Endocrine System

Hormone Classes

Hormones are classified by chemical structure, which dictates their mechanism of action. Peptide and protein hormones (e.g., insulin, glucagon, GH, FSH, LH, ACTH, PTH, calcitonin) are water-soluble chains of amino acids. They are synthesized as preprohormones on the rough ER, cleaved to prohormones, packaged into secretory vesicles in the Golgi, and released by exocytosis in response to a stimulus. Because they are hydrophilic, they cannot cross the plasma membrane; they bind cell-surface receptors and act through intracellular second-messenger cascades (cAMP, IP3/DAG, Ca2+, tyrosine kinase cascades). Steroid hormones (e.g., cortisol, aldosterone, testosterone, estradiol, progesterone, vitamin D) are derived from cholesterol. They are lipophilic, synthesized on demand (not stored), and transported in blood bound to carrier proteins. They cross the plasma membrane freely, bind intracellular receptors (cytoplasmic or nuclear), and the hormone-receptor complex acts as a transcription factor—directly regulating gene expression. Amino-acid derivative hormones: catecholamines (epinephrine, norepinephrine, dopamine) are tyrosine derivatives that act like peptide hormones (cell-surface receptors, second messengers). Thyroid hormones (T3, T4) are also tyrosine derivatives but are lipophilic and act like steroid hormones (intracellular receptors, gene transcription).

Peptide versus Steroid Hormones

The peptide vs. steroid distinction is the most tested concept in MCAT endocrinology because it determines everything: synthesis, storage, transport, receptor location, mechanism, speed of onset, and duration of effect. Peptide hormones are water-soluble, stored in vesicles, released by exocytosis, travel freely in plasma (short half-life), bind cell-surface receptors, act through signal transduction cascades (often activating or inhibiting existing enzymes via phosphorylation), rapid onset (seconds to minutes), short duration. Steroid hormones are lipid-soluble, NOT stored (synthesized on demand from cholesterol in smooth ER and mitochondria), diffuse across the membrane immediately upon synthesis, travel in blood bound to carrier proteins (albumin, sex-hormone-binding globulin, corticosteroid-binding globulin—extending their half-life to hours or days), dissociate from carriers to cross target cell membranes, bind intracellular receptors, and the hormone-receptor complex binds hormone response elements (HREs) on DNA to regulate transcription. This genomic mechanism means steroid effects are slow in onset (hours to days) but long-lasting. The MCAT loves to ask: 'Which hormone would you expect to find receptors for in the nucleus?' (Answer: steroid and thyroid hormones.) 'Which would act fastest?' (Answer: peptide hormones using pre-existing second-messenger machinery—epinephrine raises blood glucose within seconds.)

Hypothalamic-Pituitary Axes

The hypothalamus is the master integrator, receiving neural, hormonal, and metabolic input and translating it into endocrine output. The pituitary (hypophysis) has two anatomically and functionally distinct lobes. The posterior pituitary is neural tissue (extension of the hypothalamus): hypothalamic neurons with cell bodies in the supraoptic and paraventricular nuclei synthesize oxytocin and vasopressin (ADH) and transport them down axons to the posterior pituitary, where they are stored and released into the systemic circulation. These are neurohormones, not tropic hormones. The anterior pituitary is glandular tissue, connected to the hypothalamus by the hypophyseal portal system—a specialized capillary network that carries hypothalamic releasing and inhibiting hormones directly to the anterior pituitary at high concentration without dilution in systemic circulation. Hypothalamic hormones: TRH (thyrotropin-releasing hormone → TSH), CRH (corticotropin-releasing hormone → ACTH), GnRH (gonadotropin-releasing hormone → FSH and LH), GHRH (growth hormone-releasing hormone → GH), somatostatin (inhibits GH), dopamine (inhibits prolactin). Anterior pituitary tropic hormones: TSH (thyroid), ACTH (adrenal cortex), FSH and LH (gonads), GH (liver and other tissues), prolactin (mammary glands). Each axis follows the same pattern: hypothalamic releasing hormone → anterior pituitary tropic hormone → peripheral gland hormone → negative feedback at hypothalamus and pituitary. Prolactin is unique: its primary hypothalamic control is tonic inhibition by dopamine; removing dopamine inhibition (e.g., during lactation) increases prolactin secretion.

Thyroid, Adrenal, Pancreatic, and Gonadal Hormones

The thyroid axis: TRH (hypothalamus) → TSH (anterior pituitary) → T3 and T4 (thyroid follicular cells). T3 is the more active form; most T4 is converted to T3 in peripheral tissues. Thyroid hormones increase basal metabolic rate, potentiate catecholamine effects, and are essential for normal growth and CNS development. Calcitonin (thyroid parafollicular C cells) lowers serum Ca2+ by inhibiting osteoclasts—a minor player in human calcium homeostasis compared to PTH. The adrenal gland: cortex (steroid hormones) and medulla (catecholamines). Zona glomerulosa: mineralocorticoids (aldosterone → Na+ retention, K+ secretion, regulated by angiotensin II and K+). Zona fasciculata: glucocorticoids (cortisol → gluconeogenesis, protein catabolism, lipolysis, immunosuppression, regulated by ACTH). Zona reticularis: adrenal androgens (DHEA). Adrenal medulla: chromaffin cells secrete epinephrine (80%) and norepinephrine (20%) in response to sympathetic preganglionic stimulation (acetylcholine → nicotinic receptors). Pancreatic islets: alpha cells (glucagon → raises blood glucose via glycogenolysis and gluconeogenesis), beta cells (insulin → lowers blood glucose via glucose uptake, glycogenesis, lipogenesis; anabolic hormone), delta cells (somatostatin → paracrine inhibition of both insulin and glucagon). Gonadal hormones: testes produce testosterone (Leydig cells, stimulated by LH) and inhibin (Sertoli cells, stimulated by FSH, inhibits FSH). Ovaries produce estradiol (follicular granulosa cells under FSH and LH), progesterone (corpus luteum under LH), and inhibin (inhibits FSH).

Negative Feedback Loops

Negative feedback is the fundamental regulatory principle of the endocrine system: the output of a pathway inhibits its own production, maintaining homeostasis around a set point. The classic pattern: hypothalamic releasing hormone stimulates anterior pituitary tropic hormone, which stimulates peripheral gland hormone, which feeds back to suppress hypothalamic and pituitary secretion. This is long-loop negative feedback. Short-loop feedback: anterior pituitary hormone feeds back to inhibit hypothalamic releasing hormone. Ultra-short feedback: hypothalamic hormone inhibits its own release. The distinction matters for pathology: primary hypothyroidism (thyroid gland failure) → low T3/T4 removes negative feedback → elevated TRH and TSH. Secondary hypothyroidism (pituitary failure) → low TSH → low T3/T4 (TRH is high because T3/T4 feedback is lost, but the pituitary cannot respond). Tertiary hypothyroidism (hypothalamic failure) → low TRH → low TSH → low T3/T4. The pattern of hormone levels (primary = high tropic, low peripheral; secondary = low tropic, low peripheral) is diagnostic and heavily tested. Positive feedback is rarer and self-amplifying: the LH surge before ovulation (estrogen at high sustained levels switches from negative to positive feedback on the hypothalamus), and oxytocin during childbirth (uterine contractions → more oxytocin → stronger contractions).

Hormonal Coordination of Metabolism

Metabolic homeostasis is maintained by the opposing actions of insulin and counter-regulatory hormones (glucagon, epinephrine, cortisol, GH). In the fed state (high blood glucose): pancreatic beta cells release insulin → glucose uptake into muscle and adipose tissue (via GLUT4 translocation), glycogenesis in liver and muscle, glycolysis, lipogenesis, protein synthesis. In the fasting state (low blood glucose): pancreatic alpha cells release glucagon → glycogenolysis and gluconeogenesis in liver, lipolysis in adipose tissue, ketogenesis with prolonged fasting. Epinephrine (acute stress, exercise) provides rapid glucose mobilization via glycogenolysis in liver and muscle. Cortisol (chronic stress, fasting) promotes gluconeogenesis and protein catabolism over hours to days, providing amino acid substrates for glucose production while sparing glucose for the brain. Growth hormone is diabetogenic: it promotes lipolysis and inhibits glucose uptake, raising blood glucose. Insulin is the only hormone that LOWERS blood glucose—all others raise it. This asymmetry means insulin deficiency (type 1 diabetes mellitus) produces hyperglycemia that no other hormone can compensate for. The MCAT tests this coordination in integrated passages: given a hormone profile, deduce the metabolic state (fed, fasting, stress, exercise).

How it works

Endocrine signaling can be summarized by three principles. First, hormone classification predicts mechanism: peptide = membrane receptor + second messenger (fast, enzymatic); steroid = intracellular receptor + gene transcription (slow, genomic). Second, the hypothalamic-pituitary axis is a three-tier hierarchy with negative feedback at every level—identify which tier is broken by checking whether tropic hormone levels are elevated (primary gland failure) or depressed (secondary/tertiary failure). Third, metabolic hormones operate in antagonistic pairs: insulin (storage, anabolic) vs. glucagon/epinephrine/cortisol/GH (mobilization, catabolic). When the MCAT shows you a hormone profile table, first categorize each hormone by class and axis, then look for the feedback pattern that explains the data. The answer is almost always in the feedback loop.

How it works

Endocrine signaling can be summarized by three principles. First, hormone classification predicts mechanism: peptide = membrane receptor + second messenger (fast, enzymatic); steroid = intracellular receptor + gene transcription (slow, genomic). Second, the hypothalamic-pituitary axis is a three-tier hierarchy with negative feedback at every level—identify which tier is broken by checking whether tropic hormone levels are elevated (primary gland failure) or depressed (secondary/tertiary failure). Third, metabolic hormones operate in antagonistic pairs: insulin (storage, anabolic) vs. glucagon/epinephrine/cortisol/GH (mobilization, catabolic). When the MCAT shows you a hormone profile table, first categorize each hormone by class and axis, then look for the feedback pattern that explains the data. The answer is almost always in the feedback loop.

Comparisons

• B/B (Peptide vs. steroid): Know which hormones use cell-surface vs. intracellular receptors and the signaling cascades involved (GPCR, RTK, JAK-STAT).
• B/B (Axis pathology): Primary vs. secondary vs. tertiary disorders—given TSH and T3/T4 levels, identify whether the defect is thyroid, pituitary, or hypothalamic.
• B/B (Diabetes): Type 1 (autoimmune beta-cell destruction, insulin deficiency) vs. Type 2 (insulin resistance, hyperinsulinemia early, beta-cell exhaustion late).
• C/P (Second messengers): cAMP pathway (Gs protein → adenylyl cyclase → cAMP → PKA), IP3/DAG pathway (Gq → phospholipase C → IP3 releases Ca2+ from ER, DAG activates PKC).
• C/P (Steroid synthesis): Cholesterol → pregnenolone (rate-limiting step, mitochondrial, StAR protein, side-chain cleavage enzyme = CYP11A1).
• P/S (Stress response): SAM (sympathetic-adrenal-medullary) axis for acute stress (epinephrine), HPA (hypothalamic-pituitary-adrenal) axis for chronic stress (cortisol).

Common confusions

• Confusing posterior and anterior pituitary. Posterior = neural, stores oxytocin and ADH made in hypothalamus. Anterior = glandular, synthesizes and secretes its own hormones under hypothalamic portal control.
• Thinking all peptide hormones use cAMP. Different peptide hormones use different second-messenger systems: glucagon and ACTH use cAMP; GnRH and angiotensin II use IP3/DAG/Ca2+; insulin and GH use tyrosine kinase cascades.
• Forgetting that thyroid hormones act like steroids. T3/T4 are tyrosine derivatives but are lipophilic and bind intracellular receptors—receptors are in the nucleus, not on the cell surface.
• Misidentifying 'tropic' hormones. Tropic hormones target other endocrine glands (TSH, ACTH, FSH, LH). GH has both tropic (liver → IGF-1) and direct metabolic effects. Prolactin and ADH are NOT tropic.
• Confusing primary vs. secondary endocrine pathology. Primary = gland failure, tropic hormone HIGH (lost negative feedback). Secondary = pituitary failure, tropic hormone LOW. This pattern is tested for thyroid, adrenal, and gonadal axes.
• Forgetting that insulin is the ONLY hypoglycemic hormone. Every other hormone raises blood glucose. This asymmetry is why insulin deficiency is catastrophic while glucagon deficiency is manageable.
• Assuming all hormones are proteins. Steroids are lipids (cholesterol-derived), thyroid hormones are modified amino acids, catecholamines are modified tyrosine.
• Applying negative-feedback logic to positive-feedback examples. The LH surge and oxytocin during labor are positive feedback—the output amplifies the stimulus rather than suppressing it.

Quick review

• Peptide hormones: water-soluble, cell-surface receptors, second messengers, rapid onset, short duration. Steroid hormones: lipid-soluble, intracellular receptors, gene transcription, slow onset, long duration.
• Posterior pituitary: neural tissue, stores/releases oxytocin and ADH made in hypothalamus. Anterior pituitary: glandular, portal system from hypothalamus, secretes TSH, ACTH, FSH, LH, GH, prolactin.
• Thyroid axis: TRH → TSH → T3/T4. T3 more active. Thyroid hormones increase BMR, are lipophilic, bind nuclear receptors.
• Adrenal cortex layers (from outside in): Glomerulosa (aldosterone, salt), Fasciculata (cortisol, sugar), Reticularis (androgens, sex). Mnemonic: Salt, Sugar, Sex — the deeper you go, the sweeter it gets.
• Adrenal medulla: chromaffin cells, epinephrine (80%) and norepinephrine (20%), sympathetic stimulation via ACh at nicotinic receptors.
• Pancreatic islets: alpha (glucagon → raises glucose), beta (insulin → lowers glucose), delta (somatostatin → inhibits both).
• Insulin is the ONLY hypoglycemic hormone. Glucagon, epinephrine, cortisol, GH all raise blood glucose.
• Primary vs. secondary endocrine pathology: Primary = gland fails, tropic hormone HIGH. Secondary = pituitary fails, tropic hormone LOW.
• Negative feedback: output inhibits its own production (most endocrine axes). Positive feedback: output amplifies its own production (LH surge, oxytocin in labor).
• Prolactin: unique—hypothalamic control is tonic DOPAMINE INHIBITION. Removing dopamine (lactation, pituitary stalk damage) increases prolactin.
• Steroid synthesis: cholesterol → pregnenolone (rate-limiting step, StAR protein, CYP11A1 in mitochondria).
• Fed state: insulin dominates (glucose uptake, glycogenesis, lipogenesis). Fasted state: glucagon dominates (glycogenolysis, gluconeogenesis, lipolysis, ketogenesis).