Built from Endocrine Lecture 02 (LOs 1–6). Close notes. Fill from memory. Reveal only after a genuine attempt.

LO 1

ON EXAM — Rathke's pouch (oral ectoderm, ascends) becomes anterior pit; infundibulum (neural ectoderm, descends) becomes posterior pit; meet ~6 wk gestation. Adenohypophysis = pars distalis + intermedia + tuberalis; neurohypophysis = pars nervosa + infundibular stem + median eminence. Anterior pit reached ONLY by hypothalamic-hypophyseal PORTAL system (2 capillary plexuses); posterior pit by hypothalamic AXONS through the stalk. Median eminence is OUTSIDE blood-brain barrier (a circumventricular organ, fenestrated capillaries). Sella turcica of sphenoid; bordered by cavernous sinus laterally (CN III, IV, V₁, V₂, VI, ICA), optic chiasm above, sphenoid sinus below. Stalk transection → hypopituitarism EXCEPT prolactin (rises — loses dopamine brake)

Embryology of the pituitary (LO 1)

Component	Embryonic origin	Direction of growth	Tissue type	Persistent remnant / pathology
Anterior pit (adenohypophysis)
Pars intermedia
Posterior pit (neurohypophysis)

When does Rathke's pouch meet the infundibulum? Around week 6 of gestation. Persistent connection between pharynx and pituitary = craniopharyngeal canal. Pharyngeal pituitary = ectopic anterior pit tissue along this path.

Subdivisions — what each part contains (LO 1)

Subdivision	Parent (anterior or posterior)	Cell type / content	Function
Pars distalis
Pars intermedia
Pars tuberalis
Pars nervosa
Infundibular stem (stalk)
Median eminence

Sellar region anatomy — what lies above, beside, below (LO 1)

Bone forming the sellar fossa

Dural roof over the sella

Superior neighbor (and classic visual deficit if compressed)

Lateral neighbor (and 6 structures inside)

Inferior neighbor (and surgical relevance)

Posterior neighbor (third ventricle floor)

Hypothalamic-hypophyseal PORTAL system — 2 plexuses in series (LO 1)

Element	Location	Source artery / connecting vessel	Function
PRIMARY capillary plexus
Long portal veins
SECONDARY capillary plexus
Short portal vessels
Inferior hypophyseal artery
Venous drainage

WHY a portal system? Concentrated delivery of tiny amounts of releasing hormones directly to anterior pit cells without systemic dilution. The median eminence is outside the blood-brain barrier (a circumventricular organ with FENESTRATED capillaries) — large peptides can exit without crossing BBB.

Neurohypophysis: hypothalamohypophyseal tract (LO 1)

Two hypothalamic nuclei whose AXONS become the tract

Cell type (parvocellular vs magnocellular)?

Hormones synthesized

How are hormones transported down axons?

What is co-secreted with each hormone? (carrier protein)

Histologic finding at axon terminals (stored vesicle pools)

Where is hormone released — into a synapse or a vessel?

Tuberoinfundibular tract — tonic prolactin inhibition (LO 1)

Origin nucleus → destination

Neurotransmitter / hormone delivered

Receptor + signaling on lactotroph (D₂, what G protein?)

Why is prolactin the only anterior pit hormone that RISES with stalk injury?

Functional summary — how hypothalamus reaches each pituitary part (LO 1)

Pituitary target	Connection type	Vehicle	Hormones delivered	Result of stalk transection
Anterior pit
Posterior pit
Lactotroph (anterior — special)

Anatomic failure points → classic syndromes (LO 1)

Sheehan syndrome — vascular mechanism + which gland infarcts

Pituitary apoplexy — what is it, and clinical triad

Craniopharyngioma — embryologic origin + key imaging finding

Empty sella syndrome — anatomic mechanism

Bitemporal hemianopsia — which fibers are compressed?

Cavernous sinus invasion — which CN and vessel can be affected?

Transsphenoidal surgical route — through what structures?

Rathke's cleft cyst — what is it, and where is it located?

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; 4 releasing (CRH, TRH, GnRH, GHRH) + 2 inhibiting (somatostatin, dopamine)

Hypothalamic nuclei (LO 2)

Nucleus	Hormone(s) / function	Clinical / mnemonic
Arcuate
PVN
SON
Preoptic
SCN
Lateral
VMN (ventromedial)
Anterior (temp.)
Posterior (temp.)

Releasing vs inhibiting hormones (LO 2)

Hypothalamic hormone	Effect	Nucleus	Pituitary target
CRH
TRH
GnRH
GHRH
Somatostatin (SRIF)
Dopamine (PIF)

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; posterior = pituicytes + axons + Herring bodies + neurophysin

Anterior pit cell types (LO 3)

Cell	%	Hormone	Stain	Classic tumor
Somatotrophs
Lactotrophs
Corticotrophs
Gonadotrophs
Thyrotrophs

POMC — corticotroph precursor (LO 3)

POMC stands for

Three peptides cleaved from POMC

Why does primary adrenal insufficiency cause hyperpigmentation?

Why don't exogenous steroids cause hyperpigmentation?

Posterior pituitary histology (LO 3)

Two cell types/structures

Herring bodies — what are they?

Carrier protein co-secreted with ADH/oxytocin

Why is posterior pit called a "neurohemal organ"?

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; prolactin under tonic dopamine inhibition

Pituitary axis table (LO 4)

Axis	Hypothalamic regulator	Pituitary hormone	Target	End-organ effect
HPA (stress)
HPT (thyroid)
HPG — males
HPG — females
Somatotropic
Lactotropic

Posterior pituitary hormones (LO 4)

Hormone	Nucleus	Stimulus	Receptor + effect
ADH
Oxytocin

Receptor class map (LO 4)

TRH, GnRH

CRH, GHRH

Somatostatin, dopamine

ACTH, TSH, LH, FSH, MSH

ADH (V₁ vs V₂)

GH, prolactin

LO 5

ON EXAM — LONG loop (target → hypothalamus + pituitary); SHORT loop (pituitary → hypothalamus); ULTRA-SHORT (hormone → own hypothalamic neurons); POSITIVE = mid-cycle estradiol → LH surge + oxytocin parturition (Ferguson reflex). Continuous GnRH desensitizes; pulsatile maintains.

Feedback loops (LO 5)

Loop	Origin	Target	Example
Long (negative)
Short (negative)
Ultra-short
Positive

Pulsatile vs continuous signaling (LO 5)

Why must GnRH be PULSATILE to maintain LH/FSH?

Continuous GnRH (or GnRH agonist like leuprolide) → what happens?

Clinical uses of GnRH agonists (3 examples)

What signals an LH SURGE at mid-cycle?

Dynamic tests based on feedback (LO 5)

Low-dose dexamethasone suppression test — what does FAILURE to suppress mean?

High-dose dex — differentiates which causes of Cushing?

ACTH (cosyntropin) stim test — what does failure to respond mean?

TRH stim test — what does an exaggerated TSH response indicate?

LO 6 — ALL ITERATIONS

ON EXAM — for each axis, work through 6 ITERATIONS: hypothalamic hormone ↑, hypothalamic ↓, pituitary ↑, pituitary ↓, target ↑, target ↓. Apply general rule: an autonomous LESION at one level → OPPOSITE direction at upstream regulators (negative feedback). Distinguish primary (end-organ) from secondary (pituitary) from tertiary (hypothalamic). Exogenous administration mimics target hormone ↑.

HPA axis — predict at every level (LO 6)

Iteration	CRH	ACTH	Cortisol	Adrenal size (each side)	Real-world cause
CRH ↑ (CRH-secreting tumor)
CRH ↓ (hypothalamic damage)
ACTH ↑ (Cushing disease)
ACTH ↑ (ECTOPIC, e.g., small-cell lung)
ACTH ↓ (Sheehan, pituitary infarct)
Cortisol ↑ (adrenal adenoma)
Cortisol ↓ (Addison)
Exogenous prednisone (chronic)

HPT axis — predict at every level (LO 6)

Iteration	TRH	TSH	Free T₄	Real-world cause
TRH ↑ (rare TRH tumor)
TRH ↓ (tertiary hypothyroidism)
TSH ↑ (TSH-oma — rare)
TSH ↓ (Sheehan, pituitary)
T₄ ↑ (Graves)
T₄ ↓ (Hashimoto, primary)
Exogenous T₄ (over-replacement)
1st-trimester pregnancy (hCG)

HPG axis — predict at every level (LO 6)

Iteration	GnRH	LH / FSH	Sex steroid (T or E₂)	Real-world cause
GnRH ↑ (rare)
GnRH ↓ (Kallmann)
LH/FSH ↑ (gonadotrope adenoma; or rare)
LH/FSH ↓ (Sheehan)
Sex steroid ↑ (e.g., testosterone-secreting tumor)
Sex steroid ↓ (Klinefelter, mumps orchitis)
Anabolic steroid abuse (exogenous T)
Continuous GnRH agonist (leuprolide)

Somatotropic + lactotropic + posterior — predictions (LO 6)

Iteration	Hypothalamic	Pituitary	Target / effect
GH ↑ (acromegaly — somatotroph adenoma)
GH ↓ (childhood GHD)
IGF-1 ↑ (autonomous — rare)
Prolactin ↑ (prolactinoma)
Dopamine ↓ (stalk transection)
ADH ↑ (SIADH)
ADH ↓ (central diabetes insipidus)
ADH normal but kidney resistant (nephrogenic DI)

Master prediction rules (LO 6)

Rule 1: Autonomous tumor at level X → what happens to upstream regulators?

Rule 2: Damage at level X → what happens to downstream hormones?

Rule 3: How to distinguish PRIMARY from SECONDARY disease in one trophic-hormone measurement?

Rule 4: Exogenous administration of target hormone behaves like which iteration?

Rule 5: Stalk damage → which hormone direction is paradoxical, and why?

LO 1–6 · USMLE Step 1 Style

10 questions — weighted toward expanded LOs (anatomy + portal system, prediction iterations).

Q1. Which embryologic origin BEST describes the cells of the anterior pituitary?

A. Neural crest, migrating from the dorsal neural tube
B. Oral (surface) ectoderm of Rathke's pouch, ascending from the roof of the primitive oral cavity
C. Neural ectoderm of the diencephalic floor, descending as the infundibulum
D. Endoderm of the foregut
E. Splanchnic mesoderm

B — Rathke's pouch (oral ectoderm).
The anterior pituitary derives from oral surface ectoderm that ascends as Rathke's pouch from the roof of the primitive oral cavity (~3–4 weeks). The infundibulum (option C) descends from the diencephalic floor and forms the POSTERIOR pituitary. The two meet around week 6. Persistent Rathke's remnants → craniopharyngioma (kids 5–14, adults 50–70) or Rathke's cleft cyst.

Q2. A neurosurgeon notes the hypothalamic-hypophyseal portal system contains TWO capillary plexuses. Where is the FIRST (primary) plexus located, and what is its functional significance?

A. In the anterior pituitary; receives systemic arterial blood
B. In the posterior pituitary; collects hormones secreted by axon terminals
C. In the median eminence; supplied by the superior hypophyseal artery; collects hypothalamic releasing hormones for delivery to anterior pit
D. In the cavernous sinus; drains the gland
E. In the optic chiasm; supplies the visual pathway

C — Primary plexus in the median eminence.
Branches of the superior hypophyseal artery form the primary capillary plexus at the median eminence, which is a fenestrated CIRCUMVENTRICULAR ORGAN (outside the BBB). Hypothalamic neurons release releasing/inhibiting hormones into this plexus → long portal veins descend through the infundibulum → secondary plexus in anterior pit → concentrated delivery to anterior pit cells without systemic dilution.

Q3. A 35-year-old woman has severe postpartum hemorrhage with prolonged hypotension. Three weeks later she cannot lactate, has amenorrhea, and is fatigued. Free T₄ low; TSH inappropriately low; cortisol low. Posterior pituitary function is preserved (no diabetes insipidus). Which BEST explains this pattern of selective hormone loss?

A. Thyroid autoimmune destruction
B. Pregnancy-associated lactotroph hyperplasia outgrew the anterior pituitary's blood supply → ischemic infarct of adenohypophysis from postpartum hypotension; posterior pit is supplied by inferior hypophyseal artery and spared
C. Hypothalamic stroke
D. Adrenal hemorrhage (Waterhouse-Friderichsen)
E. Empty sella syndrome

B — Sheehan syndrome.
Pregnancy-associated lactotroph hyperplasia makes the anterior pit outgrow its portal-system blood supply. Postpartum hemorrhage with hypotension → ischemic infarct of the adenohypophysis. The posterior pituitary is supplied directly by the inferior hypophyseal artery (NOT by the portal system) → usually spared (no DI). Sequence of loss often: PRL → FSH/LH → TSH → ACTH.

Q4. A patient sustains complete pituitary STALK transection from head trauma. Which of the following describes the expected anterior pit hormone response 2 weeks later?

A. ACTH, TSH, LH/FSH, GH, and prolactin all FALL
B. ACTH, TSH, LH/FSH, GH FALL; prolactin RISES (loss of dopamine inhibition)
C. All anterior pit hormones rise (loss of inhibition)
D. Only ADH falls; anterior pit unaffected
E. Only prolactin falls

B — PRL ↑; ACTH/TSH/LH/FSH/GH all ↓.
Anterior pit depends entirely on portal delivery of hypothalamic releasing hormones. Stalk cut → no CRH/TRH/GnRH/GHRH reach pituitary → respective hormones fall. Prolactin is the only one under tonic dopaminergic inhibition via the tuberoinfundibular tract — losing dopamine releases the brake → prolactin RISES. Posterior pit also affected → central DI (ADH ↓).

Q5. A 42-year-old man with a pituitary macroadenoma develops new bitemporal hemianopsia. Which fibers are being compressed, and where do they normally cross?

A. Uncrossed fibers from the temporal halves of each retina, in each optic tract
B. Crossed fibers from the NASAL halves of each retina, at the optic chiasm directly above the pituitary
C. Crossed fibers from the temporal halves of each retina, in the lateral geniculate nucleus
D. Optic radiations in the 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 that grows superiorly compresses these crossing fibers → loss of both temporal visual fields = bitemporal hemianopsia. The uncrossed temporal retinal fibers (carrying nasal field) are typically spared.

Q6. A 58-year-old man has been on chronic high-dose prednisone for sarcoidosis for 8 months. Predict the state of the HPA axis.

A. CRH ↑, ACTH ↑, endogenous cortisol ↑, both adrenals enlarged
B. CRH ↓, ACTH ↓, endogenous cortisol ↓, both adrenals ATROPHIED → abrupt withdrawal → adrenal crisis
C. CRH normal, ACTH ↑, cortisol ↑, contralateral adrenal atrophy
D. CRH ↑, ACTH ↓, cortisol ↑
E. All HPA hormones normal because prednisone does not cross the blood-brain barrier

B — CRH/ACTH/endogenous cortisol all suppressed; bilateral adrenal atrophy.
Prednisone mimics cortisol → suppresses CRH and ACTH chronically → endogenous cortisol production falls → both adrenals atrophy (loss of trophic ACTH stimulation). Abrupt withdrawal → atrophied adrenals can't respond → adrenal crisis. ALWAYS taper steroids after >3 weeks of supraphysiologic dosing. Compare to a unilateral adrenal adenoma: only the contralateral adrenal atrophies because the adenoma drives ACTH down, but the adenoma itself is autonomous.

Q7. A 42-year-old woman with Hashimoto thyroiditis is started on excessive levothyroxine. Six weeks later her labs are checked. Predict the expected pattern.

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

B — TRH & TSH suppressed; free T₄ ↑.
Exogenous levothyroxine raises free T₄, which provides negative feedback at both the hypothalamus (suppresses TRH) and pituitary (suppresses TSH). Over-replacement is functionally identical to autonomous T₄ excess (Graves) at the level of the HPT axis: TSH is the most sensitive indicator of over-replacement. Same iteration as “target hormone ↑.”

Q8. A 26-year-old male competitive bodybuilder has been using exogenous testosterone for 18 months. Predict the state of his HPG axis.

A. GnRH ↑, LH ↑, endogenous testosterone ↑, testes enlarged
B. GnRH SUPPRESSED, LH & FSH SUPPRESSED, endogenous testosterone ↓, testes ATROPHIED, oligo/azoospermia, infertility
C. GnRH ↑, LH ↓, endogenous testosterone ↑
D. GnRH ↓, LH ↑, FSH ↑, sperm count ↑
E. All HPG hormones normal

B — Suppressed axis with testicular atrophy.
Exogenous testosterone provides target-hormone feedback → GnRH, LH, and FSH all suppressed. Without LH stimulation, Leydig cells stop making endogenous testosterone; without FSH and intratesticular testosterone, Sertoli cells lose support of spermatogenesis → testicular atrophy and azoospermia. Recovery after discontinuation can take 6–12+ months. This is functionally identical to “sex steroid ↑” in the prediction matrix.

Q9. A 32-year-old man with metastatic prostate cancer is started on a long-acting GnRH agonist (leuprolide). Predict the SUSTAINED steady-state effect on the HPG axis after 3 months.

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

B — Medical castration via receptor desensitization.
Pituitary gonadotropes require pulsatile GnRH (every 60–90 min) to maintain LH/FSH release. Continuous GnRH agonism initially causes a transient surge (“flare” — cover with antiandrogen first 2–4 weeks for prostate cancer), then GnRH receptors are downregulated and desensitized → LH/FSH suppressed → testosterone falls to castrate range. Used for prostate cancer, endometriosis, central precocious puberty, IVF protocols.

Q10. A 45-year-old woman has weight gain, cold intolerance, fatigue, and milky nipple discharge (galactorrhea). TSH 42 µIU/mL (high), free T₄ low, prolactin 65 ng/mL (mildly elevated). Predict the underlying mechanism for hyperprolactinemia.

A. Prolactin-secreting pituitary microadenoma
B. Pregnancy
C. Primary hypothyroidism → low T₄ → TRH ↑ → TRH stimulates BOTH thyrotrophs (TSH ↑) and lactotrophs (prolactin ↑)
D. Adrenal insufficiency
E. Renal failure

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

Hypothalamic-Pituitary Relationships I — Active Recall