Hypothalamic-Pituitary Axis

Hypothalamic control and feedback

The command chain. Hypothalamic neurons release their hormones into capillaries at the median eminence, and the hypophyseal portal veins carry them directly to the anterior pituitary, whose cells in turn drive the target glands. Target-gland products (cortisol, thyroid hormone, sex steroids, IGF-1) feed back negatively on both the hypothalamus and the pituitary.

• TRH → TSH, and also prolactin
• CRH → ACTH
• GnRH → FSH and LH; pulsatile GnRH stimulates them, whereas continuous exposure (leuprolide) suppresses them
• GHRH → GH
• Somatostatin inhibits GH and TSH
• Dopamine tonically inhibits prolactin

Reading feedback. Failure of a target gland raises its pituitary hormone (primary hypothyroidism: high TSH), whereas pituitary or hypothalamic failure lowers both the trophic and the target hormone (low TSH with low free T4).

Dopamine keeps prolactin down. Prolactin is the one anterior pituitary hormone held mainly under inhibitory control, by tonic hypothalamic dopamine. Prolactin itself suppresses GnRH, lowering FSH and LH and causing amenorrhea, infertility and low libido. TRH stimulates prolactin, so primary hypothyroidism (high TRH) can raise it. Anything that removes the dopamine brake raises prolactin: D2-blocking antipsychotics, metoclopramide, and any sellar mass that compresses the stalk (the "stalk effect"). Dopamine agonists (cabergoline, bromocriptine) lower it.

This is why antipsychotics cause galactorrhea and why primary hypothyroidism can mimic a prolactinoma; a large mass with only a modest prolactin rise suggests stalk compression rather than a prolactinoma.

Anterior and posterior pituitary

Anterior pituitary. The adenohypophysis arises from Rathke pouch, an upgrowth of oral ectoderm, and secretes FLAT PiG: FSH, LH, ACTH, TSH, Prolactin, GH. Basophils make the FLAT hormones; acidophils make GH and prolactin. Its blood arrives through the portal system rather than direct arteries. TSH, LH, FSH and placental hCG share a common α subunit, with the β subunit conferring specificity. ACTH is cleaved from POMC, which also yields MSH, so high-ACTH states can darken the skin.

B-FLAT: Basophils make FSH, LH, ACTH, TSH; the acidophils make GH and prolactin.

Posterior pituitary. The neurohypophysis is neural ectoderm and synthesizes no hormones of its own. ADH (mainly supraoptic nucleus) and oxytocin (mainly paraventricular nucleus) are made in hypothalamic neurons, transported down their axons, then stored and released here. ADH inserts aquaporin-2 channels in the collecting duct through V2 receptors; oxytocin drives milk letdown and uterine contraction.

Pituitary adenomas and mass effect

Prolactinoma. The most common pituitary adenoma. Women present early with amenorrhea, galactorrhea and low libido; men present later with erectile dysfunction or mass effects, so their tumors are larger at diagnosis. Large tumors compress the optic chiasm, as in a young woman with galactorrhea, amenorrhea and failing peripheral vision. Unlike most tumors, even a macroadenoma is treated medically first: a dopamine agonist (cabergoline, or bromocriptine) both lowers prolactin and shrinks the tumor. Surgery is reserved for resistance or intolerance.

Acromegaly. A GH-secreting adenoma after epiphyseal closure enlarges the hands, feet and jaw (rings and shoes stop fitting), coarsens the features and causes macroglossia and organomegaly; before closure it causes gigantism. GH acts largely by raising hepatic IGF-1 and is diabetogenic, so insulin resistance, diabetes, hypertension, sweating, carpal tunnel syndrome and sleep apnea are common. Because GH is pulsatile, a random level is unhelpful: screen with IGF-1 and confirm by failure of an oral glucose load to suppress GH. Cardiac disease is the leading cause of death. Persistent disease after surgery is treated with octreotide (somatostatin analog) or pegvisomant (GH receptor antagonist).

Cushing disease. An ACTH-secreting pituitary adenoma is the most common cause of endogenous Cushing syndrome. Excess ACTH drives bilateral adrenal cortisol output: central obesity, moon facies, striae, hypertension and hyperglycemia. The adenoma retains partial feedback, so high-dose dexamethasone suppresses a pituitary source but not ectopic ACTH. If bilateral adrenalectomy is performed instead, the unchecked adenoma can enlarge and cause hyperpigmentation (Nelson syndrome).

Bitemporal hemianopia. An adenoma growing upward compresses the optic chiasm, where the crossing nasal retinal fibers carry the temporal visual fields, knocking out both temporal fields. It is the classic visual sign of any macroadenoma (≥1 cm) or craniopharyngioma. Lateral spread into the cavernous sinus can affect cranial nerves III, IV, V1, V2 and VI.

Hypopituitarism

Causes and pattern. Hypopituitarism follows mass lesions, surgery, radiation, apoplexy, Sheehan syndrome or an empty sella (arachnoid herniation of CSF flattening the gland, often an incidental finding). GH is usually the first axis lost, followed by the gonadotropins; ACTH loss is the most dangerous.

Craniopharyngioma. The classic childhood sellar mass arises from Rathke pouch remnants. It is calcified, with cystic "motor-oil" fluid rich in cholesterol crystals, and causes bitemporal hemianopia and growth failure; hypothalamic involvement can add central DI. It has a bimodal age peak (children and older adults) and is the most common childhood supratentorial tumor.

Sheehan syndrome. Ischemic necrosis of the pituitary after postpartum hemorrhage. The gland enlarges in pregnancy through lactotroph hyperplasia but its blood supply does not, so peripartum hypotension infarcts it. It presents with failure to lactate (low prolactin), amenorrhea, fatigue, hypotension and cold intolerance, with low free T4 alongside low TSH and low morning cortisol.

Pituitary apoplexy. Sudden hemorrhage into a pituitary adenoma causes thunderclap headache, vision loss or ophthalmoplegia (cavernous sinus compression), and acute adrenal crisis from abrupt loss of ACTH and cortisol. It is an endocrine emergency requiring immediate stress-dose glucocorticoids, with surgical decompression for worsening vision.

In any patient with hypopituitarism, replace glucocorticoid before thyroid hormone: levothyroxine speeds cortisol clearance and can precipitate adrenal crisis.

Diabetes insipidus

Definition. DI is polyuria with dilute urine and a rising serum sodium, from either too little ADH (central) or a kidney that cannot respond to it (nephrogenic).

Nephrogenic DI therapy. Thiazides work paradoxically: mild volume contraction increases proximal sodium and water reabsorption, so less filtrate reaches the collecting duct. Amiloride blocks the ENaC channel through which lithium enters principal cells, making it the natural choice for lithium-induced DI; NSAIDs such as indomethacin also reduce urine output.

SIADH is the mirror image of DI: excess ADH produces inappropriately concentrated urine and euvolemic hyponatremia.