What should be covered in a comprehensive lecture entitled Introduction to Endocrinology?

Introduction to Endocrinology: A Comprehensive Lecture Framework

I. Foundational Concepts and Historical Context

Endocrinology is the study of hormones and their regulatory functions throughout the body, encompassing growth, metabolism, reproduction, and electrolyte balance through chemical messengers produced by ductless glands. 1

• The term "hormone" was introduced in 1905 by Starling to describe chemical messengers like secretin, discovered by Bayliss and Starling in 1902, marking the formal recognition of endocrinology as a distinct scientific discipline 2, 3
• The field emerged from centuries of organotherapy and clinical observations, particularly Claude Bernard's work on internal secretions (1855), Thomas Addison's description of adrenal disease (1855), and Brown-Séquard's experiments with testicular extracts (1889) 2, 3
• Modern endocrinology integrates molecular biology, pathophysiology, and clinical medicine to understand orphan receptors, functional genomics, and novel therapeutic targets 4

II. The Hypothalamic-Pituitary Axis: Central Control System

The hypothalamus serves as the master regulator, producing releasing and inhibiting hormones that control pituitary function, which in turn regulates peripheral endocrine glands through hormonal cascades. 1

Key Regulatory Pathways:

• Hypothalamic hormones include corticotropin-releasing hormone (CRH), which stimulates ACTH release from the anterior pituitary 5
• Pituitary hormones include ACTH (stimulating cortisol), TSH (stimulating thyroid hormone), LH and FSH (stimulating sex hormones), with some acting on target glands and others directly on target organs 1
• Feedback mechanisms maintain homeostasis through negative feedback loops, where elevated target gland hormones suppress hypothalamic and pituitary secretion 1

Clinical Relevance:

• Pituitary apoplexy presents with sudden headache, visual disturbances, and hormonal deficiencies requiring immediate high-dose glucocorticoid therapy and neurosurgical evaluation 6
• Hypophysitis causes central hormonal deficiencies requiring corticosteroid replacement for adrenal insufficiency and endocrinology consultation 6

III. Major Endocrine Glands and Their Functions

A. Adrenal Glands

The adrenal cortex produces cortisol (20 mg/day baseline, increasing five-fold to 100 mg/day during major stress), while the adrenal medulla produces adrenaline. 5, 7

• Cortisol physiology: Released in pulsatile fashion with circadian rhythm (reference range 140-700 nmol/L at 0900,80-350 nmol/L at midnight), 60-80% bound to cortisol-binding globulin, 15-35% to albumin, with 5% free active fraction 5
• Adrenal insufficiency can be primary (affecting both glucocorticoid and mineralocorticoid production, requiring fludrocortisone 0.05-0.1 mg/day plus hydrocortisone) or secondary (affecting only glucocorticoid production) 7
• Adrenal crisis presents with severe hypotension refractory to fluids, fever, altered mental status, hyponatremia, and hyperkalemia, requiring immediate hydrocortisone 100 mg IV bolus followed by 100-300 mg/day continuous infusion 6, 7

B. Thyroid Gland

The thyroid produces thyroid hormone under TSH control, with dysfunction manifesting as hypothyroidism or hyperthyroidism, both requiring specific diagnostic and therapeutic approaches. 5

• Subclinical thyroid disease is defined by abnormal TSH with normal free T4 levels, with prevalence and clinical significance varying by age and TSH degree of elevation 5
• Thyroid storm is a life-threatening emergency characterized by severe thyrotoxicosis with multi-organ dysfunction, requiring beta-blockers (atenolol or propranolol), thionamides (methimazole or propylthiouracil), hydration, and supportive care 6
• Myxedema coma presents with altered mental status and hypothermia, requiring ventilatory support if needed, careful fluid management, and treatment of precipitating factors 6
• Checkpoint inhibitor-related thyroid dysfunction occurs more commonly with PD-1/PD-L1 inhibitors (hypothyroidism incidence up to 13.2% with combination therapy) than with CTLA-4 inhibitors 5

C. Parathyroid Glands and Calcium Homeostasis

Parathyroid hormone regulates calcium balance, with severe hypercalcemia (>14 mg/dL) requiring aggressive IV fluid resuscitation, bisphosphonates, and calcitonin. 6

• Severe hypocalcemia (<7.5 mg/dL or symptomatic) requires IV calcium gluconate for severe symptoms and vitamin D supplementation 6
• Tetany after thyroidectomy results from inadvertent parathyroid removal, as demonstrated by Gley in the 1890s 2

D. Pancreatic Islets

The islets of Langerhans produce insulin and glucagon, with their dysfunction leading to diabetes mellitus, a condition described since the first century but only understood as an endocrine disorder in the late 19th century. 2

• Diabetic ketoacidosis (DKA) presents with hyperglycemia, ketosis, and metabolic acidosis, requiring IV fluids, insulin therapy, electrolyte replacement, and treatment of precipitating factors 6
• Hyperosmolar hyperglycemic state (HHS) features severe hyperglycemia and hyperosmolality without significant ketosis, requiring aggressive fluid resuscitation and insulin therapy 6
• Severe hypoglycemia (<54 mg/dL with neurological symptoms) requires IV glucose (D50W) for unconscious patients or glucagon injection if IV access unavailable 6
• Checkpoint inhibitor-associated diabetes can lead to severe hyperglycemia and DKA, requiring urgent endocrine consultation 8

E. Gonads (Ovaries and Testes)

The gonads produce sex hormones under LH and FSH control, with dysfunction causing reproductive endocrine disorders including infertility, menstrual irregularities, and premature ovarian failure. 5

Evaluation of Reproductive Endocrine Disorders:

• Menstrual irregularities include polymenorrhoea (<23 days), oligomenorrhoea (>35 days), and amenorrhoea (no bleeding >6 months), requiring investigation for PCOS, hypothalamic amenorrhoea, hyperprolactinaemia, and thyroid dysfunction 5
• Hormonal assessment includes LH/FSH ratio (>2 suggests PCOS), FSH >35 IU/L and LH >11 IU/L (suggesting ovarian failure), prolactin >20 μg/L (requiring exclusion of hypothyroidism or pituitary tumor), progesterone <6 nmol/L mid-luteal (indicating anovulation), and testosterone >2.5 nmol/L (suggesting PCOS or valproate effect) 5
• Imaging studies include transvaginal ultrasound (more sensitive than transabdominal for ovarian pathology) and pituitary MRI for suspected hypothalamic-pituitary axis abnormalities 5

Special Populations:

• Premature ovarian failure (POF) after gonadotoxic therapy requires counseling about risks, with anti-Müllerian hormone (AMH) showing promise as a predictor of ovarian reserve and timing of menopause 5
• Hormone replacement therapy (HRT) differs for prepubertal versus postmenarchal patients, with timing and tempo crucial for acceptable final height in pubertal patients 5
• Precocious puberty (age <8 years) requires endocrine consultation, FSH/LH/estradiol measurement, bone age X-ray, and pelvic ultrasound to rule out ovarian tumor 5

IV. Diagnostic Approach to Endocrine Disorders

Laboratory Testing Principles:

Specific laboratory tests should be obtained before initiating treatment when possible, with timing and methodology critical for accurate interpretation. 6

• Adrenal axis: AM cortisol, ACTH, basic metabolic panel, renin and aldosterone (with cortisol samples taken as average of three estimations 20 minutes apart) 5, 6
• Thyroid axis: TSH, free T4, free T3 (with subclinical disease defined by abnormal TSH with normal free T4) 5, 6
• Pituitary axis: Comprehensive hormone panel including ACTH, cortisol, TSH, free T4, LH, FSH, testosterone/estrogen 6
• Reproductive hormones: Measured on days 3-6 of cycle for LH, FSH, testosterone; mid-luteal phase for progesterone; morning resting levels for prolactin (not postictal) 5

Imaging Studies:

• Pelvic ultrasonography indicated for clinical features or hormonal tests suggesting ovarian pathology, with transvaginal approach more sensitive than transabdominal 5
• Pituitary MRI indicated for galactorrhoea or hyperprolactinaemia, though small lactotroph adenomas may be beyond resolution 5

V. Endocrine Emergencies: Recognition and Management

Critical Recognition Principles:

Immediate recognition and treatment are essential to reduce morbidity and mortality, with endocrinology consultation recommended for all suspected endocrine emergencies. 6

Specific Emergency Protocols:

• Adrenal crisis management: Hydrocortisone 100 mg IV bolus immediately, followed by 200 mg/24h continuous infusion (or 50 mg IV/IM every 6 hours if infusion unavailable), with full-dose therapy continued minimum 3 days or until vasopressors discontinued 6, 7
• Thyroid storm management: Beta-blockers for symptomatic relief, thionamides, hydration, and supportive care 6
• Severe hypercalcemia management: Aggressive IV fluid resuscitation, bisphosphonates, calcitonin, and treatment of underlying cause 6

Common Pitfalls:

• Never delay treatment for suspected adrenal crisis while awaiting laboratory confirmation, as mortality risk is significantly higher in untreated adrenal insufficiency 7
• Avoid bolus-only regimens for major stress, as they create subtherapeutic troughs between doses 7
• Recognize checkpoint inhibitor-related endocrinopathies promptly, as failure to do so can result in severe consequences 5, 8

VI. Perioperative Endocrine Management

Stress Dose Steroid Strategy:

For patients with adrenal insufficiency undergoing major surgery, administer hydrocortisone 50-100 mg IV at induction, followed by 200 mg/24h continuous infusion, with minor surgery not requiring stress dosing. 5, 7

• Pregnancy considerations: Hydrocortisone 100 mg IV bolus at onset of active labor, followed by 200 mg/24h continuous infusion or 50 mg IM every 6 hours 5, 7
• Tapering protocol: Begin when hemodynamically stable, tolerating oral intake, and vasopressors discontinued; switch to oral hydrocortisone at double maintenance dose, continuing for 48 hours to 1 week 7

Steroid Equivalencies:

• Hydrocortisone 20 mg = prednisone 5 mg = dexamethasone 0.75 mg 5
• Dexamethasone 8 mg = hydrocortisone 200 mg, but lacks mineralocorticoid activity and is inadequate for primary adrenal insufficiency 5

VII. Referral Guidelines and Coordination of Care

Immediate/Urgent Referrals:

Immediate endocrine consultation is required for suspected adrenal crisis, thyroid storm, myxedema coma, diabetic ketoacidosis, and pituitary apoplexy due to high morbidity and mortality rates. 8

• Checkpoint inhibitor-associated diabetes requires urgent consultation due to risk of severe hyperglycemia and DKA 8
• Multiple endocrine neoplasia syndromes require referral to specialized centers, with family members needing genetic counseling and DNA analysis 8

Non-Urgent but Important Referrals:

• Difficult-to-control diabetes (HbA1c >7% despite optimization) requires endocrinology referral to improve glycemic control 8
• Checkpoint inhibitor-related endocrinopathies (hypophysitis, thyroid dysfunction, adrenal insufficiency) require prompt consultation 8
• Perioperative stress dosing guidance for patients with adrenal insufficiency requires endocrinology involvement to prevent adrenal crisis 8

Coordination Principles:

The endocrinologist serves as medical counselor providing evidence-based knowledge, managing grey areas, and balancing aggressive versus conservative approaches for complex endocrine diseases. 8

VIII. Special Considerations in Modern Endocrinology

Immune Checkpoint Inhibitor-Related Endocrinopathies:

Different ICI regimens produce distinct patterns of endocrine dysfunction, with hypophysitis characteristic of ipilimumab and thyroid dysfunction more common with PD-1/PD-L1 inhibitors. 5

• Incidence patterns: Hypothyroidism 3.8% with ipilimumab, up to 13.2% with combination therapy; hyperthyroidism higher with PD-1 versus PD-L1 inhibitors (OR 5.36) 5
• Median time to onset: 1.75-5 months for ipilimumab, 1.4-4.9 months for PD-1 inhibitors 5
• Management approach: Hormone replacement therapy with endocrine consultation recommended for all suspected immune-related endocrinopathies 5, 6

Patient Education Requirements:

All patients with adrenal insufficiency must receive education on emergency hydrocortisone injection kit use, medical alert bracelet/necklace, stress dosing instructions, and when to seek emergency care. 7

• Maintenance dosing: Hydrocortisone preferred with 2/3 daily dose in morning, 1/3 in early afternoon for physiologic replacement 7
• Expected adverse effects: Hyperglycemia and hypernatremia during stress dosing, with no increased risk of secondary infections or GI bleeding 7