Neuroendocrinology and pituitary

Question 1

SIADH

Answer 1

Causes

Drugs

Certain drugs enhance release or effects of ADH. These inc chlorpropamide (increases # of ADH receptors in tubules), carbamazepine, oxcarbazepine, high dose IV ciclophosphamide (patients are also given lots of IVFT which can lead to severe hypoNa), SSRI’s, vincristine, cisplatin, haloperidol, amitriptyline, MAOI’s, melphalan, MTX, opiates, NSAIDs, amiodaron, ciproflox, high dose imatinib, ecstasy

Question 2

Pituitary - Growth hormone

Answer 2

IGF-1

IGF-1 is a peptide hormone that mediates most of the biological actions of growth hormone. Circulating IGF-1 is principally composed of endocrine IGF-1 produced in the liver under GH stimulation. A small amount of autocrine IGF-1 is also produced in peripheral tissues (such as in bone) and can be controlled by other factors released from surrounding cells. IGF-1 has a very high affinity for binding proteins (IGFBPs) and circulates in a ternary complex, bound to IGFBP-3 and the acid-labile subunit. It exerts its effect by activation of the IGF-1 receptor which is widely distributed in many tissues

Question 3

Pituitary - Growth hormone deficiency

Answer 3

Growth hormone deficiency

Causes: pituitary tumor, post surgical/radiotherapy, craniopharyngioma (extra-pituitary), sarcoidosis, Sheehan syndrome.

Other risk fx: hypothalamic pituitary disease, cranial radiotherapy, head injury, other clinically or biochemically detectable pituitary hormone abnormalities

Clinical presentation:

• short stature
• decrease lean body mass, BMD, increase fat mass, increase fractures
• fatigue, poor exercise capacity, abdominal obesity, and impaired psychosocial function.
• panhypopituitarism

Diagnosis

• Random GH measurements is unhelpful as GH has pulsatile release during the day.
• 24hour serum GH profile. Useful only if using highly sensitive assay for GH. Time / resource consuming.
• 24hour urine GH: 90% sensitivity but low specificity, esp in older adults (sensitivity ranges from 36-79%)
• IGF-1 levels can be measured as they remain stable during the day. But IGF-1 is low in malnutrition, hypothyroidism, diabetes, renal failure, cancer. Studies suggest sensitiviity 84%, specificity 76%, PPV 84%, NPV 76%. IGF-1 levels must be measured according to their age/gender. Serum IGF-1 and or IGFBP-3 can be normal in patients with GHD. Low IGF-1 in the presence of panhypopituitarism is highly suggestive of GHD (no provoc test req). If IGF-1 is equivocal, or if other factors present, must proceed to provocation tests.
• IGFBP-3 levels are stable during the day (IGFBP-3 is the major serum carrier for IGF-1). In kids, it is a better screening test than IGF-1.

Provocation tests still remain the most useful test for GH deficiency, and is required in most cases. If IGF-1 was normal, pts often need 2 x abnormal provocation tests to confirm diagnosis (no provoc test is 100% specific).

International consensus guidelines have converged around the insulin tolerance test and the growth-hormone releasing hormone (GHRH) + arginine test (combined test) as the best available test of GHD in adults, providing sufficient sensitivity and specificity to establish a reliable diagnosis when appropriate cutoffs are used. The glucagon stimulation test is a second-line test but is nonetheless well validated for assessing GH secretory capacity when first line tests are unavailable or contra-indicated. Other tests are available but less well validated.

Provocation tests:

• insulin tolerance test “gold standard” –> IV insulin (0.15u/kg) induces hypoglycemia which is a potent stimulator of GH. Measure GH 15-30minutely for 2hrs. This stimulation test has highest diagnostic accuracy but is not safe in pts with hx of seizure or heart disease, and not well tolerated by pts so adequate hypo isn’t always achieved. Resource heavy.
• arginine and GHRH (GH releasing hormone) stimulation test. Recommended if available, better tolerated. Bolus of IV GHRH + arginine infusion over 30min; serial GH measurements. Falsely normal in pts with secondary GHD. So therefore this test involves combining GHRH with clonidine to create stronger stimulus
• macimorelin stimulation test (can be performed if GHRH not available). Macimorelin stimulates GH release. This test has 92% sensitivity, 96% specificity, 97% reproducibility.
• glucagon stimulation test (If GHRH or macimorelin not available). Reliable, safe alternative. IM glucagon; test GH 30minutely; cut-off is <3ng/ml. Can induced nausea. Reasonable sensitivity / specificity

Results of provocation tests can be falsely positive in obese ppl.

Should also test for panhypopituitarism (low TSH, ACTH, gonadotropins) and hypothalamic disease.

Prognosis

• reduced life expectancy despite replacement of hormones
  https: //www.ncbi.nlm.nih.gov/pmc/articles/PMC3412109/

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