# Lecture 25: The Endocrine System — Thyroid, Adrenal, and Pancreas

## Anatomy and Physiology I

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## Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the anatomy and histology of the thyroid gland and the synthesis of thyroid hormones
2. Explain the actions of thyroid hormones and the regulation of the HPT axis
3. Describe the function of calcitonin and parathyroid hormone in calcium homeostasis
4. Describe the anatomy and functional zones of the adrenal gland
5. Explain the actions and regulation of cortisol, aldosterone, and adrenal androgens
6. Describe the adrenal medulla as a modified sympathetic ganglion
7. Describe the endocrine pancreas and the roles of insulin and glucagon in glucose homeostasis

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## Lecture Content

### I. The Thyroid Gland

#### Anatomy

The thyroid gland is a butterfly-shaped gland located on the anterior neck, inferior to the larynx and straddling the trachea at the level of rings 2 through 4. It consists of two lateral lobes connected by a midline **isthmus**. The gland is highly vascular, receiving approximately 80-120 mL of blood per minute, one of the highest blood flow rates per gram of tissue in the body. It is innervated by sympathetic fibers that regulate blood flow and by parasympathetic fibers from the vagus nerve (CN X).

#### Histology

The functional units of the thyroid are spherical **thyroid follicles**, each lined by a single layer of **follicular cells (thyrocytes)** surrounding a central lumen filled with **colloid**. The colloid is a gel-like protein-rich substance composed primarily of **thyroglobulin (Tg)**, the storage form of thyroid hormones. Scattered between and around the follicles are **parafollicular cells (C cells)**, which produce **calcitonin**.

#### Thyroid Hormone Synthesis

Thyroid hormones are unique among amino acid-derived hormones in being lipid-soluble because they are iodinated tyrosine derivatives. Their synthesis proceeds through several steps. First, follicular cells synthesize thyroglobulin and secrete it into the colloid by exocytosis. Second, **iodide trapping** occurs as follicular cells actively transport iodide from the blood into the cell via the **sodium-iodide symporter (NIS)** on the basolateral membrane (TSH stimulates NIS expression). Third, iodide moves to the apical membrane where **thyroid peroxidase (TPO)** oxidizes it to iodine and attaches it to tyrosine residues on thyroglobulin in the colloid, forming monoiodotyrosine (MIT, with one iodine) and diiodotyrosine (DIT, with two iodines). Fourth, TPO catalyzes **coupling** of iodinated tyrosines: MIT plus DIT yields **T3 (triiodothyronine)** with three iodines, and DIT plus DIT yields **T4 (thyroxine)** with four iodines. The hormones remain stored as part of the thyroglobulin molecule in the colloid for weeks to months. Finally, when TSH stimulates secretion, follicular cells endocytose colloid, lysosomes cleave T3 and T4 from thyroglobulin, and the free hormones are released into the blood.

The thyroid secretes mostly **T4** (approximately 90%) with a small amount of T3 (approximately 10%). Peripheral tissues (liver, kidneys, muscle) convert T4 to the more biologically active **T3** using **deiodinase enzymes**, with T3 being approximately 3-5 times more potent than T4. In the blood, most T3/T4 circulates bound to **thyroxine-binding globulin (TBG)**, with only free T3/T4 being biologically active.

#### Actions of Thyroid Hormones

Thyroid hormones act on virtually every cell in the body by binding to **intracellular (nuclear) receptors** and altering gene transcription. Their metabolic effects include increasing the **basal metabolic rate (BMR)** by stimulating oxygen consumption and heat production (the calorigenic effect) in most tissues, increasing carbohydrate metabolism (glucose absorption, glycolysis, gluconeogenesis), increasing lipolysis and decreasing cholesterol levels, and increasing protein synthesis at physiological levels (though they are catabolic at excess levels).

For growth and development, thyroid hormones are essential for normal growth (working synergistically with GH), critical for **brain development** in the fetus and infant (deficiency causes irreversible intellectual disability known as cretinism or congenital hypothyroidism), and promote bone growth and maturation. Cardiovascularly, they increase heart rate, contractility, and cardiac output by upregulating beta-1 adrenergic receptors on the heart, increasing sensitivity to catecholamines. They also increase alertness, responsiveness, and reflexes in the nervous system, increase GI motility and secretion, and exert permissive effects by being required for the normal action of other hormones such as catecholamines and GH.

#### Regulation — HPT Axis

The hypothalamic-pituitary-thyroid axis operates through a cascade: the **hypothalamus** releases TRH, which stimulates the **anterior pituitary** to release TSH, which stimulates the **thyroid** to release T3/T4. Negative feedback occurs as T3/T4 inhibit TRH release from the hypothalamus and TSH release from the anterior pituitary. Cold exposure stimulates TRH release to increase metabolic heat production.

<image>A multi-panel diagram of the thyroid gland. Panel A: Anterior view of the thyroid gland on the trachea, showing the two lateral lobes, isthmus, and the superior and inferior thyroid arteries. The four parathyroid glands are shown on the posterior surface. Panel B: A histological cross-section showing thyroid follicles — spherical structures lined by follicular cells (cuboidal epithelium) surrounding pink colloid. Parafollicular C cells are shown between follicles. Panel C: A step-by-step diagram of thyroid hormone synthesis within a single follicle. The basolateral membrane shows the NIS transporting iodide into the cell. The apical membrane shows TPO oxidizing iodide and attaching it to tyrosine residues on thyroglobulin in the colloid (MIT and DIT formation). Coupling of MIT+DIT to form T3 and DIT+DIT to form T4 is shown within the colloid. Endocytosis of colloid, lysosomal cleavage of T3/T4 from thyroglobulin, and secretion of T3/T4 into the blood are illustrated. Panel D: The HPT axis feedback loop — TRH from the hypothalamus stimulates TSH from the anterior pituitary, which stimulates T3/T4 from the thyroid. Dashed negative feedback arrows show T3/T4 inhibiting both TRH and TSH release.</image>

### II. Calcitonin and Calcium Homeostasis

#### Calcitonin

Calcitonin is produced by the **parafollicular C cells** of the thyroid and released in response to **elevated blood calcium**. Its actions include inhibiting osteoclast activity (reducing bone resorption) to lower blood calcium, promoting calcium deposition in bone, and increasing renal calcium excretion. However, its physiological significance in adults is relatively minor, with PTH being far more important for calcium regulation. Calcitonin is more important during childhood bone development. Clinically, calcitonin (salmon calcitonin) is used as a drug to treat hypercalcemia and osteoporosis.

#### Parathyroid Glands and PTH

The parathyroid glands consist of **four small glands** embedded on the posterior surface of the thyroid. They are composed of **chief (principal) cells** that produce **parathyroid hormone (PTH)** and **oxyphil cells** whose function remains uncertain but may become active with age.

#### Parathyroid Hormone (PTH)

PTH is the most important hormone for calcium homeostasis. It is released in response to **low blood calcium**, detected by calcium-sensing receptors (CaSR) on chief cells. All of its actions serve to raise blood calcium. In **bone**, PTH stimulates osteoclast activity (via osteoblast-mediated RANKL signaling), increasing bone resorption and releasing calcium and phosphate into the blood. In the **kidneys**, it increases calcium reabsorption in the distal convoluted tubule, decreases phosphate reabsorption (increasing phosphate excretion to prevent calcium-phosphate precipitation), and stimulates 1-alpha-hydroxylase, which converts 25-hydroxyvitamin D to **1,25-dihydroxyvitamin D (calcitriol)**, the active form of vitamin D. Indirectly through calcitriol, PTH increases intestinal absorption of calcium and phosphate.

PTH is regulated by negative feedback: elevated blood calcium inhibits PTH release. Clinically, **hyperparathyroidism** causes hypercalcemia with the classic presentation of "bones, stones, abdominal groans, and psychic moans" (bone pain and fractures, kidney stones, constipation and nausea, confusion and depression). **Hypoparathyroidism**, often occurring after thyroid surgery, causes hypocalcemia manifesting as muscle cramps, tetany, paresthesias, and cardiac arrhythmias, with positive Chvostek and Trousseau signs.

### III. The Adrenal Glands

#### Anatomy

The adrenal glands are two small, pyramid-shaped glands sitting atop each kidney (suprarenal). Each gland has two functionally distinct regions: the **adrenal cortex** (outer 80-90%, derived from mesoderm, secreting steroid hormones) and the **adrenal medulla** (inner 10-20%, derived from neural crest, secreting catecholamines).

### IV. The Adrenal Cortex

The adrenal cortex is organized into three zones from outer to inner, remembered by the mnemonic **"GFR — Salt, Sugar, Sex."**

#### Zona Glomerulosa (Outermost)

The zona glomerulosa produces **mineralocorticoids**, primarily **aldosterone**. Aldosterone acts on the distal convoluted tubule and collecting duct of the kidney, increasing sodium reabsorption (with water following) and potassium secretion. The net effect is increased blood volume and blood pressure along with prevention of hyperkalemia.

Aldosterone regulation is not primarily controlled by ACTH. Instead, the **renin-angiotensin-aldosterone system (RAAS)** is the primary regulator. When decreased blood pressure, decreased blood volume, or decreased sodium delivery to the macula densa is detected, the kidneys release **renin**, which converts angiotensinogen from the liver to **angiotensin I**. **ACE** (angiotensin-converting enzyme, in the lungs) converts angiotensin I to **angiotensin II**, which stimulates aldosterone release from the zona glomerulosa. Angiotensin II also causes vasoconstriction, stimulates ADH release, and stimulates thirst. Additionally, elevated blood potassium directly stimulates aldosterone release, while ACTH has only a minor permissive role.

#### Zona Fasciculata (Middle — Largest Zone)

The zona fasciculata produces **glucocorticoids**, primarily **cortisol**. Cortisol has wide-ranging actions. Metabolically, it increases blood glucose through gluconeogenesis in the liver, reduces glucose uptake by most tissues, promotes lipolysis, and promotes protein catabolism in muscle (providing amino acids for gluconeogenesis), ensuring that energy substrates are available during stress. Its **anti-inflammatory and immunosuppressive** effects include inhibiting inflammatory mediators (prostaglandins, leukotrienes, histamine), reducing immune cell activity, and stabilizing lysosomal membranes. These properties form the basis for therapeutic use of glucocorticoids such as prednisone and dexamethasone. As a key stress hormone, cortisol mobilizes energy reserves and enhances cardiovascular responses to catecholamines through its permissive effect. It also affects mood and cognition, promotes bone resorption (excess causes osteoporosis), and inhibits wound healing at high levels.

Cortisol is regulated by the **HPA axis**: the hypothalamus releases CRH, the anterior pituitary releases ACTH, and the adrenal cortex releases cortisol. Negative feedback occurs as cortisol inhibits both CRH and ACTH. Cortisol secretion follows a circadian rhythm, peaking in the early morning (approximately 6-8 AM) and reaching its lowest point around midnight. Stress can override negative feedback and increase cortisol secretion.

#### Zona Reticularis (Innermost)

The zona reticularis produces **adrenal androgens**, primarily **DHEA (dehydroepiandrosterone)** and **androstenedione**. These are weak androgens converted to testosterone and estrogens in peripheral tissues. In females, adrenal androgens are the primary source of androgens, contributing to libido, pubic hair, and axillary hair growth. In males, they are relatively insignificant compared to testicular testosterone. They are regulated primarily by ACTH. Clinically, **congenital adrenal hyperplasia (CAH)** results from enzyme deficiency (most commonly 21-hydroxylase) that blocks cortisol synthesis. The loss of negative feedback leads to excessive ACTH, which drives adrenal androgen overproduction, causing virilization in females and precocious puberty in males.

### V. The Adrenal Medulla

The adrenal medulla is a modified sympathetic ganglion in which **chromaffin cells** serve as the equivalent of postganglionic neurons. It is innervated directly by preganglionic sympathetic fibers from the greater splanchnic nerve and secretes **epinephrine (approximately 80%)** and **norepinephrine (approximately 20%)** into the blood. Its actions are identical to sympathetic nervous system effects, amplifying the fight-or-flight response: increased heart rate and contractility (beta-1), bronchodilation (beta-2), glycogenolysis, lipolysis, and increased blood glucose (beta-2 and alpha-1), and vasoconstriction in skin and viscera (alpha-1) with vasodilation in skeletal muscle (beta-2). The hormonal release provides a more prolonged and widespread effect than direct sympathetic nerve stimulation alone. Clinically, a **pheochromocytoma** is a catecholamine-secreting tumor of the adrenal medulla causing episodic hypertension, headache, sweating, tachycardia, and anxiety ("spells").

<image>A cross-section of the adrenal gland showing the cortex and medulla. The cortex is divided into three distinct zones from outer to inner: zona glomerulosa (thin outer layer producing aldosterone — with an arrow to the kidney showing Na+ reabsorption and K+ secretion), zona fasciculata (thick middle layer with lipid-laden cells arranged in columns producing cortisol — with arrows showing metabolic effects: gluconeogenesis, anti-inflammatory, stress response), and zona reticularis (inner layer producing DHEA and androstenedione — with arrows to peripheral conversion to sex steroids). The medulla is shown in the center with chromaffin cells producing epinephrine and norepinephrine, with a preganglionic sympathetic fiber (ACh) synapsing on the chromaffin cells. A summary mnemonic is included: "GFR = Salt, Sugar, Sex" for the three zones. The RAAS pathway for aldosterone regulation and the HPA axis for cortisol regulation are shown as small flow diagrams alongside the appropriate zones.</image>

### VI. The Endocrine Pancreas

#### Anatomy

The pancreas is both an exocrine gland (producing digestive enzymes) and an endocrine gland. It is located retroperitoneally, posterior to the stomach, extending from the duodenal C-loop (head) to the spleen (tail). The endocrine portion consists of the **islets of Langerhans**, approximately 1-2 million clusters of endocrine cells scattered among the exocrine acinar tissue, constituting about 1-2% of pancreatic mass.

#### Islet Cell Types

The islets contain several cell types. **Alpha cells** (approximately 15-20% of islet cells) produce glucagon. **Beta cells** (approximately 65-80%, located in the center of the islet) produce insulin. **Delta cells** (approximately 3-10%) produce somatostatin, which locally inhibits both insulin and glucagon release. **PP cells (F cells)** produce pancreatic polypeptide, regulating pancreatic exocrine secretion. **Epsilon cells** are rare and produce ghrelin, which stimulates appetite and GH release.

### VII. Insulin

Insulin is a peptide hormone consisting of two chains (A and B) linked by disulfide bonds. It is produced as preproinsulin, processed to proinsulin, and then cleaved to yield insulin plus C-peptide (C-peptide levels are used clinically to assess endogenous insulin production). Its primary stimulus for release is elevated blood glucose, with additional stimulation from amino acids, fatty acids, GIP and GLP-1 (incretins from the GI tract that amplify the insulin response to oral glucose), and parasympathetic stimulation. It is inhibited by low blood glucose, sympathetic stimulation (via alpha-2 adrenergic receptors on beta cells), and somatostatin.

#### Mechanism of Insulin Secretion (from Beta Cells)

Insulin secretion follows a well-defined sequence. Glucose enters the beta cell via **GLUT2** transporters and is metabolized through glycolysis and oxidative phosphorylation, increasing intracellular ATP. ATP closes **ATP-sensitive potassium channels** (KATP channels), causing potassium to accumulate inside the cell and producing **depolarization**. This depolarization opens **voltage-gated calcium channels**, and the resulting calcium influx triggers **exocytosis** of insulin-containing granules.

#### Actions of Insulin (the "hormone of abundance")

Insulin is the only hormone that lowers blood glucose. It acts primarily on the liver, skeletal muscle, and adipose tissue via the **insulin receptor** (a receptor tyrosine kinase). In the **liver**, insulin stimulates glycogenesis (glycogen synthesis from glucose), glycolysis, and lipogenesis while inhibiting gluconeogenesis and glycogenolysis. In **skeletal muscle**, it stimulates glucose uptake by promoting **GLUT4 transporter** insertion into the membrane, stimulates glycogenesis and protein synthesis, and inhibits protein catabolism. In **adipose tissue**, it stimulates glucose uptake (via GLUT4), stimulates lipogenesis (triglyceride synthesis from glucose and fatty acids), and inhibits lipolysis. The overall effect is to promote glucose uptake and storage, lower blood glucose, and promote anabolism (building up glycogen, protein, and fat).

### VIII. Glucagon

Glucagon is a peptide hormone produced by alpha cells. Its primary stimulus for release is low blood glucose, with additional stimulation from amino acids (especially after a protein-rich meal), sympathetic stimulation (via beta-2 adrenergic receptors), exercise, and cortisol. It is inhibited by elevated blood glucose, insulin, and somatostatin. Glucagon acts primarily on the liver, stimulating glycogenolysis (glycogen breakdown to glucose), gluconeogenesis (synthesis of new glucose from amino acids and glycerol), and lipolysis with ketogenesis. Its overall effect is to raise blood glucose, making it the primary counter-regulatory hormone to insulin.

### IX. Glucose Homeostasis — Insulin and Glucagon Balance

In the **fed state** after a meal, blood glucose rises, beta cells secrete insulin, glucose uptake and storage increase, and blood glucose returns to normal. In the **fasting state** between meals, blood glucose falls, alpha cells secrete glucagon, glycogenolysis and gluconeogenesis increase, and blood glucose returns to normal. Insulin and glucagon work as antagonistic partners to maintain blood glucose within a narrow range of approximately 70-110 mg/dL fasting. Other hormones that raise blood glucose (counter-regulatory hormones) include cortisol, GH, epinephrine, and thyroid hormones, which together oppose insulin's effects.

<image>A two-panel diagram illustrating glucose homeostasis. Panel A (Fed state — high blood glucose): An upward arrow shows rising blood glucose after a meal. The pancreatic beta cell detects high glucose via GLUT2. The insulin secretion pathway is shown: glucose metabolism increases ATP, ATP closes KATP channels, depolarization opens Ca2+ channels, Ca2+ triggers insulin exocytosis. Insulin travels to target tissues: the liver (stimulates glycogenesis, inhibits gluconeogenesis), skeletal muscle (GLUT4 insertion, glucose uptake, glycogenesis), and adipose tissue (GLUT4 insertion, lipogenesis). Blood glucose falls back to normal. Panel B (Fasting state — low blood glucose): A downward arrow shows falling blood glucose. The alpha cell releases glucagon. Glucagon acts on the liver: stimulates glycogenolysis and gluconeogenesis, releasing glucose into the blood. Blood glucose rises back to normal. A horizontal balance/seesaw in the center shows insulin and glucagon as opposing forces maintaining blood glucose at approximately 70-110 mg/dL. Counter-regulatory hormones (cortisol, GH, epinephrine) are shown supporting glucagon's glucose-raising effects.</image>

### X. Clinical Correlations

#### Thyroid Disorders

**Hypothyroidism** is caused by Hashimoto thyroiditis (autoimmune destruction, the most common cause in iodine-sufficient areas), iodine deficiency (the most common cause worldwide), or post-thyroidectomy. Symptoms include fatigue, weight gain, cold intolerance, constipation, bradycardia, dry skin, hair loss, myxedema (non-pitting edema), elevated TSH, and low T3/T4. Treatment is levothyroxine (synthetic T4). **Hyperthyroidism** is caused by Graves disease (autoimmune TSH receptor-stimulating antibodies, the most common cause), toxic multinodular goiter, or toxic adenoma. Symptoms include weight loss, heat intolerance, diarrhea, tachycardia and palpitations, tremor, anxiety, exophthalmos (bulging eyes, specific to Graves disease), low TSH, and high T3/T4. Treatment options include antithyroid drugs (methimazole), radioactive iodine ablation, and surgery. **Goiter**, an enlarged thyroid, can occur in both hypothyroidism and hyperthyroidism. Iodine deficiency goiter results from reduced T3/T4 production, loss of negative feedback, and TSH-driven thyroid enlargement.

#### Adrenal Disorders

**Addison disease (primary adrenal insufficiency)** involves destruction of the adrenal cortex (autoimmune is the most common cause in developed countries; tuberculosis in developing countries), resulting in deficiency of cortisol, aldosterone, and adrenal androgens. Symptoms include fatigue, weight loss, hypotension, hyperkalemia, hyperpigmentation (from excess ACTH/MSH due to loss of cortisol feedback), and salt craving. Addisonian crisis is acute adrenal insufficiency causing life-threatening hypotension and hypoglycemia, triggered by stress in an undertreated patient. **Cushing syndrome** (cortisol excess) was covered in the previous lecture.

#### Diabetes Mellitus

**Type 1 diabetes** results from autoimmune destruction of beta cells, producing absolute insulin deficiency. It typically presents in childhood or adolescence and requires insulin therapy. Without insulin, patients develop hyperglycemia, polyuria (osmotic diuresis), polydipsia (thirst), polyphagia (hunger), weight loss, and diabetic ketoacidosis (DKA), in which uncontrolled lipolysis produces ketone bodies causing metabolic acidosis. **Type 2 diabetes** involves insulin resistance (target cells respond poorly to insulin) and progressive beta cell dysfunction. It typically presents in adulthood and is associated with obesity, sedentary lifestyle, and genetic predisposition. Initially, there is hyperglycemia with hyperinsulinemia, followed by eventual beta cell exhaustion. Treatment options include lifestyle modification, metformin, sulfonylureas, GLP-1 receptor agonists, SGLT2 inhibitors, and insulin if needed. Both types share long-term complications including retinopathy, nephropathy, neuropathy, cardiovascular disease, and poor wound healing, all resulting from chronic hyperglycemia damaging blood vessels and nerves.