Built from Endocrine Lecture 02 (LOs 1–6). Expanded on anatomy/portal system (LO 1) and prediction iterations (LO 6). Use this to check your work after the active recall sheet.

LO 1

ON EXAM — Rathke's pouch (oral ectoderm, ascends) → anterior pit; infundibulum (neural ectoderm, descends) → posterior pit; meet ~6 wk. Adenohypophysis = pars distalis + intermedia + tuberalis; neurohypophysis = pars nervosa + infundibular stem + median eminence. Anterior pit reached ONLY via portal system (2 plexuses); posterior pit by AXONS. Median eminence = circumventricular organ. Stalk cut → all anterior hormones fall EXCEPT prolactin (rises).

Embryology (LO 1)

Component	Origin	Direction	Tissue	Remnant / pathology
Anterior pit	Oral (surface) ectoderm — Rathke's pouch (roof of primitive oral cavity)	ASCENDS toward diencephalon	Glandular epithelium	Craniopharyngeal canal, pharyngeal pituitary, CRANIOPHARYNGIOMA (cystic, calcified, suprasellar)
Pars intermedia	Posterior wall of Rathke's pouch (oral ectoderm)	Sits between pars distalis and pars nervosa	Melanotrophs (POMC → MSH); rudimentary in humans	Rathke's cleft cyst (benign cystic remnant of pouch lumen)
Posterior pit	Neural ectoderm — downgrowth of diencephalic floor (infundibulum)	DESCENDS downward, meets Rathke's at ~week 6	Modified neural tissue: unmyelinated axons from SON/PVN + pituicytes + Herring bodies	Central DI after trauma / stalk injury

Rathke's pouch meets the infundibulum around week 6. Persistent connection = craniopharyngeal canal; ectopic anterior pit tissue = pharyngeal pituitary; tumor = craniopharyngioma.

Subdivisions — what each part contains (LO 1)

Subdivision	Parent	Cells / content	Function
Pars distalis	Anterior pit (bulk)	5 cell types: somato-, lacto-, cortico-, gonado-, thyrotrophs	Synthesizes + releases 6 anterior pit hormones (GH, PRL, ACTH, TSH, LH, FSH) in response to portal-delivered releasing hormones
Pars intermedia	Anterior pit (between distalis & nervosa)	Melanotrophs (vestigial in humans)	α/β-MSH from POMC cleavage; largely vestigial in humans; rudimentary pigmentation role
Pars tuberalis	Anterior pit (sleeve around infundibular stalk)	Mostly thyrotroph-like, TSH-immunoreactive	Photoperiodic / circadian regulation (TSH + melatonin signaling)
Pars nervosa	Posterior pit (bulb)	Pituicytes + axon terminals from SON/PVN magnocellular neurons; Herring bodies	Stores + releases ADH and oxytocin (synthesized in hypothalamus)
Infundibular stem	Posterior pit (stalk)	Hypothalamohypophyseal axons + glia + portal vessels	Conduit for axonal transport to pars nervosa + long portal veins to anterior pit
Median eminence	Posterior pit unit (base of hypothalamus)	Axon terminals of hypothalamic releasing neurons + primary capillary plexus	CIRCUMVENTRICULAR ORGAN (outside BBB; fenestrated) — release site for hypothalamic hormones into primary portal plexus

Sellar region anatomy (LO 1)

Bone

Sella turcica of the SPHENOID bone ("Turkish saddle")

Dural roof

Diaphragma sellae — dural sheet with a small opening for the infundibulum

Superior neighbor

Optic chiasm → compression → BITEMPORAL HEMIANOPSIA (crossing nasal fibers lost)

Lateral neighbor

Cavernous sinus (each side): CN III, IV, V₁, V₂, VI + internal carotid artery. Invasion → ophthalmoplegia, facial sensory loss

Inferior neighbor

Sphenoid sinus — TRANSSPHENOIDAL surgical approach goes through nasal cavity → sphenoid → sella

Posterior neighbor

Floor of third ventricle; large suprasellar masses can obstruct CSF → hydrocephalus

Portal system — 2 plexuses in series (LO 1)

Element	Location	Source / connection	Function
Primary plexus	Median eminence	Branches of SUPERIOR HYPOPHYSEAL ARTERY (off internal carotid)	Picks up hypothalamic releasing/inhibiting hormones from axon terminals
Long portal veins	Descend through infundibular stalk	Drain primary plexus	Carry concentrated hypothalamic hormones to anterior pit, bypassing systemic dilution + degradation
Secondary plexus	Within anterior pituitary (pars distalis)	Drainage of long portal veins	Delivers concentrated hypothalamic hormones to anterior pit cells; carries anterior pit hormones (ACTH, TSH, etc.) into systemic circulation
Short portal vessels	Between posterior & anterior pit	Off inferior hypophyseal territory	Minor additional cross-communication; clinical relevance limited
Inferior hypophyseal artery	Posterior pituitary (DIRECTLY)	Off internal carotid (cavernous segment)	Direct arterial supply to neurohypophysis — why posterior pit is often SPARED in Sheehan (portal-system ischemia)
Venous drainage	Cavernous sinus + inferior petrosal sinus	→ internal jugular vein	Inferior petrosal sinus sampling differentiates Cushing disease from ectopic ACTH

WHY a portal system? To deliver tiny amounts of releasing hormones DIRECTLY + CONCENTRATED to anterior pit cells without systemic dilution. The median eminence is a circumventricular organ (outside BBB, fenestrated capillaries) — large peptides (CRH, TRH, GnRH) can exit without crossing BBB.

Hypothalamohypophyseal tract (LO 1)

Nuclei

Supraoptic (SON) + Paraventricular (PVN)

Cell type

MAGNOCELLULAR neurons (large cell bodies) — distinct from parvocellular neurons to median eminence

Hormones

ADH (mostly SON) + Oxytocin (mostly PVN) — both 9-aa cyclic peptides

Axonal transport

Synthesized as preprohormones in cell bodies, packaged with neurophysin in secretory vesicles, transported anterograde by kinesin/microtubules down axons

Carrier

Neurophysin II (with ADH) + neurophysin I (with oxytocin) — co-secreted; no functional role in periphery

Histologic marker

Herring bodies — eosinophilic swellings along axon terminals representing accumulated neurosecretory vesicles

Release site

Into a CAPILLARY (NOT a synapse) — why posterior pit is a "neurohemal organ"

Tuberoinfundibular tract (LO 1)

Origin → destination

Arcuate nucleus → axon terminals at median eminence (NOT in posterior pit)

NT / hormone

DOPAMINE — released into primary capillary plexus → long portal veins → reaches anterior pit lactotrophs

Receptor / signal

D₂ receptor on lactotroph; coupled to Gi → ↓cAMP → INHIBITS prolactin synthesis + release

Why PRL paradox with stalk cut

Stalk transection blocks dopamine delivery → loss of tonic inhibition → prolactin RISES. All other anterior pit hormones FALL (lose positive releasing-hormone delivery)

Functional summary (LO 1)

Target	Connection	Vehicle	Hormones delivered	Stalk cut result
Anterior pit	Vascular only (portal system)	Hypothalamic hormones in portal blood	CRH, TRH, GnRH, GHRH (releasing); somatostatin, dopamine (inhibiting)	ACTH, TSH, LH/FSH, GH all FALL (lose releasing-hormone delivery)
Posterior pit	Neural (direct axonal)	Action potentials → Ca²⁺ → exocytosis at terminals	ADH + oxytocin	Central DI (ADH loss) + oxytocin failure
Lactotroph (special)	Vascular (portal) — same as other anterior pit cells	Dopamine in portal blood (TONIC INHIBITION)	Dopamine (inhibits); TRH, estrogen (stimulate)	PROLACTIN RISES (loses dopamine brake) — the famous paradox

Clinical syndromes (LO 1)

Sheehan

Postpartum ischemic infarction of anterior pit. Pregnancy → lactotroph hyperplasia → gland outgrows portal supply → infarcts with postpartum hypotension. Posterior pit (direct inferior hypophyseal artery) usually SPARED. Sequence: PRL → FSH/LH → TSH → ACTH loss

Apoplexy

Acute hemorrhage / infarction INTO existing adenoma. Triad: sudden severe headache + visual loss + ophthalmoplegia. Acute adrenal crisis → STRESS-DOSE STEROIDS. Medical emergency

Craniopharyngioma

Rathke's pouch remnant tumor; suprasellar, cystic + solid + CALCIFICATIONS, "motor-oil" fluid. Bimodal: kids 5–14, adults 50–70. Bitemporal hemianopsia + hypopituitarism + DI

Empty sella

CSF herniates through defective diaphragma sellae → compresses pituitary; sella appears "empty". Often asymptomatic, normal function. Primary (congenital diaphragm defect) vs secondary (post-op, post-radiation, post-apoplexy)

Bitemporal

Crossing NASAL retinal fibers at optic chiasm (directly above pituitary) compressed → loss of both temporal visual fields. Uncrossed temporal fibers typically spared

Cavernous sinus

Contains CN III, IV, V₁, V₂, VI + internal carotid. Invasion → diplopia, ptosis, facial sensory deficits, possible carotid involvement (rare)

Transsphenoidal

Endoscopic nasal cavity → sphenoid sinus → posterior wall → sella turcica. Spares brain. Standard for pituitary adenoma resection

Rathke cleft cyst

Benign cystic remnant of Rathke's pouch LUMEN; usually asymptomatic. Large cysts → headache, visual loss, hypopituitarism. Distinct from craniopharyngioma (no calcifications)

LO 2

ON EXAM — Arcuate (GHRH, GnRH, dopamine); PVN (CRH, TRH, ADH, oxytocin); SON (ADH, oxytocin); Preoptic (GnRH); SCN (circadian); Lateral (hunger); VMN (satiety); Anterior=Cooling; Posterior=heating

Hypothalamic nuclei (LO 2)

Nucleus	Hormone(s) / function	Clinical / mnemonic
Arcuate	GHRH, GnRH, DOPAMINE (PIF)	Median eminence neurons → portal. Damage → hyperprolactinemia
PVN	CRH, TRH, ADH + oxytocin (some)	Parvocellular → anterior pit; magnocellular → posterior pit. Central stress hub
SON	ADH (majority) + oxytocin	Magnocellular axons → posterior pit. Lesion → central DI
Preoptic	GnRH (major source) + thermoregulation	Damage impairs puberty / fertility
SCN	Circadian pacemaker (no direct hormone)	Direct retinal input; drives cortisol/melatonin rhythm
Lateral	HUNGER center (orexin/hypocretin)	"Lateral Lanky" — destroyed → anorexia. Narcolepsy = orexin deficiency
VMN	SATIETY center	"Ventromedial Very Massive" — destroyed → hyperphagia, obesity, savagery
Anterior (temp.)	Heat DISSIPATION (sweat, vasodilation)	"A/C Anterior/Cooling" — damage → hyperthermia
Posterior (temp.)	Heat CONSERVATION (shiver, vasoconstriction)	Damage → poikilothermia

Releasing vs inhibiting hormones (LO 2)

Hormone	Effect	Nucleus	Pituitary target
CRH	RELEASES ACTH	PVN	Corticotroph → Gs-cAMP
TRH	RELEASES TSH + PRL	PVN	Thyrotrophs + lactotrophs → Gq-IP₃
GnRH	RELEASES LH + FSH (pulsatile)	Arcuate + preoptic	Gonadotroph → Gq-IP₃
GHRH	RELEASES GH	Arcuate	Somatotroph → Gs-cAMP
Somatostatin	INHIBITS GH (+ TSH, insulin, glucagon, gastrin)	Arcuate / periventricular	Somatotroph + others → Gi-↓cAMP
Dopamine	INHIBITS prolactin (tonic)	Arcuate (tuberoinfundibular tract)	Lactotroph → D₂, Gi-↓cAMP

MNEMONIC: Releasing = "CRH TRH GnRH GHRH" (all -RH). Inhibiting = Somatostatin + Dopamine. TRH ALSO releases prolactin — primary hypothyroidism → TRH ↑ → both TSH & PRL rise (galactorrhea).

LO 3

ON EXAM — somatotrophs (50%, GH, acidophil), lactotrophs (15-20%, PRL, acidophil), corticotrophs (15%, ACTH, basophil), gonadotrophs (10%, FSH/LH, basophil), thyrotrophs (5%, TSH, basophil); "B-FLAT"; POMC → ACTH + β-endorphin + MSH

Anterior pit cell types (LO 3)

Cell	%	Hormone	Stain	Classic tumor
Somatotrophs	~50%	GH	ACIDOPHIL	Acromegaly (adults) / gigantism (kids)
Lactotrophs	~15–20%	Prolactin	ACIDOPHIL	Prolactinoma (most common); treat with cabergoline
Corticotrophs	~15%	ACTH (from POMC) + β-endorphin + MSH	BASOPHIL	Cushing disease; Nelson syndrome
Gonadotrophs	~10%	FSH + LH	BASOPHIL	Usually non-functional ("silent") adenomas
Thyrotrophs	~5%	TSH	BASOPHIL	Rare TSH-oma → central hyperthyroidism

POMC — corticotroph precursor (LO 3)

POMC stands for

Pro-opiomelanocortin — single precursor protein cleaved in corticotrophs

Three peptides

ACTH + β-endorphin + MSH (α-MSH, β-MSH); also β-lipotropin

Addison hyperpigmentation

Low cortisol removes negative feedback → POMC transcription soars → ACTH and MSH rise together. MSH activates melanocyte receptors → hyperpigmentation (palmar creases, gums, areolae, scars)

Exogenous steroids

Prednisone SUPPRESSES POMC transcription → no MSH rise → no hyperpigmentation (instead: striae, moon face, central obesity)

Posterior pituitary histology (LO 3)

Two components

Pituicytes (modified glia) + unmyelinated axon terminals from hypothalamic SON/PVN neurons

Herring bodies

Eosinophilic swellings along axon terminals — accumulated ADH/oxytocin secretory granules

Carrier protein

Neurophysin — co-packaged + co-secreted with ADH (NPII) or oxytocin (NPI)

Neurohemal organ

Hypothalamic NEURONS deliver hormone directly into BLOOD at terminals (no synapse) → neural-vascular junction

LO 4

ON EXAM — 6 axes (HPA, HPT, HPG, somatotropic, lactotropic, posterior); TRH/GnRH/ADH-V1/oxytocin = Gq; CRH/GHRH/ACTH/TSH/LH/FSH/MSH/ADH-V2 = Gs; somatostatin/dopamine = Gi; GH/PRL = JAK-STAT

Pituitary axis table (LO 4)

Axis	Hypothalamic regulator	Pituitary hormone	Target	End-organ effect
HPA	CRH (PVN)	ACTH (corticotroph)	Adrenal zona fasciculata	Cortisol
HPT	TRH (PVN)	TSH (thyrotroph)	Thyroid follicular cells	T₄ + T₃
HPG males	GnRH pulsatile (arcuate/preoptic)	LH + FSH	Leydig (LH) + Sertoli (FSH)	Testosterone + spermatogenesis + inhibin B
HPG females	GnRH pulsatile	LH + FSH	Theca (LH) + granulosa (FSH) + corpus luteum	Estradiol, progesterone, inhibin
Somatotropic	GHRH (+) / somatostatin (−)	GH (somatotroph)	Liver + periphery	IGF-1 (liver); GH direct: lipolysis, ↓ glucose uptake
Lactotropic	Dopamine (−) + TRH (+) + estrogen	Prolactin (lactotroph)	Mammary gland	Lactogenesis + suppresses GnRH

Posterior pituitary hormones (LO 4)

Hormone	Nucleus	Stimulus	Receptor + effect
ADH	SON (majority) + PVN	Plasma osmolality >280 mOsm (osmoreceptors) OR volume loss >10%	V₂ (Gs-cAMP) on collecting duct → AQP-2 insertion; V₁ (Gq) on vascular smooth muscle → vasoconstriction
Oxytocin	PVN (majority) + SON	Cervical stretch (Ferguson reflex) + nipple suckling + psychological cues	Gq-IP₃ on uterine smooth muscle + breast myoepithelial cells → contraction + milk ejection

Receptor class map (LO 4)

TRH, GnRH

Gq (IP₃/DAG/Ca²⁺)

CRH, GHRH

Gs (cAMP)

Somatostatin, dopamine

Gi (↓cAMP) — inhibitory

ACTH, TSH, LH, FSH, MSH

Gs (cAMP) — all anterior pit peptides on target tissue

ADH V₁ vs V₂

V₁ = Gq (vasoconstriction); V₂ = Gs (renal AQP-2)

GH, prolactin

JAK-STAT (cytokine family) → JAK2 → STAT5

LO 5

ON EXAM — LONG loop (target → hypothalamus + pituitary); SHORT loop (pituitary → hypothalamus); ULTRA-SHORT (hormone → own neurons); POSITIVE = mid-cycle LH surge + oxytocin parturition (Ferguson reflex)

Feedback loops (LO 5)

Loop	Origin	Target	Example
Long (negative)	Target-organ hormone (T₄, cortisol, testosterone)	Hypothalamus + anterior pituitary	Cortisol suppresses CRH + ACTH
Short (negative)	Pituitary hormone (TSH, ACTH, LH)	Hypothalamus	ACTH suppresses CRH release
Ultra-short	Hypothalamic hormone itself	Same hypothalamic neurons (autoregulation)	GnRH inhibits its own release
Positive	Sustained high mid-cycle estradiol	Hypothalamus + pituitary	LH SURGE → ovulation. Also oxytocin in parturition (Ferguson reflex)

Pulsatile vs continuous (LO 5)

Why pulsatile GnRH

Gonadotropes need pulses every 60–90 min to maintain LH/FSH transcription and receptor sensitivity

Continuous GnRH

Receptor desensitization + downregulation → LH/FSH suppressed → "medical castration"

GnRH agonist uses

(1) Prostate cancer, (2) Endometriosis / fibroids, (3) Central precocious puberty, (4) IVF protocols

LH surge trigger

Sustained high estradiol (>200 pg/mL for ~48 h) at mid-cycle FLIPS feedback from negative to POSITIVE → LH surge → ovulation

Dynamic tests (LO 5)

Low-dose dex

1 mg overnight suppresses morning cortisol <1.8 μg/dL normally. FAILURE to suppress = Cushing syndrome (any cause). Screens IN Cushing

High-dose dex

8 mg: SUPPRESSES pituitary ACTH (Cushing DISEASE) but NOT ectopic ACTH or adrenal adenoma. Differentiates causes

ACTH stim

Cosyntropin IV. Normal: cortisol >18. Primary adrenal insufficiency: no response. Secondary: blunted acutely, improves with repeat dosing

TRH stim

TRH IV. Normal: TSH rises 2–3×. Exaggerated = primary hypothyroidism. Flat = secondary (pituitary). Rarely used today

LO 6 — ALL ITERATIONS

ON EXAM — for each axis, work through 6 ITERATIONS: hypothalamic ↑/↓, pituitary ↑/↓, target ↑/↓. Rule: autonomous lesion at level X suppresses upstream regulators via negative feedback. Primary (end-organ) vs secondary (pituitary) vs tertiary (hypothalamic). Exogenous administration mimics target hormone ↑

HPA axis predictions (LO 6)

Iteration	CRH	ACTH	Cortisol	Adrenal size	Real-world cause
CRH ↑	↑ (autonomous)	↑ (driven)	↑	Bilateral hyperplasia	Ectopic CRH (very rare; some bronchial carcinoids)
CRH ↓	↓ (autonomous loss)	↓ (no CRH)	↓	Bilateral ATROPHY	TERTIARY adrenal insufficiency — craniopharyngioma, hypothalamic injury, irradiation
ACTH ↑ (Cushing dz)	↓ (cortisol feedback)	↑↑ (autonomous adenoma)	↑↑	Bilateral hyperplasia	Cushing DISEASE (pituitary adenoma) — high-dose dex SUPPRESSES
ACTH ↑ ectopic	↓ (cortisol feedback)	↑↑ from tumor	↑↑	Bilateral hyperplasia	Ectopic ACTH: small-cell lung CA, carcinoid. High-dose dex does NOT suppress
ACTH ↓	↑ or normal	↓↓ (pituitary failure)	↓	Bilateral ATROPHY	SECONDARY adrenal insufficiency — Sheehan, adenoma, surgery, radiation, TBI
Cortisol ↑ adenoma	↓ (suppressed)	↓↓ (suppressed)	↑↑ (autonomous)	Adenoma enlarged; contralateral ATROPHIES	Adrenal cortisol-secreting adenoma (Cushing syndrome, adrenal-type)
Cortisol ↓ (Addison)	↑↑ (no feedback)	↑↑ (drives POMC → MSH → HYPERPIGMENTATION)	↓↓	Bilateral atrophy / destruction	Addison disease (autoimmune), TB, hemorrhage, congenital lipoid CAH
Exogenous prednisone	↓↓ (mimics cortisol)	↓↓ (suppressed)	Endogenous ↓↓	BILATERAL ATROPHY	Iatrogenic. Abrupt withdrawal → crisis. TAPER if >3 weeks

HPT axis predictions (LO 6)

Iteration	TRH	TSH	Free T₄	Real-world cause
TRH ↑	↑↑ (autonomous; rare)	↑	↑	Central hyperthyroidism — almost never seen clinically
TRH ↓	↓	↓ (no TRH drive)	↓	TERTIARY hypothyroidism — hypothalamic damage (craniopharyngioma, radiation)
TSH ↑ (TSH-oma)	↓ (suppressed by T₄)	↑↑ (autonomous adenoma)	↑	TSH-secreting adenoma — rare. Treat surgically + somatostatin analogs
TSH ↓	↑ or normal	↓↓ (pituitary failure)	↓	SECONDARY hypothyroidism — Sheehan, adenoma, surgery
T₄ ↑ (Graves)	↓ (suppressed)	↓↓ (suppressed)	↑↑ (autonomous)	Graves: TSI antibodies bind TSHR → drive synthesis
T₄ ↓ (Hashimoto)	↑ (no feedback)	↑↑	↓↓	PRIMARY hypothyroidism — anti-TPO + anti-Tg antibodies
Exogenous T₄(excess)	↓	SUPPRESSED (most sensitive marker)	↑	Iatrogenic thyrotoxicosis if over-replaced
1st-trimester hCG	Normal	LOW-normal (transiently low)	Normal-to-slightly-↑	hCG α-subunit cross-reacts with TSHR. Resolves after ~10 weeks

HPG axis predictions (LO 6)

Iteration	GnRH	LH / FSH	Sex steroid	Real-world cause
GnRH ↑	↑ (autonomous; exceedingly rare)	↑	↑	No pure GnRH-excess syndrome
GnRH ↓	↓ (no GnRH neurons)	↓	↓	Kallmann syndrome (anosmia + hypogonadotropic hypogonadism) — failed GnRH neuron migration
LH/FSH ↑	↓ (suppressed)	↑ (autonomous; rare)	↑ (rare)	Gonadotrope adenomas — mostly clinically silent
LH/FSH ↓	↑ or normal	↓↓	↓	SECONDARY hypogonadism — Sheehan, hyperprolactinemia, exogenous androgens, pituitary tumor
Sex steroid ↑	↓↓ (suppressed)	↓↓ (suppressed)	↑↑ (tumor)	Sertoli/Leydig tumor, granulosa cell tumor, theca lutein cyst, exogenous anabolics
Sex steroid ↓	↑↑ (no feedback)	↑↑	↓↓	PRIMARY hypogonadism — Klinefelter, cryptorchidism, mumps orchitis, chemo, menopause
Anabolic steroid abuse	↓↓	↓↓	Endogenous T ↓↓	TESTICULAR ATROPHY + azoospermia. Recovery 6–12+ months after stopping
Continuous GnRH agonist	Receptor desensitized	↓↓	Castrate range	"Medical castration" (leuprolide) — prostate CA, endometriosis, precocious puberty, IVF

Somatotropic, lactotropic, posterior predictions (LO 6)

Iteration	Hypothalamic	Pituitary	Target / effect
GH ↑ (acromegaly)	GHRH ↓ (suppressed by IGF-1)	GH ↑↑ (autonomous somatotroph adenoma)	IGF-1 ↑↑ → acromegaly/gigantism. Dx: IGF-1 ↑ + fail to suppress GH on OGTT
GH ↓ (GHD)	GHRH normal / ↑	GH ↓	IGF-1 ↓ → growth failure (kids), central adiposity (adults). Laron = receptor defect (high GH, low IGF-1; treat with mecasermin)
IGF-1 ↑	GHRH ↓↓	GH ↓↓	Rare autonomous IGF-1 tumor; or NICTH (big-IGF2 activates IGF-1R → hypoglycemia)
PRL ↑ (prolactinoma)	Dopamine normal but overpowered	PRL ↑↑ from adenoma	GnRH ↓ → LH/FSH ↓ → hypogonadism + galactorrhea. Tx: cabergoline
Dopamine ↓	Dopamine ↓ (lost stalk delivery)	PRL ↑ (loss of inhibition)	All other anterior pit hormones ↓. STALK TRANSECTION pattern
ADH ↑ (SIADH)	SON/PVN firing inappropriate	ADH ↑↑	Free water retention → hyponatremia, low serum osm, INAPPROPRIATELY concentrated urine, euvolemic. SCLC, CNS injury, drugs
ADH ↓ (central DI)	SON/PVN damage or stalk injury	ADH ↓↓	Free water loss → hypernatremia, polyuria, dilute urine. RESPONDS to desmopressin
Nephrogenic DI	Normal	ADH normal / ↑	Kidney V₂ or AQP-2 unresponsive. Same labs as central DI but DOES NOT respond to DDAVP. Causes: lithium, hypercalcemia, hypokalemia, congenital

Master prediction rules (LO 6)

Rule 1 (autonomous tumor)

Autonomous tumor at level X SUPPRESSES upstream regulators via negative feedback. E.g., adrenal adenoma making cortisol → ACTH ↓ → CRH ↓

Rule 2 (damage)

Damage at level X reduces all DOWNSTREAM hormones (no upstream stimulation). Upstream regulators may rise due to lost feedback

Rule 3 (primary vs secondary)

In UNDER-activity: trophic hormone HIGH = primary, LOW = secondary. In OVER-activity: trophic hormone SUPPRESSED = primary (autonomous target), HIGH = secondary (autonomous pituitary adenoma)

Rule 4 (exogenous)

Exogenous hormone (prednisone, T₄, testosterone) functionally mimics "target hormone ↑" — suppresses upstream trophic hormones, endogenous gland ATROPHIES. Sudden withdrawal → crisis

Rule 5 (stalk paradox)

Stalk transection: PRL RISES (loses dopamine inhibition); all other anterior pit hormones fall (lose releasing-hormone delivery); posterior pit also fails → central DI. Paradox unique to prolactin

LO 1–6 · USMLE Step 1 Style

10 questions — answers pre-revealed.

Q1. Embryologic origin of anterior pituitary?

A. Neural crest
B. Oral (surface) ectoderm — Rathke's pouch
C. Neural ectoderm — infundibulum
D. Endoderm
E. Splanchnic mesoderm

B — Rathke's pouch (oral ectoderm).
Ascending from the roof of the primitive oral cavity at 3–4 weeks. The infundibulum (option C) descends from the diencephalic floor and forms the POSTERIOR pituitary. They meet ~week 6. Persistent Rathke's remnants → craniopharyngioma or Rathke's cleft cyst.

Q2. Where is the PRIMARY capillary plexus of the portal system, and what is its significance?

A. Anterior pit; receives systemic arterial blood
B. Posterior pit; collects axon-terminal hormones
C. Median eminence; supplied by superior hypophyseal artery; collects hypothalamic releasing hormones
D. Cavernous sinus; drainage
E. Optic chiasm

C — Primary plexus in median eminence.
Branches of the superior hypophyseal artery form the primary capillary plexus at the median eminence (a circumventricular organ, outside BBB with fenestrated capillaries). Hypothalamic neurons release releasing/inhibiting hormones here → long portal veins → secondary plexus in anterior pit → concentrated delivery without systemic dilution.

Q3. Postpartum woman with severe hemorrhage, 3 weeks later cannot lactate, amenorrhea, fatigue. Labs: TSH low, T₄ low, cortisol low. Posterior pit function preserved. Best explanation?

A. Thyroid autoimmune destruction
B. Pregnancy lactotroph hyperplasia outgrew portal blood supply → ischemic infarct of adenohypophysis; posterior pit spared (supplied by inferior hypophyseal artery)
C. Hypothalamic stroke
D. Waterhouse-Friderichsen
E. Empty sella

B — Sheehan syndrome.
Pregnancy → lactotroph hyperplasia → anterior pit outgrows its portal blood supply → postpartum hypotension → ischemic infarction of adenohypophysis. Posterior pit is supplied directly by the inferior hypophyseal artery, so it's typically spared (no DI). Hormone loss sequence often: PRL → FSH/LH → TSH → ACTH.

Q4. Complete pituitary stalk transection. Expected anterior pit hormones 2 weeks later?

A. All anterior hormones fall
B. Prolactin RISES; ACTH, TSH, LH/FSH, GH fall
C. All anterior hormones rise
D. Only ADH falls; anterior unaffected
E. Only prolactin falls

B — PRL ↑, others ↓.
Anterior pit depends entirely on portal delivery of releasing hormones. Stalk cut → no CRH/TRH/GnRH/GHRH delivered → ACTH/TSH/LH/FSH/GH fall. Prolactin is uniquely under tonic dopaminergic inhibition via the tuberoinfundibular tract — losing dopamine releases the brake → prolactin RISES. Also expect central DI from lost axon-terminal ADH delivery.

Q5. Bitemporal hemianopsia from pituitary adenoma — which fibers are compressed?

A. Uncrossed temporal retinal fibers in optic tract
B. Crossing NASAL retinal fibers at optic chiasm directly above pituitary
C. Crossed temporal fibers in LGN
D. Optic radiations in parietal lobe
E. Pretectal nuclei

B — Crossing nasal fibers at the optic chiasm.
Nasal retinal fibers carry information from the temporal visual fields and CROSS at the optic chiasm, which sits directly above the pituitary fossa. A pituitary mass growing superiorly compresses these crossing fibers → loss of both temporal visual fields. Uncrossed temporal retinal fibers (carrying nasal field) are typically spared.

Q6. 58-year-old on chronic high-dose prednisone for 8 months. Predict HPA axis.

A. CRH ↑, ACTH ↑, endogenous cortisol ↑, adrenals enlarged
B. CRH ↓, ACTH ↓, endogenous cortisol ↓, bilateral adrenal ATROPHY → abrupt withdrawal → crisis
C. CRH normal, ACTH ↑, cortisol ↑
D. CRH ↑, ACTH ↓
E. All normal

B — Suppressed axis; bilateral adrenal atrophy.
Prednisone mimics cortisol → suppresses CRH and ACTH chronically → endogenous cortisol falls → both adrenals atrophy. Abrupt withdrawal → atrophied adrenals can't respond → adrenal crisis. Always TAPER steroids after >3 weeks of supraphysiologic dosing.

Q7. Hashimoto patient started on excessive levothyroxine. Labs 6 weeks later?

A. TRH ↑, TSH ↑, T₄ ↑
B. TRH ↓, TSH SUPPRESSED, T₄ ↑
C. TRH ↑, TSH ↓, T₄ ↓
D. TRH normal, TSH normal, T₄ ↑
E. TRH ↓, TSH ↑, T₄ normal

B — TRH & TSH suppressed; T₄ ↑.
Exogenous levothyroxine raises free T₄ → negative feedback at hypothalamus (suppresses TRH) and pituitary (suppresses TSH). TSH is the most sensitive indicator of over-replacement. Functionally identical to “target hormone ↑.”

Q8. 26-year-old male bodybuilder on exogenous testosterone for 18 months. Predict HPG axis.

A. GnRH ↑, LH ↑, endogenous T ↑
B. GnRH suppressed, LH/FSH suppressed, endogenous T ↓, testes ATROPHIED, oligo/azoospermia
C. GnRH ↑, LH ↓
D. GnRH ↓, LH ↑
E. Normal

B — Suppressed axis with testicular atrophy.
Exogenous testosterone provides target-hormone feedback → GnRH, LH, FSH all suppressed. Without LH/FSH + intratesticular testosterone, spermatogenesis fails → testicular atrophy and azoospermia. Recovery takes 6–12+ months after stopping. Functionally identical to “sex steroid ↑.”

Q9. Prostate cancer patient on long-acting GnRH agonist (leuprolide) for 3 months. Predict HPG axis.

A. LH/FSH ↑, testosterone ↑
B. LH/FSH ↓, testosterone ↓ (desensitization → medical castration)
C. LH/FSH normal, T ↑
D. LH/FSH ↑, T ↓ (direct testicular toxicity)
E. No effect

B — Medical castration.
Pituitary gonadotropes need pulsatile GnRH (every 60–90 min). Continuous agonist initially causes a flare (cover with antiandrogen first 2–4 weeks), then GnRH receptors are downregulated/desensitized → LH/FSH suppressed → testosterone falls to castrate range.

Q10. 45-year-old woman: weight gain, cold intolerance, galactorrhea. TSH 42, T₄ low, prolactin mildly elevated. Cause of hyperprolactinemia?

A. Prolactinoma
B. Pregnancy
C. Primary hypothyroidism → low T₄ → TRH ↑ → TRH stimulates BOTH thyrotrophs (TSH ↑) and lactotrophs (PRL ↑)
D. Adrenal insufficiency
E. Renal failure

C — TRH-driven hyperprolactinemia.
In primary hypothyroidism, low T₄ removes negative feedback → TRH ↑ → TRH stimulates BOTH TSH and prolactin (lactotrophs also have TRH receptors). Treating with levothyroxine normalizes both. Always check TSH BEFORE pursuing pituitary MRI in hyperprolactinemia workup.

Hypothalamic-Pituitary Relationships I — Answer Key