• The hypothalamic-pituitary-end organ axis is governed by feedback loops.
• Hypothalamic hormones are released in a pulsitile manner (hence, so are pituitary hormones)
• stimulatory effect on pituitary except for prolactin (dopamine provides tonic inhibition on pituitary release of PL)
• disruption of hypothalamic-pituitary communication Þ Ý PL, ß all other hormones

• Physiological Pituitary Hyperfunction – without pituitary lesion
• failure of the target organ – leads to loss of normal feedback inhibition – e.g., thryroid failure Þ TSH hypersecretion
• chronic hypersecretion can lead to pituitary hypertrophy (reduced to normal with replacement therapy)
• pregnancy – estrogen surges stimulate hypersecretion of lactotrophs (prolactin from the pituitary)
• stress – infection, starvation, etc will alter hormone secretion (especially ACTH; also GH)
• Pathologic Pituitary Hyperfunction – involves hypothalamic-pituitary axis
• pituitary adenoma – most common pituitary pathology (5-15% at autopsy, assymptomatic)
• almost always benign; can grow to be locally invasive
• monoclonal, primarily arise from somatic cells (evidence that they are primary pituitary tumors)
• 85% are functional (secrete hormone): PL (40%); GH (20%); gonadotrophs (15%); ACTH (10%); others rare

Prolactin Hypersecretion – one of most common pituitary hormone abnormalities

• Normal function: prolactin is one of three lactogenic hormones
• promotes production of milk, questionable role in breast and gonadal development
• stimulation: TRH, VIP, seretonin; inhibition: dopamine, somatostatin; modulation: estrogen, glucocorticoids (stim)
• pulsitile release, more at night; women have higher levels due to estrogen; fetus has higher level from mom’s estrogen
• Etiology
• pituitary adenoma – most important to think about, but not the most common cause
• in women: more common, discovered earlier so tend to be smaller Þ more likely to be microprolactinomas
• in men: discovered later because of more insidious symptoms, tend to be larger Þ macroprolactinomas
• hypothalamic disease (Ý PL, ß other pit. hormones) – tumor (primary or metastatic), inflam., infiltrative disease, etc.
• injury to pituitary-hypothalamic communication – compress/disrupt stalk or blood flow
• drugs – dopamine receptor antagonists (i.e. phenothiazines) Þ ß inhibitory effect of hypothalamus on PL secretion
• estrogen (exogenous, endogenous) Þ directly stimulate lactotrophs (prolactin secreting cells)
• chronic hypothyroidism: elevated TRH in hypothyroidism can stimulate pituitary to secrete PL
• Clinical Presentation
• females – amenorrhea (PL inhibits GnRH Þ ß LH Þ ß estrogen), galactorrhea (milk secretion), infertility
• males – ß libido, impotence, ß sperm count (PL inhibits GnRH Þ ß LH Þ ß testosterone); loss of facial hair
• gynecomastia and galactorrhea less common (result of decreased testosterone)
• both – hypogonadism leads to decreased bone mass; adenoma can cause headaches, visual symptoms (mech effects)
• Diagnosis
• clinical signs and prolactin levels most important (some overlap, but PL > 200 m g/L Þ prolactinoma)
• CT or MRI used to diagnose adenoma
• Treatment
• treatment strategy determined by tumor size
• microprolactinomas – treatment only symptoms indicate (i.e. infertility)
• macroprolactinomas (> 1 cm) – should always be treated due to risk of local invasion/compression
• drugs – dopamine antagonists (i.e. bromocriptine) are 85-95% effective, but Sx return when drug discontinued
• surgery – good success rate (60-70%)
• radiation – almost never used, since it can result in hypopituitarism; also lower success rate

Growth Hormone (Somatotropin) Hypersecretion – acromegaly in adults; gigantism in children

• Regulation – GH is regulated by GHRH (stimulates secretion) and somatostatin (inhibits secretion)
• Normal Function – GH has direct and indirect action
• direct action – insulin resistance, lipolysis, ketogenesis, Na⁺/water retention, hyperglycemia
• indirect action – stimulation of Insulin-like Growth Factor 1 (IGF-1); produced in many cells, but mainly liver
• mediates all growth promoting effects of GH: cell prolif, Ý aa transport, Ý protein synth and muscle mass, etc
• Etiology
• GH secreting tumor – most common, accounts for 20% of pituitary adenomas
• most are macroadenomas (> 1 cm); diagnosis at any age, most common 40-60 yrs
• ectopic secretion of GHRH – rare; causes pituitary hyperplasia; once tumor is removed, patient returns to normal
• Clinical Presentation
• excessive bone growth – length if open physis leading to gigantism, width if closed physis leading to acromegaly
• connective tissue proliferation – extracellular matrix proliferation, intercellular edema
• soft tissue swelling of hands and feet – rings, hats, gloves, shoes Ý in size dramatically
• coarse facial features – large nose and lips; mandible overgrows and protrudes (prognathism)
• coarse body hair and excessive sweating
• enlarged tongue – sleep apnea (apnea also has some central component – unknown contribution)
• edema and larynx growth in larynx – deepening of voice
• hypertension, CHF, diabetes, hypogonadism
• symptoms of hyperprolactinemia – since GH can also stimulate PL receptors
• mechanical effects of tumor – headaches, impaired vision, interference with secretion of other hormones
• early death – due to CV, neoplasms, sleep apnea
• Diagnosis – mainly made through physical appearance and measurement of GH
• dynamic GH measurement (basal level is useless) – GH should drop upon glucose challenge (gold standard)
• can also measure IGF-1
• CT or MRI to diagnose tumor
• only way to distinguish between ectopic GHRH and adenoma is to measure GHRH levels
• Treatment
• drugs
• dopamine receptor agonists – suppress GH, but not as well as they supress PL (30% effective)
• somatostatin analogs (octreotide, sandostatin) – longer duration of action than somatostatin itself
• 65% of patients return to normal IGF-1; ß tumor size by 1/3 in 30-50% of patients
• GH receptor antagonists – new treatment; normalizes IGF-1 in 90% of patients; no change in GH level or tumor size
• surgery – 50% effective
• radiation – dangerous to rest of the gland; takes years for effects to be noticed