AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

The pituitary gland is called the master endocrine gland of the body because it controls the function of other endocrine organs. The anterior pituitary produces the hormones thyrotropin (thyroid-stimulating hormone [TSH]), corticotropin (adrenocorticotropic hormone [ACTH]), luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and prolactin (PRL). The anterior pituitary is controlled by specific hypothalamic-releasing hormones. The posterior pituitary produces vasopressin (antidiuretic hormone [ADH]) and oxytocin.

Panhypopituitarism is a condition of inadequate or absent production of the anterior pituitary hormones. It is frequently the result of other problems that affect the pituitary gland and either reduce or destroy its function or interfere with hypothalamic secretion of the varying pituitary-releasing hormones. Panhypopituitarism can be the end result of various clinical scenarios. The signs and symptoms are diverse. Manifestations of congenital anterior hypopituitarism include micropenis, midline defects, optic atrophy, hypoglycemia, and poor growth.

Pathophysiology

The effects of hypopituitarism in children depend on the affected hormones. GH deficiency can result in hypoglycemia and short stature. Gonadotropin deficiency leads to prenatal micropenis and delayed or interrupted puberty in older children. Corticotropin deficiency interferes with normal carbohydrate, protein, and lipid metabolism and may result in weight loss, hypoglycemia, fatigue, hypotension, and death. Thyrotropin deficiency leads to hypothyroidism.

Frequency

United States

Few data are available for each of the varied hormone deficiencies individually or combined. Data from the Northwest Regional Screening program estimate the frequency of congenital TSH deficiency at 1 case per 29,000 live births.¹

Mortality/Morbidity

Morbidity and mortality due to hypopituitarism are caused by the individual hormone deficiencies or the underlying cause of hypopituitarism. Individual hormonal deficiencies are discussed in greater detail in the specific articles, and the underlying causes of death are not discussed here.

Acute mortality due to hormonal deficiencies is rare. When deaths occur due to hormonal deficiencies, they are usually caused by adrenal insufficiency secondary to ACTH deficiency. These deaths are most likely to occur when an accompanying illness prevents appropriate oral glucocorticoid replacement.

Growing, but not completely conclusive, evidence indicates that childhood hypopituitarism may be associated with a shortened adult lifespan, even with adequate hormonal replacement.² The increased mortality is due to cardiovascular abnormalities that are related to GH deficiency and past practices of not treating a GH deficiency when growth is complete.^{3, 4} Children and adolescents with GH deficiency have been shown to have impaired vascular function.⁵ In adults, GH treatment restores improves cardiovascular risk factors, but long-term studies that demonstrate reduced cardiovascular disease have not been reported.^{6, 7}

CLINICAL

Section 3 of 11  

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History

• Congenital hypopituitarism
• • Suspect hypopituitarism in children with midline defects or optic atrophy (suggestive of septo-optic dysplasia)^{8, 9} and in boys with micropenis (suggestive of gonadotropin deficiency).^{10, 11}
  • Evaluate hypopituitarism prior to the development of overt problems due to hormonal deficiencies.
  • Infants with hypopituitarism without such abnormalities present in various ways. For example, children with severe growth hormone (GH) deficiency and adrenocorticotropic hormone (ACTH) deficiency may develop hypoglycemia, which leads to the diagnosis.
  • Another presentation is hypernatremic dehydration due to diabetes insipidus. Accompanying cortisol deficiency may obscure diabetes insipidus because cortisol is necessary to excrete a free water load.¹²
  • Some infants come to medical attention because of low thyroid hormone concentrations discovered on neonatal thyroid screen. Children with milder defects present with poor growth at varying ages. The symptoms include fatigue, dry skin, and constipation due to thyroid-stimulating hormone (TSH) deficiency and concomitant hypothyroidism and/or nausea, vomiting, and malaise due to ACTH and cortisol deficiency.
• Acquired hypopituitarism
• • Similar to children with congenital hypopituitarism, many children with acquired hypopituitarism are identified before symptoms are observed.
  • Routinely evaluate pituitary function before and after treatment in children with craniopharyngiomas or other hypothalamic or pituitary tumors. The same is true for children who have received cranial irradiation (eg, before bone marrow transplant or for cranial tumors).
  • Children without a known hypothalamic or pituitary insult with hypopituitarism frequently present with growth failure because of GH deficiency. Some children come to medical attention because of abnormal thyroid function test results suggestive of central hypothyroidism.
  • Older children may present because of absent or interrupted puberty. Girls have primary or secondary amenorrhea.
  • Polyuria and polydipsia due to central diabetes insipidus may also be a presenting symptom.
  • Rarely, patients with ACTH deficiency may present with hyponatremia. This is not due to mineralocorticoid deficiency because aldosterone secretion is not primarily under pituitary control but is likely due to excess vasopressin release because (as mentioned above) cortisol helps the body excrete a free water load and circulating intravascular volume is depleted in cortisol deficiency.¹²

Physical

• Neonates
• • Evaluate a newborn with midline defects of the nose, lip, teeth, or mouth.
  • Evaluate the pituitary function in a newborn with nystagmus and optic nerve atrophy on funduscopic examination.
  • Hypogonadotrophism is suggested in the male with a small, normally shaped penis and small testes.
  • Hypopituitarism leading to ambiguous genitalia has been reported.
  • The child with hypoglycemia secondary to hypopituitarism is irritable, jittery, or lethargic. Seizures may be present.
• Older children
• • The most common presenting feature suggestive of hypopituitarism is growth failure with decreased growth rate for age.
  • Examine optic disks for papilledema and visual fields for bilateral hemianopsia, a sign of optic chiasm compression. These findings quickly suggest the possibility of a craniopharyngioma, other pituitary tumor, or a hypothalamic tumor.
  • Assessing the child's sexual maturation is also important.

Causes

• Congenital hypopituitarism
• • Congenital midline defects, such as septo-optic dysplasia (de Morsier syndrome), midline facial clefts, or single central incisors, may be accompanied by varying anterior pituitary deficiencies.⁹
  • Mutations in various genes have been demonstrated to cause congenital pituitary abnormalities in HESX1, LHX3, LHX4, PROP1, and POU1F1 (formerly known as PIT1), with varying combinations of one or more hormonal abnormalities with or without anatomic abnormalities. These homeobox genes code various pituitary transcription factors responsible for pituitary development.^{13, 14, 15}
  • Neonatal hypopituitarism, although not truly congenital, may also result from severe asphyxia either at birth or shortly thereafter.
• Acquired hypopituitarism: Causes of acquired hypopituitarism are frequently the result of hypothalamic or pituitary tumors and their surgical or radiologic treatment. Craniopharyngiomas, pituitary dysgerminomas, and optic gliomas are particularly common causes of hypopituitarism.¹⁶ Other causes include trauma and autoimmune lymphocytic hypophysitis.^{17, 18, 19, 20}

DIFFERENTIALS

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Other Problems to be Considered

Septo-optic dysplasia

WORKUP

Section 5 of 11  

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Lab Studies

The diagnostic evaluation of a child with hypopituitarism is divided into 2 portions: recognition of the hormonal deficiencies and determination of the cause. Genetic testing is available at various commercial and academic laboratories for mutations associated with hypopituitarism.

• Thyroid-stimulating hormone (TSH) deficiency
• • Hypothyroidism secondary to TSH deficiency is the easiest of hormonal abnormalities to diagnose. Children have decreased free thyroxine (T4) levels and TSH levels that are within the reference range or low. Occasionally, a child with hypothalamic hypopituitarism has a mildly elevated TSH level.
  • Test any child with TSH deficiency for adrenal function prior to T4 replacement. Correction of hypothyroidism without appropriate cortisol replacement can precipitate an adrenal crisis. This is most likely because of accelerated cortisol metabolism upon thyroid hormone treatment.
• Adrenocorticotropic hormone (ACTH) deficiency
• • Testing for ACTH deficiency is more complex. The key element is not the basal cortisol level present but the response to stress.
  • In the past, the most frequently used test was the intravenous ACTH stimulation test. In this test, 250 mcg of ACTH 1-24 (Cortrosyn) is administered as an intravenous bolus with measurements of cortisol at 0 minutes, 30 minutes, and 60 minutes. This test has a high specificity. A peak cortisol level below 18 mcg/dL is suggestive of cortisol deficiency either because of ACTH deficiency or because of primary adrenal disease. The test has low sensitivity. Many patients with ACTH deficiency as determined by insulin tolerance test results have responses over 18 mcg/dL. Because of its ease of performance, it may be a reasonable first test but a result within the reference range should never be accepted as an indication of ACTH sufficiency.²¹
  • A low-dose 1-mcg ACTH stimulation test can be used to increase the specificity of the high-dose test. Results of the 1-mcg test correspond well with results from insulin-induced hypoglycemia. The low dose of ACTH does not stimulate cortisol production in an unprimed adrenal gland. However, care must be taken in diluting the ACTH to obtain the 1-mcg dose.²²
  • The insulin tolerance test is much more sensitive and equally specific for ACTH deficiency but entails significant risks.
  • • Draw a baseline cortisol level and administer insulin (0.075-0.1 U/kg intravenously).
    • Blood is obtained every 15 minutes for 1 hour to measure cortisol and glucose levels.
    • For the test to be adequate, the plasma glucose level should decrease to less than 45 mg/dL. This usually happens at the 15-minute sample.
    • The plasma cortisol level should increase to more than 18 mcg/dL, or at least double, in response to hypoglycemia.²¹
    • Obviously, this test involves significant risk to the patient. Therefore, intravenous access must be assured and trained personnel must be present to immediately treat a serious hypoglycemic reaction with intravenous dextrose if needed. Such treatment does not negate the results of the test, and blood sampling should continue until the completion of the study.
  • The glucagon stimulation test is one last convenient test that may be used. Glucagon, 0.1 mg/kg (maximum 1 mg), is administered intravenously or intramuscularly and blood is obtained every 30 minutes for 3 hours for glucose and cortisol levels. An increase in the plasma cortisol level should occur during the fall in plasma glucose levels over the last 1-2 hours of the test.²³
  • This test is useful in neonates, in whom the adequacy of venous access is a concern, if dextrose must be administered during insulin-induced hypoglycemia. As in the insulin tolerance test, the cortisol response that occurs in the glucagon stimulation test depends on an increase in the patient's own ACTH secretion and is therefore useful in assessing the entire hypothalamic-pituitary-adrenal axis.
  • Recently, single measurement of plasma dehydroepiandrosterone sulfate levels has been shown to be at least a reasonable screening test for ACTH deficiency with good sensitivity and sensitivity when compared with the insulin tolerance test. The disadvantage to this test is that normal levels are age dependent, and, thus, the laboratory must have age-matched control normal levels available.²⁴
• Gonadotropin deficiency
• • Gonadotropin deficiency is difficult to assess in girls prior to puberty or in boys after age 3-6 months and before puberty.
  • Infant males aged 20-60 days have peak testosterone levels of 60-400 ng/dL. At this age, a level below this range with low luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels suggests gonadotropin deficiency.
  • At puberty, testosterone levels and LH levels in boys should increase, but the reference range testosterone level depends on the pubertal stage. A circadian variation is observed, with higher levels during the night. Suspect hypogonadotropism if a boy has not started puberty by age 16 years, starts puberty but does not progress to completion, or has completed puberty but has a testosterone level less than 300 ng/dL with low LH and FSH levels.
  • Girls have minimal estradiol secretion during infancy, thus making the diagnosis of gonadotropin deficiency difficult at this age.
  • Estradiol levels vary throughout the menstrual cycle. Suspect gonadotropin deficiency in girls with no breast development by age 14 years, no periods by age 16 years, or secondary amenorrhea and low LH and FSH levels.
  • Testing with any one of numerous short-acting gonadotropin-releasing hormone (GnRH) analogues may also be helpful. For leuprolide acetate, the dose is 20 mcg/kg, and samples are obtained to measure LH and FSH levels at baseline and at 2 hours, 4 hours, 6 hours, and 24 hours after the leuprolide. For males, baseline and 24-hour testosterone levels may also be helpful.
  • In healthy pubertal children, the LH response exceeds the FSH response. In prepubertal children, the FSH response exceeds the LH response. In patients with complete gonadotropin deficiency, little to no response of either LH or FSH occurs. An intermediate response does not distinguish the prepubertal child with gonadotropin deficiency from the child with simple delayed puberty. Hence, this test is of limited value. An increase in testosterone levels in males after 24 hours suggests an intact hypothalamic-pituitary-gonadal axis.
• Growth hormone (GH) deficiency
• • The best method to diagnose a GH deficiency is controversial.
  • In the poorly growing child, low baseline measurements of insulinlike growth factor 1, insulinlike growth factor 2, and insulinlike growth factor–binding protein 3 suggest GH deficiency. GH levels less than 5 ng/dL at the time of spontaneous hypoglycemia also suggest GH deficiency. Beyond this, other stimulatory tests are used.
  • Most physicians perform a combination of 2 tests on children with suspected GH deficiency. Again, the criterion standard is insulin-induced hypoglycemia, as described for cortisol deficiency. Arginine infusion with 0.5 mg/kg over 30 minutes is probably equally efficacious. Beyond these 2 tests, other drugs used include glucagon, clonidine, and propranolol.²⁵
  • The biggest controversy is likely establishing the cutoff point for diagnosis of GH deficiency. Over the past 15 years, a peak level less than 10 ng/dL measured by routine radioimmunoassay was considered diagnostic. Before that, a level of 7 ng/dL was used. Differences in radioimmunoassay techniques may alter reported GH levels. Recent studies question the reliability of any testing. A study of children without deficiencies demonstrates a lower 95% confidence interval of 1.9 ng/mL in prepubertal individuals primed with sex steroids.²⁶

Imaging Studies

• Head MRI
• • Perform this test in all children with panhypopituitarism. Look for either underlying structural abnormalities or tumors that may be the cause of the hypopituitarism.
  • The value of such imaging in children with an isolated pituitary hormonal deficiency is not clear. Perform imaging in such cases based on the clinical judgment of the physician.
  • Perform imaging in all patients with central diabetes insipidus because diabetes insipidus is frequently associated with an organic mass lesion.
• Left hand and wrist radiography for bone age
• • This radiograph must be read by an experienced individual. The result can provide guidance regarding the patient's growth potential and sex hormone exposure.
  • Bone ages are frequently delayed in patients with hypopituitarism. The diagnostic sensitivity and specificity are low.

TREATMENT

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Medical Care

• Adrenocorticotropic hormone (ACTH) deficiency
• • Cortisol deficiency requires prompt recognition and treatment. This is particularly true for the child who may be facing surgery or experiencing other significant stresses related to the cause of hypopituitarism.
  • Oral replacement is usually with hydrocortisone, usually administered twice daily but can be administered 3 times daily. Prednisone may be considered advantageous because of twice-daily dosing (at about 20-25% of the dose for hydrocortisone). However, growth suppression is a more common problem with prednisone, which should generally be avoided.²⁷
• Thyroid-stimulating hormone (TSH) deficiency
• • The dose of L-thyroxine replacement is age dependent. Monitor free T4 levels and adjust the dose of T4 to maintain reference range levels.
  • Evaluate and treat cortisol deficiency before starting T4 replacement to avoid precipitating an adrenal crisis.
• Gonadotropin deficiency: Begin sex steroid replacement at puberty.
• Growth hormone (GH) deficiency: Administer GH replacement in doses of 0.18-0.3 mg/kg/wk subcutaneously divided in 6-7 doses. Higher doses up to 0.7 mg/kg/wk may be beneficial in puberty.

Surgical Care

• Use surgical treatment for operable pituitary and hypothalamic tumors. If the patient has panhypopituitarism prior to surgery, pituitary function is unlikely to recover.

Consultations

• In all incidents of suspected pituitary dysfunction, a pediatric endocrinologist should be involved in the evaluation and treatment of the child.
• Determine additional consultations based on the cause of the hypopituitarism.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Hormones

These medications are used for replacement of deficient hormones.

FOLLOW-UP

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Further Outpatient Care

• Patients with hypopituitarism need close, ongoing, and regular follow-up by a pediatric endocrinologist.
• Closely monitor growth and measure free T4 levels on a regular basis to assess the adequacy of T4 replacement.
• Body size and symptoms and signs of cortisol deficiency (eg, anorexia, recurrent abdominal pain, malaise) or cortisol excess (eg, excess weight gain, Cushingoid features, hypertension) determine the adequacy of cortisol replacement.
• Close monitoring of pubertal status is also appropriate.

Complications

• Adrenal crisis, as mentioned, is the most acute complication that can arise in the treatment of patients with hypopituitarism and occurs when glucocorticoid replacement is not appropriately administered or, more likely, when the child develops a concurrent illness or medical treatment that increases the requirement for glucocorticoid and prevents oral replacement.
• Growth hormone (GH) therapy is reported to cause some rare adverse effects. These include benign intracranial hypertension and slipped capital femoral epiphyses. Treatment also increases insulin resistance and, therefore, possibly increases the risk of diabetes. Although questions have been raised about malignancy, most data show little or no risk.
• Appropriate monitoring should minimize any risks from thyroid or sex steroid treatment.

Patient Education

• Educate parents about the dangers of adrenal insufficiency when the child is unable to take oral medication. Instruct parents to rapidly seek medical care. Many families can intramuscularly administer hydrocortisone at home if the child is unable to take oral medications. The home dose is generally 25 mg in children younger than 2 years, 50 mg in children younger than 5 years, and 100 mg in all other children. If children require intramuscular medication, they should be brought to the emergency department. If the family is unable to administer the intramuscular injection, they can take the parenteral hydrocortisone with them to the emergency department to avoid delays in administering appropriate treatment.²⁸
• Parents also need to be taught home stress coverage with doubling the dose of glucocorticoid for less serious illnesses, such as fever greater than 38°C.
• For excellent patient education resources, visit eMedicine's Endocrine System Center and Growth Hormone Deficiency Center. Also, see eMedicine's patient education articles Hypopituitarism in Children, Growth Hormone Deficiency in Children, Growth Failure in Children, and Understanding Growth Hormone Deficiency Medications.

MISCELLANEOUS

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Medical/Legal Pitfalls

• The major error that can be made is the failure to adequately evaluate all parts of anterior pituitary function. Of primary importance in this area is the failure to establish adequacy of cortisol function in a child with secondary hypothyroidism prior to T4 replacement. T4 replacement increases cortisol degradation and leads to adrenal crisis in a child with limited adrenocorticotropic hormone (ACTH) reserve.

MULTIMEDIA

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Media file 1:  Pathophysiology of panhypopituitarism.
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REFERENCES

Section 11 of 11

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2. Bates AS, Van't Hoff W, Jones PJ, Clayton RN. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab. Mar 1996;81(3):1169-72. [Medline].
3. Rosen T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet. Aug 4 1990;336(8710):285-8. [Medline].
4. Twickler TB, Wilmink HW, Schreuder PC, et al. Growth hormone (GH) treatment decreases postprandial remnant-like particle cholesterol concentration and improves endothelial function in adult-onset GH deficiency. J Clin Endocrinol Metab. Dec 2000;85(12):4683-9. [Medline].
5. Hoffman RP. Growth hormone (GH) treatment does not restore endothelial function in children with GH deficiency. J Pediatr Endocrinol Metab. Apr 2008;21(4):323-8. [Medline].
6. Lanes R, Soros A, Flores K, Gunczler P, Carrillo E, Bandel J. Endothelial function, carotid artery intima-media thickness, epicardial adipose tissue, and left ventricular mass and function in growth hormone-deficient adolescents: apparent effects of growth hormone treatment on these parameters. J Clin Endocrinol Metab. Jul 2005;90(7):3978-82. [Medline].
7. O'Neal D, Hew FL, Sikaris K, Ward G, Alford F, Best JD. Low density lipoprotein particle size in hypopituitary adults receiving conventional hormone replacement therapy. J Clin Endocrinol Metab. Jul 1996;81(7):2448-54. [Medline].
8. Matthai SM, Smith CS. Pituitary hypoplasia associated with a single central maxillary incisor. J Pediatr Endocrinol Metab. Sep-Oct 1996;9(5):543-4. [Medline].
9. Willnow S, Kiess W, Butenandt O, et al. Endocrine disorders in septo-optic dysplasia (De Morsier syndrome)--evaluation and follow up of 18 patients. Eur J Pediatr. Mar 1996;155(3):179-84. [Medline].
10. Burgner DP, Kinmond S, Wallace AM, et al. Male pseudohermaphroditism secondary to panhypopituitarism. Arch Dis Child. Aug 1996;75(2):153-5. [Medline].
11. Setian N, Aquiar CH, Galvao JA. Rathke's cleft cyst as a cause of growth hormone deficiency and micropenis. In: Child's Nervous System. Vol 5. 1999:271-3.
12. Rajaratnam S, Seshadri MS, Chandy MJ, Rajshekhar V. Hydrocortisone dose and postoperative diabetes insipidus in patients undergoing transsphenoidal pituitary surgery: a prospective randomized controlled study. Br J Neurosurg. Oct 2003;17(5):437-42. [Medline].
13. Rosenbloom AL, Almonte AS, Brown MR, et al. Clinical and biochemical phenotype of familial anterior hypopituitarism from mutation of the PROP1 gene. J Clin Endocrinol Metab. Jan 1999;84(1):50-7. [Medline].
14. Ward L, Chavez M, Huot C, et al. Severe congenital hypopituitarism with low prolactin levels and age- dependent anterior pituitary hypoplasia: a clue to a PIT-1 mutation. J Pediatr. Jun 1998;132(6):1036-8. [Medline].
15. Vieira TC, Boldarine VT, Abucham J. Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency. Arq Bras Endocrinol Metabol. Oct 2007;51(7):1097-103. [Medline].
16. van Aken MO, Lamberts SW. Diagnosis and treatment of hypopituitarism: an update. Pituitary. 2005;8(3-4):183-91. [Medline].
17. Bettendorf M, Fehn M, Grulich-Henn J, et al. Lymphocytic hypophysitis with central diabetes insipidus and consequent panhypopituitarism preceding a multifocal, intracranial germinoma in a prepubertal girl. Eur J Pediatr. Apr 1999;158(4):288-92. [Medline].
18. Maghnie M, Genovese E, Sommaruga MG, et al. Evolution of childhood central diabetes insipidus into panhypopituitarism with a large hypothalamic mass: is 'lymphocytic infundibuloneurohypophysitis' in children a different entity?. Eur J Endocrinol. Dec 1998;139(6):635-40. [Medline].
19. Mikami-Terao Y, Akiyama M, Yanagisawa T, et al. Lymphocytic hypophysitis with central diabetes insipidus and subsequent hypopituitarism masking a suprasellar germinoma in a 13-year-old girl. Childs Nerv Syst. Mar 25 2006;[Medline].
20. Tanriverdi F, Senyurek H, Unluhizarci K, et al. High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and at 12-months after the trauma. J Clin Endocrinol Metab. Mar 7 2006;[Medline].
21. Abdu TA, Elhadd TA, Neary R, Clayton RN. Comparison of the low dose short synacthen test (1 microg), the conventional dose short synacthen test (250 microg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease. J Clin Endocrinol Metab. Mar 1999;84(3):838-43. [Medline].
22. Streeten DH. Shortcomings in the low-dose (1 microg) ACTH test for the diagnosis of ACTH deficiency states. J Clin Endocrinol Metab. Mar 1999;84(3):835-7. [Medline].
23. Chanoine JP, Rebuffat E, Kahn A, et al. Glucose, growth hormone, cortisol, and insulin responses to glucagon injection in normal infants, aged 0.5-12 months. J Clin Endocrinol Metab. Oct 1995;80(10):3032-5. [Medline].
24. Fischli S, Jenni S, Allemann S, et al. Dehydroepiandrosterone sulfate in the assessment of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab. Feb 2008;93(2):539-42. [Medline].
25. Carel JC, Tresca JP, Letrait M, et al. Growth hormone testing for the diagnosis of growth hormone deficiency in childhood: a population register-based study. J Clin Endocrinol Metab. Jul 1997;82(7):2117-21. [Medline].
26. Marin G, Domene HM, Barnes KM, et al. The effects of estrogen priming and puberty on the growth hormone response to standardized treadmill exercise and arginine-insulin in normal girls and boys. J Clin Endocrinol Metab. Aug 1994;79(2):537-41. [Medline].
27. DeVile CJ, Stanhope R. Hydrocortisone replacement therapy in children and adolescents with hypopituitarism. Clin Endocrinol (Oxf). Jul 1997;47(1):37-41. [Medline].
28. Charmandari E, Lichtarowicz-Krynska EJ, Hindmarsh PC, et al. Congenital adrenal hyperplasia: management during critical illness. Arch Dis Child. Jul 2001;85(1):26-8. [Medline].

Article Last Updated: Sep 25, 2008