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ENDOCRINE SYSTEM NOTES
The purpose of the endocrine system is to maintain the body’s homeostasis using hormones. Hormones are signaling molecules. Although a wide variety of hormones function within the body, they share certain general characteristics:
Hormones have specific rates and rhythms of secretion. Three basic secretion patterns are: (1) circadian or diurnal patterns, (2) pulsatile and cyclic patterns, and (3) patterns that depend on levels of circulating substrates (e.g., calcium, sodium, potassium, or the hormones themselves).
Hormones operate within feedback systems, either positive or negative, to maintain an optimal internal environment.
Hormones affect only cells with specific receptors and then act on those cells to initiate specific cell functions or activities.
When an endocrine cell receives a stimulus or command, this stimulates the endocrine cell to secrete hormones into the blood stream. The hormones will then target and bind onto a specific receptor on a target cell. This will cause the target cell to initiate a response as shown in the diagram below:
Signaling Hormones
It is important to understand the signaling aspect of hormones. First, there are three types of signaling hormones, steroid, peptide and amine. The table below provides a description of the signaling hormones and their properties.
Class Description Properties Examples
Steroid
Lipids derived from cholesterol
Lipophilic – can cross membrane Testosterone Undergoes constitutive secretion
Estrogen / Progesterone
Peptide
Short polypeptide chains
Hydrophilic – cannot cross membrane Insulin Undergoes regulatory secretion Glucagon
Amine
Derived from aromatic amino acid
Hydrophilic – cannot cross membrane Undergoes regulatory secretion
Thyroxine
Note that peptide and amine hormones are hydrophilic (water- soluble). This means that they are easily dissolved in fluid and do not have to bind to a protein in order to circulate. Characteristically, they also have a short half-life of just seconds to minutes as they are catabolized by circulating enzymes. Insulin, for example is a peptide hormone. Shortly after its release, it is catabolized by insulinase enzymes within 3- minutes.
Lipid-soluble hormones, in contrast, are transported bound to a protein. Because they are bound, they can remain in the blood for hours to days. It is very important to note here that when a hormone is bound to a protein, it cannot exert its effects. Only free circulating hormones can initiate responses inside of a target cell. This will be revisited as we delve into the diseases of the endocrine system. Upon arrival to the cell membrane, the protein-bound hormone must disengage from the protein in order to diffuse into the cell where its effects can be exerted.
Hormone Regulation Two important concepts to understand before reviewing endocrine system disorders is how hormone release is regulated and once arriving to the target cell, how it enters the cell to exert its effect. Let’s begin with hormone regulation. Hormone regulation:
- Hormone release is regulated by chemical factors (e.g. blood glucose), endocrine factors (e.g. a hormone from one gland controls another gland) and neural control.
- Hormone release is regulated by feedback systems. These are responsible for monitoring and controlling the cellular environment. You are likely familiar with the negative and positive feedback system. The negative feedback system will activate when there is a change in endocrine, chemical or neural response. It will decrease the synthesis and secretion of a hormone. In contrast, positive feedback systems result when the endocrine, chemical or neural response increases the synthesis and secretion of a hormone. This is illustrated in the diagram below.
The feedback loop processes are simple. Positive feedback results when the hormone is needed to exert its effects on the target cell. The hormone is produced and secreted. When there is less need for the hormone, negative feedback results that stops the production and release of the hormone. The positive and negative feedback system is illustrated in an example below in response to a low blood glucose level. Because glucose is a necessary source of energy for the body, it will attempt to restore a normal blood glucose level in order to maintain homeostasis. Therefore, the endocrine system will attempt to increase blood glucose levels by stimulating an endocrine cell. In this case, it is the alpha cell of the pancreas. The alpha cell will then secrete a hormone, glucagon into the blood stream. Glucagon will travel through the blood stream to the liver which is the target cell. When glucagon binds to a receptor on the target cell (liver cell), it will stimulate the liver to break down glycogen to secrete glucose in the blood. The response of the liver cell is the creation of more glucose in the blood. As the blood glucose is increased, a negative feedback signal is sent to the pancreas to stop the secretion of glucagon.
Cellular Communication After a hormone arrives to the target cell, it must be able to enter the cell in order to exert its effects. Before going any further with our discussion of hormones, it is important to consider cellular biology in terms of cellular communication, signal transduction and membrane transport. Under this week’s readings, there is a recommended chapter from your textbook that will
need to be bound to a protein in order to circulate to the target cell. It circulates freely and binds to its specific receptor on the cell membrane, enters the cell and then exerts its effects. Lipid- soluble hormones do circulate bound to a protein. When it arrives to the cell membrane, it must disengage from the protein in order to cross the cell membrane. Note that in the diagram below, this hormone binds to the receptor once inside the cell. In order to get there, some type of
energy is necessary to move it across.
Origination of Hormones In this section the origination of hormones will be reviewed. First, there are many hormones in the body that perform different functions and have different responses. The responses occur in the endocrine glands located throughout the body. The diagram below depicts the types of endocrine glands and their location in the body.
Hypothalamus The hypothalamus is responsible for releasing hormones to anterior and posterior pituitary. Hypothalamic releasing hormones are summarized below. It is also responsible for producing the regulatory hormones which will be discussed shortly. The hypothalamus also produces antidiuretic hormones (ADH) and oxytocin. Once produced, they are passed on to the
posterior pituitary gland. It is also responsible for producing the regulatory hormones which will be discussed shortly. Transcript Link
Pituitary Gland The pituitary gland are located just below the hypothalamus and consist of two lobes, the anterior and posterior lobes.
- Posterior lobe: The posterior lobe secretes oxytocin and ADH after it is produced by the hypothalamus. The hypothalamus sends oxytocin and ADH to the posterior pituitary where they are secreted into the blood. When secreted, ADH targets the kidney tubules to retain water. Oxytocin targets breast tissue (lactation) and the uterus (uterine contraction during childbirth).
- Anterior lobe: The anterior lobe differs from the posterior lobe in that it produces its own hormones. But these hormones can only be secreted when the hypothalamus confirms that it is fine to do so. The hypothalamus does this by secreting regulatory hormones that either stimulate or inhibit the anterior pituitary hormones. The anterior pituitary secretes prolactin that targets the breast to simulate milk production, secretes growth hormone that targets the bone to promote growth, and secretes gonadotropic hormones (Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH)) that target the testes and the ovaries. It also secretes thyroid stimulating hormone (TSH) to stimulate the thyroid gland to secrete T3 and T4. Finally, it can secrete adrenocorticotropic hormone (ACTH) which will target the adrenal gland to stimulate the release of cortisol.
The diagram below shows the location of the anterior and posterior pituitary as well as the connection of the anterior pituitary to the hypothalamus where regulatory hormones are released to allow the anterior pituitary to secrete or inhibit its hormones produced there.
Other Endocrine Glands
- Pineal gland: The pineal gland secretes melatonin which is responsible for regulating the sleep-wake cycle.
- Thyroid gland: The thyroid gland is responsible for secreting thyroxine (T4), Triiodothyronine (T3) and Calcitonin.
The Thyroid Gland The thyroid gland surrounds the trachea and sits just below the cricoid cartilage. It consists of two lobes and the isthmus that connects the two lobes) as shown in the diagram below: The thyroid gland consists of two types of cells:
- Follicular cells: these are most abundant and are the secretory cells. They secrete thyroid hormone (Thyroxine or T4). Note that T4 is a lipid-soluble hormone.
- Parafollicular cells (C cells): these are fewer in number and secrete calcitonin.
Also note the colloid area of the cell. T is stored here. Triiodothyronine (T3) is the second and most active thyroid hormone. T4 is transformed into T3 in the liver although some is produced in the thyroid as discussed below. It is important to know how T4 and T3 are produced. Refer to the diagram below as we explore their production. Iodine is mentioned first in its role in thyroid hormone production. Through diet, iodine is absorbed from the gastrointestinal tract (GI) and then taken up by the thyroid gland and transported into the follicular cells. Energy is required for this to happen. The energy source is a N+/I- cotransport system and ATPase pump. It is activated when TSH binds to the thyroid epithelial cells. Once iodine is taken up by the thyroid gland, it becomes oxidized by peroxide where I- becomes I+. The oxidized form of iodine enters the follicular cells to assist in producing the thyroid hormones.
Thyroglobulin Next, we consider the role of tyrosine that is located on thyroglobulin. Thyroglobulin (Tg) is a glycoprotein that is produced in the follicular cells and is used exclusively in the thyroid gland. It is the main precursor to thyroid hormones. Thyroid hormones are produced when tyrosine on the thyroglobulin combines with I+. I+ essentially splits the thyroglobulin that results in diiodotyrosine and monoiodotyrosine. Diiodotyrosine is associated with the production of T while monoiodotyrosine is associated the production of T3. Note the amount of T and T3 produced. Although T3 is produced in much smaller amounts, it is the most active of the two. Following the production of T4, it can be stored in the thyroid follicle (colloid) or released into the blood stream. Because it is a lipid-soluble hormone, it will be bound to a protein carrier. 99% of T4 is bound to protein and inactive. The amount of unbound T4, known as the free T4 (FT4), is the amount of freely circulating hormone which can affect the body tissues. The production, storage, and release of T4 (and FT4) are under control of TSH. TSH is released from the anterior pituitary gland and travels in the blood stream to bind with a receptor on the thyroid epithelial cells. Refer to our diagram above.
Thyroid Function Thyroid function is measured first by assessing the amount of thyroid stimulating hormone (TSH) in the blood. Small changes in the TSH are early indicators of disease and can be often seen before a patient becomes symptomatic. A high TSH indicates that the thyroid is not making enough thyroid hormone (low FT4). When the pituitary gland sense that there is too little thyroid hormone in the blood, it produces more TSH in order to stimulate the thyroid gland to produce more active hormone. If the TSH is low, the pituitary senses too much thyroid hormone (high FT4) in the blood, and it will decrease the production of TSH so that the thyroid gland decreases the amount of thyroid hormone. Patients who do not existing thyroid disease are screened by assessing serum TSH levels. If the TSH is too high or too low, a FT4 is drawn to more accurately assess the thyroid production of hormone available for use. The TSH and FT4, when used together, aid in the diagnosis of hypothyroidism and hyperthyroidism.
Hypothyroidism affects all body systems. The symptoms can vary among individuals as their severity depends on the extent of thyroid depletion. Overall, the body’s metabolism is lowered and is associated with decreased heat production, lethargy and fatigue. A goiter may be seen on exam because of the overproduction TSH in attempt to stimulate the thyroid gland to secrete more thyroid hormone. Signs and symptoms of hypothyroidism are summarized in the diagram below:
Hypothyroidism Diagnosis and Treatment
Diagnosis Clinical symptoms of primary hypothyroidism, increased TSH level and decreased total T3, total T4 and free T provide the basis for a diagnosis.
Treatment Hormone replacement therapy is indicated. Levothyroxine is the drug of choice for hypothyroidism. Dosing will be based on the patient’s age, the severity of the symptoms and the presence of other associated disorders.
Hyperthyroidism Pathophysiology Hyperthyroidism (thyrotoxicosis) is characterized by an increase the amount secreted thyroid hormone (TH) from the thyroid gland. Thyroid hormones are regulated by the negative feedback system that involves the hypothalamus, anterior pituitary gland and thyroid gland shown in the diagram below:
There are several reasons why an individual may have excessive thyroid hormone. In Grave’s disease the overproduction of thyroid hormone is due to the follicular cells producing excessive amounts of T4 and T3 due to stimulation from the TSH receptor autoantibody (TSH-R). Other conditions that may lead to an overproduction of thyroid hormone includes:
- Patients with multinodular goiter who take inorganic iodine (e.g. potassium iodide) or an organic iodine such as amiodarone.
- Patients with multinodular goiter who develop multiple nodules and secrete excessive amounts of T4 or T3.
- Patients with large follicular adenomas can produce excessive thyroid hormone.
Regardless of the cause of hyperthyroidism, there will be increased serum thyroid hormones. The remainder of the pathophysiology section will focus on Grave’s disease and in subsequent sections where clinical manifestations, diagnosis and treatment are discussed. Grave’s disease, also an autoimmune disease, is the most common cause of hyperthyroidism. It typically occurs in ages 30-40 years but may occur at any age. There is a familial connection associated with Grave’s disease. Genetically, it is associated with HLA-B17 in Black individuals, HLA-Bw46 and HLA-B5 in Asian individuals, and HLA -B8 and HLA-DR3 histocompatibility antigens in Caucasian individuals. As an autoimmune disease, autoantibodies against the TSH receptor located on the follicular cells stimulate the thyroid gland. The autoantibodies involved include thyroid-stimulating antibodies (TSAbs) or thyroid receptor antibodies (TRAbs). They override the negative feedback system that normally occurs. Lymphocytes also infiltrate the receptor site. The effect of thyroid stimulating antibodies on the TSH receptor results in hyperplasia of the thyroid gland (goiter) and increased synthesis of thyroid hormone, especially T3. A diagram of a thyroid goiter is provided below: In Grave’s disease, there are two main distinguishing effects from actions of the thyroid stimulating antibodies:
- Ophthalmopathy (exophthalmos): this is an inflammatory disorder of the periorbital tissues. It includes upper eyelid retraction, lid lag, swelling, erythema, conjunctivitis and bulging eyes. It may result in eye irritation, increased lacrimation, photophobia, blurred vision, decreased visual acuity, papilledema, keratosis and corneal ulceration.
- Dermopathy (pretibial myxedema): this is an autoimmune inflammatory disorder characterized by thickening of the skin in the pretibial area. There is also subcutaneous swelling on the anterior legs. The symptoms are due to T- lymphocytes that stimulate excess hyaluronic acid production in the dermis and subcutaneous tissue.
Clinical Manifestations of Hyperthyroidism The symptoms of hyperthyroidism are varied and affect all body systems as shown in the following activity:
A magnified view of the islets of Langerhans are shown in the diagram below. The islets are composed of four types of cells that secrete hormones that are involved in regulating carbohydrate, fat, and protein metabolism.
- A or alpha cells are located at the periphery and are responsible for secreting glucagon.
- Beta cells are responsible for secreting insulin and amylin, which is a peptide hormone connected to insulin. It inhibits glucagon secretion and performs some exocrine functions.
- Delta cells are responsible for secreting gastrin and somatostatin.
- F (PP cells) secrete pancreatic polypeptide that stimulates gastric secretions and antagonizes cholecystokinin.
Note in the diagram that the alpha, beta, and delta cells most abundant in the anterior lobe of the pancreas. This area is perfused by the superior mesenteric artery. The celiac artery perfuses the posterior lobe of the pancreas. This perfusion is important for oxygenation and the delivery of hormones secreted by the islet cells to their target cells.
Insulin is only synthesized in the beta cells. To understand its synthesis, we start with preproinsulin. This is a biologically inactive precursor to an active insulin hormone. Preproinsulin is converted by signal peptidases to proinsulin. Proinsulin is in the endoplasmic reticulum of the cell. It is exposed to endopeptidases that separate the C-peptide to generate the active form of insulin. Insulin, along with the free C-peptide are packaged in the Golgi apparatus into secretory cells. When the beta cell is stimulated, insulin is secreted from the cell and diffuses into the islet capillary blood. The C-peptide is also secreted in the blood, but its action is unknown.
Insulin Secretion Now that the insulin has been produced, it is waiting to be stimulated and released to its target cell. Insulin secretion increases when the beta cells are stimulated by the parasympathetic nervous system. This usually occurs before eating a meal. Insulin secretion is primarily stimulated when blood glucose levels rise. Other factors that increase insulin secretion are increased amino acids and gastrointestinal hormones (glucagon, gastrin, cholecystokinin, secretin). Factors that decrease insulin secretion include hypoglycemia, high insulin
levels through the negative feedback to the beta cells and sympathetic stimulation of the islet cells. Prostaglandins also inhibit insulin secretion. Let’s focus on insulin secretion due to elevated blood glucose levels. When the beta cells are stimulated because of elevated glucose in the beta cell, it is transported via facilitated diffusion through a glucose transporter. As glucose continues to elevate in the beta cell, it causes the cell membrane to depolarize which allows an influx of calcium into the cell. Increased glucose in the beta cells also activate calcium-independent pathways that play a role in insulin secretion.
As glucose increases in the beta cell, insulin secretion occurs that results in a dramatic increase in plasma insulin levels immediately. The reason for the dramatic increase initially is because the insulin was already preformed and waiting in the secretory cells. But the preformed insulin disappears quickly. Then a secondary insulin increase occurs because of newly formed insulin that is immediately released.
Now that insulin is released, it needs to travel to the target cell. To do this, insulin binds with an enzyme-linked plasma membrane receptor depicted in the diagram below. This receptor contains tyrosine kinase. Once insulin binds to the receptor, a cascade of activity occurs. Signals are sent to activate glucose transporters (primarily GLUT4) to allow entry of glucose into the cell. GLUT4 is activated by the insulin receptor and then translocated to the surface of the cell to facilitate diffusion of glucose into the cell. Let’s pause here to think about insulin sensitivity, an individual’s response to insulin. This can be affected by the individual’s age, weight, physical activity and the amount of abdominal fat. Under these conditions, insulin resistance may occur. Obesity, as well as lack of exercise is a major factor in the development of insulin resistance because adipocytes release hormones altered by obesity that reduces the individual’s reaction to insulin. As an NP in clinical practice, it will be extremely important to educate patients on the benefits of weight loss and exercise.
Insulin Actions Once in the cell, insulin promotes glucose uptake mostly in the liver, muscle and adipose tissue. It also affects proteins, carbohydrates, and lipids by increasing their synthesis. The overall effect of insulin in the tissues is stimulation of protein and fat synthesis and a decreased blood glucose level. Insulin also drives the transport of potassium, phosphate and magnesium into the cell.
Feature Diabetes Type 1 Diabetes Type 2
Strong association with HLA-DQA and HLA-DQB genes Inherited defects in beta-cell mass and function combined with peripheral tissue insulin resistance Associated with long-duration obesity
Age < 10-20 years of age Usually > 40 years of age
Genetic association
Weak association Strong association
Acute Complications
Diabetic ketoacidosis Hyperosmolar nonketotic coma
Association with obesity
No Yes
Presenting symptoms
Polyuria, polyphagia, polydipsia Weakness, weight loss, infections
In the following sections, Type 1 and 2 DM, hypoglycemia, diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic non-ketoacidosis syndrome (HHNK) are reviewed. Type 1 DM is an autoimmune process where environmental and genetic factors trigger cell-mediated responses that destroy pancreatic beta cells. T-lymphocytes react against islet cells. Although it can occur in any age, it most often affects younger individuals (10-20 years of age). There may also be a nonimmune, idiopathic DM 1 that is much less common. Environmental factors that contribute to the development of Type 1 DM include viral infections, vitamin D deficiency, air pollution, vaccinations, stress and ingestion of cow’s milk. Genetic associations include HLA- DR3 and HLA-DR4. Individuals seem to be genetically susceptible that leads to intolerance to self-antigens and the formation of autoantigens. Cytotoxic T- cells and macrophages (cellular immunity) and humoral immunity (autoantibodies) are stimulated that causes destruction of the beta cells and apoptosis. Most of the pancreatic beta cells are destroyed by the time the individual presents with hyperglycemia due to decreased insulin synthesis.
Decreased insulin synthesis leads to increased glucagon secretion that acts in the liver to stimulate glycogenolysis and gluconeogenesis. There is also decreased amylin secretion. Remember from our previous discussion of amylin, its function is to
decrease glucagon release from the alpha cells. Beta and alpha cells function abnormally that lead to excess glucagon that contributes also contributes to hyperglycemia.
Type 1 DM Diagnosis and Treatment
Diagnosis Before reviewing the diagnostic criteria for Type 1 DM, it is important to mention screening. Some studies are now suggesting the measurement of islet autoantibodies in individuals who may be genetically at-risk (e.g. having relatives with Type 1 DM). Screening, along with the provision of education about Type 1 DM and ongoing follow-up may help to establish an earlier diagnosis. The diagnosis for Type 1 DM is based on the American Diabetes Association diagnostic criteria below. Note that the same diagnostic criteria are also used to diagnose Type 2 DM.
FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h* OR 2-h PG ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water* OR A1C ≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay* OR In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random
- Alterations in oxidative phosphorylation in the cell’s mitochondria that contributes to insulin resistance.
Diabetes can be masked for years due to compensatory hyperinsulinemia that prevents the appearance of symptoms. Over time, beta-cell dysfunction becomes prevalent that leads to a reduction in insulin activity. Islet dysfunction occurs because of a decrease is beta-cells and reduction in beta cell function. Glucagon is increased in Type 2 diabetes because alpha cells in the pancreas become less responsive to glucose inhibition. This results in more glucagon being secreted. High glucagon levels stimulate glycogenolysis and gluconeogenesis. As in Type 1 DM, amylin deficiency also contributes to increased glucagon levels. The GI tract contributes to insulin resistance by releasing hormones. Ghrelin is produced in the stomach and pancreatic islets. It regulates food intake, energy balance and hormonal secretion. When Ghrelin is decreased, it contributes to insulin resistance. Incretins (previously discussed) are also released from the GI tract when food is ingested. It increases synthesis and secretion of insulin as well as beta cell proliferation and regeneration. In Type 2DM, beta-cells have a decreased responsiveness to incretin.
Type 2 DM Diagnosis The diagnosis for Type 2 DM is based on the American Diabetes Association diagnostic criteria below. Note that the same diagnostic criteria are also used to diagnose Type 1 DM.
FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h*
OR
2-h PG ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water*
OR
A1C ≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay*
OR
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L)
*In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results from the same sample or in two separate test samples
Type 2 DM Treatment
The goal of treatment is to restore the individual’s glucose level to as close to normal as possible and correct any metabolic disorders. Weight loss is recommended to help improve insulin sensitivity and glucose tolerance as well as to preserve beta-cell function. Weight loss can also help to prevent the progression of Type 2 DM. Exercise can help in weight loss and the reduction of postprandial blood glucose level. It also diminishes insulin requirements. It also lowers triglyceride and cholesterol levels and increases high-density lipoprotein (HDL) cholesterol. Diet should include complex carbohydrates instead of simple sugars, low fat foods, and adequate protein and fiber. Some individuals with morbid obesity may have bariatric surgery when weight loss does not occur despite following diet and exercise measures. It’s effectiveness, though, is still being evaluated. Many individuals with T2DM require oral hypoglycemic medications. There are many from which to select. In general, Metformin is the primary choice for the treatment of Type 2 DM. A second oral agent may be added (GLP-1 receptor agonist) or even insulin if the target HbA1c level is not maintained for over a three- month period. Insulin is often needed in the later stages of Type 2 DM because of the progressive loss of beta cell function over time.
