Hypopituitarism (Panhypopituitarism) Workup

Hormonal studies should be performed in pairs of target glands and their respective stimulatory pituitary hormone for proper interpretation, as follows ^[3] :

• ACTH (Cortrosyn) stimulation test (or morning cortisol and ACTH)

• TSH and thyroxine (free T4)

• FSH, LH, and either estradiol (if amenorrheic) or morning testosterone (as appropriate for gender)

• Prolactin

• GH provocative testing with various stimulation tests

• IGF-1 levels

Corticotropin deficiency may be evident with the finding of a decreased serum cortisol level. However, a low cortisol level may not help to distinguish primary adrenal insufficiency from secondary adrenal insufficiency due to hypopituitarism. The conditions can be differentiated on clinical grounds. A patient with secondary causes due to pituitary dysfunction has a relatively pale complexion (not hyperpigmented), a normal aldosterone response, normal serum potassium, and low/normal morning ACTH level, measured in the morning due to its highest circadian levels. Hyponatremia may occur.

The opposite is true for primary adrenal insufficiency. Hyperpigmentation in primary adrenal insufficiency is due to increased ACTH production with concomitant overproduction of melanocyte-stimulating hormone, which is coupled with ACTH in a mutual precursor. ACTH elevation, measured any time, suggests an adrenal etiology. Hyperkalemia may be present, owing to concomitant aldosterone deficiency, which does not occur with ACTH insufficiency. Hyponatremia may result from cortisol insufficiency, and thus does not separate pituitary from adrenal disease.

Histologic findings in hypopituitarism depend on etiology (eg, tumors, infiltrations, infections, empty sella). Other tests to ascertain the likely underlying etiology are indicated by the patient's presentation.

The ACTH stimulation test, which evaluates the hypothalamic-pituitary-adrenal axis, is a superior tool in the diagnosis of adrenal insufficiency, but it does not generally separate pituitary from adrenal causation. This dynamic test measures serum cortisol levels before and after a 1- or 250-mcg dose of ACTH. The cortisol level should be greater than 500 pmol/L (may be  less in some assays) 30 minutes after ACTH administration in patients with normal adrenal function.

A low cortisol level that fails to rise after ACTH administration represents an abnormal cortisol response, a response seen in primary adrenal insufficiency. However, because of adrenal atrophy with chronic ACTH insufficiency, the cortisol response is often abnormal in patients with hypopituitarism. A poor response requires the serum ACTH, or other clinical clues, to separate pituitary from primary adrenal disease.

Other provocative tests for ACTH/cortisol function are the insulin-induced hypoglycemia test and the glucagon stimulation test. These may be needed within the acute stage of ACTH deficiency, such as following pituitary surgery.

Assessment of thyroid function is important in the evaluation of ACTH deficiency. In a hypothyroid state, cortisol clearance decreases, causing an increase in the serum cortisol level. If thyroid replacement is initiated, the cortisol level may be inappropriate to the new state, initiating an adrenocortical crisis.

In suspected TSH deficiency, measure serum TSH and thyroxine. A normal level of total free T4 rules out hypothyroidism. A low thyroxine and low/normal serum TSH and a small, soft thyroid gland confirm the diagnosis of TSH deficiency.

LH and FSH deficiencies may indicate secondary hypogonadism. Elevated FSH and LH levels differentiate primary hypogonadism from secondary hypogonadism. A low testosterone level in a man, or an amenorrheic woman with low estradiol and low/normal serum FSH/LH, indicates secondary hypogonadism.

In men, measuring testosterone levels is useful, if properly performed. A decreased testosterone level should be associated with an increase in FSH and LH levels if pituitary function is normal. Low or normal FSH or LH levels in the face of low testosterone indicate hypopituitarism. Serum testosterone is best measured early in the morning owing to a diurnal rhythm that falls through the day. There may be other causes of a low testosterone level, such as poor nutrition, stress, hyperprolactinemia, or chronic opioid use. A low level of sex hormone binding protein may give a low total testosterone level (but with the free testosterone level being normal). A finding of low total testosterone needs to be confirmed with a repeat test, which should include a measurement of non-protein-bound (free) testosterone.

Semen analysis also may be performed. A normal semen sample usually excludes hypogonadism from a primary or secondary source. Semen analysis is performed only if fertility is being considered.

GH provocative testing and prolactin testing

Given that GH secretion is pulsatile and low in most adults through most of the day, a single low serum level cannot be interpreted, whereas a single elevated or normal serum GH level can exclude the diagnosis of GH deficiency. Best is a provocative test for GH secretion. The serum IGF-1 may be useful for GH deficiency in children but not in adults, as up to a third of adults with proven GH deficiency by provocative testing may have a normal serum IGF-1. There are various GH stimulation tests, with glucagon and hypoglycemia being the most definitive. GH-releasing hormone (GHRH) for such testing is difficult to obtain.

Prolactin deficiency can also be verified by directly measuring serum levels. As with most other pituitary hormones, secretion of prolactin is episodic; more than 1 value is necessary for diagnosis. However, testing is rarely necessary since most patients are asymptomatic, and the results are not clinically relevant unless a woman wishes to lactate.

A water deprivation test can help to differentiate psychogenic polydipsia from diabetes insipidus and nephrogenic diabetes insipidus. Supervise patients constantly to inhibit water intake, as patients with psychogenic polydipsia often use any means possible to consume water (eg, drinking from a toilet bowl). While withholding water, take urine samples hourly to measure urine osmolalities, with serum osmolarity measured at the beginning and end.

If the cause is psychogenic, urine osmolality increases while serum osmolality remains normal. If urinary concentrations do not increase in a water deprivation test, despite the rise in serum osmolarity, the diagnosis of diabetes insipidus is established (central or nephrogenic).

At the time of stability of the urine osmolarity, a vasopressin stimulation test may assist in discriminating between central and nephrogenic diabetes insipidus. Administer either 5 units of aqueous vasopressin or 1-2 mcg of desmopressin (DDAVP) subcutaneously. After 1 hour, acquire an additional set of serum and urine specimens. An increase in urine osmolality and a decrease in serum osmolality support a central cause of diabetes insipidus and a lack of arginine vasopressin (AVP). If osmolalities remain unchanged, the patient has nephrogenic diabetes insipidus (resistance to AVP).

This test is with some limitations in interpretation, so added serum measurements of AVP or copeptin (the C terminus of the vasopressin precursor) may improve test interpretation.

A study by Li et al concluded that magnetic resonance imaging (MRI) findings can be correlated with pituitary function and can provide evidence of multiple pituitary hormone deficiencies. The study included 96 pituitary hormone ̶ deficient children and 90 controls. The authors used MRI findings from the hypothalamic-pituitary region to divide the hormone-deficient patients into 5 stages. Based on serum concentrations of ACTH, cortisol, GH, insulinlike growth factor-1 (IGF-1), free T4, TSH, FSH, LH, testosterone, estradiol, and prolactin in the patients and controls, a positive correlation was found between the MRI-based stages and the number of pituitary hormone deficiencies in patients. ^{[23, 24]}  However, MRI does not eliminate the need for appropriate biochemical testing.

In the presence of clinical or biochemical evidence of hypopituitarism, visualization of the sellar/suprasellar areas is needed to identify the nature of the causative disease process. This is best performed through computed tomography (CT) scanning or MRI. The presence of a mass with hormonal hypersecretion indicates that it is likely a secretory pituitary adenoma. In the absence of hypersecretion, any mass/infiltrate may be of unknown etiology, but certain characteristics on CT scanning/MRI may suggest the pathologic cause in some cases. The presence of a lesion requires correlation with the clinical/biochemical data, and the absence of any visible lesion suggests a nonorganic cause in most cases.