PHA 467 (L1) - General Topics, Adrenal Physiology and Pharmacology

What are the three basic components of the endocrine system and their functions?

Endocrine glands/cells secrete hormones into interstitial fluid and circulation; hormones are chemical messengers; target tissues contain specific receptors that produce biological responses.

What are the major physiological functions of the endocrine system?

Reproduction, growth and development, electrolyte/water/nutrient balance, cellular metabolism, energy balance, and behavior.

Which organ has both endocrine and exocrine functions?

The pancreas.

What are the three general classes of hormones and how are they produced?

1. Proteins/polypeptides: transcription and translation. 2. Steroids: derived from cholesterol. 3. Tyrosine derivatives: synthesized from tyrosine.

What are examples of protein/polypeptide, steroid, and tyrosine-derived hormones?

Proteins: insulin, glucagon, GLP-1, TRH, TSH, CRH, ACTH, GnRH, LH, FSH. Steroids: aldosterone, cortisol, testosterone, estrogen, progesterone. Tyrosine derivatives: epinephrine, T3, T4.

How do protein/polypeptide hormones differ from steroid hormones in storage and release?

Proteins/polypeptides are synthesized, stored, and released after stimulation. Steroids are lipophilic and generally released immediately after synthesis.

How does hormone structure determine receptor location?

Peptides and many amines act through cell-surface receptors such as GPCRs; steroids bind intracellular nuclear receptors. Thyroid hormones also act through nuclear receptors.

How does hormone structure influence hormone half-life?

Catecholamines have short half-lives (approximately 2–3 minutes); polypeptides approximately 4–40 minutes; steroids/proteins approximately 4–170 minutes; thyroid hormones approximately 0.75–7 days.

How is hormone secretion regulated?

Through positive and negative feedback loops. Hormone concentrations fluctuate with circadian rhythms, age, seasons, and other physiological conditions; cortisol generally peaks around awakening.

What are the three types of endocrine stimuli and examples of each?

Humoral: changes in blood substances, e.g., glucose stimulates insulin, low calcium stimulates PTH, decreased sodium can stimulate aldosterone. Neural: direct nerve stimulation, e.g., SNS stimulates adrenal medulla catecholamines. Hormonal: hormones from another gland, e.g., hypothalamic hormones stimulate anterior pituitary hormones.

How does the hypothalamus communicate with the anterior versus posterior pituitary?

Anterior pituitary: hormonal communication through hypothalamic releasing/inhibiting hormones transported in portal blood. Posterior pituitary: neural communication through hypothalamic axons.

Where are ADH and oxytocin synthesized, stored, and released, and what are their targets?

Both are synthesized in the hypothalamus and stored/released by the posterior pituitary. ADH targets kidney tubules; oxytocin targets uterine muscles and mammary glands.

What are the five major anterior pituitary cell types and their hormones?

Thyrotropes → TSH; corticotropes → ACTH; somatotropes → GH; gonadotropes → FSH/LH; lactotropes → prolactin.

What are the approximate proportions of the major anterior pituitary cell types?

Somatotropes 30–40%; corticotropes approximately 20%; thyrotropes 3–5%; gonadotropes 3–5%; lactotropes 3–5%.

Describe the sequence of hypothalamic regulation of the anterior pituitary.

Hypothalamic neuron releases regulating hormone at median eminence → portal blood carries it to anterior pituitary → binds specific GPCR on endocrine cell → stimulates or inhibits pituitary hormone secretion → target tissue response.

What hypothalamic hormone and receptor stimulate TSH secretion?

TRH activates TRH-R on thyrotropes, stimulating TSH secretion.

What hypothalamic hormone and receptor stimulate ACTH secretion?

CRH/CRF activates CRH-R1 on corticotropes, stimulating ACTH secretion.

How is growth hormone release stimulated and inhibited?

GHRH activates GHRH-R on somatotropes to stimulate GH; GHIH/somatostatin activates SST receptors to inhibit GH.

What hypothalamic hormone stimulates LH and FSH release?

GnRH activates GnRH-R on gonadotropes, stimulating LH and FSH secretion.

How is prolactin release regulated?

Dopamine, also called prolactin-inhibitory hormone (PIH), activates D2 receptors on lactotropes to tonically inhibit prolactin release.

What is hyperpituitarism and which disorders are associated with excess hormones?

Excess pituitary hormone secretion, potentially caused by pituitary adenomas, carcinomas, nonpituitary tumors, or hypothalamic disorders. Examples: excess GH → acromegaly; ACTH → Cushing disease; TSH → hyperthyroidism.

What is hypopituitarism and which disorders can result?

Decreased pituitary hormone secretion due to hypothalamic or pituitary dysfunction. Examples: GH deficiency → pituitary dwarfism; TSH deficiency → hypothyroidism; ACTH deficiency → secondary adrenal insufficiency.

What are the two major adrenal gland regions, their approximate proportions, and embryological origins?

Adrenal cortex: approximately 80%, derived from mesoderm, primarily secretory. Adrenal medulla: approximately 20%, derived from neural crest, primarily neuronal.

What hormones are produced by the adrenal medulla and what cells synthesize them?

Chromaffin cells synthesize catecholamines: dopamine, norepinephrine, and epinephrine.

What are the three adrenal cortex zones and their primary hormones?

Zona glomerulosa → aldosterone (mineralocorticoid); zona fasciculata → cortisol (glucocorticoid); zona reticularis → DHEA (androgen precursor).

What mnemonic identifies the adrenal cortex zones and their functions?

GFR: Glomerulosa = salt (aldosterone); Fasciculata = sugar (cortisol); Reticularis = sex (androgens).

What is the starting material for adrenal steroid synthesis, and what enzyme initiates the pathway?

Cholesterol is converted to pregnenolone by P450-SCC (cholesterol side-chain cleavage enzyme), which removes the cholesterol side chain.

What are the major steroid hormone biosynthesis pathways emphasized in the lecture?

Cholesterol → pregnenolone → progesterone and other intermediates → mineralocorticoids, glucocorticoids, or androgens/estrogens.

What does 17α-hydroxylase do, and what happens when it is inhibited?

Supports cortisol and androgen synthesis. Inhibition decreases cortisol and androgen production.

What does 11β-hydroxylase do, and what happens when it is inhibited?

Converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone. Inhibition decreases cortisol and causes upstream precursors to accumulate.

What are the major adrenal cortical hormone classes and examples?

Mineralocorticoids: aldosterone. Glucocorticoids: cortisol/hydrocortisone. Androgens: DHEA, which can contribute to testosterone and estrogen production.

What type of receptors do steroid hormones use?

Intracellular nuclear receptors that regulate gene transcription.

Describe the basic mechanism of steroid nuclear receptor signaling.

Steroid enters cell → binds intracellular receptor associated with heat-shock proteins → receptor activation/dimerization → interaction with DNA hormone-response elements → altered transcription and mRNA production.

What steroid hormone receptors were illustrated in the lecture?

GR: glucocorticoid receptor; MR: mineralocorticoid receptor; AR: androgen receptor; ER: estrogen receptor; PR: progesterone receptor.

How do steroid classes differ in their basic carbon skeletons?

Cholesterol has 27 carbons; pregnane-derived corticosteroids/progesterone have 21; androgens have 19; estrogens have 18.

What is the HPA axis and its hormonal sequence?

Hypothalamic-pituitary-adrenal axis: hypothalamus releases CRH → anterior pituitary releases ACTH → adrenal cortex produces cortisol.

What stimuli activate the HPA axis, and which adrenal zones respond to ACTH?

Stress, emotion, circadian rhythm, pain/nociception, and inflammation activate the axis. ACTH primarily stimulates zona fasciculata and zona reticularis.

How does cortisol regulate the HPA axis through negative feedback?

Increased cortisol suppresses hypothalamic CRH and anterior pituitary ACTH release.

What receptor and intracellular signaling pathway does ACTH activate?

ACTH binds MC2R → activates Gs → increases cAMP → activates PKA.

How does ACTH increase steroid synthesis through rapid and transcriptional mechanisms?

PKA phosphorylates steroidogenic regulators including P450-SCC-associated processes; PKA also activates CREB, increasing transcription/translation of steroidogenic enzymes and growth-related proteins.

What are the primary physiological functions of cortisol?

Increases blood glucose through gluconeogenesis, suppresses immune/inflammatory responses, helps maintain blood pressure, and regulates carbohydrate, fat, and protein metabolism.

How do glucocorticoids increase blood glucose?

Stimulate hepatic gluconeogenesis from amino acids/glycerol, promote glycogen storage, decrease peripheral glucose utilization, and increase insulin resistance.

How do glucocorticoids affect protein and fat metabolism?

Increase protein breakdown, decrease peripheral protein synthesis, promote lipolysis, and provide substrates for gluconeogenesis.

How do glucocorticoids suppress inflammation?

Decrease inflammatory mediators including prostaglandins, leukotrienes, and proinflammatory cytokines; suppress immune-cell proliferation and activity.

How do glucocorticoids affect major immune cell types?

Lymphocytes: decreased proliferation/circulation; B cells: decreased antibody production; NK cells: decreased cytotoxicity; macrophages: decreased inflammatory cytokines; T cells: suppressed immune activation.

What are the major metabolic and cardiovascular adverse effects of systemic glucocorticoids?

Hyperglycemia, insulin resistance, elevated A1C, diabetes risk, increased lipids/TG, central fat accumulation, hypertension, and edema.

What electrolyte abnormalities can occur with glucocorticoids that have mineralocorticoid activity?

Increased sodium/water retention and potassium excretion → hypertension, edema, hypokalemia, and metabolic alkalosis.

What are the major bone, muscle, skin, and immune adverse effects of chronic glucocorticoids?

Osteoporosis, decreased calcium absorption, reduced growth in children, muscle weakness/atrophy, poor wound healing, increased infection risk, and reactivation of latent infections.

What are important CNS and body-fat changes associated with glucocorticoid excess?

Insomnia, stimulation, mood changes, depression/psychosis, moon face, buffalo hump, central obesity, and peripheral muscle/fat wasting.

Why can abrupt discontinuation of prolonged systemic glucocorticoids cause withdrawal or adrenal insufficiency?

Exogenous glucocorticoids suppress CRH and ACTH through negative feedback, reducing endogenous cortisol production. Abrupt withdrawal may cause fatigue, nausea/vomiting, hypotension, fever, pain, and weakness.

Why are systemic glucocorticoids tapered after prolonged therapy?

Gradual dose reduction allows the suppressed HPA axis to recover and endogenous cortisol production to increase, reducing risk of adrenal insufficiency.

What are the major adrenal gland dysfunctions discussed in the lecture?

Medulla: pheochromocytoma. Cortex hyperfunction: Cushing's syndrome and hyperaldosteronism. Cortex hypofunction: Addison's disease, acute adrenal insufficiency, and hypoaldosteronism.

What is pheochromocytoma and what is its major cardiovascular effect?

A catecholamine-secreting adrenal medulla tumor that can cause severe hypertension.

What is Cushing's syndrome and what causes it?

Excess cortisol/glucocorticoid exposure. Endogenous causes discussed include anterior pituitary adenoma, abnormal hypothalamic function, and adrenal cortical adenoma.

How does Cushing disease differ from Cushing's syndrome?

Cushing disease specifically results from excessive pituitary ACTH secretion; Cushing's syndrome refers to the broader state of glucocorticoid excess.

What are the characteristic physical findings of Cushing's syndrome?

Moon face, buffalo hump, central obesity, thin arms/legs, muscle weakness, purple striae, easy bruising, thin skin, and poor wound healing.

What metabolic, cardiovascular, and immune effects occur in Cushing's syndrome?

Hyperglycemia/glucose intolerance, hypertension, increased infections, impaired wound healing, osteoporosis, and mood changes.

What is hyperaldosteronism and what are common causes?

Excess aldosterone secretion, often due to a zona glomerulosa adenoma or bilateral adrenal hyperplasia.

What are the major clinical consequences of hyperaldosteronism?

Increased sodium/water retention and potassium excretion → hypertension, hypokalemia, and possible edema.

What is Addison's disease and what is its major cause?

Primary adrenal insufficiency caused by adrenal cortex failure, commonly autoimmune cortical destruction/atrophy.

How do glucocorticoid and mineralocorticoid deficiencies produce Addison's symptoms, and how are they replaced?

Low cortisol → impaired glucose homeostasis, weakness, fatigue; low aldosterone → sodium/water loss, volume depletion, hypotension. Treatment replaces glucocorticoid activity and, when needed, mineralocorticoid activity (e.g., fludrocortisone).

What is mitotane (Lysodren), and what enzymes does it inhibit according to the lecture?

An adrenocortical steroidogenesis inhibitor. The lecture emphasizes inhibition of P450-SCC (cholesterol side-chain cleavage enzyme) and 11β-hydroxylase.

What happens at high doses of mitotane, and what is its major clinical use?

High-dose mitotane is metabolized by adrenal cortex mitochondria into a toxic metabolite that causes adrenal cortical cell death and suppresses steroidogenesis. Used primarily for adrenocortical carcinoma.

How does mitotane affect the zona fasciculata and reticularis?

Produces adrenolytic effects, decreasing glucocorticoid and adrenal androgen production.

What is metyrapone (Metopirone), and what is its mechanism?

A relatively selective 11β-hydroxylase inhibitor that decreases cortisol synthesis and increases upstream steroid precursors.

What happens to cortisol and 11-deoxycortisol after metyrapone administration?

Cortisol decreases because 11β-hydroxylase is blocked; 11-deoxycortisol accumulates upstream.

How is metyrapone used to evaluate a normal HPA axis?

Metyrapone lowers cortisol → reduced negative feedback → increased CRH and ACTH → increased 11-deoxycortisol.

What does failure to increase ACTH and 11-deoxycortisol after metyrapone suggest?

Possible HPA-axis dysfunction involving hypothalamic CRH release or anterior pituitary ACTH secretion.

What is the mechanism of ketoconazole at higher doses?

Inhibits adrenal and gonadal steroidogenesis, especially CYP17/17α-hydroxylase; at even higher doses the lecture describes P450-SCC inhibition.

How does levoketoconazole compare with ketoconazole according to the lecture?

The levo enantiomer is described as more potent at inhibiting steroidogenesis and having less liver toxicity.

Compare the mechanisms of mitotane, metyrapone, and ketoconazole/levoketoconazole.

Mitotane: inhibits P450-SCC and 11β-hydroxylase, with high-dose adrenolytic toxicity. Metyrapone: selectively inhibits 11β-hydroxylase. Ketoconazole/levoketoconazole: inhibit CYP17 and other steroidogenic enzymes at higher doses.