Endocrine Pathophysiology and Pharmacology

Concepts of Endocrine Dysfunction

• Learning Objectives
  • Define hormone hyposecretion and hypersecretion, and identify some common causes.
  • Outline the relationship between the hypothalamus and pituitary gland with respect to neuroendocrine regulation.

Endocrine System

• Works with the neural system to coordinate and regulate normal body functions.
• Referred to as the "Wi-Fi system" of the body.
• Influences the body through hormones, which are chemical messengers.
• Tightly controlled by feedback mechanisms.

Stimuli for Hormone Release

• Humoral stimuli
  • Hormones secreted due to concentration of substances in the blood.
  • Example: release of insulin in response to high levels of blood glucose.
• Neural stimuli
  • Mainly through the Sympathetic Nervous System.
  • Example: release of adrenaline and noradrenaline in response to stress.
• Hormonal stimuli
  • Hormones released in response to hormones produced by other endocrine organs.
  • The hormone carries the signal to the endocrine organ/gland to release hormones
  • Example: releasing and inhibiting hormones produced by the hypothalamus regulate the secretion of most anterior pituitary hormones.

Hormone Hyposecretion

• Characterized by a hormone-deficient state.
• Can occur when glandular cells are injured or destroyed by pathophysiological processes.
  • Autoimmune attack.
  • Invasive tumor growth.
  • Infections.
  • Chronic inflammation.
• Glandular cells unable to make the endocrine product.
  • Genetic defect affecting enzyme availability.
  • Absence of a specific precursor substance needed to make the hormone.

Hormone Hypersecretion

• Characterized by excessive hormone production.
• Can occur if another tissue is able to produce the hormone; known as ectopic hormone secretion, which occurs in certain types of cancer.
• Can be associated with endocrine gland hypertrophy and hyperplasia.
  • An endocrine gland that is overstimulated can undergo enlargement leading to increased hormone output.
• Can occur due to impairment of negative feedback.
• Some medicines can increase activity.

Hypothalamus & Pituitary Gland

• The hypothalamus and pituitary form important parts of the negative feedback mechanism.
• Disorders can occur at:
  1. Hypothalamus (rare)
  2. Pituitary (more common)
  3. The endocrine organ (very common).

Hypothalamus and Posterior Pituitary Gland

• Action potentials travel down the axons of hypothalamic neurons, causing hormone release from their axon terminals in the posterior pituitary.
• The posterior pituitary's function:
  • Hypothalamic neurons synthesize oxytocin or antidiuretic hormone (ADH).
  • Oxytocin and ADH are transported down the axons of the hypothalamic-hypophyseal tract to the posterior pituitary.
  • Oxytocin and ADH are stored in axon terminals in the posterior pituitary.
  • When associated hypothalamic neurons fire, action potentials arriving at the axon terminals cause oxytocin or ADH to be released into the blood.

Hypothalamus and Anterior Pituitary Gland

• Hypothalamic hormones released into special blood vessels (the hypophyseal portal system) control the release of anterior pituitary hormones.
  • When appropriately stimulated, hypothalamic neurons secrete releasing or inhibiting hormones into the primary capillary plexus.
  • Hypothalamic hormones travel through portal veins to the anterior pituitary where they stimulate or inhibit release of hormones made in the anterior pituitary.
  • In response to releasing hormones, the anterior pituitary secretes hormones into the secondary capillary plexus, which in turn empties into the general circulation.
• A portal system is two capillary plexuses (beds) connected by veins.

Pituitary Disorders

• Learning Objectives
  • Describe the causes, clinical manifestations, and management of hypopituitarism.
  • Describe the pathophysiology and clinical manifestations of hyperpituitarism.

Pituitary Gland Function

• ADH (Vasopressin):
  • Source: Posterior Pituitary
  • Target: Kidney and blood vessels
  • Effects:
    • Stimulates renal tubules to reabsorb water; promotes vasoconstriction
  • Regulation:
    • Increased by: Blood osmolality, decreased blood volume
    • Decreased by: Adequate hydration and alcohol
• Oxytocin:
  • Source: Posterior Pituitary
  • Target: Breast and Uterus
  • Effects:
    • Breast: Milk ejection
    • Uterus: Uterine contractions
  • Regulation:
    • Increased by: Suckling, cervical, and/or uterine stretch.
    • Decreased by: Lack of appropriate neural stimuli
• TSH (Thyroid Stimulating Hormone):
  • Source: Anterior Pituitary
  • Target: Thyroid
  • Effects: Stimulates release of thyroid hormone from the thyroid
  • Regulation:
    • Increased by: Cold temperatures
    • Decreased by: Somatostatin
• ACTH (Adrenocorticotropic Hormone):
  • Source: Anterior Pituitary
  • Target: Adrenal Cortex
  • Effects: Stimulates release of glucocorticosteroids and androgens
  • Regulation:
    • Increased by: CRH (corticotropin-releasing hormone), fever
    • Decreased by: Glucocorticosteroids
• Prolactin:
  • Source: Anterior Pituitary
  • Target: Breast
  • Effects: Stimulates production of breast milk
  • Regulation:
    • Increased by: PRH (prolactin-releasing hormone), breastfeeding
    • Decreased by: Dopamine
• GH (Growth Hormone):
  • Source: Anterior Pituitary
  • Target: Liver, Bone, and Muscle
  • Effects:
    • Stimulates growth
    • Mobilizes fats
    • Spares glucose
  • Regulation:
    • Increased by: GHRH (growth hormone-releasing hormone), GH levels, hypoglycemia, estrogens
    • Decreased by: GH levels, IGF, hyperglycemia, obesity, hyperlipidemia
• FSH (Follicle Stimulating Hormone):
  • Source: Anterior Pituitary
  • Target: Ovaries and Testes
  • Effects:
    • Females: Stimulates ovarian follicle maturation and estrogen production
    • Males: Sperm production
  • Regulation:
    • Increased by: GnRH (gonadotropin-releasing hormone)
    • Decreased by: Females: Estrogen and progesterone; Males: Inhibin and testosterone
• LH (Luteinizing Hormone):
  • Source: Anterior Pituitary
  • Target: Ovaries and Testes
  • Effects:
    • Females: Triggers ovulation and production of estrogen and progesterone
    • Males: Testosterone production
  • Regulation:
    • Increased by: GnRH
    • Decreased by: Females: Estrogen and progesterone; Males: Testosterone
• MSH (Melanocyte Stimulating Hormone):
  • Source: Anterior Pituitary
  • Target: Skin (melanocytes)
  • Effects: Stimulates Melanin Production
  • Regulation:
    • Increased by: Pregnancy
    • Decreased by: ??

Hypopituitarism

• Can lead to partial or complete failure of pituitary function.
• Causes:
  • Pituitary infarction.
  • Brain infections.
  • Head injury.
  • Neurosurgical damage.
  • Hypothalamic or pituitary gland dysfunction.
  • Destruction of the anterior lobe.
• Loss of pituitary function means normal stimulation of the thyroid and adrenal glands, and gonads does not occur.

Hypopituitarism Clinical Manifestations

• Depends on the cause of the problem.
  • Acute:
    • Headache
    • Altered mental state
    • Postural hypotension
    • Hyponatremia (low sodium levels)
    • Hypoglycemia
    • Visual defects (pressure on optic nerve/chiasm)
  • Chronic:
    • All of the acute signs & symptoms
    • Weight loss
    • Atrophy of other endocrine glands and organs
    • Hair loss
    • Dry, soft skin
    • Low body temperature
    • Obesity
    • Loss of libido
    • Erectile dysfunction
    • Testicular atrophy
    • Amenorrhea (abnormal absence of menstruation)
    • Hypometabolism
    • Cold intolerances
    • Delayed reflexes

Management of Hypopituitarism

• Surgery: Removal of the tumor that is causing the problem.
• Hormone replacement therapy
  • Generally implemented after surgery.
  • Lifelong replacement therapy.
  • Education is essential.
  • Replace the missing hormones, not the pituitary hormones.

Hyperpituitarism

• Characterized by an increase in secretion of two or more pituitary hormones.
• Most common cause is slow-growing benign tumors of the pituitary gland.
• Patient presentation will depend on where it occurs.
• Pressure from the tumor can affect other areas of the pituitary gland and nearby brain tissue and cranial nerves.

Clinical Manifestations of Hyperpituitarism

• Gigantism (Growth Hormone affected):
  • Increased height, bony prominences become more prominent, enlarged hands and feet, mild hyperphosphatemia.
• Prolactin increase in women:
  • Breast enlargement and non-gestational lactation, weight gain, and absence of menstruation (amenorrhea).
• Prolactin increase in men:
  • Increased breast development (gynecomastia).
• Glucocorticoids increase:
  • Increased blood pressure, fluid retention, euphoria, increased susceptibility to infection, 'moon-faced', 'buffalo hump', osteoporosis, muscle atrophy, paper-thin skin, poor wound healing, skin easily bruised.

Thyroid Disorders: Hypothyroidism

• Learning Objectives
  • Describe the pathophysiology, clinical manifestations, and management of hypothyroidism (Hashimoto’s disease).

Thyroid Gland

• Key role in endocrine function.
• Three hormones secreted by the thyroid gland:
  • Thyroxine (T4)
  • Triiodothyronine (T3)
  • Calcitonin
• Involved in calcium ion balance and sets the basal metabolic rate.

Hypothyroidism

• Hypoactive state: deficient production of thyroid hormone by the thyroid gland.
  • Primary hypothyroidism
    • Congenital defects.
    • Defective hormone production resulting from autoimmune thyroiditis, iodine deficiency, or antithyroid drugs.
    • Loss of thyroid tissue after surgical or radioactive treatment for cancer or hyperthyroidism.
  • Secondary hypothyroidism: Inadequate release of thyroid-stimulating hormone (TSH).
  • Tertiary hypothyroidism: Inadequate secretion of thyrotropin-releasing factor from the hypothalamus.

Synthesis of Thyroid Hormone

• Thyroid follicular cells are involved in the:
  • Synthesis of Thyroglobulin: synthesized and discharged into the follicle lumen.
  • Iodide Trapping: Iodide is actively transported into the cell.
  • Iodide Oxidation: Iodide is oxidized to iodine.
  • Iodination of Tyrosine: Iodine is attached to tyrosine in colloid, forming DIT and MIT.
    (MIT + DIT = T3) (DIT + DIT = T4)
  • Coupling of MITs and DITs: Iodinated tyrosines are linked together to form T3 and T4.
  • Colloid Endocytosis: Thyroglobulin colloid is endocytosed and combined with a lysosome.
  • Hormone Release: Lysosomal enzymes cleave T4 and T3 from thyroglobulin, and the hormones diffuse into the bloodstream.

Goitre

• Definition: A swelling of the neck that results from an enlargement of the thyroid gland.
• Can enlarge in both hypothyroid and hyperthyroid states.
• Hypothyroidism: Increase in thyroid-stimulating hormone (TSH) released from the pituitary gland, gland increases in size, no increase in hormone levels.

Pathophysiology of Primary Hypothyroidism

• Lack of thyroid hormone usually occurs due to the inability to produce sufficient thyroid hormone.
• TSH level is usually high, but due to an inability to produce thyroid hormone due to thyroid gland dysfunction, the level of thyroid hormone does not increase sufficiently.
• As a result, the thyroid gland may enlarge, which is known as goiter.

Pathogenesis: Hashimoto’s Disease

• Most common cause of hypothyroidism and is an autoimmune disease.
• Abnormal antibodies are formed against the thyroid gland blocking the normal synthesis of thyroid hormones.
• Hormone secretion decreases, the thyroid gland becomes atrophic and fibrotic, and hypothyroidism develops.
• Antibodies target the formation of thyroid hormones leading to hormone insufficiency.

Clinical Manifestations of Hypothyroidism

• Decreased metabolic rate
• Bradycardia
• Constipation
• Decreased appetite
• Fatigue/lethargy
• Slow speech and thought processes
• Hyporeflexia
• Muscle weakness
• Cold intolerance
• Weight gain
• Myxoedema (dough like puffy skin)
• Mental retardation (cretinism) and thyroid dwarfism if occurs in children.

Management of Hypothyroidism

• Levothyroxine (T4):
  • Thyroid hormone replacement therapy maintained for the rest of their life.
• Mechanism of Action:
  • Converted to L-triiodothyronine by peripheral tissues and effects last for up to two to three weeks.
• Clinical Considerations:
  • Need to take consistently to ensure return to normal thyroid levels.
  • Has a very long half-life (9 – 10 days in hypothyroidism).
  • Allow six weeks after adjusting dosage to test the outcome.
  • Take on an empty stomach, usually before breakfast.
  • Start at a low dose and slowly increase depending on the underlying cause.

Thyroid Disorders: Hyperthyroidism

• Learning Objectives
  • Describe the pathophysiology, clinical manifestations, and management of hyperthyroidism (Graves’ disease).

Hyperthyroidism

• Elevated levels of thyroid hormones.
• Most common cause has an autoimmune basis: Graves’ disease.
• Incidence is higher in women and can be familial.
• Causes:
  • Onset tends to be associated with major life changes: menopause, pregnancy, menarche (first occurrence of menstruation).
  • Linked to bacterial infections caused by Yersinia enterocolitica and vitamin D deficiency.
  • Tumor development (pituitary or thyroid gland).
  • Excessive iodine availability.

Thyroid Storm

• Occurs following a sudden increase in circulating thyroid hormone, leading to a hypermetabolic state.
• Usually precipitated by stresses, intercurrent illnesses, pregnancy, or surgery
• Also can be from reducing or stopping antithyroid medications.
• Clinical Features: Tachycardia, high blood pressure, hyperthermia, and can be fatal if not treated.

Pathogenesis: Graves’ Disease

• Abnormal antibodies called Thyroid Stimulating Antibodies are formed.
• These antibodies bind to the thyroid-stimulating hormone (TSH) receptors on the thyroid gland.
• This stimulates the continuous release of excessive amounts of thyroid hormones, and diffuse enlargement of the gland occurs.
• Clinical features of hyperthyroidism develop.

Clinical Manifestation of Hyperthyroidism

• Increased metabolic rate
• Tachycardia
• Palpitations and angina
• Muscle weakness and fatigue
• Increased gastrointestinal motility
• Heat intolerance
• Increased appetite (may include weight loss)
• Nervousness
• Tremors
• Hyperreflexia
• Insomnia
• Exophthalmos:
  • Seen in Graves’ disease.
  • Eyeballs bulge forward due to localized autoantibody-induced inflammation and increased connective tissue behind the eye.

Management of Hyperthyroidism

• Antithyroid medicines – first choice of therapy.
• Radioactive isotopes
  • Used to treat toxic thyroid adenomas, multinodular goiter, and relapsed Graves’ disease, commonly in older people.
  • Destroys the thyroid tissue – most people cured with one dose.
• Surgery: Indicated for pregnancy, allergies to antithyroid medicines, very large goiters, and severe exophthalmos.

Antithyroid Medicines in Hyperthyroidism

• Carbimazole: Reduces the level of circulating thyroid hormones.
• Mechanism of Action: Prevents iodine from being incorporated into the hormone structure and inhibits the synthesis and release of thyroid hormones.
• Adverse Effects:
  • Pruritis and rashes may occur during the early stages.
  • Rare: agranulocytosis – fever, mouth ulcers, rash, or sore throat, which needs quick treatment.
• Clinical Considerations:
  • Takes three to four weeks to see benefit due to the storage of preformed hormones.
  • Propylthiouracil is preferred during pregnancy.
  • Once normal thyroid function is established, reduce it to the lowest possible dose.

Parathyroid Disorders

• Learning Objectives
  • Describe the clinical manifestations and management of hypoparathyroidism and hyperparathyroidism.

Parathyroid Gland

• Usually 4 glands on the posterior aspect of the thyroid gland.
• Produces parathyroid hormone (PTH).
• Important in controlling blood calcium levels.
• Correct calcium levels are critical for functions such as nerve transmission, muscle contraction, and blood clotting.

Hypoparathyroidism

• Characterized by low blood calcium levels (hypocalcaemia).
• Permanent condition:
  • Damage from neck surgery or thyroidectomy.
  • Congenitally malformed parathyroid glands.
  • Autoimmune damaged glands.
• Transient condition is more common.
• Magnesium has an important role in the activation of parathyroid receptors and secretion of PTH.

Hypoparathyroidism Signs/Symptoms and Management

• Signs and Symptoms:
  • Muscle twitches and spasms
  • Tingling or prickling of the skin
  • Fatigue
  • Changes in emotional and mood state
  • Cardiac dysrhythmias
  • Milder hyperphosphatemia
  • Severe hypocalcemia: laryngeal spasms, tetany, and seizures
• Management:
  • Raise serum calcium levels to normal
  • Diet high in calcium and low in phosphate
  • Oral calcium gluconate supplements
  • Oral magnesium supplements
  • Vitamin D supplements to increase absorption
  • Synthetic PTH – common to have an allergic reaction to it.

Hyperparathyroidism

• Characterized by high blood calcium levels (hypercalcaemia)
  • Excessive bone resorption.
  • Increased gastrointestinal absorption of calcium.
  • Less calcium excretion.
• Causes:
  • Benign adenoma of the parathyroid tissue.
  • Glandular hyperplasia.
  • Some carcinomas may secrete PTH.
  • Chronic renal failure with imbalances in calcium and phosphate.
  • Radiotherapy to the head or neck.

Hyperparathyroidism Signs/Symptoms and Management

• Signs and Symptoms:
  • Fatigue
  • Depression
  • Poor concentration
  • Fractures
  • Hypercalciuria (increased renal calcium excretion), leading to renal stones
  • Hypophosphatemia
  • Severe – gastrointestinal disturbances, polyuria, dehydration, and cardiac dysrhythmias
• Management:
  • Surgical removal of relevant parathyroid gland(s).
  • High fluid intake to prevent renal stones, constipation, and dehydration.
  • Calcium intake should be restricted.
  • Increase weight-bearing activity.

Adrenal Gland Disorders

• Learning Objectives
  • Describe the pathophysiology, clinical manifestations, and management of Addison’s disease and Cushing’s disease.

Adrenal Cortex Hormones

• Aldosterone (mineralocorticoid)
  • Target: Kidney
  • Effects:
    • Stimulates the reabsorption of sodium, which causes water retention and increased BP
    • Reduces serum potassium
  • Regulation:
    • Increased by: Renin-angiotensin mechanism, decrease in BP or blood volume, increase in serum Na+ and decrease in K+
• Cortisol (glucocorticoid)
  • Target: Almost all cells
  • Effects:
    • Hepatic gluconeogenesis and glycogenolysis
    • Protein catabolism and suppresses immunity
    • Sensitizes arterioles to noradrenaline
  • Regulation:
    • Increased by: Adrenocorticotropic hormone
    • Decreased by: Cortisol
• DHEA (gonadocorticoid)
  • Target: Various cells
  • Effects:
    • Influence masculinization
    • Responsible for libido in females
  • Regulation: Not well understood

Addison’s Disease

• Primary adrenal insufficiency: Hyposecretion of aldosterone, cortisol, and androgens.
• Majority is caused by autoimmune adrenalitis.
• Other causes involve chronic inflammation, cancer, congenital malformation, and adrenal infections (e.g., tuberculosis).

Pathophysiology: Addison’s Disease

• Abnormal antibodies are formed against the adrenal cortex selectively destroy the adrenal cortex.
• The secretion of adrenocortical hormones is impaired leading to adrenal insufficiency.

Clinical Manifestations: Addison’s Disease

• Poor responsiveness to stress
• Hypoglycemia
• Sparse body hair
• Fatigue and depressed mood
• Anorexia and weight loss
• Chronic hypotension
• Decreased heart size
• Muscle weakness
• Hyponatremia and hyperkalemia
• Altered skin pigmentation

Management: Addison’s Disease

• Replace the hormones that are lacking (e.g., cortisol).
• If aldosterone is lacking: oral mineralocorticoid medicines.
• Patient education is key.
• Must carry a medical alert device that has the relevant details included.

Cushing’s Disease

• Related to excessive cortisol secretion.
• Causes:
  • Tumor that secretes cortisol or stimulates cortisol production.
  • Adrenal hyperplasia.
  • Adrenal adenoma.
  • Excess ACTH secretion by pituitary tumor.
  • Ectopic ACTH secretion (e.g., some types of lung cancer).

Pathophysiology: Cushing’s Disease

• Excessive secretion of ACTH by the adenoma, leading to excessive stimulation of the adrenal cortex.
• Adrenal cortical hyperplasia then leads to excessive production of glucocorticoids.

Clinical Manifestations: Cushing’s Disease

• Redistribution of subcutaneous fat to the face, abdomen, and upper thoracic region of the back
• Moon face and buffalo hump
• Weight gain (sodium and water retention)
• Increased blood pressure
• Insulin resistance
• Hypercalcemia (kidney stones)
• Immune suppression
• Irritability and psychotic behavior and depression altering with euphoria
• Androgen effects – excess body hair and acne

Management: Cushing’s Disease

• Depends on the cause.
• Pituitary-dependent
  • Surgical removal of tumor.
  • Hydrocortisone until cortisol levels stabilize.
• Radiation therapy: Takes longer than surgery to control the symptoms.