Pediatrics

Hypopituitarism, congenital and acquired

OVERVIEW: What every practitioner needs to know Are you sure your patient has hypopituitarism? What are the typical findings for hypopituitarism?

Hypopituitarism or pituitary hormone deficiency is a condition in which one or more of the pituitary hormones is are deficient. The pituitary, which plays an important role in regulation of growth, development, and metabolism, consists of both an anterior and posterior lobe that are embryonically derived from both the oral ectodermal and neuroectodermal tissues. The anterior pituitary consists of five major cell types, each producing a specific hormone (noted in brackets): somatotrophs (growth hormone [GH]), thyrotropes (thyroid stimulating hormone (TSH), gonadotropes (luteinizing hormone [LH] and follicle-stimulating hormone (LH, [FSH]), corticotropes (adrenocorticotrophic hormone (ACTH]) and lactotropes (prolactin (Prl).

The posterior pituitary consists of axonal projections of neurons from the hypothalamus that secrete vasopressin and oxytocin. The presenting symptoms of pituitary hormone deficiency are dependent on which hormones are deficient. A complete history, including a review of systems, and physical examination will often provide clues regarding the presence of pituitary hormone deficiency.

Findings such as poor growth, absent sexual development or midfacial dysmorphism can assist the clinician in making a diagnosis. In addition, the measurement of specific hormone levels, whether random or through iatrogenic stimulation, will help determine hormone deficiency. Finally, a radiologic evaluation with MRI will often identify structural pituitary abnormalities or rule out secondary causes of pituitary dysfunction.

Although the provider may have suspicion of specific hormone deficiencies, in clinical practice a complete pituitary evaluation is undertaken because some hormone deficiencies may have subtle clinical findings. Once a deficiency has been diagnosed, the appropriate hormone replacement is prescribed.

The signs and symptoms of pituitary hormone deficiency are typically variable and insidious; the clinical presentation is dependent on which hormones are deficient as well as on the age of the patient. Quite often the clinical history can alert the provider of a patient's risk for hypopituitarism, especially if there is a history of neurologic insult or evidence of poor growth and/or development.

These signs and symptoms have been outlined based on age as follows.

Neonates

Hypoglycemia

Micropenis

Conjugated hyperbilirubinemia

Adrenal crisis secondary to hypocortisolism (vomiting, hypotension)

Failure to thrive

Midline defects (cleft palate)

Neurodevelopmental abnormalities (septo-optic dysplasia, holoprosencephaly)

Polyuria

Polydipsia

Dehydration with hypernatremia

Child/adolescent

Reduced growth velocity/short stature

Pubertal delay/no pubertal development

Central obesity

Delayed dentition

Adrenal insufficiency/crisis secondary to hypocortisolism (nausea, vomiting, hypotension),

Fatigue

Signs of diabetes insipidus (DI): polyuria, polydipsia, dehydration with hypernatremia

What other disease/condition shares some of these symptoms?

Neonate: prematurity, neonatal jaundice, sepsis, isolated growth hormone deficiency (IGHD), primary congenital hypothyroidism, nephrogenic DI

Infant/child: IGHD, failure to thrive, primary hypothyroidism, delayed puberty, Kallman syndrome, Addison disease, nephrogenic DI

What caused this disease to develop at this time?

The development of hypopituitarism is most often acquired secondary to neurologic insult, including head injury/trauma (this may include birth trauma), diseases such as autoimmune lymphocytic hypophysitis, infections (meningitis, tuberculosis, syphilis), infiltrative disorders (tumors), and iatrogenic neurologic insult (cranial radiotherapy, neurosurgery).

Furthermore, idiopathic or congenital forms also exist for which no cause of hormone deficiency can be identified. More commonly these patients present as neonates or infants. These congenital forms of hypopituitarism have been associated with genetic abnormalities in several developmental factors that are necessary for appropriate pituitary development and function.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

If there is suspicion of one or more deficiencies of pituitary hormones, a complete pituitary evaluation including pituitary imaging is recommended. This evaluation initially involves the measurement of pituitary hormone levels:

Growth hormone axis: Insulin growth factor 1 (IGF-1) and IGF binding protein 3; if low, confirmation of GH deficiency requires a GH stimulation test using two provocative agents by recommendation of an endocrinologist.

Thyroid axis: total T4 or free T4 (TSH is not useful in this circumstance)

Adrenocorticotropic hormone (ACTH): A cortisol level drawn at 8 AM can screen for adrenal insufficiency. A more complete evaluation of the axis should include an ACTH stimulation test. Initially, the cortisol level is measured at time 0 minutes (baseline) followed by the administration of ACTH (1 µg or 250 µg). Subsequent cortisol levels are checked at 30 and 60 minutes.

Typically a baseline or rise in cortisol level greater than or equal to 18 µg/dL suggests normal adrenal function. At present, there still exists some controversy as to which dose of ACTH (1 µg or 250 µg) is most sensitive for adequately determining adrenal insufficiency or sufficiency. In general, the utility of the 1 µg ACTH stimulation appears more appropriate in patients with secondary adrenal insufficiency or those with a suspected recent loss of ACTH production. Consultation with a pediatric endocrinologist is recommended before performing this test.

Pubertal axis: The lack of any signs or failure to progress through pubertal development by a certain age in boys (14 years) or girls (13 years) may warrant evaluation. The measurement of LH and FSH along with testosterone (boys) or estrogen (girls) levels are checked at 8 AM. If levels are undetectable, a gonadotropin-releasing hormone stimulation test can be administered by an endocrinologist to verify a rise in gonadotropin levels; a lack of rise in levels suggests central hypogonadism.

Prolactin level

In addition to evaluating hormone levels, there are other laboratory test results that suggest pituitary dysfunction.

Serum and urine osmolarity:A high serum osmolality with a low or low/normal urine osmolality is suggestive of DI. A water-deprivation test is the gold standard, but this should be performed only in a closely monitored setting.

Metabolic panel: electrolyte disturbances (hyponatremia, hyperkalemia), hyperbilirubinemia, hypoglycemia

Would imaging studies be helpful? If so, which ones?

Magnetic resonance imaging is the most sensitive study to evaluate the pituitary.

Confirming the diagnosis

When hypopituitarism is suspected or confirmed, a complete pituitary evaluation should be completed. Although some patients may present with only one or two hormone deficiencies, the development of hypopituitarism is both variable and dynamic in regard to the cell type and timing of hormonal deficiencies.

Investigating the follow-up for hormonal deficiencies is highly dependent on the cause, which may affect the likelihood and timing of future hormonal deficiency. For example, a postoperative patient with a sudden development of DI that is acute versus a patient who has received high-dose radiation and pituitary hormonal injury that may not manifest with hormonal deficiency for months to years after treatment.

If you are able to confirm that the patient has hypopituitarism, what treatment should be initiated?

Therapy is directed at correcting specific hormone deficiencies.

Immediate treatment is indicated in the following situations:

Adrenal crisis presenting with hypotension, electrolyte abnormalities and/or hypoglycemia: hydrocortisone in doses equivalent to 50-100 mg/m2/dose intramuscularly/intravenously is given during crisis or times of severe illness when an oral dose is typically not recommended or tolerated. Acutely, electrolyte imbalances and hypoglycemia can be addressed with appropriate resuscitation fluids.

DI: In patients presenting with severe hypernatremia, care must be taken to ensure a slowly controlled return to normal sodium levels using intravenous saline fluids. Typically these patients are moderately to severely dehydrated. In addition, for ongoing urine output, control can be achieved with vasopressin or DDAVP by intravenous, subcutaneous, oral, or intranasal routes. This type of resuscitation should typically be accomplished in an emergency room or hospital setting to ensure adequate observation and reassessment.

GHdeficiency (with associated hypoglycemia): Acutely this may be treated with intravenous dextrose-containing fluids. Resolution of this symptom in neonates requires initiating treatment with recombinant human GH injections.

Hormone replacement (in nonacute settings):

GHdeficiency: Treatment with subcutaneous injections of recombinant human GH injections. Dosage adjusted by monitoring growth velocity and IGF-1 levels. Treatment is typically continued until patient is postpubertal and growth has ceased.

Adrenal insufficiency: Maintenance dosing of hydrocortisone is 6-10 mg/m2/d orally divided twice daily (BID) or three times daily (TID). In times of stress (fever, illness, minor trauma), the hydrocortisone dose is increased to 50-75 mg/m2/d orally divided BID or TID until the illness resolves or the patient is afebrile for at least 24 hours. If the patient is unable to tolerate an oral stress dose (e.g., gastroenteritis or unconscious), hydrocortisone intramuscular injection (50-100 mg) should be administered. Recommendations should be for patient to seek further clinical evaluation. Treatment for this deficiency is lifelong.

Gonadotropin deficiency: At an age usually associated with puberty, estradiol for girls or testosterone for boys can be titrated to induce puberty. Serum levels of either testosterone or estradiol in boys and girls, respectively, can be used to titrate and monitor therapy. Currently, the options for testosterone replacement include intramuscular, transdermal, or topical preparations. In regard to estrogen replacement, both oral and transdermal preparations are available.

Thyroid hormone deficiency: Treatment is accomplished with oral levothyroxine replacement with dose adjustments made based on total T4 or free T4 serum levels. Treatment for this deficiency is lifelong.

Initial starting dosing for patients is typically based on age. A guideline to treatment is given below. The provider must note that these are simply guidelines for initiating replacement treatment. Appropriate treatment of hypothyroidism is dependent on both the reevaluation of patients who have started treatment and follow-up periodic thyroid function tests. This will determine if replacement is both appropriate and sufficient.

AgeDose (µg/kg/d)

Neonates 10-15

1-3 years 4-6

3-10 years 3-5

10-16 years 2-4

Adults 1-2

DI: A daily maintenance dose of DDAVP by the oral or intranasal route every day BID is prescribed to avoid dehydration and hypernatremia from free water loss. Patients with an intact thirst mechanism should be allowed to drink freely because this is a safer way to assist in regulating one's hydration status and the body's free water. Dosing of DDAVP should allow for breakthrough urination, although not excessive to negatively impact the patient's activities of daily life. More importantly, dehydration can potentially develop quickly in patients who are completely deficient in vasopressin.

What are the adverse effects associated with each treatment option?

Adrenal insufficiency: Overtreatment with hydrocortisone may result in iatrogenic cortisol excess, which leads to diminished linear growth, excess weight gain, and decreased bone mineral density. In turn, undertreatment can lead to symptoms of adrenal insufficiency (fatigue, nausea) or failure to adequately handle stress, an adrenal crisis.

GH deficiencies:The (rare) adverse effects associated with recombinant human GH are slipped capital femoral epiphyses and increased intracranial pressure (pseudotumor cerebri), and more commonly worsening of scoliosis.

Thyroid hormone deficiency:Overtreatment may result in signs and symptoms consistent with hyperthyroidism. Undertreatment may result in signs and symptoms of hypothyroidism and negatively impact growth. In addition, if a diagnosis of central hypothyroidism is made, it is essential that the provider evaluate the ACTH axis before treatment is started. Thyroid hormone replacement therapy in a patient who has adrenal insufficiency can lead to a potential adrenal crisis. If adrenal insufficiency is diagnosed, hydrocortisone replacement should begin before replacement of thyroid hormone.

DI: Overtreatment with DDAVP may cause hyponatremia.

What are the possible outcomes of hypopituitarism?

In general, hormone replacement significantly decreases the morbidity and mortality associated with pituitary hormone deficiencies.

What causes this disease and how frequent is it?

The prevalence of this disease is 46/100,000 and the incidence is 4/100,000.

The frequency of hypopituitarism is dependent on the cause. Neurologic insults, such as brain tumors and their treatment and traumatic brain injury, along with idiopathic hypopituitarism, are more common causes in the pediatric population than infectious or autoimmune causes.

Patients with idiopathic hypopituitarism may have a genetic basis for the pituitary dysfunction. Several pituitary developmental factors have been identified to be required for the proper development and function of specific pituitary cell types. Mutations and deletions of these factors have been described in patients with hypopituitarism. Currently, commercial testing for only a few of these factors is available.

How do these pathogens/genes/exposures cause the disease?

Genetic causes typically affect the development of one or more cell types in the pituitary, which causes hormonal deficiency. Cell apoptosis or autoimmune destruction may also contribute to the development of hormone deficiencies; this phenomenon is not well understood.

Pituitary/hypothalamic tumors may cause mass effect on pituitary cells, leading to cell death. Surgical treatment of tumors may remove pituitary tissue, causing deficiencies. Radiation may cause cell death years after exposure.

What complications might you expect from the disease or treatment of the disease?

Complications from hypopituitarism:

Long-term mortality is higher in patients with hypopituitarism. Specific pathologic features that cause this increase remain somewhat unclear; however, contributing factors may be adrenal insufficiency and risk of adrenal crisis or the increased risk of cardiovascular disease in patients with GH deficiency.

Complications from treatment of hypopituitarism:

Appropriate hormone replacement typically carries a low risk of complications if patients are routinely monitored; however, the clinical presentation of hormone deficiency may evolve over time for patients initially diagnosed with only one or two pituitary hormone deficiencies. Therefore, continued observation of these patients is crucial.

Some other major points to consider:

The treatment of adrenal insufficiency can potentially unmask central DI.

The treatment of hypothyroidism must not precede confirmation of an intact ACTH-adrenal axis. Thyroid hormone replacement therapy can lead to adrenal crisis in patients who have underlying adrenal insufficiency.

Are additional laboratory studies available; even some that are not widely available?

For patients diagnosed with idiopathic pituitary hormone deficiency, genetic screenings for some of the pituitary developmental factors that have been associated with hypopituitarism are available. Several academic centers have established protocols to screen patients with hypopituitarism for mutations within a research setting rather than for diagnostic purposes.

What is the evidence?

Cooke, DW, Melmed, S, Polonsky, KS, Reed, P. "Normal and aberrant growth". Williams Textbook of Endocrinology. Saunders. 2011. pp. 935-1053.

Richmond, EJ, Rogol, AD. "Growth hormone deficiency in children". Pituitary. vol. 11. 2008. pp. 115-20.

Romero, CJ, Nesi-França, S, Radovick, S. "The molecular basis of hypopituitarism". Trends Endocrinol Metab. vol. 20. 2009. pp. 506-16.

Sperling, M. Pediatric Endocrinology. Saunders. 2008. pp. 281-310.

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