylate cyclase (Step 3), which converts adenosine triphosphate (ATP) to cAMP (Step 4). As the second messenger, cAMP activates numerous proteins through a process called phosphorylation, thereby changing the activity of the cell.

Figure 4. Binding of Water-Soluble Hormones

The phosphorylation of cellular proteins can trigger a wide variety of effects, from nutrient metabolism to the synthesis of different hormones and other products. The effects vary according to the type of target cell, the G proteins and kinases involved, and the phosphorylation of proteins. There are numerous second messenger systems.  While each activating and deactivating different cell processes, they all follow a similar arrangement with an extracellular receptor, and an intracellular second messanger that is able to stimulate numerous changes in the cell.

## Factors Affecting Target Cell Response

You will recall that target cells must have receptors specific to a given hormone if that hormone is to trigger a response. But several other factors influence the target cell response. For example, the presence of a significant level of a hormone circulating in the bloodstream can cause its target cells to decrease their number of receptors for that hormone. This process is called downregulation, and it allows cells to become less reactive to the excessive hormone levels. When the level of a hormone is chronically reduced, target cells engage in upregulation to increase their number of receptors. This process allows cells to be more sensitive to the hormone that is present. Cells can also alter the sensitivity of the receptors themselves to various hormones.

Two or more hormones can interact to affect the response of cells in a variety of ways. The three most common types of interaction are as follows:

• The permissive effect, in which the presence of one hormone enables another hormone to act. For example, thyroid hormones have complex permissive relationships with certain reproductive hormones. A dietary deficiency of iodine, a component of thyroid hormones, can therefore affect reproductive system development and functioning.
• The synergistic effect, in which two hormones with similar effects produce an amplified response. In some cases, two hormones are required for an adequate response. For example, two different reproductive hormones—FSH from the pituitary gland and estrogens from the ovaries—are required for the maturation of female ova (egg cells).
• The antagonistic effect, in which two hormones have opposing effects. A familiar example is the effect of two pancreatic hormones, insulin and glucagon. Insulin increases the liver’s storage of glucose as glycogen, decreasing blood glucose, whereas glucagon stimulates the breakdown of glycogen stores, increasing blood glucose.

## Regulation of Hormone Secretion

To prevent abnormal hormone levels and a potential disease state, hormone levels must be tightly controlled. The body maintains this control by balancing hormone production and degradation. Feedback loops govern the initiation and maintenance of most hormone secretion in response to various stimuli.

### Role of Feedback Loops

The contribution of feedback loops to homeostasis will only be briefly reviewed here. Positive feedback loops are characterized by the release of additional hormone in response to an original hormone release. The release of oxytocin during childbirth is a positive feedback loop. The initial release of oxytocin begins to signal the uterine muscles to contract, which pushes the fetus toward the cervix, causing it to stretch. This, in turn, signals the pituitary gland to release more oxytocin, causing labor contractions to intensify. The release of oxytocin decreases after the birth of the child.

The more common method of hormone regulation is the negative feedback loop. Negative feedback is characterized by the inhibition of further secretion of a hormone in response to adequate levels of that hormone. This allows blood levels of the hormone to be regulated within a narrow range. An example of a negative feedback loop is the release of glucocorticoid hormones from the adrenal glands, as directed by the hypothalamus and pituitary gland. As glucocorticoid concentrations in the blood rise, the hypothalamus and pituitary gland reduce their signaling to the adrenal glands to prevent additional glucocorticoid secretion (Figure 5).

Figure 5. Negative Feedback Loop

The release of adrenal glucocorticoids is stimulated by the release of hormones from the hypothalamus and pituitary gland. This signaling is inhibited when glucocorticoid levels become elevated by causing negative signals to the pituitary gland and hypothalamus.

### Role of Endocrine Gland Stimuli

Reflexes triggered by both chemical and neural stimuli control endocrine activity. These reflexes may be simple, involving only one hormone response, or they may be more complex and involve many hormones, as is the case with the hypothalamic control of various anterior pituitary–controlled hormones.

Humoral stimuli are changes in blood levels of non-hormone chemicals, such as nutrients or ions, which cause the release or inhibition of a hormone to, in turn, maintain homeostasis. For example, osmoreceptors in the hypothalamus detect changes in blood osmolarity (the concentration of solutes in the blood plasma). If blood osmolarity is too high, meaning that the blood is not dilute enough, osmoreceptors signal the hypothalamus to release ADH. The hormone causes the kidneys to reabsorb more water and reduce the volume of urine produced. This reabsorption causes a reduction of the osmolarity of the blood, diluting the blood to the appropriate level. The regulation of blood glucose is another example. High blood glucose levels cause the release of insulin from the pancreas, which increases glucose uptake by cells and liver storage of glucose as glycogen.

An endocrine gland may also secrete a hormone in response to the presence of another hormone produced by a different endocrine gland. Such hormonal stimuli often involve the hypothalamus, which produces releasing and inhibiting hormones that control the secretion of a variety of pituitary hormones.

In addition to these chemical signals, hormones can also be released in response to neural stimuli. A common example of neural stimuli is the activation of the fight-or-flight response by the sympathetic nervous system. When an individual perceives danger, sympathetic neurons signal the adrenal glands to secrete norepinephrine and epinephrine. The two hormones dilate blood vessels, increase the heart and respiratory rate, and suppress the digestive and immune systems. These responses boost the body’s transport of oxygen to the brain and muscles, thereby improving the body’s ability to fight or flee.

## Chapter Review

Hormones are derived from amino acids or lipids. Amine hormones originate from the amino acids tryptophan or tyrosine. Larger amino acid hormones include peptides and protein hormones. Steroid hormones are derived from cholesterol.

Steroid hormones and thyroid hormone are lipid soluble. All other amino acid–derived hormones are water soluble. Hydrophobic hormones are able to diffuse through the membrane and interact with an intracellular receptor. In contrast, hydrophilic hormones must interact with cell membrane receptors. These are typically associated with a G protein, which becomes activated when the hormone binds the receptor. This initiates a signaling cascade that involves a second messenger, such as cyclic adenosine monophosphate (cAMP). Second messenger systems greatly amplify the hormone signal, creating a broader, more efficient, and faster response.

Hormones are released upon stimulation that is of either chemical or neural origin. Regulation of hormone release is primarily achieved through negative feedback. Various stimuli may cause the release of hormones, but there are three major types. Humoral stimuli are changes in ion or nutrient levels in the blood. Hormonal stimuli are changes in hormone levels that initiate or inhibit the secretion of another hormone. Finally, a neural stimulus occurs when a nerve impulse prompts the secretion or inhibition of a hormone.

### Critical Thinking questions

Structure versus function: The position of a receptor within a cell is dependent upon the structure of the molecule it is detecting.  A hydrophilic signaling molecule will be unbable to cross the hydrophobic phospholipid bilayer.  Therefore, a receptor detecting a hydrophilic signaling molecule must be located on the cell’s surface.  A hydrophobic signaling molecule (such as a steroid hormone) can easily cross the phospholipid bilayer.  As a result, steroid hormone receptors can be located intracellularly. Instead, steroid hormones require binding proteins to assist their movement across aqueous compartments such as the extracellular matrix and cytosol.

1. How would the movement of steroid hormones across a membrane change if the membrane’s phospholipid bilayer was instead a hydrophilic carbohydrate bilayer?
2. Describe the mechanism of hormone response resulting from the binding of a hormone with an intracellular receptor.

## Glossary

adenylyl cyclase: membrane-bound enzyme that converts ATP to cyclic AMP, creating cAMP, as a result of G-protein activation

cyclic adenosine monophosphate (cAMP): second messenger that, in response to adenylyl cyclase activation, triggers a phosphorylation cascade

downregulation: decrease in the number of hormone receptors, typically in response to chronically excessive levels of a hormone

first messenger: hormone that binds to a cell membrane hormone receptor and triggers activation of a second messenger system

G protein: protein associated with a cell membrane hormone receptor that initiates the next step in a second messenger system upon activation by hormone–receptor binding

hormone receptor: protein within a cell or on the cell membrane that binds a hormone, initiating the target cell response

phosphorylation cascade: signaling event in which multiple protein kinases phosphorylate the next protein substrate by transferring a phosphate group from ATP to the protein

second messenger: molecule that initiates a signaling cascade in response to hormone binding on a cell membrane receptor and activation of a G protein

upregulation: increase in the number of hormone receptors, typically in response to chronically reduced levels of a hormone