The Endocrine System

The Endocrine System

• The hypothalamus produces ADH, oxytocin, and regulatory hormones.
• The pineal gland produces melatonin.
• The pituitary gland (anterior lobe) produces ACTH, TSH, GH, PRL, FSH, LH, and MSH.
• The pituitary gland (posterior lobe) releases oxytocin and ADH.
• The thyroid gland produces thyroxine (T4), triiodothyronine (T3), and calcitonin (CT).
• The parathyroid glands produce parathyroid hormone (PTH).
• The heart produces natriuretic peptides: ANP and BNP.
• The kidneys produce renin, erythropoietin (EPO), and calcitriol.
• The adrenal glands (medulla) produce epinephrine (E) and norepinephrine (NE).
• The adrenal glands (cortex) produce cortisol, corticosterone, aldosterone, and androgens.
• The pancreas produces insulin and glucagon.
• Adipose tissue produces leptin and resistin
• The digestive tract produces numerous hormones.
• The testes produce androgens (especially testosterone) and inhibin.
• The ovaries produce estrogens, progestins, and inhibin.
• The thymus (undergoes atrophy during adulthood) produces thymosins

Thyroid Hormone Functions

• Plays a role in growth and development.
• Stimulates heart rate and contraction.
• Stimulates the synthesis of proteins and carbohydrates.
• Degrades cholesterol and triglycerides.
• Enhances beta-adrenergic receptors to catecholamines.
• Increases Vitamin requirements.
• Excess thyroid hormone causes muscle wasting, bone loss, and increased heart rate.
• Beneficial effects of thyroid hormones include reduced bad cholesterol and fat loss.
• Increased metabolism, growth and development, and increased catecholamine effect
• Affects the liver, heart, CNS, immunity, bones, vision, and audition

Thyroid Hormone Synthesis and Regulation

• The hypothalamus releases thyroid-releasing hormone (TRH).
• TRH stimulates the pituitary gland to secrete thyroid-stimulating hormone (TSH).
• TSH is absorbed into the thyroid, stimulating the thyroid to absorb iodine and synthesize hormones
• TSH binds to receptors on the plasma membrane of the thyroid gland.
• TSH stimulates the production of T3 and T4.
• T3 and T4 are essential for cell building, repair, and energy.
• Thyroid hormones provide negative feedback for thyrotropin production through a homeostatic feedback loop.
• Thyroxine (T4) makes up 90% of the hormones produced by the thyroid.
• Triiodothyronine (T3) makes up 10% of the hormones produced by the thyroid and has the greatest metabolic activity.

Thyroid Pharmacology

• Drugs are used to alter the action of thyroid hormones in two conditions:
• Hypothyroidism (hyposecretion of hormone)
• Hyperthyroidism (hypersecretion of hormone)

Hypothyroidism

• Occurs due to hyposecretion of thyroid hormone.
• Etiology
  • Familial enzyme defects
  • Intake of goitrogens during pregnancy
  • Auto-immune thyroiditis
  • Hyposecretion of thyroid hormones may occur as a result of glandular destruction, which is produced by excessive exposure to:
    • radiation (X-ray),
    • lack of iodine, pituitary dysfunction (lack of TSH),
    • surgical removal of thyroid tissue (thyroidectomy).
• Hyposecretion of T3 and T4 in adults results in nontoxic goiter.
• When thyroid hormone secretion is suppressed, the feedback loop acts on the thyroid to secrete more T3 and T4.
• When little to no T3 and T4 circulates in the blood, TSH continues to stimulate the thyroid gland to release hormones it cannot produce.
• The thyroid increases in size, it protrudes from the front of the neck, causing a swollen appearance. This is known as glandular enlargement (hypertrophy).

Classification of Hypothyroidism

• Primary Thyroid Defect (usually associated with goiter):
  • chronic autoimmune thyroiditis
  • endemic iodine deficiency
  • radioiodine therapy
  • Hashimoto thyroiditis
  • previous thyroidectomy
• Central Hypothyroidism is secondary to hypothalamic or pituitary lesions (not associated with goiter):
  • pituitary tumor
  • radiation
  • surgery
  • TSH deficiency
  • TRH deficiency

Signs and Symptoms of Hypothyroidism

• Symptoms include hair loss, fatigue, sensitivity to cold, constipation, increased cholesterol, weight gain and dry skin

Grading of Goiters

• Grade 0: Not visible neck extended & Not palpable
• Grade 1: Not visible, but palpable
• Grade 2: Visible only when neck is extended & on swallowing
• Grade 3: Visible in all positions
• Grade 4: Large goiter

Hashimoto's Disease

• Hashimoto's Disease is the most common cause of hypothyroidism in North America (not iodine deficiency!).
• It involves autoimmune destruction of thyroid cells and chronic lymphocytic thyroiditis.
• It is more common in females than males, and runs in families
• Antithyroid antibodies include: Thyroglobulin Ab (TG Antibody), Thyroid Peroxidase (TPO) Ab, and TSH-Receptor Ab
• Signs of Hashimoto's disease include:
  • Feeling very tired or sluggish
  • Being very sensitive to cold
  • Weight gain
  • Body or joint pain
  • Feeling depressed

Diagnosis of Hypothyroidism

• Diagnosis
  • early detection by neonatal screening
  • high index of suspicion in all infants with increased risk
  • overt clinical presentation
  • confirmation of diagnosis by appropriate lab and radiological tests
• Laboratory Tests
  • Primary Hypothyroidism
    • Congenital
    • Radiation damage
    • Surgical removal
    • Viral infection
    • Auto-immune
    • T3 levels are decreased
    • T4 levels are decreased
    • TSH levels are increased
  • Secondary Hypothyroidism
    • Damage to the pituitary gland
    • T3 levels are decreased
    • T4 levels are decreased
    • TSH levels are decreased

Treatment of Hypothyroidism

• Life-long hormone replacement therapy
• Five types of preparations are available:
  • L-thyroxine (T4)
  • Triiodothyronine (T3)
  • Synthetic mixture T4/T3 in 4:1 ratio
  • Desiccated thyroid (38mg T4 & 9mg T3/grain)
  • Thyroglobulin (36mg T4 & 12mg T3/grain)
• L-Thyroxin is the drug of choice and should be started with small doses to avoid cardiac strain.
• Dose is 10 mg/kg/day in infancy
• In older children start with 25 mg/day and increase by 25 mg every 2 weeks until the required dose.
• Clinical progress and hormone levels should be monitored
• In hypothyroidism and pregnancy the changes in thyroid function include:
  • Increased hCG causes increased T4 and decreased TSH.
  • Increased Estrogen causes increased TBG.
  • Increased TBG causes increased Demand for T4 and T3 as well as increases Total T4 and T3
  • Increased Iodine clearance causing increased Dietary requirement for iodine and decreased TH production in iodine-deficient women as well as increased Goiter development in iodine-deficient women
• Risks of hypothyroidism during pregnancy: increased spontaneous abortion, HTN, preterm pregnancy, and low IQ points for fetus.
• Need TSH at baseline & q2mos while pregnant LT4 (Category A): 2 ug/kg/d and check TSH q4wk until euthyroid
• TSH increased but 10 you should increase dose by 50 ug/d
• For Hashimoto's Disease:
  • use Thyroid Hormone Replacement.
  • Levothyroxine (T4) is effective.
  • Use T3 or T3/T4 combination.
  • Giving iodine has no benefit.
• Daily adult maintenance doses:
  • Levothyroxine sodium (T4) 100-200 mcg PO; 50-100 mcg IM, IV
  • Liothyronine sodium (T3) 25-75 mcg PO
  • Liotrix (T3+T4) 1Thyrolar-1 tablet to 1 Thyrolar-2 tablet**(equals 60-120 mg hormone) /day PO
  • Thyroid (desiccated thyroid) (T3+T4) 60-120 mcg PO

Hormone Replacement

• Thyroid hormones are approved for use in children and adults as replacement or supplement in hypothyroidism from any cause.
• Thyroid hormones are also used in the treatment of thyroid nodules and thyroid cancer because they suppress TSH, and in the diagnosis of hyperthyroid conditions.
• They are not approved or indicated for use in the treatment of obesity.
• Symptoms may include psychotic behavior, diarrhea, increased blood pressure and heart rate, fever, and angina attacks, stimulation may result in weight loss, menstrual irregularities, and sweating, tremors, headache, nervousness, and insomnia.
• When using Thyroid hormones use extreme caution in patients who have cardiovascular or renal disease.
• Bone density must be evaluated prior to therapy in order to adequately monitor the hormone's effect and adjust the dose to minimize bone demineralization.
• Drug Interactions: Cholestyramine, Lithium, Oral anticoagulant warfarin, Insulin or oral hypoglycemic drugs, Estrogens.

Hyperthyroidism

• Hyperthyroidism occurs due to the hypersecretion of thyroid hormone.
• Hypersecretion of thyroid hormones may be produced by tumors (thyroid, pituitary, or hypothalamic malignancies), or autoimmune disease (Graves' disease).

Cause of Hyperthyroidism

• Graves Disease – Diffuse Toxic Goiter
• Plummer's Disease - Toxic MNG
• Toxic phase of Sub Acute Thyroiditis - SAT
• Toxic Single Adenoma – STA
• Pituitary Tumors - excess TSH
• Molar pregnancy & Choriocarcinoma (↑↑ BHCG)
• Metastatic thyroid cancers (functioning)
• Struma Ovarii (Dermoid and Ovarian tumors)
• Thyrotoxicosis Factitia; Amiodarone

Signs and Symptoms of Hyperthyroidism

• Symptoms include fine, brittle hair, trouble sleeping, excessive sweating, weight loss, high blood pressure, anxiety and moist skin

Graves' Disease

• The immune system mistakenly attacks the thyroid gland, but instead of destroying the gland, an antibody called thyrotropin receptor antibody (TRAb) stimulates the thyroid to make excessive amounts of thyroid hormone
• The most common cause of thyrotoxicosis (50-60%).
• Organ specific auto-immune disease
• The most important autoantibody is : Thyroid Stimulating Immunoglobulin (TSI) or TSA
• Symptoms: Anxiety or irritability, Bulging eyes, Sensitivity to heat, Unexplained weight loss, Shaking hands or fingers, Tiredness, and fast or irregular heartbeat
• Patients exhibit responses of chronic thyroid stimulation leading to protrusion of the eyeballs (exophthalmos)
• The exophthalmos results from swelling of the tissues and muscles behind the eye.

Diagnosis of Hyperthyroidism

• Hyperthyroidism diagnosis is associated with increased secretion and circulation of T3 and T4, leading to added heat production, increased cell metabolism, tachycardia, muscle weakness, anxiety, and weight loss
• Tests in diagnosis Thyroid antibody tests, Thyroid examination, TFT (Thyroid Function Test), Clinical presentation
• Disorders and test profile
  • Graves disease, Toxic adenoma, Multi-nodular goitre and Thyroid hormone overdose
  • T3 and T4 are elevated
  • TSH is decreased

Treatment of Hyperthyroidism

• Treatment Options: - Symptom relief medications - Anti Thyroid Drugs – ATD - Methimazole, Carbimazole - Propylthiouracil (PTU) - Radio Active Iodine treatment – RAI Rx. - Thyroidectomy - Subtotal or Total - NSAIDs and Corticosteroids – for SAT

Symptom Reliefs

• Rehydration is the first step.
• Β -blockers to decrease the sympathetic excess: Propranalol, Atenelol, Metoprolol
• Rate limiting CCBs can be used if Β-blockers are contraindicated
• Treatments of CHF, Arrhythmias
• Calcium supplementation
• SSKI or Lugol solution for ↓ vascularity of the gland
• Treating with Antithyroid Drugs
  • Potassium iodide and iodine (Lugol's solution): 2-6 drops PO TID for 10 days prior to surgery
  • Radioactive iodide: 4-10 millicuries PO or IV (hyperthyroidism) and 50 millicuries PO (thyroid carcinoma)

Methimazole

• 15-60 mg/day PO (initial) TID
• 5-15 mg/day PO (maintenance) TID

Propylthiouracil

• 300-400 mg/day PO (initial) TID
• 100-150 mg/day PO (maintenance) TID
• Inhibits thyroid hormone synthesis by interfering with inhibiting thyroid peroxidase (TPO) catalyzed reactions between iodine and tyrosine, which inhibits thyroid hormone synthesis at the iodine organification step
• Also blocks coupling of the iodothyronines
• Propylthiouracil also inhibits peripheral deiodination of T4 to T3
• Methimazole is very potent.
• Propylthiouracil is potent
• Methimazole has a long-acting duration BID/OD
• Propylthiouracil has a short-acting duration QID/TID
• Methimazole is contraindicated in pregnancy.
• Propylthiouracil can be safely given during pregnancy.
• Methimazole has no action in regards to conversion of T4 to T3
• Propylthiouracil inhibits the conversion of T4 to T3
• methimazole causes rashes and Neutropenia
• Propylthiouracil causes rashes and increased Neutropenia
• methimazole can be dosed at 20 to 40 mg/ OD PO
• Propylthiouracil can be dosed at 100 to 150mg qid PO

Thyrotoxicosis

• The incidence in pregnancy is 0.05-0.2%.
• Risks of pregnancy include fetal anomalies, spontaneous abortion, preterm labor, and fetal hyperthyroidism as well as thyroid storm in labor
• Treatment include:
  • Keep FT4 levels in high normal range
  • No RAI ever
  • Rx. options: ATD or 2nd trimester thyroidectomy
  • PTU drug of choice (avoid MTZ due to scalp defects)
• Adverse Effects:
  • Symptoms include rash, headache, sore gums, hypersalivation, pruritus, fever, myalgia, jaundice, and nausea
• Precautions:
  • Antithyroid drugs will cross the placenta and inhibit fetal thyroid development, resulting in neonatal goiter and cretinism.
  • Propylthiouracil is used because placental transfer is much lower than for methimazole.
  • Patients should be evaluated for sensitivity to iodides, particularly prior to parenteral administration.
  • Patients receiving radioactive iodide should be instructed not to expectorate and to use good toilet habits because saliva and urine may be radioactive ("hot") for 24 hours after drug exposure.
• Drug Interactions: Lithium carbonate and Anticoagulants
• Contraindication: Patient with pulmonary edema