The author: Professor Yasser Metwally
October 8, 2010 — The most concerning cause of acquired hypopituitarism is a tumor in the hypothalamic-pituitary region. The most common tumor that arises in this region in childhood is a craniopharyngioma. While craniopharyngiomas are derived from epithelial remnants of Rathke’s pouch, the same tissue that forms the anterior pituitary gland, they are not usually found exclusively within the pituitary gland, but more likely they are confined to the suprasellar region or are found in both suprasellar and intrasellar locations. The presenting symptoms are dependent both on the main location of the tumor and on the direction(s) that the tumor grows. For example, if the tumor grows downward, it may cause alterations in the anterior and posterior clinoid bones or in the floor of the sella turcica and/or compress the pituitary gland. If the tumor grows upward, it may compromise vision by effects on the optic nerves.
While medical textbooks typically describe the most common visual change in patients with craniopharyngioma as "bitemporal hemianopsia" (loss of the outer visual fields of both eyes) due to compression of the optic chiasm, this rarely occurs so precisely. More likely is the development of "quadrianopsias," which are smaller, more irregular field cuts. If the tumor grows even farther upward beyond the visual tracts, it may block the third ventricle and cause obstructive hydrocephalus, leading to headaches, vomiting, and/or blurry vision (in association with papilledema). Craniopharyngiomas are benign tumors histologically, but they are often described as "geographically malignant" based on their location and ability to wrap around vital structures (eg, optic nerves) precluding complete surgical removal. As stated previously, tumors originating in the pituitary gland are uncommon causes of acquired hypopituitarism in children. However, any surgery to remove a tumor in the hypothalamic-pituitary region may lead to hypopituitarism if it is not already present.
Figure 1. A, Craniopharyngioma, compressing the optic chiasma, hypothalamus and extending upward into the lateral ventricle. The tumour is partially cystic with calcified material. B, A sagittal section of the brain shows a large craniopharyngioma below the cerebral ventricle. Note the stippled pattern of the tumor.
Another cause of acquired hypopituitarism is radiation treatment of a cancerous tumor in the head or neck region. More specifically, the radiation that is required to cure the child’s tumor may, of necessity, damage normal tissue in its path or beyond. When hypopituitarism ensues in this situation, it is usually the result of radiation-induced damage to the hypothalamus, as the pituitary gland is relatively resistant to radiation. Different hypothalamic-pituitary axes have different sensitivities to radiation. Doses as low as 18 Gy using conventional fractionation can interfere with GH dynamics; doses higher than 40 Gy can cause deficiencies of gonadotropins, TSH, and ACTH, while >50 Gy may cause hyperprolactinemia, especially among young women.
Other causes of acquired hypopituitarism in childhood include previous brain infection (encephalitis and/or meningitis), hydrocephalus (even without an underlying tumor), vascular abnormalities (such as a varix in the hypothalamic-pituitary area), and major head trauma usually associated with a significant loss of consciousness.
Potential Anterior Pituitary Hormone Deficiencies
In childhood hypopituitarism, GH is the most commonly underproduced pituitary hormone, often as the result of loss of hypothalamic GH-releasing hormone (GHRH) (Table 2). The deficiency of GH primarily leads to short stature and slow height velocity. Untreated GH deficiency in children also causes disturbed body composition, with a reduction in lean body mass (ie, muscle) and an excess of fat, the latter accumulating predominantly in the cheeks of the face and in the abdomen, creating a cherubic or angel-like appearance.
Table 2. Hierarchy of Hypothalamic-Pituitary-Target Organ Hormones
Growth hormone-releasing hormone (GHRH)
Growth hormone (GH)
Insulin-like growth factor-1 (IGF-1)
Thyrotropin-releasing hormone (TRH)
Thyroid-stimulating hormone (TSH)
Gonadotropin-releasing hormone (GnRH)
Luteinizing hormone (LH)
Follicle-stimulating hormone (FSH)
Corticotropin-releasing hormone (CRH)
Antidiuretic hormone (ADH)
Deficiency of hypothalamic thyrotropin-releasing hormone (TRH) or pituitary TSH causes central hypothyroidism. Unlike children whose hypothyroidism is due to thyroid gland damage, those with hypopituitarism typically have somewhat higher thyroid hormone levels and thus may have few or no symptoms. In other cases, as occurs in patients with primary thyroid disease, short stature and slow height velocity, relative weight excess, constipation, dry skin, cold intolerance, and fatigue may be present.
Younger children with deficiencies of either hypothalamic gonadotropin-releasing hormone (GnRH) or the pituitary gonadotropins typically show no abnormalities since luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels are normally low prior to puberty. In contrast, adolescent-aged children with deficiencies of the gonadotropins present with failure to start or progress through puberty (breast development and menstrual periods in girls and enlargement of the testicles and penis in boys). Infrequently and paradoxically, central sexual precocity can be seen in the setting of hypopituitarism.
Loss of hypothalamic corticotropin-releasing hormone (CRH) or pituitary ACTH results in an ability of the adrenal zonas fasciculata and reticularis to manufacture normal amounts of cortisol (central adrenal insufficiency). If deficient, this hormone is most likely to place a child in a life-threatening situation. While there would likely be no symptoms under normal circumstances, except maybe mild fatigue, lack of cortisol in the setting of infection, fever, surgery, trauma, etc, may cause vomiting, dehydration, shock, and even death. Biochemical correlates of cortisol deficiency include hypoglycemia and hyponatremia (with normokalemia). In this setting, mineralocorticoid function is completely normal, as aldosterone production by the zona glomerulosa of the adrenal cortex is regulated by the renin-angiotensin and not the CRH-ACTH system.
Potential Anterior Pituitary Hormone Excess
Serum levels of prolactin are usually normal or only mildly increased (if there is disruption of the hypothalamic-pituitary stalk) secondary to the loss of a normally predominant inhibitory signal from the hypothalamus. Although there are typically no symptoms in this situation, in rare cases a small amount of galactorrhea might occur.
Potential Posterior Pituitary Hormone Excess
As stated previously, a deficiency of ADH causes central or neurogenic DI. Infants and toddlers manifest DI with excessively wet diapers. If unrecognized and hence untreated, dehydration with elevated serum sodium concentrations will ensue in this age group as young children cannot report and easily satisfy heightened thirst. Older children with DI typically present with excessive day-and night-time urination, new onset of bed-wetting, and increased thirst. DI most often occurs unintentionally as a result of surgical treatment of a hypothalamic-pituitary tumor, such as a craniopharyngioma. In some cases, DI is temporary due to local postsurgical edema, but it will be permanent if surgical sacrifice close to the hypothalamus or of the stalk itself is required for complete cure of a brain tumor in the suprasellar region. DI may also occur in association with a diencephalic germinoma.
Figure 2. Craniopharyngioma. (A) Sagittal T1-weighted image shows a cystic mass in the suprasellar region. (B) Coronal T1-weighted image shows a large cystic mass in the suprasellar region with compression of the optic chiasm. (C) Coronal postcontrast T1-weighted image shows enhancement of the irregular cyst wall. (D) Sagittal postcontrast T1-weighted image demonstrates enhancement of the cyst wall with a nodular area on the right side.
Figure 3. Craniopharyngioma. (A) Axial postcontrast CT scan shows a cystic mass with rim enhancement in the suprasellar region. (B) Sagittal T1-weighted image shows a large cystic mass involving the sellar and suprasellar regions. The mass shows high signal intensity on T1-weighted imaging, consistent with high protein content. A fluid-fluid level is seen within the cystic lesion. (C) Coronal T2-weighted image demonstrates a high signal intensity mass with suprasellar extension and slight parasellar extension into the cavernous sinuses.
Figure 4. Sarcoidosis. (A) Coronal T1-weighted image demonstrates a suprasellar isointense mass. (B) Coronal postcontrast T1-weighted image shows intense enhancement of the mass just inferior to the optic chiasm.
Figure 5. Histiocytosis. (A) Sagittal postcontrast T1-weighted image demonstrates an enhancing mass in the suprasellar region involving the infundibulum. (B) Coronal postcontrast T1-weighted image shows an enhancing mass in the suprasellar region along the infundibulum. Compression of the optic chiasm is seen. (C) Coronal postcontrast T1-weighted image obtained 3 months later after treatment shows a significant decrease in the size of the mass lesion along the infundibulum.
Figure 6. A, Postmortem case of hypothalamic tuberculoma. B, Tuberculous infection of the hypothalamus (arrow)
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