CH 10- Endocrine System and Adrenal/Pituitary/Thyroid Disorders

Physiology of the Endocrine System

• Definition and Function:

  • The endocrine system is a network of glands and hormone-secreting tissues.

  • It regulates long-term physiological processes by releasing biochemical signaling molecules called hormones directly into the bloodstream.

  • Hormones act on specific target cells to maintain homeostasis, coordinate growth and development, and regulate metabolism, reproduction, and response to stress.

• Comparison to the Nervous System:

  • Slower in Onset: Signaling takes longer to begin compared to neurological impulses.

  • Long-lasting in Effect: The influence of hormones persists for a longer duration.

  • Widespread in Action: Effects are often systemic rather than localized.

• Hormones:

  • Biochemical signaling molecules secreted by endocrine glands.

  • They travel through the circulatory system (bloodstream).

  • They bind to specific receptors on target cells to alter cellular activity.

• Major Types of Hormones:

  • Steroid Hormones: Derived from cholesterol. Their effects are typically slow but long-lasting.

  • Peptide and Protein Hormones: Composed of amino acids. Examples include insulin, glucagon, growth hormone (GH), and antidiuretic hormone (ADH). These have rapid effects that are short-lived.

  • Amine Hormones: Derived from amino acids such as tyrosine. Examples include thyroid hormones ($T_3$ and $T_4$) and epinephrine. These can exhibit characteristics of either steroid or peptide hormones.

Major Endocrine Glands and Their Functions

• Hypothalamus:

  • Acts as the link between the nervous and endocrine systems.

  • Produces releasing and inhibiting hormones.

  • Controls the activity of the pituitary gland.

• Pituitary Gland ("Master Gland"):

  • Anterior Pituitary: Secretes trophic hormones such as Thyroid-Stimulating Hormone (TSH), Adrenocorticotropic Hormone (ACTH), and Growth Hormone (GH).

  • Posterior Pituitary: Releases Antidiuretic Hormone (ADH) and Oxytocin.

  • Regulates other endocrine glands throughout the body.

• Thyroid Gland:

  • Produces Triiodothyronine ($T_3$) and Thyroxine ($T_4$).

  • Regulates the basal metabolic rate, heat production, and overall growth and development.

• Parathyroid Glands:

  • Secrete Parathyroid Hormone (PTH).

  • Regulate the balance of calcium and phosphate in the blood.

• Adrenal Glands:

  • Adrenal Cortex: Secretes aldosterone (electrolyte balance) and cortisol (stress and metabolism).

  • Adrenal Medulla: Secretes epinephrine and norepinephrine (fight-or-flight response).

• Pancreas (Endocrine Function):

  • Insulin: Lowers blood glucose levels.

  • Glucagon: Raises blood glucose levels.

  • Maintains glucose homeostasis.

• Gonads:

  • Ovaries: Secrete estrogen and progesterone.

  • Testes: Secrete testosterone.

  • Control reproduction and the development of secondary sex characteristics.

Regulation of Hormone Secretion

• Negative Feedback (Most Common Mechanism):

  • A rise in hormone levels inhibits further release of that hormone.

  • Maintains homeostasis.

  • Example: Elevated levels of $T_3$ and $T_4$ inhibit the release of TSH from the pituitary and TRH from the hypothalamus.

• Positive Feedback (Rare):

  • Hormone release amplifies further secretion.

  • Occurs only briefly for specific processes.

  • Example: Oxytocin release during labor.

• Interactions with Other Systems:

  • Nervous System: Rapid control versus the long-term regulation of the endocrine system.

  • Cardiovascular System: Responsible for the transport of hormones.

  • Renal System: Involved in hormone activation and excretion.

  • Immune System: Hormones modulate various immune responses.

• Modes of Endocrine Dysfunction:

  • Hyposecretion: Producing too little hormone (e.g., hypothyroidism).

  • Hypersecretion: Producing too much hormone (e.g., Cushing syndrome).

  • Receptor Defects: Hormone levels may be normal, but cells fail to respond (e.g., Type $2$ Diabetes Mellitus).

  • Symptom Characteristics: Symptoms of endocrine disorders are typically systemic, gradual in onset, and affect multiple organ systems.

The Adrenal Glands

• Anatomy:

  • Paired organs located superior to each kidney.

  • Critical for stress response, metabolism, blood pressure regulation, electrolyte balance, and sympathetic nervous system activity.

• Functional Regions:

  • Adrenal Cortex (Outer Layer): Produces steroid hormones.

    • Aldosterone (Mineralocorticoid): Regulates sodium ($Na^+$) and potassium ($K^+$) balance. It increases sodium and water reabsorption in the kidneys and increases potassium excretion to maintain blood volume and blood pressure.

    • Cortisol (Glucocorticoid): Regulates metabolism by increasing blood glucose via gluconeogenesis, promoting protein and fat breakdown, and providing anti-inflammatory and immunosuppressive effects. Essential for long-term stress response.

    • Androgens: Contribute to secondary sex characteristics; significant source of androgens in females and prepubertal individuals.

  • Adrenal Medulla (Inner Core): Produces catecholamines (epinephrine and norepinephrine).

    • Mediates the "fight-or-flight" response.

    • Increases heart rate, cardiac output, and blood pressure.

    • Dilates airways and increases blood glucose.

    • Redirects blood flow to skeletal muscle. The effects are rapid and short-lived.

• Stress Response Roles:

  • Acute Stress: Mediated by the adrenal medulla (epinephrine and norepinephrine).

  • Chronic Stress: Mediated by the adrenal cortex (cortisol and aldosterone).

Cortisol and Thyroid Pathways (Hypothalamic-Pituitary Axis)

• Cortisol Pathway:

  • Hypothalamus releases Corticotropin-Releasing Hormone (CRH+).

  • Stimulates Anterior Pituitary (Corticotroph cells) to release Adrenocorticotropic Hormone (ACTH).

  • ACTH stimulates the Adrenal Glands to produce Cortisol.

  • Cortisol provides negative feedback to the pituitary and hypothalamus.

• $T_4/T_3$ Pathway:

  • Hypothalamus releases Thyrotropin-Releasing Hormone (TRH+).

  • Stimulates Anterior Pituitary (Thyrotroph cells) to release Thyroid-Stimulating Hormone (TSH).

  • TSH stimulates the Thyroid gland to produce $T_4$ and $T_3$.

  • $T_4$ and $T_3$ provide negative feedback to the pituitary and hypothalamus.

Diseases of the Adrenal Cortex: Cushing Syndrome

• Definition: Clinical effects resulting from chronic excess of cortisol (hypercortisolism).

• Distinction:

  • Cushing Syndrome: Refers to all causes of excess cortisol.

  • Cushing Disease: Specifically refers to a pituitary adenoma secreting excess ACTH (a subset of the syndrome).

• Pathophysiology of Excess Cortisol:

  • Persistent catabolic state.

  • Altered fat distribution.

  • Insulin resistance and hypertension.

  • Immune suppression.

• Etiology:

  • Exogenous (Most Common): Prolonged glucocorticoid therapy (e.g., prednisone), which causes ACTH suppression.

  • Endogenous (ACTH-dependent): Cushing disease (pituitary adenoma) or ectopic ACTH production (e.g., small-cell lung carcinoma).

  • Endogenous (ACTH-independent): Adrenal adenoma, adrenal carcinoma, or adrenal hyperplasia.

• Clinical Manifestations:

  • Metabolic: Truncal (central) obesity, "Moon face," "Buffalo hump," and thin extremities due to muscle wasting.

  • Skin: Purple striae on abdomen/thighs, thin fragile skin, easy bruising, poor wound healing, and acne.

  • Musculoskeletal: Proximal muscle weakness, osteoporosis, and increased fracture risk.

  • Cardiovascular/Endocrine: Hypertension, hyperglycemia/diabetes, dyslipidemia, increased infection risk, menstrual irregularities, and decreased libido.

  • Neuropsychiatric: Mood changes, depression, irritability, and cognitive impairment.

• Management and Prognosis:

  • Management: Tapering exogenous steroids, surgical removal of tumors (pituitary or adrenal), radiation, or medications that inhibit cortisol synthesis.

  • Prognosis: Good with early diagnosis; untreated, it leads to cardiovascular disease, diabetes, osteoporosis, and increased mortality.

  • Imaging: CT or MRI is used after biochemical confirmation to locate the source but does not diagnose hypercortisolism on its own.

Aldosteronism

• Definition: Excess secretion of aldosterone causing sodium/water retention and potassium loss.

• Function of Aldosterone: Increases $Na^+$ reabsorption and $H_2O$ retention in distal nephrons; increases $K^+$ and $H^+$ excretion. Regulated by the Renin-Angiotensin-Aldosterone System (RAAS).

• Types:

  • Primary Aldosteronism (Conn Syndrome): Adrenal gland problem (adenoma, hyperplasia, or carcinoma). Characterized by High Aldosterone and Low Renin.

  • Secondary Aldosteronism: Caused by extra-adrenal RAAS activation (e.g., renal artery stenosis, heart failure, cirrhosis, nephrotic syndrome).

• Clinical Manifestations:

  • Hypertension (due to sodium retention).

  • Polyuria and polydipsia.

  • Hypokalemia: Leading to muscle weakness, fatigue, cramps, and cardiac arrhythmias.

• Management:

  • Primary: Surgical removal of adenoma or mineralocorticoid receptor antagonists for hyperplasia.

  • Secondary: Treat the underlying cause (e.g., heart failure).

  • Imaging: Performed after laboratory confirmation to differentiate unilateral adenoma from bilateral hyperplasia.

Adrenogenital Syndrome (Congenital Adrenal Hyperplasia - CAH)

• Definition: Inherited endocrine disorders caused by enzyme deficiencies in steroid synthesis, most commonly $21$-hydroxylase deficiency.

• Mechanism: Impaired cortisol and aldosterone synthesis leads to excess androgen production due to lack of negative feedback on ACTH.

• Types of $21$-Hydroxylase Deficiency:

  • Classic - Salt-Wasting Type: Severe deficiency of cortisol and aldosterone. Clinical features: dehydration, hyponatremia, hyperkalemia, hypotension, shock, and life-threatening adrenal crisis in infancy.

  • Classic - Simple Virilizing Type: Cortisol deficiency with adequate aldosterone. Clinical features: Virilization (masculinization), ambiguous genitalia in newborns, precocious puberty, hirsutism, and acne.

  • Non-classic (Late-onset): Partial deficiency. Symptoms appear in childhood/adulthood: hirsutism, acne, menstrual irregularities, and infertility (PCOS-like presentation).

• Diagnosis and Management:

  • Diagnosis: Newborn screening, hormone assays, ACTH stimulation test, and genetic testing. Glands may appear enlarged on imaging due to hyperplasia.

  • Management: Lifelong hormone replacement (glucocorticoids to replace cortisol and suppress ACTH; mineralocorticoids for salt-wasting) and electrolyte management.

Hypoadrenalism and Adrenal Insufficiency

• Classification:

  • Primary Adrenal Insufficiency (Addison Disease): Destruction of the adrenal cortex. Results in low cortisol, low aldosterone, and low androgens. ACTH levels are elevated.

  • Secondary Adrenal Insufficiency: Inadequate ACTH from the anterior pituitary. Aldosterone is usually normal (regulated by RAAS). ACTH is low or normal.

  • Tertiary Adrenal Insufficiency: Hypothalamic dysfunction resulting in low CRH, often due to sudden withdrawal of chronic corticosteroids.

• Etiology:

  • Primary: Autoimmune adrenalitis (most common in developed nations), TB, cancer metastasis, hemorrhage, or infections (HIV).

  • Secondary/Tertiary: Pituitary tumors, surgery, chronic exogenous steroid use, or TBI.

• Clinical Manifestations:

  • General: Chronic fatigue, weight loss, anorexia, nausea, and dizziness.

  • Primary Specific: Hyperpigmentation (due to high ACTH/MSH), hyperkalemia, and hyponatremia.

  • Secondary Specific: Hyponatremia and hypotension, but no hyperpigmentation.

• Addisonian (Adrenal) Crisis: A medical emergency precipitated by stress. Symptoms include severe hypotension/shock, hypoglycemia, hyponatremia, and hyperkalemia. Requires immediate IV hydrocortisone and fluid resuscitation.

• Diagnosis: ACTH (Cosyntropin) stimulation test and imaging to identify structural disease.

Adrenal Medulla and Cortex Tumors

• Adrenal Carcinoma (Adrenocortical Carcinoma - ACC):

  • Rare, aggressive malignancy.

  • Functional ACC: Secretes hormones (Cortisol, Aldosterone, Androgens, or Estrogens) causing rapid-onset symptoms like Cushing syndrome or virilization.

  • Nonfunctional ACC: Presents late via mass effect (abdominal pain, flank pain).

  • Imaging: CT is primary (size > 4\text{--}6\,cm, irregular margins, heterogeneous density).

  • Treatment: Complete surgical resection (open adrenalectomy) is the only curative option.

• Pheochromocytoma:

  • Benign catecholamine-secreting tumor of the chromaffin cells (Adrenal Medulla).

  • Classic Triad: Episodic headache, sweating (diaphoresis), and palpitations.

  • Critical Rule: NEVER biopsy an adrenal mass until pheochromocytoma is ruled out, as biopsy can trigger a fatal hypertensive crisis.

  • Imaging: CT or MRI (MRI shows "light-bulb bright" appearance).

• Neuroblastoma:

  • Malignant tumor of the adrenal medulla; most common extracranial solid tumor in childhood (median age < 2 years).

  • Manifestations: Abdominal mass, bone pain, and paraneoplastic syndromes (Opsoclonus-myoclonus syndrome: "dancing eyes, dancing feet").

  • Prognosis: Poor indicators include MYCN amplification and age > 18 months.

  • Imaging: Ultrasound is first-line in pediatrics (shows calcifications and displacement of the kidney).

The Pituitary Gland ("Master Gland")

• Physiology: Pea-sized ($\sim 1\,cm$) gland in the sella turcica. Regulated by the hypothalamus.

• Anterior Pituitary (Adenohypophysis): Glandular tissue linked by the Hypothalamic-Hypophyseal Portal System.

  • GH (Growth Hormone): Promotes tissue growth. Deficiency causes dwarfism; excess causes gigantism (children) or acromegaly (adults).

  • TSH: Stimulates thyroid to release $T_3/T_4$.

  • ACTH: Stimulates adrenal cortex for cortisol.

  • FSH and LH: Regulate gonadal function (estrogen, progesterone, testosterone, and sperm/egg production).

  • Prolactin (PRL): Stimulates milk production; inhibited by dopamine.

• Posterior Pituitary (Neurohypophysis): Neural tissue; stores hormones made in the hypothalamus.

  • Antidiuretic Hormone (ADH): Regulates water balance. Deficiency causes Diabetes Insipidus.

  • Oxytocin: Stimulates uterine contractions and milk ejection (positive feedback).

Pituitary Disorders

• Hyperpituitarism: Often caused by functional Pituitary Adenomas.

  • Hyperprolactinemia: Causes galactorrhea, amenorrhea, and infertility. Treated with dopamine agonists.

  • Growth Hormone Excess: Causes acromegaly (enlarged hands, feet, jaw, and insulin resistance).

  • Cushing Disease: ACTH-secreting adenoma.

  • Mass Effects: Bitemporal hemianopsia (compression of optic chiasm) and headache.

• Hypopituitarism: Partial or complete deficiency. Causes include adenomas, surgery, radiation, or Sheehan syndrome (postpartum necrosis).

  • MRI is the gold standard for imaging

• Diabetes Insipidus (DI): Disorder of water balance (polyuria and polydipsia) due to ADH deficiency or resistance.

  • Central DI: Inadequate ADH production (Hypothalamus/Pituitary problem). Treated with Desmopressin.

  • Nephrogenic DI: Kidney resistance to ADH (often due to lithium or CKD).

  • Water Deprivation Test: Used for diagnosis (DI urine remains dilute).

The Thyroid Gland

• Anatomy: Butterfly-shaped, located in the anterior neck inferior to the larynx. Consists of follicles (follicular cells) and parafollicular (C) cells.

• Hormones:

  • $T_4$ (Thyroxine): Most abundant; less active.

  • $T_3$ (Triiodothyronine): Most biologically active; responsible for most physiologic effects.

  • Calcitonin: From C cells; lowers blood calcium (minor role in adults).

• Physiologic Effects: Increases basal metabolic rate, oxygen consumption, heat production, heart rate, and cardiac output. Essential for brain development in infants.

Thyroid Dysfunction and Imaging

• Radioactive Iodine (RAI) Scanning:

  • Hot Nodule: Focal increased uptake; usually benign (toxic adenoma).

  • Cold Nodule: Absent uptake; increased risk of malignancy ($\sim 5\text{--}10\%$).

  • Diffuse Increased Uptake: Uniformly bright; suggests Graves Disease.

  • Patchy Uptake: Suggests toxic multinodular goiter.

• Hyperthyroidism:

  • Graves Disease: Autoimmune (TSI activates TSH receptors). Features: Exophthalmos (bulging eyes), diffuse goiter, and pretibial myxedema.

  • Thyroid Storm: Life-threatening extreme hyperthyroidism (fever, tachycardia, delirium).

• Hypothyroidism:

  • Hashimoto Thyroiditis: Most common cause; autoimmune destruction. Features: weight gain, cold intolerance, bradycardia, lethargy, and myxedema (puffy face).

  • Cretinism (Congenital Hypothyroidism): Severe deficiency at birth. Leads to permanent intellectual impairment and stunted growth if not treated within the first $2\text{--}3$ weeks of life.

  • Myxedema Coma: Rare medical emergency (hypothermia, altered mental status).

• Goiter: Gland enlargement regardless of hormone level. Common in iodine deficiency (causing high TSH).

Thyroid Tumors and Cancer

• Benign Adenoma: Solitary, encapsulated. Functioning ones appear "hot" on RAI scan.

• Thyroid Carcinoma:

  • Papillary: Most common ($\sim 80\%$); slow-growing; best prognosis; spreads via lymphatics.

  • Follicular: Second most common; spreads via blood (bone, lungs); cannot be diagnosed by Fine Needle Aspiration (FNA) alone (requires histology showing invasion).

  • Medullary: From C cells; produces calcitonin marker; associated with MEN $2$.

  • Anaplastic: Rare; highly aggressive; occurs in older adults; poor prognosis.

The Parathyroid Glands and Calcium Homeostasis

• Parathyroid Hormone (PTH): Increases serum calcium ($Ca^{2+}$) and decreases serum phosphate.

  • Bone: Stimulates Resorption (releases $Ca^{2+}$ and phosphate).

  • Kidneys: Increases $Ca^{2+}$ reabsorption and stimulates activation of Vitamin D.

  • GI Tract: Indirectly increases $Ca^{2+}$ absorption via Vitamin D.

• Hyperparathyroidism:

  • Primary: Usually a single adenoma. Signs: "Bones, stones, groans, and psychiatric overtones" (fractures, kidney stones, abdominal pained/ulcers, and confusion).

  • Secondary: Compensatory rise in PTH due to chronic hypocalcemia (e.g., Chronic Kidney Disease).

• Hypoparathyroidism: Usually post-surgical. Results in low $Ca^{2+}$.

  • Signs: Tetany, Chvostek sign (facial twitch), and Trousseau sign (carpal spasm with BP cuff).

• Pseudohypoparathyroidism (PHP): Genetic end-organ resistance to PTH. Leads to hypocalcemia despite high PTH.

  • Albright Hereditary Osteodystrophy (AHO): Features of PHP including short stature, round face, and shortened $4$th and $5$th metacarpals.

Diabetes Mellitus (DM)

• Definition: Chronic metabolic disorder of hyperglycemia due to insulin deficiency or resistance.

• Types:

  • Type 1 (T1DM): Autoimmune destruction of pancreatic $\beta$-cells. Absolute insulin deficiency. Sudden onset; risk of Diabetic Ketoacidosis (DKA).

  • Type 2 (T2DM): Insulin resistance with relative deficiency. Associated with obesity and lifestyle. Gradual onset.

  • Gestational DM: Occurs during pregnancy.

• Classic Symptoms: Polyuria (excess urination), Polydipsia (excess thirst), Polyphagia (excess hunger), and weight loss (especially T1DM).

• Diagnosis: Fasting plasma glucose, random plasma glucose $\ge 200\,mg/dL$ with symptoms, or Oral Glucose Tolerance Test (OGTT).

• Complications:

  • Acute: DKA, Hyperosmolar Hyperglycemic State (HHS), and hypoglycemia.

  • Microvascular: Retinopathy (blindness), Nephropathy (kidney failure), and Neuropathy.

  • Macrovascular: Coronary artery disease, stroke, and peripheral vascular disease.