Pituitary Hormone Agents

Somatostatin (growth hormone–inhibiting hormone) is made in the gut, pancreas, hypothalamus and brain. It inhibits secretion of growth hormone, TSH, prolactin, insulin, glucagon and many gut hormones, and it slows bile flow and pancreatic enzyme secretion. Its five receptor subtypes are G protein–coupled; activating them lowers intracellular cAMP and calcium, so the target tissue secretes less. Because natural somatostatin has a short half-life, longer-acting analogs are used.

Octreotide acts like somatostatin but is an even more potent inhibitor of growth hormone, glucagon and insulin; it also inhibits serotonin, gastrin, VIP and other gut hormones. That is why it treats acromegaly (lowering GH and IGF-1), the flushing and diarrhea of metastatic carcinoid tumors, and the watery diarrhea of VIPomas. Lanreotide binds mainly somatostatin receptors 2 and 5; it is used long term in acromegaly, in carcinoid syndrome, and to improve progression-free survival in unresectable gastroenteropancreatic neuroendocrine tumors. Octreotide also comes as an oral capsule (Mycapssa) for maintenance in acromegaly, taken on an empty stomach.

The harms follow from switching hormones off. Less gallbladder contraction and bile secretion → gallstones and sludge. Upsetting the balance of insulin, glucagon and growth hormone → hypoglycemia or hyperglycemia. Suppressed TSH → hypothyroidism. Less pancreatic enzyme and bile acid → steatorrhea. Octreotide and lanreotide can also slow the heart (bradycardia, conduction abnormalities).

Growth hormone acts directly on its receptors and indirectly through IGF-1, which the liver secretes in response to it. Somatropin is recombinant human growth hormone. In children it stimulates linear growth at the epiphyseal plates, and it is labeled for growth failure from growth hormone deficiency, Prader-Willi syndrome, small-for-gestational-age birth, Turner syndrome and idiopathic short stature; in adults it replaces growth hormone in growth hormone deficiency.

Its warnings follow from growth hormone’s actions. It opposes insulin, so glucose intolerance or diabetes may be unmasked. It can cause fluid retention (edema, arthralgia, carpal tunnel syndrome), intracranial hypertension, and in children slipped capital femoral epiphysis and progression of scoliosis. It can unmask hypothyroidism and, because it inhibits the enzyme that activates cortisone (11βHSD-1), hypoadrenalism. It is contraindicated in acute critical illness, active malignancy, active proliferative or severe non-proliferative diabetic retinopathy, children with closed epiphyses (for growth), and children with Prader-Willi syndrome who are severely obese or have severe respiratory impairment — sudden deaths have been reported.

In acromegaly the problem is the reverse: too much growth hormone and IGF-1. Pegvisomant (Somavert) binds the growth hormone receptor and blocks endogenous GH, so IGF-1 falls — and IGF-1 is the marker followed, since GH levels may rise and pegvisomant cross-reacts in GH assays. It can elevate liver tests, so liver tests are checked before and during treatment, and as GH action falls glucose tolerance may improve, causing hypoglycemia in patients on diabetes drugs.

Prolactin secretion by the anterior pituitary is tonically inhibited by dopamine from the hypothalamus. Cabergoline and bromocriptine are ergot-derived dopamine agonists: cabergoline has high affinity for D2 receptors and directly inhibits prolactin secretion, and bromocriptine inhibits prolactin and lowers growth hormone in most patients with acromegaly. Cabergoline treats hyperprolactinemic disorders, idiopathic or from pituitary adenomas; bromocriptine treats hyperprolactinemia-associated dysfunction, prolactin-secreting adenomas and acromegaly (and Parkinson disease, on the antiparkinson nursing class). For prolactinomas cabergoline is generally preferred.

A once-morning bromocriptine product, Cycloset, is labeled for type 2 diabetes as an adjunct to diet and exercise; timed morning dosing is associated with increased insulin sensitivity and reduced hyperglycemia without raising insulin.

The shared ergot risks are cardiac valvulopathy and pericardial, pleural, pulmonary or retroperitoneal fibrosis — an echocardiogram is done before treatment and repeated during it — plus orthostatic hypotension, impulse control disorders (gambling, spending, sexual urges), and with bromocriptine somnolence and sudden sleep. Neither is used to suppress postpartum lactation: that use of bromocriptine was linked to hypertension, stroke, myocardial infarction, seizures and death.