Endocrine Module 02Hypothalamic-Pituitary Relationships (Part 1)

1 · Anatomy at a glance

• Hypothalamus:
  • Part of the diencephalon.
  • Forms the floor and lateral walls of the third ventricle.
  • Sits just above the pituitary.Costanzo 6e ch 9
• Pituitary gland:
  • Resides in the sella turcica ("Turkish saddle") of the sphenoid bone.
  • Covered superiorly by the diaphragma sellae, a dural fold.
  • Cavernous sinuses on either side contain CN III, IV, V1, V2, VI and the internal carotid.FA 2024 Neuro/Endo
• Optic chiasm:
  • Sits directly above the pituitary.
  • Crossing fibers come from the nasal halves of each retina.
  • Pituitary masses compress these crossing fibers → bitemporal hemianopsia.Pathoma 2024 ch 15; B&B Endo

• Step 1 for any sagittal diagram:
  • Find the optic chiasm — it marks anterior.
  • The anterior pituitary sits toward the chiasm; the posterior lobe sits behind it.

2 · The hypophyseal portal system

• Inflow:
  • Superior hypophyseal arteries (branches of the internal carotid) enter the median eminence.
• Primary capillary plexus:
  • Forms in the median eminence (a circumventricular organ — no BBB here).
  • Hypothalamic releasing/inhibiting hormones are secreted into these capillaries by axon terminals from hypothalamic neurons.Guyton 14e ch 75
• Portal veins:
  • Carry the hormone-rich blood down the infundibulum.
  • Low-pressure system (venous).
• Secondary capillary plexus:
  • Located in the anterior pituitary.
  • Delivers hypothalamic hormones at high concentration directly to secretory cells — without systemic dilution.
  • Finally drains into the systemic venous circulation.

• Low-pressure vulnerability:
  • The portal system is a low-pressure venous loop.
  • During pregnancy the pituitary enlarges but its blood supply doesn't scale proportionally.
  • Peripartum hemorrhage → hypoperfusion → pituitary infarction = Sheehan syndrome.Pathoma 2024 ch 15; FA 2024 Endo
• Stalk transection:
  • Cutting the infundibulum cuts off dopamine (PIH) from the lactotropes.
  • Result: all anterior pituitary hormones fall EXCEPT prolactin, which rises.

3 · Direct axonal connections to the posterior pituitary

• Magnocellular neurons:
  • Large neurons in the supraoptic nucleus (SON) and paraventricular nucleus (PVN).
  • Synthesize ADH and oxytocin (bound to their carrier protein neurophysin).
  • Axons travel through the infundibulum to the posterior pituitary.Costanzo 6e ch 9

• Herring bodies:
  • Eosinophilic axon-terminal swellings in the posterior pituitary.
  • Packed with neurosecretory granules (ADH/oxytocin).Guyton 14e ch 75
• Pituicytes:
  • Glial support cells of the neurohypophysis.
  • Appear as basophilic nuclei on H&E.
• Release mechanism:
  • Action potentials travel down the axon → Ca²⁺ entry at terminal → vesicle fusion.
  • ADH and oxytocin diffuse into adjacent fenestrated capillaries → systemic circulation.

4 · Circumventricular organs (CVOs)

• CVOs:
  • Areas of the brain near ventricles where the blood-brain barrier is minimal or absent.
  • Allow direct neural sensing of circulating molecules and direct hormone release into blood.B&B Endo; Guyton 14e

• Median eminence:
  • Site of the primary capillary plexus of the hypophyseal portal system.
• Neurohypophysis (posterior pituitary):
  • ADH and oxytocin released directly into fenestrated capillaries.
• OVLT (organum vasculosum of the lamina terminalis):
  • Senses plasma osmolarity.
  • Drives ADH release and thirst when plasma is hyperosmotic.
• Pineal gland:
  • Releases melatonin on a circadian rhythm.
• Others:
  • Area postrema (vomiting center), subfornical organ (thirst/AngII sensing).

1 · Releasing vs. inhibiting hormones

• Releasing hormone (-RH):
  • Stimulates secretion of a specific anterior pituitary hormone.
  • Examples: GnRH, TRH, CRH, GHRH.
• Inhibiting hormone (-IH):
  • Suppresses secretion of a specific anterior pituitary hormone.
  • Examples: somatostatin (GHIH), dopamine (PIH), GnIH.Costanzo 6e ch 9

• Only non-peptide:
  • Dopamine (PIH) is a monoamine (catecholamine) — all other hypothalamic hormones are peptides.
  • Synthesized in the arcuate nucleus (tuberoinfundibular pathway).
  • Tonically inhibits prolactin.FA 2024 Endo
• Why this matters:
  • Dopamine antagonists (antipsychotics, antiemetics like metoclopramide) → hyperprolactinemia.
  • Dopamine agonists (bromocriptine, cabergoline) are first-line for prolactinoma.

2 · The nuclei map (focused, not every nucleus)

• Supraoptic (SON):
  • Primary source of ADH.
  • Smaller contribution to oxytocin.
• Paraventricular (PVN):
  • Primary source of oxytocin.
  • Also makes some ADH, CRH, TRH — "Swiss Army nucleus."Guyton 14e ch 75

• Medial preoptic → GnRH:
  • Master of the reproductive axis.
  • Must be released in pulses (~every 60–90 min) to avoid gonadotrope desensitization.
• Dorsomedial → GnIH:
  • Directly opposes GnRH.
• Paraventricular + anterior nuclei → TRH, CRH:
  • Drive the thyroid and adrenal axes.
• Ventromedial → GHRH:
  • VMN is also the "satiety center" — lesions cause hyperphagia and obesity.
• Periventricular → somatostatin (GHIH):
  • Opposes GHRH.
  • Also inhibits TSH secretion (mild contribution).
• Arcuate → dopamine (PIH) + GHRH:
  • Arcuate is the only nucleus that sends a monoamine to the anterior pituitary.
  • Also participates in appetite regulation (NPY/AgRP and POMC neurons live here).

3 · Posterior pituitary hormones (ADH & oxytocin)

• Nonapeptides:
  • Both ADH and oxytocin are 9-amino-acid peptides.
  • Differ by only 2 amino acids.Costanzo 6e ch 9
• Neurophysin carriers:
  • Each hormone is co-packaged with a specific neurophysin.
  • Neurophysin I carries oxytocin; neurophysin II carries ADH.

• V2 receptor (renal collecting duct, principal cells):
  • Gs → cAMP → inserts aquaporin-2 channels into apical membrane.
  • Increases water reabsorption → concentrated urine.
• V1 receptor (vascular smooth muscle):
  • Gq → IP3/Ca²⁺ → vasoconstriction.
  • Supports BP in hypovolemia.FA 2024 Pharm
• Stimuli for ADH release:
  • Increased plasma osmolarity (sensed by OVLT, subfornical organ).
  • Decreased blood volume or pressure (sensed by baroreceptors).

• Uterine contraction:
  • Triggers labor contractions.
  • Ferguson reflex: cervical stretch → more oxytocin → more contraction (positive feedback).
• Milk let-down:
  • Suckling → spinal afferents → oxytocin release → contraction of myoepithelial cells → milk ejection.
• Other effects:
  • Social bonding, pair bonding, stress modulation.

4 · Hypothalamic hormone structure summary

• Peptide sizes (approximate):
  • TRH = 3 AA (tripeptide) — smallest.
  • GnIH ≈ 8 AA.
  • Oxytocin / ADH = 9 AA (nonapeptides).
  • GnRH = 10 AA (decapeptide).
  • Somatostatin = 14 or 28 AA (cyclic).
  • CRH = 41 AA.
  • GHRH = 44 AA — largest of this set.Guyton 14e ch 75
• Dopamine:
  • Not a peptide. Catecholamine synthesized from tyrosine.

5 · The pulsatility rule

• Pulsatile GnRH:
  • Normal physiologic release every 60–90 minutes.
  • Pulses maintain gonadotrope responsiveness.
• Continuous exposure = paradoxical suppression:
  • Receptor desensitization and down-regulation.
  • GnRH agonists (leuprolide) used CONTINUOUSLY suppress LH/FSH → chemical castration (prostate cancer, endometriosis).Lippincott Pharm 7e
  • The same drug given PULSATILELY can treat hypogonadism (e.g., Kallmann) by mimicking physiology.

1 · The three parts of each lobe

• Pars distalis:
  • Largest portion.
  • Houses the 5 secretory cell types (somatotropes, lactotropes, gonadotropes, corticotropes, thyrotropes).Costanzo 6e ch 9
• Pars intermedia:
  • Thin layer between adeno- and neurohypophysis.
  • Contains densely packed basophilic cells and characteristic colloid-filled cysts.
  • Vestigial in adults; active in fetuses, young children.
  • Makes MSH (via POMC cleavage).
• Pars tuberalis:
  • Sleeve of tissue that wraps around the infundibular stalk.
  • Mainly gonadotropes.

• Pars nervosa:
  • Main posterior lobe.
  • Packed with axon terminals from SON and PVN.
  • Herring bodies visible as eosinophilic swellings.
  • Pituicytes (glia) fill the stroma.
• Median eminence:
  • Not a part of the anterior pituitary, but the site of primary capillary plexus.
  • Where hypothalamic hormones enter the portal system.
• Infundibular stalk:
  • Connects hypothalamus to pituitary.
  • Carries both portal veins (to adenohypophysis) and axons (to neurohypophysis).

2 · Embryology

• Adenohypophysis:
  • Originates from Rathke's pouch — an outpouching of oral ectoderm.
  • Migrates upward to meet the descending neuroectoderm.FA 2024 Embryo; B&B Endo
• Neurohypophysis:
  • Originates from the floor of the diencephalon (neuroectoderm).
  • Descends to meet Rathke's pouch.
• Fusion:
  • Rathke's pouch closes, leaving the pars intermedia at the junction.
  • Residual cells of Rathke's pouch can persist → craniopharyngioma in children.

3 · Cell staining and identification

• Appearance:
  • Eosin-staining (pink) cytoplasmic granules.
  • Packed with hormone.
• Hormones:
  • GH (somatotrope).
  • PRL (lactotrope).
  • You can't distinguish somatotrope from lactotrope on H&E alone — immunohistochemistry required.

• Appearance:
  • Hematoxylin-staining (purple/blue) granules.
  • Often PAS-positive due to heavy glycosylation (glycoprotein hormones).Pathoma 2024 ch 15
• Hormones:
  • FSH, LH (gonadotropes).
  • ACTH (corticotropes) — also generates MSH, β-endorphin, β-lipotropin from POMC.
  • TSH (thyrotropes).

• What they are:
  • Pale/colorless cells with few granules.
  • Include non-secretory support cells and "exhausted" secretory cells.
• Clinical note:
  • Most pituitary adenomas appear chromophobic on H&E (functional or non-functional).

4 · Pars intermedia & POMC

• One precursor, many products:
  • ACTH, MSH (α, β, γ), β-endorphin, β-lipotropin.FA 2024 Endo
• Cleavage pattern varies:
  • Anterior pituitary corticotropes cleave POMC mainly to ACTH.
  • Pars intermedia cleaves POMC mainly to MSH (in species that have an active intermedia).

• Primary adrenal insufficiency (Addison):
  • Low cortisol → no negative feedback → ↑ CRH, ↑ POMC.
  • ↑ POMC → ↑ ACTH AND ↑ MSH → cutaneous hyperpigmentation.
  • Classic skin darkening of palmar creases, scars, buccal mucosa.

5 · Clinical pairing — cells to tumors

• Prolactinoma (lactotrope adenoma):
  • Most common functional pituitary adenoma.
  • Galactorrhea, amenorrhea, infertility, ED.
  • Treat with dopamine agonists (bromocriptine, cabergoline).Pathoma 2024 ch 15
• Somatotrope adenoma:
  • Before epiphyseal closure → gigantism (very tall).
  • After epiphyseal closure → acromegaly (enlarging hands/feet/jaw, coarse features, DM, cardiomegaly).
• Corticotrope adenoma:
  • Cushing disease — high ACTH, high cortisol.
• Thyrotrope / gonadotrope adenoma:
  • Rare functional tumors.
• Non-functional adenomas:
  • Often chromophobic; present with mass effect (headaches, bitemporal hemianopsia).
• Craniopharyngioma:
  • Remnant of Rathke's pouch in children.
  • Suprasellar, calcified, "motor oil" cyst fluid.
  • Bitemporal hemianopsia + endocrine dysfunction (commonly GH deficiency, central DI).

1 · The FLAT PiG framework

• Basophils (FLAT):
  • FSH, LH (gonadotropes).
  • ACTH (corticotropes).
  • TSH (thyrotropes).
  • All are "tropic" (go to an endocrine gland).FA 2024 Endo
• Acidophils (PiG):
  • PRL (lactotropes).
  • GH (somatotropes).
  • Both act directly on non-endocrine targets (mammary tissue, liver/bone/muscle).

2 · GH axis — the growth hormone story

• Positive regulators:
  • GHRH (pulsatile from ventromedial / arcuate nuclei).
  • Ghrelin (from stomach).
  • Deep sleep (stages 3/4).
  • Stress, exercise, hypoglycemia.Costanzo 6e ch 9
• Negative regulators:
  • Somatostatin (periventricular nucleus).
  • IGF-1 (long-loop feedback).
  • GH itself (short loop) and hyperglycemia.

• Receptor type:
  • GH binds a JAK-STAT receptor on liver.
  • Induces transcription of IGF-1.FA 2024 Biochem
• Dual effects:
  • Direct: lipolysis, insulin resistance (diabetogenic).
  • Indirect via IGF-1: linear bone growth, muscle/organ growth.

• IGF-1 level:
  • Stable marker (unlike pulsatile GH).
  • First-line screening test for acromegaly.
• Oral glucose suppression test:
  • Normally glucose suppresses GH.
  • In acromegaly, GH fails to suppress → confirms diagnosis.B&B Endo — Acromegaly
• GH deficiency testing:
  • Insulin tolerance test (gold standard) — hypoglycemia should stimulate GH.
  • Arginine or glucagon stimulation test.

3 · PRL axis — the dopamine exception

• Why it's unique:
  • Prolactin is the only anterior pituitary hormone primarily controlled by inhibition rather than stimulation.
  • Tuberoinfundibular dopamine neurons (arcuate nucleus) continuously suppress lactotropes.FA 2024 Endo
• Predictable consequences:
  • Stalk section → no dopamine → ↑ PRL.
  • D2 antagonists (antipsychotics, metoclopramide) → ↑ PRL.
  • Primary hypothyroidism → ↑ TRH → ↑ PRL (TRH is a mild PRL stimulator).

• Suckling:
  • Afferent signal to hypothalamus → ↓ dopamine → ↑ PRL.
• Estrogen:
  • Pregnancy → high estrogen → lactotrope hyperplasia.
  • Postpartum drop in estrogen + suckling → robust milk production.

• Inhibition of GnRH:
  • High PRL suppresses GnRH → ↓ LH/FSH → amenorrhea and infertility (lactational amenorrhea or prolactinoma).

4 · HPT axis — thyroid

• Cascade:
  • TRH (hypothalamus) → TSH (thyrotropes) → thyroid → T3/T4.
  • T3/T4 feed back negatively on pituitary and hypothalamus.Guyton 14e ch 77
• Somatostatin:
  • Also mildly suppresses TSH (not just GH).
• Clinical:
  • Primary hypothyroidism (Hashimoto): low T4 → high TSH.
  • Central hypothyroidism (pituitary or hypothalamic): low T4 with low or inappropriately normal TSH.

5 · HPA axis — cortisol Clinical detail primarily end19 / 20 / 21

• Cascade:
  • CRH → ACTH → adrenal cortex (zona fasciculata) → cortisol.
  • Cortisol feeds back on pituitary and hypothalamus.
• Diurnal variation:
  • Cortisol peaks ~6 am, troughs ~midnight.
  • Used diagnostically (midnight salivary cortisol for Cushing screen).
• ADH synergy:
  • ADH potentiates CRH-driven ACTH release during stress.

6 · HPG axis — gonads

• Cascade:
  • GnRH (pulsatile) → LH + FSH → gonads → sex steroids + inhibin.
• Feedback pattern:
  • Sex steroids usually provide NEGATIVE feedback.
  • Mid-cycle: rising estradiol for ~48 h switches to POSITIVE feedback → LH surge → ovulation.FA 2024 Repro; Costanzo 6e ch 10
• Inhibin B:
  • Released by Sertoli (males) and granulosa (females).
  • Selectively inhibits FSH.

7 · Posterior pituitary — ADH & oxytocin in depth

• V1 (vascular smooth muscle):
  • Gq → IP3/Ca²⁺ → vasoconstriction.
  • Important in hypovolemic shock.
• V2 (renal collecting duct principal cells):
  • Gs → cAMP → aquaporin-2 insertion → water reabsorption.FA 2024 Renal
• V3 (anterior pituitary):
  • Potentiates CRH-induced ACTH release.

• Diabetes insipidus:
  • Central DI: low ADH (posterior pituitary lesion).
  • Nephrogenic DI: kidney unresponsive (V2 or AQP-2 mutation; lithium).
  • Water deprivation test + DDAVP challenge distinguishes.
• SIADH:
  • Excess ADH → dilutional hyponatremia.
  • Causes: small-cell lung CA, CNS lesions, drugs (SSRI, carbamazepine), pulmonary dz.

• Receptor:
  • OT-R (Gq) on uterine myometrium and mammary myoepithelial cells.
• Labor physiology:
  • Cervical stretch → spinal afferents → oxytocin release → stronger contraction (Ferguson reflex, positive feedback).
• Lactation:
  • Suckling → oxytocin release → myoepithelial contraction → milk ejection ("let-down").

1 · Ultrashort loop — hypothalamic autoinhibition

• Axon collaterals:
  • Hypothalamic neurons send collateral branches back onto themselves (and neighboring neurons).
  • These collaterals deliver an inhibitory signal.Guyton 14e ch 75
• Consequence:
  • Once a neuron fires, it temporarily inhibits itself.
  • Creates a pulsatile secretion pattern.

• Prevents target-cell desensitization:
  • Continuous exposure → receptor down-regulation and loss of responsiveness.
  • Pulses give receptors time to recycle/re-sensitize.
• Clinical application — GnRH:
  • Physiologic GnRH pulses every 60–90 minutes → normal LH/FSH output.
  • Continuous GnRH agonist (leuprolide) → chemical castration (prostate CA, endometriosis).
  • Pulsatile GnRH (via pump) → fertility treatment in Kallmann syndrome.FA 2024 Pharm; Lippincott Pharm 7e

2 · Short loop — pituitary on hypothalamus

• Mechanism:
  • The pituitary hormone itself is sensed by the hypothalamus.
  • Reduces further hypothalamic releasing-hormone output.
• Examples:
  • ACTH suppresses CRH.
  • GH suppresses GHRH (and stimulates somatostatin).
  • PRL increases dopamine secretion from tuberoinfundibular neurons (self-inhibition).Costanzo 6e ch 9

3 · Long loop — target organ on hypothalamus + pituitary

• Pattern:
  • The peripheral hormone (the "output" of the axis) feeds back on both the pituitary and the hypothalamus.
• Canonical examples:
  • Cortisol → inhibits CRH and ACTH (HPA).
  • T3/T4 → inhibit TRH and TSH (HPT).
  • Testosterone/estradiol → inhibit GnRH and LH/FSH (HPG, usually negative).
  • IGF-1 → inhibits GHRH and GH.
• Clinical relevance:
  • Exogenous cortisol → suppresses CRH + ACTH → adrenal atrophy.
  • Exogenous thyroid hormone (e.g., surreptitious levothyroxine use) → suppresses TSH.
  • Anabolic steroid abuse → suppresses LH → testicular atrophy.FA 2024 Endo

4 · Positive feedback — rare but critical

• Normally negative:
  • Estradiol normally suppresses GnRH and LH/FSH.
• The switch:
  • Late follicular phase: sustained high estradiol (>200 pg/mL for ~48 h) switches feedback to POSITIVE.
  • Triggers a massive LH surge → ovulation.Costanzo 6e ch 10
• After ovulation:
  • Corpus luteum produces progesterone and estradiol.
  • Negative feedback re-establishes; LH and FSH fall.

• Mechanism:
  • Cervical stretch → spinal afferents → oxytocin release → stronger uterine contraction → more stretch.
  • Self-amplifying cascade that terminates with delivery.

• Mechanism:
  • Suckling → afferent spinal signal → oxytocin release → myoepithelial contraction → milk ejection.
  • Conditioned response (baby's cry can trigger let-down).

5 · Diurnal and cyclic patterns

• Cortisol:
  • Peak ~6 am, trough near midnight.
  • Midnight salivary cortisol — key Cushing screening test.B&B Endo — Cushing
• GH:
  • Largest pulses during deep (slow-wave) sleep.
  • Why chronic sleep deprivation impairs growth.
• TSH:
  • Mild nocturnal peak.
• Menstrual cycle:
  • Estradiol, progesterone, LH, FSH — cyclical, with mid-cycle LH surge.

6 · Testing feedback clinically

• Dexamethasone suppression test:
  • Low-dose: suppresses ACTH in normals; fails in any Cushing.
  • High-dose: suppresses only in pituitary-origin Cushing DISEASE; fails in adrenal tumor or ectopic ACTH.FA 2024 Endo
• ACTH stimulation test (cosyntropin):
  • Tests adrenal response. Normal: cortisol rises. Primary adrenal insufficiency: cortisol fails to rise.
• GnRH stimulation test:
  • Tests pituitary gonadotrope function — LH/FSH should rise after IV GnRH.
• Glucose suppression test for acromegaly:
  • Normally GH suppresses. Fails to suppress in acromegaly.

1 · The predict-it-all framework

• Step 1 — Identify the axis:
  • HPA (cortisol), HPT (thyroid), HPG (gonads), or GH?
• Step 2 — Locate the broken link:
  • Target organ = primary.
  • Pituitary = secondary.
  • Hypothalamus = tertiary.
• Step 3 — Apply feedback logic:
  • If the target hormone is LOW → loss of negative feedback → upstream hormones RISE (unless the upstream is also broken).
  • If the target hormone is HIGH → strong negative feedback → upstream hormones FALL.
• Step 4 — Sanity check downstream:
  • If the lesion is upstream, the downstream hormones follow the driver.
  • E.g., hypothalamic failure → low TRH → low TSH → low T4 (tertiary hypothyroidism).FA 2024 Endo; Costanzo 6e ch 9

2 · HPT axis iterations — the worked examples

• Cascade:
  • Thyroid fails → ↓ T4.
  • No feedback on pituitary/hypothalamus → ↑ TRH, ↑ TSH.
  • Patient: cold intolerance, weight gain, constipation, bradycardia, goiter possible.Pathoma 2024 ch 15
• Collateral effects:
  • High TRH stimulates lactotropes → ↑ PRL → galactorrhea, amenorrhea possible.

• Cascade:
  • Pituitary fails → ↓ TSH → ↓ T4.
  • TRH RISES (loss of T4 feedback).
• Common cause:
  • Pituitary adenoma compressing normal pituitary, Sheehan, apoplexy.

• Cascade:
  • Hypothalamus fails → ↓ TRH → ↓ TSH → ↓ T4.
  • All three are low.

• Mechanism:
  • Stimulating TSH-receptor antibodies → ↑ T3/T4.
  • T3/T4 feedback → ↓ TSH, ↓ TRH.

• Mechanism:
  • Pituitary adenoma secretes TSH → ↑ TSH and ↑ T4 together.
  • A rare but boards-favorite pattern (inappropriate TSH with high T4).

3 · HPA axis iterations

• Cascade:
  • Adrenal destruction (autoimmune, TB, adrenalitis) → ↓ cortisol (and ↓ aldosterone).
  • ↑ CRH, ↑ ACTH; ↑ POMC → ↑ MSH → hyperpigmentation.Pathoma 2024 ch 15; FA 2024 Endo
• Hyponatremia + hyperkalemia:
  • Loss of aldosterone.

• Cascade:
  • Pituitary fails → ↓ ACTH → ↓ cortisol.
  • ↑ CRH (feedback from low cortisol).
  • NO hyperpigmentation (ACTH is low).
  • Aldosterone usually preserved (renin-angiotensin drive is intact).

• Most common cause:
  • Chronic exogenous glucocorticoid use with abrupt withdrawal.
  • Hypothalamus has been suppressed → takes time to recover.

• Primary (adrenal adenoma/carcinoma):
  • ↑ cortisol → feedback suppresses CRH + ACTH.
• Secondary (Cushing DISEASE — pituitary adenoma):
  • ↑ ACTH → ↑ cortisol.
  • High-dose dexamethasone partially suppresses (because corticotropes retain some feedback).
• Ectopic ACTH:
  • Small-cell lung carcinoma, carcinoid.
  • ACTH very high; cortisol very high.
  • High-dose dex does NOT suppress (no feedback on ectopic source).B&B Endo — Cushing
• Exogenous glucocorticoid:
  • Suppresses CRH, ACTH, and endogenous cortisol.
  • "Cushingoid" appearance with atrophic adrenals.

4 · HPG axis iterations

• Primary hypogonadism:
  • Gonadal failure → ↓ testosterone/estradiol.
  • ↑ LH, ↑ FSH.
  • Examples: Klinefelter (XXY, primary testicular failure), Turner (XO, streak ovaries), menopause, orchitis.
• Secondary hypogonadism:
  • Pituitary fails → ↓ LH/FSH → ↓ sex steroids.
  • Pituitary adenoma mass effect, hemochromatosis.
• Tertiary hypogonadism:
  • Hypothalamus fails → ↓ GnRH → ↓ LH/FSH → ↓ sex steroids.
  • Kallmann syndrome (anosmia + delayed puberty).
  • Functional hypothalamic amenorrhea (low energy availability — exercise, anorexia, stress).

5 · Exogenous hormone effects

• Anabolic steroid abuse:
  • ↑ circulating androgens → suppresses GnRH + LH → testicular atrophy, azoospermia, gynecomastia (aromatization to estradiol).
• Oral contraceptives:
  • Estrogen + progestin → suppress GnRH → ↓ LH/FSH → no ovulation.
• Exogenous levothyroxine:
  • Suppresses TSH.
  • Factitious use: ↑ T4, ↓ TSH, no goiter, low radioactive iodine uptake (distinguishing from Graves).
• Chronic glucocorticoids:
  • Suppress HPA → adrenal atrophy → must taper slowly.