MCAT Biology: Endocrine System

Hypothalamus

• command center sitting at the base of your brain

• connects your brain to your endocrine system, mostly through the pituitary gland

GnRH (Gonadotropin-Releasing Hormone)

• ↑ FSH & LH

• Stimulates the gonads (ovaries/testes) to produce sex hormones (estrogen/testosterone) and gametes (eggs/sperm)

• Negative Feedback: inhibits GnRH and FSH/LH release

GHRH (Growth Hormone-Releasing Hormone)

• ↑ GH

• Stimulates growth, cell repair, and metabolism

• Negative Feedback: inhibits GHRH and GH

TRH (Thyrotropin-Releasing Hormone)

• ↑ TSH

• TSH goes to the thyroid → makes T3/T4, which control metabolism

• Negative Feedback: inhibits TRH and TSH

CRH (Corticotropin-Releasing Hormone)

• ↑ ACTH

• ACTH goes to the adrenal cortex → makes cortisol (stress hormone)

• Negative Feedback: inhibits CRH and ACTH

High cortisol → low ACTH and CRH?

= exogenous steroids

High prolactin → low GnRH, low FSH/LH?

= prolactinoma

Hypothalamic damage → ↓ releasing hormones

panhypopituitarism

Dopamine (Prolactin-Inhibiting Factor, PIF)

• ↓ Prolactin

• Dopamine inhibits prolactin (which stimulates milk production) — so less dopamine = more prolactin

• Prolactin is not part of a negative feedback loop — instead, dopamine suppresses it directly, and high prolactin levels can actually increase dopamine over time in a regulatory way, but it's not a classic axis like the others

ADH & Oxytocin

Made in the hypothalamus but stored & released by the posterior pituitary

• ADH: Water retention in kidneys (think: anti-dehydration) —> V2 receptors

• Oxytocin: Uterine contractions, milk letdown, bonding

Posterior Pituitary

doesn’t make its own hormones — just releases what the hypothalamus makes

Mechanism of Hormone Types in Hypothalamus

All hypothalamic hormones are peptide hormones
→ act on membrane receptors → second messengers (fast-acting)

The pancreas has two jobs

• Exocrine: Makes digestive enzymes

• Endocrine: Regulates blood glucose via islets of Langerhans

Insulin

• secreted by beta cells

• triggered by high blood glucose (after a meal)

• promotes:

  • glucose uptake into cells (esp. muscle & fat)

  • glycogen synthesis (store glucose in liver/muscles)

  • fat synthesis

Glucagon

• secreted by alpha cells

• triggered by low blood glucose (fasting/in between meals)

• promotes:

  • glycogen breakdown (glycogenolysis)

  • new glucose creation (gluconeogenesis)

  • fat breakdown (lipolysis)

Somatostatin (GHIH = Growth Hormone Inhibiting Hormone)

• delta cells

• triggered by high nutrient load (glucose, amino acids, fats are high)

• acts like a brake:

  • inhibits both insulin & glucagon

  • also inhibits GH and TSH in the pituitary

Type 1 Diabetes

No insulin (autoimmune β-cell destruction)

Type 2 Diabetes

Desensitized insulin receptors (Insulin resistance)

Glucagonoma

Rare tumor → too much glucagon → hyperglycemia

Insulinoma

Tumor → too much insulin → hypoglycemia

Peptide Hormones

• cleaved from larger polypeptides

• Golgi modifies & activates hormone

• does dissolve

• put in vesicles and released via exocytosis

• polar —> cannot pass through membrane, so uses extracellular receptor like GPCR

• common secondary messengers: cAMP, Ca2+, IP3

• Example: Insulin

Steroid Hormones

• made in gonads & adrenal cortex, from cholesterol

• doesn’t dissolve, must be carried by proteins

• non polar —> can pass through cell membrane

• activate nuclear receptors (in nucleus)

• direct action on DNA

• Example: Estrogen, Testosterone, Cortisol

Amino-Acid Derivative Hormones

• share traits from both peptide and steroid hormones

• Example: Catecholamines use GPCR, Thyroxine binds intracellularly

G-Protein Coupled Receptor (GPCR)

Membrane-bound receptor that, when activated by a ligand (like a hormone or neurotransmitter), triggers a second messenger signaling cascade.

Location: Cell membrane
Ligand: Typically hydrophilic (peptides, neurotransmitters)
Action: FAST and transient

1. Ligand binds GPCR (extracellular side)

2. GPCR undergoes a conformational change

3. On the intracellular side, it interacts with a G-protein (α, β, γ subunits)

4. This causes GDP → GTP exchange on the α-subunit

5. α-GTP dissociates from βγ complex

6. α-GTP then activates or inhibits a target enzyme:

   • Gs unit —> activates adenylyl cyclase

   • Gi unit —> inhibits adenylyl cyclase

   • Gq unit —> activates phospholipase C

Gs Pathway

1. Ligand binds GPCR

2. Gs protein activated (GDP → GTP on α-subunit)

3. α subunit activates adenylyl cyclase

4. Adenylyl cyclase converts ATP → cAMP

5. cAMP activates Protein Kinase A (PKA)

6. PKA phosphorylates targets → ↑ metabolism, transcription, glycogen breakdown

Gs Pathway common ligands

↑ cAMP, activates PKA

• Glucagon → raises blood glucose

• Epinephrine (β1, β2) → fight-or-flight

• TSH → thyroid hormone release

• ACTH → cortisol release

• LH / FSH → sex hormone release

• ADH (V2) → water reabsorption in kidneys

Key theme: Metabolism, stress, water balance

Gi Pathway

• Ligand binds GPCR

• Gi protein activated (GDP → GTP on α-subunit)

• α subunit inhibits adenylyl cyclase

• ↓ cAMP → PKA not activated

• ↓ phosphorylation → ↓ cellular activity

Gi Pathway common ligands

↓ cAMP, inhibits PKA

• Somatostatin → inhibits GH, TSH

• Dopamine (D2) → inhibits prolactin

Gq Pathway

1. Ligand binds GPCR

2. Gq protein activated (GDP → GTP on α-subunit)

3. α subunit activates phospholipase C (PLC)

4. PLC cleaves PIP₂ → IP₃ + DAG

5. IP₃ triggers Ca²⁺ release from ER

6. Ca²⁺ + DAG activate Protein Kinase C (PKC)

7. PKC & Ca²⁺ → ↑ secretion, contraction, gene activity

Gq Pathway common ligands

↑ IP₃, DAG, Ca²⁺, activates PKC

• GnRH → triggers LH/FSH release

• TRH → triggers TSH release

• Oxytocin → uterine contractions

• ADH (V1) → vasoconstriction

• Epinephrine (α1) → blood vessel constriction

Key theme: Reproductive hormone signaling + smooth muscle contraction

Direct Hormones

act directly on tissue/organ (ex: insulin)

Tropic Hormones

require an intermediary, they only affect endocrine tissues (ex: GnRH and LH)

Gonads

• testes and ovaries

• hormones: testosterone, estrogen, progesterone

• controlled by the hypothalamus-pituitary-gonadal (HPG) axis

HPG Axis

• Hormonal Control

1. Hypothalamus releases GnRH

2. Anterior Pituitary releases FSH & LH

3. Gonads release:

   • Testosterone (testes)

   • Estrogen & Progesterone (ovaries)

Testosterone

• Produced by Leydig cells in the testes

• Stimulated by LH

• Functions:

  • Male sexual development (internal + external genitalia)

  • Muscle mass, libido, sperm production

  • Voice deepening, body hair

Excess testosterone → negative feedback on GnRH, FSH, and LH

Estrogen

• Made by ovarian follicles, corpus luteum, and placenta (if pregnant)

• Stimulated by FSH

• Functions:

  • Female secondary sex characteristics (breasts, fat distribution)

  • Endometrial proliferation

  • Feedback regulation of FSH/LH

  • In pregnancy: promotes uterine growth and blood flow

Progesterone

• Made by corpus luteum and placenta

• Stimulated by LH

• Functions:

  • Maintains endometrium for implantation

  • Inhibits uterine contractions

  • Thickens cervical mucus

  • Drops before menstruation = period begins

Mnemonic: "Pro-gestation" — keeps the uterus ready for baby

Feedback Loops of the Gonads

Anabolic Steroids

→ excess testosterone → ↓ LH/FSH → testicular atrophy, infertility

Polycystic ovary syndrome (PCOS)

→ high androgens, irregular cycles

Birth control pills

= synthetic estrogen + progesterone → constant negative feedback → no LH surge = no ovulation

Pineal Gland

Location:

• Deep in the brain, between the two hemispheres, near the thalamus

• Part of the epithalamus

Primary Hormone —> Melatonin

Melatonin

• Derived from tryptophan (an amino acid)

• Secreted in response to darkness

• Regulated by light exposure via signals from the retina → suprachiasmatic nucleus (SCN) of the hypothalamus

Melatonin Functions:

• Regulates circadian rhythm (your biological sleep-wake cycle)

• Promotes sleepiness

• Inhibits wake-promoting signals

• Plays a role in seasonal reproduction in animals

Regulation:

• Darkness → ↑ melatonin release

• Light → ↓ melatonin release

  • Light inhibits the SCN → stops pineal gland from releasing melatonin

TIPS:

• Melatonin does NOT knock you out like a sedative. It just makes you feel drowsy and regulates your internal clock.

• Jet lag, insomnia, blue light exposure at night = often tied to disrupted melatonin production

• Remember, melatonin is a hormone, not a neurotransmitter.

Anterior Pituitary

• Controlled by the hypothalamus via releasing hormones through the hypophyseal portal system

• Secretes 7 peptide hormones

• Mnemonic = FLAT PEG

  • Tropic hormones = act on other endocrine glands → FLAT

  • Direct hormones = act directly on tissues → PEG

FSH (Follicle-Stimulating Hormone)

• Stimulated by: GnRH

• Males: stimulates spermatogenesis in Sertoli cells

• Females: stimulates growth of ovarian follicles

LH (Luteinizing Hormone)

• Stimulated by: GnRH

• Males: stimulates Leydig cells → testosterone

• Females: triggers ovulation, forms corpus luteum

• LH surge → causes ovulation (mid-cycle)

ACTH (Adrenocorticotropic Hormone)

• Stimulated by: CRH

• Stimulates adrenal cortex → produces glucocorticoids (esp. cortisol)

• Part of the stress response axis (CRH → ACTH → cortisol)

TSH (Thyroid-Stimulating Hormone)

• Stimulated by: TRH

• Stimulates thyroid gland → releases T3 & T4

• Feedback: ↑ T3/T4 → ↓ TRH and TSH

Prolactin

• Inhibited by: dopamine (PIF)

• Stimulates milk production in mammary glands

• During pregnancy: estrogen ↑ prolactin, but inhibits milk release

• After birth: ↓ estrogen → prolactin works, nursing maintains it

• Prolactin is the only anterior pituitary hormone primarily under inhibition (by dopamine)

Endorphins

• Natural painkillers

• Released during stress, exercise, excitement

• Same pathway affected by opioids (endorphin analogs)

GH (Growth Hormone)

• Stimulated by: GHRH

• Inhibited by: somatostatin (GHIH)

• Promotes:

  • Bone & muscle growth

  • Lipolysis

  • ↑ Blood glucose (anti-insulin effect)

• Stimulates liver to release IGF-1 (insulin-like growth factor 1)

Pathologies:

• Excess GH in childhood = gigantism

• Excess GH in adulthood = acromegaly

• GH deficiency = dwarfism

Thyroid Gland

The thyroid makes two major categories of hormones:

1. T3/T4 – regulate metabolism

2. Calcitonin – regulates calcium levels

T3 (triiodothyronine) & T4 (thyroxine)

Made by:

• Follicular cells of the thyroid

• Derived from tyrosine + iodine

Function:

• ↑ Basal Metabolic Rate (BMR)

  • ↑ oxygen consumption

  • ↑ protein and lipid turnover

  • ↑ heat production

• ↑ heart rate and cardiac output

• Important in growth and development (especially brain!)

Regulation:

• TRH (hypothalamus) → TSH (anterior pituitary) → T3/T4 (thyroid)

• Negative feedback: High T3/T4 suppress TRH + TSH

Tip:

• T4 = more stable, but less active

• T3 = shorter half-life, but more potent

Calcitonin

Made by:

• Parafollicular (C) cells of the thyroid

Function:

• ↓ Blood calcium levels by:

  • ↑ Ca²⁺ deposition in bone

  • ↓ Ca²⁺ absorption in blood

  • ↓ Ca²⁺ absorption in gut

  • ↑ Ca²⁺ excretion from kidneys

Mnemonic: Calcitonin “tones” down calcium levels in the blood

Hyperthyroidism (e.g. Grave’s disease)

↑ T3/T4 → anxiety, heat intolerance, weight loss, tachycardia

Hypothyroidism (e.g. Hashimoto’s)

↓ T3/T4 → fatigue, cold intolerance, weight gain, bradycardia

Calcitonin-secreting tumor (medullary thyroid carcinoma)

High calcitonin → hypocalcemia

Parathyroid Glands

• Tiny glands located on the posterior surface of the thyroid

• Secrete Parathyroid Hormone (PTH) in response to low blood calcium

PTH (Parathyroid Hormone)

• Low blood calcium (Ca²⁺) = trigger for ↑ PTH secretion

• Goal: Raise blood calcium levels — the opposite of calcitonin

Mechanisms of Action:

1. ↑ Ca²⁺ resorption from bone

   • Stimulates osteoclast activity → breaks down bone → releases Ca²⁺ into blood

2. ↑ Ca²⁺ reabsorption in kidneys

   • Less calcium is excreted in urine

3. ↓ Phosphate reabsorption in kidneys

   • Prevents calcium from binding phosphate → keeps free Ca²⁺ in blood

   • Result: ↑ phosphate in urine

4. ↑ Activation of vitamin D (calcitriol) in kidneys

   • PTH stimulates 1-α-hydroxylase → converts vitamin D → calcitriol

5. ↑ Ca²⁺ absorption in intestines

   • This is indirect, via calcitriol (vitamin D)

Hypoparathyroidism

↓ Ca²⁺ → muscle cramps, tetany, seizures

Hyperparathyroidism

↑ Ca²⁺ → kidney stones, bone loss ("stones, bones, groans, and psychiatric overtones")

Chronic kidney disease

↓ vitamin D activation → ↑ PTH → secondary hyperparathyroidism

Posterior Pituitary (Neurohypophysis)

• Does not make its own hormones.

• Hormones are made in the hypothalamus, then stored & released by the posterior pituitary.

ADH (Antidiuretic Hormone) aka Vasopressin

• Target: Kidneys (V2 receptors) & blood vessels (V1 receptors)

• Retains water in the kidneys (collecting ducts)

• Concentrates urine

• Raises blood pressure by increasing blood volume and causing vasoconstriction

• Functions:

  • ↓ water loss in urine (by ↑ water reabsorption in collecting ducts via aquaporins)

  • ↑ blood pressure (via vasoconstriction)

• Triggered by:

  • ↑ blood osmolarity (dehydration)

  • ↓ blood volume/pressure

• Inhibited by:

  • Alcohol

  • Low osmolarity

Oxytocin

• Targets: Uterus, mammary glands, and brain

• Functions:

  • Uterine contractions during labor

  • Milk ejection (not production — that’s prolactin)

  • Bonding and trust (mother–infant, romantic partners)

• Regulation:

  • Positive feedback loop!
    (e.g., uterine stretch → ↑ oxytocin → more contractions → more stretch…)

A patient has high plasma osmolarity and concentrated urine, this means…

ADH is likely ↑

During labor, contractions get more intense and frequent, why?

oxytocin is in a positive feedback loop

A mutation in V2 receptors leads to…

nephrogenic diabetes insipidus (ADH made but doesn't work)

Too little ADH

Diabetes Insipidus (DI)

Both types = high serum osmolarity, low urine osmolarity, increased thirst

Central DI

• No ADH production (hypothalamus/post. pituitary damage)

• Kidneys don’t reabsorb water → polyuria, dehydration

Nephrogenic DI

• ADH is made, but kidneys don’t respond (V2 receptor mutation)

• Same symptoms: dilute urine, dehydration

Too much ADH

SIADH (Syndrome of Inappropriate ADH Secretion)

• Excess ADH release (often from tumors or brain injury)

• Too much water reabsorbed → hyponatremia (diluted blood sodium), low urine volume, confusion/seizures

Adrenal Cortex

• Makes steroid hormones (cholesterol-derived)

• Split into 3 zones — each has its own hormone category

Zona Glomerulosa

→ Mineralocorticoids

Main hormone: Aldosterone

Function:

• ↑ Na⁺ reabsorption

• ↓ K⁺ reabsorption (↑ K⁺ excretion)

• Water follows Na⁺ → ↑ blood volume & pressure

Triggered by:

• Low blood pressure

• Low Na⁺, high K⁺

• Angiotensin II (RAAS system — not ACTH!)

Zona Fasciculata

→ Glucocorticoids

Main hormone: Cortisol (also cortisone)

Function:

• ↑ blood glucose (via gluconeogenesis)

• ↓ protein synthesis (muscle breakdown for fuel)

• ↓ immune system (anti-inflammatory)

• Helps body manage chronic stress

Triggered by:

• ACTH (from anterior pituitary)

• CRH → ACTH → Cortisol

Negative Feedback:

• Cortisol feeds back to inhibit CRH and ACTH

Zona Reticularis

→ Androgens

Main product: Weak androgens (e.g., DHEA → testosterone/estrogen)

Function:

• In males: minimal effect (testes take over)

• In females: contributes to pubic/axillary hair, libido

Triggered by:

• ACTH (minor role)

• No direct feedback loop like cortisol or aldosterone

"Salt, Sugar, Sex"

From outer to inner cortex: G —> F —> R

• Glomerulosa = Mineralocorticoids → Aldosterone = Salt

• Fasciculata = Glucocorticoids → Cortisol = Sugar

• Reticularis = Androgens → Testosterone = Sex

Cushing Syndrome

Too much cortisol (glucocorticoids)

Symptoms:

• Moon face, buffalo hump, central obesity

• Muscle wasting

• Striae (purple stretch marks)

• Hypertension

• Hyperglycemia

• Immune suppression

• Osteoporosis

MCAT focus:

• High cortisol = ↓ ACTH (if cause is adrenal tumor or steroids)

• Cushing disease = pituitary tumor → ↑ ACTH

Always think: cortisol excess → catabolism + high glucose + immune suppression

Addison’s Disease

Adrenal insufficiency (↓ cortisol & ↓ aldosterone)

Symptoms:

• Fatigue, weight loss

• Hypotension

• Hyperpigmentation (↑ ACTH → ↑ MSH)

• Hyponatremia, hyperkalemia (due to ↓ aldosterone)

• Craving salt

MCAT focus:

• Primary adrenal insufficiency = problem in the adrenal cortex → ↓ cortisol + ↓ aldosterone
  → Feedback: ↑ ACTH

Common cause = autoimmune destruction of adrenal cortex

Hyperaldosteronism (Conn's Syndrome)

Symptoms:

• Hypertension

• Hypokalemia

• Metabolic alkalosis

MCAT focus:

• Excess aldosterone = ↑ Na⁺ reabsorption, ↓ K⁺

  • Volume overload → high BP

  • Potassium wasting → muscle cramps/weakness

Congenital Adrenal Hyperplasia (CAH)

most commonly 21-hydroxylase deficiency

Symptoms (varies by severity/sex):

• Low cortisol

• Low aldosterone

• ↑↑ androgens

• Females: ambiguous genitalia at birth

• Salt-wasting crisis (if severe aldosterone loss)

MCAT focus:

• Enzyme block → ↓ cortisol → ↑ ACTH → adrenal hyperplasia + excess androgen production

• ↑ 17-hydroxyprogesterone (classic diagnostic marker)

Aldosterone

Released by the zona glomerulosa in response to:

• ↓ Blood pressure (via RAAS)

• ↓ Na⁺ levels

• ↑ K⁺ levels

In the distal tubule and collecting duct of the nephron:

• ↑ Na⁺ reabsorption → water follows → ↑ blood volume + BP

• ↑ K⁺ excretion → ↓ serum K⁺

• ↑ H⁺ excretion → can cause metabolic alkalosis

Scenario 3: Dehydration or blood loss

What hormone is primarily responsible for sodium reabsorption here?

Answer: Aldosterone, not ADH

• ↓ blood volume → triggers RAAS → ↑ aldosterone

• Body compensates by reabsorbing Na⁺ + water to restore BP

Key MCAT Clues Aldosterone Is Involved

• Hypertension + low K⁺ = think ↑ aldosterone

• Hypotension + high K⁺ = think ↓ aldosterone

• Na⁺ and water move together, K⁺ goes opposite

• No change in glucose (that’s cortisol’s lane)

Adrenal Medulla

Location: the inner part of the adrenal gland (surrounded by the cortex)

Function:

• Releases catecholamines:

  • Epinephrine (adrenaline)

  • Norepinephrine (noradrenaline)

These are tyrosine-derived amino acid hormones, and they act FAST via GPCRs

Triggers:

• Sympathetic nervous system activation (via preganglionic acetylcholine release)

• Emotional or physical stress

• Low blood sugar, exercise, trauma

Adrenal Medulla: Epinephrine

• Main hormone secreted by adrenal medulla (about 80%)

• Acts on β1, β2, α1 receptors

• Effects:

  • ↑ Heart rate (β1)

  • ↑ BP (vasoconstriction via α1 + vasodilation via β2 in skeletal muscle)

  • ↑ Bronchodilation (β2)

  • ↓ Histamine release (anti-allergy effect)

  • ↑ Glucose (via glycogenolysis & gluconeogenesis)

*associate epinephrine with stress, asthma treatment, and metabolic boosts

Adrenal Medulla: Norepinephrine

• Mainly acts on α1 and β1 receptors

• Effects:

  • ↑ Vasoconstriction (↑ BP) via α1

  • ↑ Heart rate via β1

  • Less effect on bronchodilation than epinephrine

*NE in questions about vasoconstriction and blood pressure maintenance

Pheochromocytoma

• Tumor of the adrenal medulla → excess catecholamines

• Classic symptoms:

  • Episodic hypertension

  • Sweating

  • Tachycardia

  • Palpitations

  • Anxiety, panic attacks

• Diagnosed by: ↑ metanephrines / catecholamine breakdown products

Catecholamines

amino acid–derived, but act like peptide hormones — bind surface receptors (GPCRs) and act fast